Naltrexone was synthesized in 1963 as an orally active competitive opioid receptor antagonist [4]. Naltrexone is structurally and functionally similar to the opioid antagonist naloxone, but it has greater oral bioavailability and a longer biologic half-life [5]. Naltrexone HCl was approved by FDA in 1984 for the treatment of opioid addiction. The typical daily dosage for opioid addiction is 50.0–100.0 mg daily, and 50.0-mg tablets are available commercially.
LDN refers to daily dosages of naltrexone that are approximately 1/10th of the typical opioid addiction treatment dosage. In most published research, the daily dosage is 4.5 mg, though the dosage can vary a few milligrams below or above that common value [7–9]. At the low dosage level, naltrexone exhibits paradoxical properties, including analgesia and anti-inflammatory actions, which have not been reported at larger dosages.
Use of LDN in chronic pain
LDN has been tested experimentally in a small number of chronic pain conditions. One such condition is fibromyalgia (FM). FM is a chronic pain disorder that is characterized by diffuse musculoskeletal pain and sensitivity to mechanical stimulation as well as profound fatigue, cognitive disruption, and sleep difficulty. Although FM does not respond to common anti-inflammatories and does not seem to be an inflammatory disorder in the classic sense [13], inflammatory processes may still be involved [14].
Evidence for a novel central anti-inflammatory action of naltrexone
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.
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.
Advantages of LDN
Low cost
Low side effects
One of the most exciting aspects of LDN is the low reported incidence of adverse side effects. We have not seen incidences of ulcers, renal insufficiency, interference with warfarin and other common medications, increased heart attack or clotting risk, or other problems that can be seen with nonsteroidal anti-inflammatory drugs. We have observed no cases of severe adverse events in our research, and none have been reported from other laboratories. We have observed no withdrawal symptoms when LDN treatment is stopped, and withdrawal is not a known effect of treatment discontinuance [46].
No known abuse potential
As an opioid antagonist, naltrexone is used as a treatment for substance abuse. LDN does not exert any euphoric or reinforcing effects, and we have observed no cases of LDN misuse or abuse. Furthermore, we have not seen the development of dependence and tolerance with the medication.
Disadvantages of LDN
As an off-label and experimental medication for pain, LDN does carry disadvantages. These disadvantages will now be discussed.
Patients creating their own dosages
At the time of writing, LDN is not available at the 4.5-mg dosage that would be typical for the management of chronic pain.
Lack of proper dosage-finding experiments
It is highly probable that 4.5 mg is not the optimal dosage for all individuals with fibromyalgia, as it is rare for any pharmaceutical to have a one-size-fits-all dosage. In addition to obvious variables such as body mass index, individuals may differ in their metabolism, opioid receptor sensitivity, or microglia sensitivity to LDN. It is plausible that individuals who do not respond to 4.5 mg daily may respond to either lower or higher dosages. Other dosing schedules, such as twice a day, have not been explored in clinical studies.
No hard data on long-term safety
Even though naltrexone has a long history of safe use with a wide range of large dosages, we know very little about the long-term safety of the drug when used chronically in low dosages.
Referência :
Clin Rheumatol. 2014;33(4):451-459.
