(Our first song for today is appropriately Junk by The Puddle, a early post on this topic from 1985.)
Naltrexone is a mu-endorphin antgonist that is used as an opioid antagonist. It will reverse intoxication from opioid analgesics and has a longer duration of action than naloxone. Naloxone is preferred in emergency settings because of its faster onset of action, but naltrexone, unlike naloxone, is effective given by mouth, and its long duration of action (10 hrs) makes it a safer treatment for overdose with long-acting opioids such as methadone (24 hrs, but the half-life of methadone can be significantly decreased by urinary acidifiers such as ascorbic acid or citric acid, and is increased by urinary alkalizers such as sodium bicarbonate as methadone has low solubility at high urinary pH). Naltrexone's most common clinical use is in doses of 50mg daily as a maintenance treatment to blockade the addictive effects of both opiates and alcohol. Recently I spoke to an AOD patient using naltrexone in this way and was surprised that they reported that the drug had an anti-depressant effect. This isn't what would we'd expect under the old endorphin receptor model from a full-time blockade; dysphoria would be the predicted side-effect.
![]()
A clue lies in the popular off-label use of naltrexone at low doses (1.25-2.5 mg nocte) as an immune-modulating agent. The Low Dose Naltrexone homepage claims
Naltrexone is a mu-endorphin antgonist that is used as an opioid antagonist. It will reverse intoxication from opioid analgesics and has a longer duration of action than naloxone. Naloxone is preferred in emergency settings because of its faster onset of action, but naltrexone, unlike naloxone, is effective given by mouth, and its long duration of action (10 hrs) makes it a safer treatment for overdose with long-acting opioids such as methadone (24 hrs, but the half-life of methadone can be significantly decreased by urinary acidifiers such as ascorbic acid or citric acid, and is increased by urinary alkalizers such as sodium bicarbonate as methadone has low solubility at high urinary pH). Naltrexone's most common clinical use is in doses of 50mg daily as a maintenance treatment to blockade the addictive effects of both opiates and alcohol. Recently I spoke to an AOD patient using naltrexone in this way and was surprised that they reported that the drug had an anti-depressant effect. This isn't what would we'd expect under the old endorphin receptor model from a full-time blockade; dysphoria would be the predicted side-effect.
A clue lies in the popular off-label use of naltrexone at low doses (1.25-2.5 mg nocte) as an immune-modulating agent. The Low Dose Naltrexone homepage claims
"FDA-approved naltrexone, in a low dose, can normalize the immune
system — helping those with HIV/AIDS, cancer, autoimmune
diseases, and central nervous system
disorders."
This is not quackery; read the NOLA Hepper blog in the blogroll to your right for a case study of LDN in the treatment of hepatitis C. Naltrexone is some potent juju, but the results have been hard to explain till recently. The mechanism that was originally stated is as followed; endorphin synthesis is highest at night. Blocking receptors for a few hours while the patient sleeps has the effect of elevating endorphin levels; these elevated endorphins have mood and immune-modulating effects. Hormesis in other words.
"The brief blockade of opioid receptors between 2 a.m. and 4 a.m. that is caused
by taking LDN at bedtime each night is believed to produce a prolonged
up-regulation of vital elements of the immune system by causing an increase in
endorphin and enkephalin production. Normal volunteers who have taken LDN in
this fashion have been found to have much higher levels of beta-endorphins
circulating in their blood in the following days. Animal research by I. Zagon, PhD, and his colleagues has shown a marked
increase in metenkephalin levels as well."
The endorphin effects of naltrexone are significant of course, but the much higher dose taken by the patient I spoke to could not work in this way; also, both opioid drugs like morphine, and morphine withdrawal states have been found to stimulate HCV replication in vitro.
Recently, beginning in about 2010, studies started to appear showing that opioids and opoid antagonists have TLR-4 activity. TLR-4 is a PAMP (pathogen associated molecular pattern) receptor. TLRs tell immune cells what type of pathogens they may (or may not) need to get agitated about. In the case of TLR-4 this is gram-negative bacteria, and the ligand is lipopolysaccharide (LPS).
Except that pathogens aren't the only organisms to produce TLR-4 ligands; probiotics, saprophytes and other benign or beneficial bacteria can also have TLR-4 activity, and this exposure is associated with lower rates of auto-immune disease, allergies, depression, cancer and great deal else besides through the "Hygiene hypothesis" or "Old Friends hypothesis" (there are some good articles on this at Emily Deans' Evolutionary Psychiatry blog linked in my blogroll on the right hand side of the page).
The effects we would expect to see from TLR-4 activation by what I might term FAMPs (friend associated molecular patterns) if the Old Friends hypothesis is correct are the same ones attributed to LDN (which increases TLR-4 expression). The illnesses LDN is claimed to treat are all diseases that have come into prominence in the wake of microbiotal extinctions. In many cases they barely seem to have existed prior to the widespread use of antibiotics, disinfectants, and antithelmetics.
Brain Behav Immun. 2012 Mar;26(3):480-8. doi: 10.1016/j.bbi.2011.12.010. Epub 2012 Jan 5.
Mu opioid receptor activation modulates Toll like receptor 4 in murine macrophages.
Source
Dipartimento di Farmacologia Chemioterapia e Tossicologia medica, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano, Italy.Abstract
Opioids have been shown to affect both innate and adaptive immunity. We previously showed that morphine affects the macrophage production of pro-inflammatory cytokines after LPS in a NFkB dependent manner.
Toll like receptors (TLRs) play a crucial role in the signaling pathways which lead to NFkB activation. TLR4 is considered the Lipopolysaccaride (LPS) receptor.
The data here presented show that, in murine macrophages, morphine impacts on the immune function acting on the early step of pathogen recognition. Morphine, when added to RAW 264.7 cells and when injected into mice (s.c. 20mg/kg) is in fact able to decrease TLR4 both at mRNA and protein level in RAW cells and peritoneal macrophages. In the same cells, the mu opioid receptor (MOR) antagonist Naltrexone increases TLR4 levels, thus suggesting a role of the endogenous opioid system in TLR4 regulation. The effect of the two drugs is moreover lost in case of co-administration.
Experiments with MOR KO mice and with DAMGO (MOR specific agonist) confirm that the effect of morphine on TLR4 mRNA in peritoneal macrophages is due to the MOR activation. Moreover the effect on TLR4 is blocked by PTX thus indicating the involvement of a G(i) protein after MOR binding. This work unveils a clear link between MOR activation and TLR4, suggesting a new possible mechanism at the basis of the peripheral immunosuppressive effect of opioids.
Make no mistake, this is edge-of-your seat scientific stuff that for my money is predictive of rapid medical progress in unexpected directions. For example: Recent evidence implicates toll-like receptor 4 (TLR4) in opioid analgesia, tolerance, conditioned place preference, and self-administration. In other words, some of the anti-addictive effect of naltrexone blockade is due to its TLR-4 agonism, not its mu-endorphin antagonism (though the two are probably indirectly connected). One obvious implication of this research is that the dose range for both LDN and addiction treatment should probably be much wider. Some people will need larger doses or more frequent dosing for LDN to work (or even smaller doses; VLDN treatment has been used to suport methadone withdrawal), while AOD patients who do not tolerate 50mg naltrexone may well benefit from lower doses. The dose thresholds for endorphin and TLR-4 effects are likely to be different and to vary between indviduals.
Exciting - nay, exhilarating. Sometimes you just gotta love science. It's one of those gifts that just keeps on giving.
(more music - Steely Dan "My Old School")
Toll like receptors (TLRs) play a crucial role in the signaling pathways which lead to NFkB activation. TLR4 is considered the Lipopolysaccaride (LPS) receptor.
The data here presented show that, in murine macrophages, morphine impacts on the immune function acting on the early step of pathogen recognition. Morphine, when added to RAW 264.7 cells and when injected into mice (s.c. 20mg/kg) is in fact able to decrease TLR4 both at mRNA and protein level in RAW cells and peritoneal macrophages. In the same cells, the mu opioid receptor (MOR) antagonist Naltrexone increases TLR4 levels, thus suggesting a role of the endogenous opioid system in TLR4 regulation. The effect of the two drugs is moreover lost in case of co-administration.
Experiments with MOR KO mice and with DAMGO (MOR specific agonist) confirm that the effect of morphine on TLR4 mRNA in peritoneal macrophages is due to the MOR activation. Moreover the effect on TLR4 is blocked by PTX thus indicating the involvement of a G(i) protein after MOR binding. This work unveils a clear link between MOR activation and TLR4, suggesting a new possible mechanism at the basis of the peripheral immunosuppressive effect of opioids.
Make no mistake, this is edge-of-your seat scientific stuff that for my money is predictive of rapid medical progress in unexpected directions. For example: Recent evidence implicates toll-like receptor 4 (TLR4) in opioid analgesia, tolerance, conditioned place preference, and self-administration. In other words, some of the anti-addictive effect of naltrexone blockade is due to its TLR-4 agonism, not its mu-endorphin antagonism (though the two are probably indirectly connected). One obvious implication of this research is that the dose range for both LDN and addiction treatment should probably be much wider. Some people will need larger doses or more frequent dosing for LDN to work (or even smaller doses; VLDN treatment has been used to suport methadone withdrawal), while AOD patients who do not tolerate 50mg naltrexone may well benefit from lower doses. The dose thresholds for endorphin and TLR-4 effects are likely to be different and to vary between indviduals.
Exciting - nay, exhilarating. Sometimes you just gotta love science. It's one of those gifts that just keeps on giving.
(more music - Steely Dan "My Old School")