Low-Dose Naltrexone: A Surprising Tool for Pain, Inflammation and Autoimmune Conditions

A few months back, I wrote a post about “the big power of small doses,” that is, the surprisingly significant benefits of a handful of well-established FDA-approved drugs but prescribed at much lower than standard doses for a broad range of “off-label” conditions: GLP-1s, lithium, PDE-5 inhibitors, and naltrexone. 

In this post, I’m going to zero in on low-dose naltrexone which doesn’t just have a growing clinical and research track record behind it but has proven itself as a valuable adjunct therapy in my own practice, helping me address a range of often hard-to-treat problems, from auto-immune diseases like Hashimoto’s and Crohn’s to chronic pain syndrome’s like fibromyalgia to post-viral syndromes like long COVID. 

In its full-dose form, typically about 50-100mg mg. a day, naltrexone works as a brain drug, tamping down cravings for opioids or alcohol. We don’t know exactly how the low-dose version, typically in the 1 to 4.5 mg. range, is proving itself such a valuable tool to treat conditions that have nothing to do with substance abuse. One working theory is that it briefly blocks receptors for the opioid-like compounds that the brain itself produces and then gets out of the way, triggering a rebound effect, pumping up the production of feel-good endorphins. As long as you’re in the hands of a doctor well-versed in treating with low doses, there’s a lot of upside here, and very little downside to exploring whether you might be one of the beneficiaries. Here’s what you should know as you think through your treatment options: 

Say hello to the one-two punch.

Our best explanation of how naltrexone at a “less is more” dose can be so broadly effective is that it works on two different systems in the body with a reinforcing or synergistic effect. As I mentioned, it affects the opioid receptors, concentrated in the brain and the spinal cord. Not only does that directly increase the supply of the body’s own good-feeling chemicals, valuable when you’re trying to combat chronic pain conditions, but indirectly it can help calm down an overrevving immune system which is responsible for any number of problems. 

Naltrexone also directly tamps inflammation by blocking so-called toll-like receptors, which are found in your immune system, particularly in the immune cells in the brain (the microglia) and on macrophages, cells that travel through the bloodstream fighting infection. 

The result – fewer circulating inflammatory cytokine molecules to stoke the fires of inflammation. That’s especially important when it comes to countering auto-immune conditions where an out-of-control immune system attacks healthy human tissues. It’s this combo – pain relief and less inflammation – that is proving itself to be such an effective ally in the fight against so many conditions. Stepping back, I think it’s fair to say that LDN isn’t acting as an immune system suppressor so much as a re-regulator, nudging the system not to overreact to less serious threats, not to inadvertently produce these enervating, long-term symptoms. 

Where’s the proof?

I don’t have to look beyond my office to know that low-dose naltrexone can be effective. I’ve seen it work, for instance, in my patients who have either Hashimoto’s disease, the immune system attacks the thyroid gland, or Crohn’s disease, where the system attacks the digestive track. Both are classic and not uncommon auto-immune conditions and both typically cause debilitating symptoms, fatigue and weight-gain in the case of Hashimoto’s, and a range of digestive problems with Crohn’s. But I should emphasize that some of my patients respond to the drug and some don’t. Why that should be so, we don’t yet have a good answer for. Because naltrexone is now a generic drug, Big Pharma doesn’t have much of a financial interest in doing expensive clinical trials. Of course, that cuts both ways. Repurposing “old” drugs allows us to try out new therapeutic approaches without being stymied by the enormous costs of bringing a new drug to market. 

As for the published research, it’s something of a patchwork affair. We still don’t have any randomized controlled trials to establish the efficacy of LD naltrexone for treating Hashimoto’s, although there are plenty of positive case reports. In the case of Crohn’s, we do have RCTs, but the results aren’t consistent – earlier, smaller trials were positive but a larger multi-center trial this year failed to find evidence of remission but did see a benefit reducing fatigue and improving quality-of-life scores. In the case of Crohn’s, as well as less severe digestive complaints, I think it’s likely that the LDN has a positive effect on the microbiome – when the good gut bacteria are doing their job, there’s less chance of leaky gut syndrome where toxins escape through the gut wall into the bloodstream and trigger inflammation potentially anywhere in the body. 

On the whole, the published results are the most encouraging when it comes to treating syndromes that physicians often find the most challenging to treat, characterized by non-specific symptoms like pain and fatigue. A well-designed Stanford study found that LDN significantly reduced daily pain and improved fatigue in fibromyalgia patients. Likewise, another RCT found pain scores dropped for patients suffering from inflammatory arthritis and osteoarthritis whose symptoms had not responded well to standard anti-inflammatory drugs. Multiple sclerosis is another nuanced case. A number of smaller studies have shown improvements in quality of life, mental health and severe fatigue, although without seeing improvements in the progression of the underlying disease process.  

Skin in the game 

Inflammatory skin conditions offer another promising therapeutic area. A number of skin problems have been looked at. So far, the most reliable results, scores of RCTs, have turned up for LDN use treating the common dermatological complaint of chronic pruritus, that is, itching that lasts for more than six weeks. But the most dramatic results have showed up in the treatment of a rare genetic disorder, Hailey-Hailey, which causes painful skin blisters and fissures. Case reports consistently show complete or almost complete symptom remission. 

Long COVID: A problem in search of a solution 

By now, we’re all familiar with the specter of long COVID, the post-viral syndrome where patients appear to clear the COVID virus and yet are plagued by a smorgasbord of different symptoms including pain, brain fog and fatigue. In other words, the kind of common symptoms that show up, not connected to any specific, readily diagnosable disease, and last for weeks, months, years. In other words, just the kind of thing that LDN has shown itself good at treating. That’s why plenty of physicians are excited that the drug therapy may be a valuable addition to our COVID armamentarium, which could certainly use a boost. And, in fact, we have research that suggests LDN may be effective at ameliorating these types of symptoms. There is a retrospective Stanford study that reported improvements in several symptoms and functional measures. What we don’t yet have is a randomized controlled trial, where we treat one group of patients with the drug, another with a placebo, and compare the results. Until that is done, we can’t say for sure it was the LDN that caused the symptom improvement. 

Cancer: the next frontier? 

To say we may only be scratching the surface of what LDNs may be able to do, and to understand how and why they’re doing it, would be an understatement. Take cancer. We have experimental evidence that LDN can modify cell signaling which may help corral the out-of-control cell growth that defines cancer. Blocking the opioid receptors on cancer cells may slow them down as well. However, the evidence is strongest that LDN can help manage the inflammation, pain and neuropathy that so often accompany standard cancer therapies. Integrative oncologists are currently using the drug as an adjunct therapy as ongoing research works to pin down just what LDN can and can’t do. 

Lifestyle to the rescue 

As we try to make sense of these encourage studies on LDN, I think it’s helpful to think about full-strength naltrexone’s designated use, to curb alcohol and drug cravings. The drug isn’t “curing” addiction. But by lessening the cravings, it’s buying time for a person in the grip of addiction to come to terms with the compulsion to self-medicate – through therapy, group support, or whatever works – without being tormented by the urge to self-medicate. Likewise, LDN may not necessarily be addressing the root cause of some inflammatory or pain syndrome, but by lessening the severity of the symptoms, it can buy time for a person to concentrate their energies on upgrading lifestyle elements like diet, movement, sleep and stress management which over the long haul may be the most effective way to get a handle of the problem.

Caveats and cautions, and items to discuss with your doc. 

Again, you should only embark on a course of LDN under the guidance of a physician familiar with the therapy. Likely, you’ll also need the services of a compounding pharmacy to get the dosage right. Typically, you’ll start at the low-end of “low-dose” and adjust upwards, as needed, according to how well you respond and how well you tolerate any side-effects. The good news here is that the common side-effects are mild, namely vivid dreams, sleep disruption, headaches and gastrointestinal issues. The caution is that we don’t yet any studies assessing the long-term safety of LDN, but we can expect to start seeing more very soon.