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.

Anti-inflammatory effects of LDN in vivo and in vitro

In describing LDN’s clinical utility, it is important to understand the dual physiologic mechanisms of naltrexone and other opioid antagonists. Most clinicians are familiar with naltrexone as a potent and nonselective opioid receptor antagonist and treatment for opioid addiction. Naltrexone, at typical dosages, significantly blocks activity at mu- and delta-opioid receptors as well as (to a lesser extent) kappa-opioid receptors [16]. Because beta-endorphin activity at mu-opioid receptors is associated with endogenous analgesic processes, it may seem counterintuitive to administer naltrexone to individuals with chronic pain, as we might expect the medication to reduce analgesia produced by beneficial endogenous opioid activity.

Naltrexone, however, exerts its effects on humans via at least two distinct receptor mechanisms. In addition to the antagonist effect on mu-opioid and other opioid receptors, naltrexone simultaneously has an antagonist effect on non-opioid receptors (Toll-like receptor 4 or TLR4) that are found on macrophages such as microglia [17]. It is via the non-opioid antagonist path that LDN is thought to exert its anti-inflammatory effects. Microglia are central nervous system immune cells that are activated by a wide range of triggers [18]. Once activated, microglia produce inflammatory and excitatory factors that can cause sickness behaviors such as pain sensitivity, fatigue, cognitive disruption, sleep disorders, mood disorders, and general malaise [19]. When chronically activated, the resulting proinflammatory cascade may become neurotoxic, causing several deleterious effects [20]. Given the wide variety of inflammatory factors produced by activated microglia (e.g., proinflammatory cytokines, substance P, nitric oxide, and excitatory amino acids) [21], a range of symptoms and medical outcomes could share the pathophysiological mechanism of central inflammation. Conditions such as fibromyalgia may involve chronic glial cell activation and subsequent production of proinflammatory factors. The hypothesis is indirectly and partially supported by the high degree of symptomatic overlap between fibromyalgia and cytokine-induced sickness behaviors.

Both naloxone and naltrexone have been demonstrated to exert neuroprotective and analgesic effects [22]. The neuroprotective action appears to result when microglia activation in the brain and spinal cord is inhibited [23]. By suppressing microglia activation, naloxone reduces the production of reactive oxygen species and other potentially neuroexcitatory and neurotoxic chemicals [24]. The anti-inflammatory effect of opioid antagonists may also extend to the periphery, as evidenced by suppressed TNF-alpha, IL-6, MCP-1, and other inflammatory agents in peripheral macrophages [25]. It should be noted that most animal work has used naloxone, while most human work has used naltrexone (because of its higher oral availability). We cannot discount the possibility that findings from one compound would imperfectly translate to the other.

The hypothesis that naltrexone and naloxone operate via glial cells to exert their beneficial actions is supported by work with dextro-naltrexone. Dextro-naltrexone is a stereoisomer of naltrexone which is active at microglia receptors but has no activity on opioid receptors [26]. Dextro-naltrexone possesses analgesic and neuroprotective properties [27]. Therefore, the analgesic, anti-inflammatory, and neuroprotective effects of naltrexone do not appear to be dependent on opioid receptors.

The majority of work to date has focused on naloxone/naltrexone’s action on microglia TLR4 (e.g., [28]). However, it should be mentioned that the data do not perfectly fit a TLR4 hypothesis [29], and other targets have been proposed, including astrocytes [30] and NADPH oxidase 2 [31]. Other sites of action, including the opioid growth factor receptor (OGFr) [32], are being discovered, raising even more potential mechanisms of action. Given the multiple and varied sites where naltrexone exhibits significant pharmacologic activity, it will be difficult to determine with certainty the paths that are critical for the clinically beneficial effects. This area of research is being vigorously pursued by multiple laboratories.

Association with general markers of inflammation

As clinical research of LDN is still in its infancy, we do not have studies in humans that parallel the work performed in animal models. However, some indirect evidence supports the concept of LDN as a novel anti-inflammatory. In the initial pilot study of LDN in fibromyalgia [15], baseline erythrocyte sedimentation rate (ESR) was a significant predictor of clinical response to LDN. ESR is a commonly employed clinical test that is sensitive to both chronic and acute inflammatory processes [33]. In our study, individuals with greater ESR at baseline experienced a greater drop in pain when taking LDN, despite that fact that FM is not considered to be a classic inflammatory disorder, and ESR values were in the normal to high-normal range.

We have now collected more data on the relationship between baseline ESR and LDN (38 individuals with fibromyalgia in total). Aggregating across studies (Fig. 2), we see that fibromyalgia patients with greater ESR levels at baseline tend to have greater pain reduction when taking LDN (left pane; r = 0.58, p = 0.0001). In contrast, there is no association between baseline ESR and pain reduction during placebo administration (right pane; r = 0.06, p = 0.744). Each participant received both LDN and placebo in a blinded fashion. The difference in correlations is significant (z = 2.52, p = 0.012), suggesting that the clinical effect of LDN may be physiologically associated with the reduction of inflammation. Unfortunately, as we collected ESR only as a screening blood test (to exclude major inflammatory disease), we did not measure ESR at the end of the LDN condition and therefore cannot determine if LDN responders had a significant decrease in their ESR.

Fig. 2 Relationship between baseline erythrocyte sedimentation rate (ESR) and change in pain during administration of LDN (left pane) and placebo (right pane). The figure uses data from earlier clinical trials [9, 15] and has not been previously published Full size image

We also note that the etiology of FM is controversial, and there is no consensus on pathophysiological mechanisms. FM is not likely to be an inflammatory disorder in the traditional sense but rather a central immune disorder associated with an amplification of pain [13] that involves at least a low level of peripheral cytokine expression (e.g., [34, 35]). The results presented here should be interpreted with caution until replicated in a larger sample. If supported in future research, however, the observed relationship between ESR and LDN response raises the intriguing possibility that other chronic conditions characterized by high ESR may also benefit from LDN therapy.

LDN has efficacy in treating known inflammatory disorders

A third piece of evidence that suggests LDN may have anti-inflammatory properties in humans is found in the nature of the chronic conditions that appear to respond to LDN treatment. The condition with the most scientific support for LDN efficacy is Crohn’s disease (CD) [7, 12, 36]. CD is an inflammatory bowel disease that exerts gastrointestinal tract and systemic effects. LDN has been reported to reduce not only self-reported pain in that condition but also objective markers of inflammation and disease severity (including the severity scores from endoscopic evaluation) [7, 12, 36]. The response rate of LDN in Crohn’s disease may be even higher than that seen in fibromyalgia, with over 80 % of the study participants exhibiting significant improvement [7, 12].

Naltrexone has also shown some promise in improving disease severity in multiple sclerosis [8], an inflammatory, demyelinating condition of the central nervous system. The evidence of LDN efficacy is not as robust as in the previously mentioned conditions. There is some evidence of reduced spasticity and improved mental health, but many clinical endpoints fail to show difference from placebo, and one study [37] did not find improvements in any of the clinical endpoints.

Limited case evidence suggests that LDN may also be effective in controlling symptoms of complex regional pain syndrome (CRPS) [38], a disease that often shows evidence of both local and low-level systemic inflammation [39]. Larger trials are needed to follow up on the one available case series report. Overall, while the literature is quite small, there is a consistent theme of LDN efficacy in controlling diseases with inflammatory components.