Most of the long-term pharmacotherapeutic options for treating chronic pain have failed us over the years in one way or another. The tragic results of opioid overprescribing need no further review. Adverse effects from nonsteroidal anti-inflammatory (NSAID) overuse are more insidious but may in fact confer (or at least contribute to) even greater morbidity and mortality given their far greater prevalence. (While gastric and renal toxicity get the most airplay, vascular injury including coronary and cerebrovascular issues may comprise the most serious harms from these ubiquitous medications.) Many of the potential long-term individual and community implications of marijuana use for pain remain unknown, but some evidence suggests involved with chronic use.
When confronted with serious chronic pain, then, what's a caring physician to do?
This month I'd like to highlight a (non-funded) carried out by our practice over the past few years on low-dose naltrexone (LDN), which builds on previous research in this area. For those in a hurry, I'll start with the highlights and circle back to basic science a little later, but for starters, I want to point out that our most intriguing and encouraging finding is that so-called neuropathic pain may benefit even more from LDN than the so-called nociceptive or inflammatory pain states that it has been directed at over the past 20 years.
The Main Points
First off, we saw no harms from LDN over the 6-year study, which relied on a retrospective cohort design using data from 2014 to 2020. In fact, no one has really ever seen (nor would we expect, based on the drug's known safety profile especially at very low doses) any adverse effects with LDN treatment.
We saw a statistically significant (P<0.001) 38% pain reduction reported by people who consistently used LDN for at least 2 months, with a number needed to treat (NNT) of 3.2 to achieve an outcome of at least 50% pain reduction. Age, gender, and disease-matched controls reported 4% improvement in pain over the study period, without significant differences in interventional procedures performed.
One statistically significant confounder was chronic opioid use; LDN patients discontinued the use of chronic opioids, or simply were not on them to begin with, whereas controls had a 65.3% prevalence of use during the study.
In part owing to small numbers (36 cases, 42 controls), we stratified disease states into two main categories: inflammatory and neuropathic. We didn't achieve statistical significance at this level of analysis, but the neuropathic group showed greater pain reduction with a slightly lower NNT.
One might argue that the controls, more of whom were using opioids, had greater disease and pain burden and thus likely would not have responded as well to the cases had they entered the treatment group. However, baseline pain ratings were indistinguishable, and from a biased assessment standpoint, objective clinical data did not support that premise either. What should be mentioned here is that, as we have discussed previously in this series, chronic opioid use in its own right frequently amplifies pain, and one of the more recently appreciated mechanisms behind that phenomenon of hyperalgesia is upregulation or activation of a specific microglial receptor known as TLR-4.
Historical Context
Our study builds on previous research on LDN use for multiple diseases. In the 2000s, trials of LDN for and began to emerge, with promising disease-modification efficacy seen in both. In the 2010s, much more widely publicized trials in chronic pain conditions began to proliferate, especially in . Most of the studies showed similar degrees of benefit to ours.
Early on, the thought process was that small doses of LDN (usually on the order of 3-5 mg, in contrast to the 50-150 mg doses usually used to treat substance use disorders) were somehow eliciting a homeostatic endorphin response.
TLR-4 and LDN
We were greatly honored to have Mark Hutchinson, PhD, one of the world's leading experts on the topic, review our manuscript. Hutchinson and Linda Watkins, PhD, at the University of Colorado, have been studying the fascinating and complex role of TLR-4 in disease and inflammation pathways for a couple decades now, and their research has implicated a very important role of these receptors on microglial cells.
The receptor itself is located on many immune cells, and serves to activate the innate immune response to bacterial endotoxin. As one might imagine, recognizing and eliminating pathogens that have breached the blood brain barrier is of critical importance. An interesting side note is that the receptor also recognizes/is activated by a host of other entities including host cell damage markers/fragments, and complex carbohydrate and lipid moieties. Perhaps even more interesting is the fact that chronic opioid use also elicits the same TLR-4 response as do these other pathologic stimuli.
Anyhow, TLR-4 activation then proceeds along two different complementary pathways to activate the nuclear factor kappa-B pathway with resultant downstream inflammatory cytokine response involving interleukin 1β, tumor necrosis factor α, and Type I interferons. The interferon β and JAK-STAT pathways are also activated, and as we referenced in our publication, a showed statistically significant reductions in most of these cytokines with a 2-month LDN trial.
Along those lines, what we know at this point is that LDN binds to a receptor known as MD2, which then binds to and modifies TLR-4, shutting down much of this pro-inflammatory activity, at least in the microglia (but not apparently in peripheral leukocytes).
Clinical Translation and Central Sensitization
From the bench, LDN doesn't appear to exert much effect outside of the central nervous system (CNS). Increasingly however, we are starting to view chronic pain as a CNS issue, with the now-mainstream adoption of the central sensitization rubric invoked as explanation for conditions as diverse as fibromyalgia and migraine to osteoarthritis pain and even chronic low back pain. Growing evidence suggests TLR-4 is involved in central sensitization, and thus it makes sense that LDN might be one of the smarter ways of addressing this widespread problem.
Of course, in clinical medicine we always have to consider the benefit:risk ratio. LDN shows no real risk while offering potential for meaningful benefit in a variety of chronic pain conditions – quite possibly the most logical broad-spectrum analgesic we've found so far. Further research is warranted.
is a board-certified anesthesiologist, pain physician, and addictionologist practicing in Alaska (the military sent him there and he decided to stay). If he wasn't trying to guide people in improving their own lives, teaching medical students to do the same, or writing about it, he'd probably be outdoors right now slogging up a mountain with a good friend or two.