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Trials and Studies of LDN for Pain.
Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical rheumatology, 33(4), 451–459. https://doi.org/10.1007/s10067-014-2517-2
Jarred Younger,
Luke Parkitny, and David McLain Stanford University, Stanford, CA USA Department of Anesthesia, Pain and Perioperative Medicine, Stanford University, 1070 Arastradero Road, Suite 200, Palo Alto, CA 94304 USA McLain Medical Associates, Birmingham, AL USA Department of Anesthesia, Pain and Perioperative Medicine, Stanford University, 1070 Arastradero Road, Room 286, Palo Alto, CA 94304 USA Jarred Younger, Phone: +1-650-7211988 begin_of_the_skype_highlighting +1-650-7211988 FREE , Fax: +1-650-7259642, Email: ude.drofnats@regnuoyj. Corresponding author. Author information ► Article notes ► Copyright and License information ► Received 2014 Jan 16; Revised 2014 Jan 22; Accepted 2014 Jan 26. Copyright © The Author(s) 2014 Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
Abstract
Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn’s disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone’s better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.
Keywords: Anti-inflammatory, Chronic pain, Fibromyalgia, Glial cell modulators, Low-dose naltrexone, Microglia Go to:
Introduction
In this review, we will discuss the concept of using low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain conditions that are suspected to be associated with inflammatory processes. Within a specific dosage window, opioid antagonists such as naltrexone can exert a “paradoxical” analgesic effect [1]. We will further present the rationale for considering LDN as a primary example of a relatively new class of therapeutic agents called glial cell modulators. This review is intended for clinicians who are seeking additional information about the background, theory, mechanism of action, and research use of LDN. We will be focusing this discussion on LDN as a monotherapy for chronic pain. The closely related concept of ultralow-dose naltrexone involves the use of microgram, nanogram, and picogram dosages of naltrexone co-administered with opioid analgesics [2]. The approach is used to both increase the efficacy of opioid analgesia therapy and reduce some adverse side effects. Ultralow-dose naltrexone has been covered extensively in previous reviews [3] and will not be discussed here.
Background
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. A more complete review of the early history of naltrexone can be found elsewhere [6].
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. LDN was reported to have interesting physiological properties (primarily enhancement of endogenous opioid production) in the 1980s [6], and the treatment approach was reported to be used clinically since the mid-1980s [10]. Basic science work examining the use of opioid antagonists for treating disease states did not start to appear until the late 1980s [11], and the first published LDN trial in humans was presented in 2007 [12]. Since that time, LDN has been studied in a small number of labs and has been slowly gaining attention as a possible treatment for some chronic medical conditions.
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]. We have shown in two separate, small clinical trials that LDN may be an effective treatment for FM. In both trials, LDN was administered at 4.5 mg daily, once at night before bedtime. In the first crossover trial, published in 2009 [15], LDN reduced fibromyalgia pain significantly greater than placebo in 6 out of the 10 women. While the pilot study was encouraging, it had limitations such as a single-blind design. To help validate the findings, a second study in 30 women with fibromyalgia was conducted [9]. In that double-blind, crossover, counterbalanced study, 57 % of the participants were observed to exhibit a significant (1/3) reduction of pain during LDN. At the end of the LDN treatment, half of the participants reported feeling “much improved” or “very much improved” from LDN (Fig. 1). Together, these two studies suggest that LDN is superior to placebo in reducing the pain associated with fibromyalgia.
Fig. 1 Fibromyalgia participants’ (N
=29) self-reported improvement in symptoms after daily LDN treatment. The figure uses data from an earlier clinical trial [9] and has not been previously published Go to:
Evidence for a novel central anti-inflammatory action of naltrexone
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.
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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
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.
An alternate explanation of LDN mechanism
While we believe much data is consistent with that claim that LDN works via novel anti-inflammatory channels, there are alternative compelling explanatory models of the LDN mechanism. The most prevalent hypothesis, advanced by Dr. Ian Zagon and colleagues, states that inducing a small and transient opioid blockade will prompt the body to compensate by upregulating both endogenous opioids and opioid receptors [40]. The opioid upregulation effect of temporary naltrexone or naloxone blockade has been demonstrated multiple times previously [41, 42]. This “opioid rebound” effect could have multiple impacts on health and quality of life, including enhanced endogenous analgesia and repression of critical immune factors [40].
Further research is needed with naltrexone and naloxone stereoisomers to determine the true mechanism of clinical action. In the meantime, we note that both the TLR4 and opioid receptor mechanisms may play a role in LDN action, as the hypotheses are not mutually exclusive.
Why a low dosage?
Successful treatment of chronic pain with naltrexone may require low dosages. Theoretically, a complete blockade of endogenous opioid systems would not be a desirable outcome with a chronic pain patient. Basic science evidence supports that concept by showing that low- and high-dose opioid antagonists have quite different impacts on the physiologic system [43].
It may initially seem strange that a medication can have an opposite effect when given at a low dosage. However, there is a strong precedent for this concept—and with opioid-related drugs in particular. A paradoxical hyperalgesic effect of low-dose morphine was first widely reported in 1987 [44]. Morphine was administered via the IV route to rats after arthritis was induced using Freund’s adjuvant. A dose of 100 μg/kg produced clear analgesia, 50 μg/kg produced less significant analgesia, and 30 μg/kg showed no difference from saline. At around 10 μg/kg, however, the researchers saw the development of morphine hyperalgesia, which became most pronounced at 6 μg/kg. This finding, which has been replicated several times (e.g., [45]), suggests that there is a small window at which opioid analgesics produce the opposite effects than those typically expected. The dosage of morphine that appears to cause paradoxical hyperalgesia is approximately 1/10th of the dosage typically used to produce analgesia. We note that the dosage of naltrexone that is used to reduce pain is also approximately 1/10th of the dosage used for substance abuse treatment.
Use of LDN in research studies
It is important to note that there are currently no guidelines for the clinical use of LDN. There is no FDA-approved use for naltrexone at any dosage for the treatment of chronic pain and inflammatory diseases. There is also no FDA-approved use of LDN for the treatment of any medical condition. Researchers using LDN must do so under an FDA Investigational New Drug (IND) application. While physicians have developed varying strategies for the use of LDN, none have been empirically validated. Therefore, in this section, we cover the use of LDN in published research trials and do not intend this discussion to be viewed as guidelines for the clinical use of LDN.
The typical dosage of LDN in published research is 4.5 mg. The medication is commonly given approximately an hour before bedtime, though some individuals reporting insomnia as a side effect are moved to a morning dosing. Individuals with side effects also have their dosage reduced to 3.0 mg. At the time of writing, naltrexone is commercially available only in a 50-mg tablet form, although one US-based company appears to be gathering regulatory approvals to market the 4.5 mg formulation. Because there is no commercial formulation of LDN, research studies obtain the medication via compounding pharmacies. Standard gelatin capsules and microcrystalline cellulose filler are commonly used.
In our research studies, the initial clinical benefits specific to LDN were difficult to distinguish from transient placebo effects. Separation from placebo may not be observed until at least 1 month after initiating treatment, with 2 months generally needed to obtain an estimate of efficacy.
There are no reports of LDN interactions with other medications. However, the sample sizes in studies have been very small, and there are undoubtedly a large number of interactions that have not been tested. Pharmacologically, there is little to expect in the way of interactions, though synergistic effects with anti-inflammatories and disease modifying antirheumatic drugs should be investigated. An obvious exception is LDN co-administered with an opioid analgesic. The most common question we receive about LDN is whether it can be given with opioid analgesics. It is possible that even a low dosage of naltrexone could cause a sufficient blockade of opioid receptors to reduce the effectiveness of opioid analgesics. In our studies, we excluded all individuals taking opioid analgesics. While there are published human data regarding ultralow-dose naltrexone co-administered with opioid analgesics [2, 3], we are not aware of the existence of co-administration studies using naltrexone in the LDN dosage range. Future studies may investigate the concomitant use of LDN and opioid analgesics—as it will likely be a commonly requested combination.
Advantages of LDN
Because LDN is still an experimental therapy for chronic pain, there must be significant promise to justify recommending its use. LDN carries several advantages that may make it an attractive treatment option, which are reviewed below.
Low cost
As a generic medication, naltrexone HCl is inexpensive. While pricing can vary considerably by region and pharmacy, the monthly cost of LDN appears to average US$35 per month. That cost includes compounding and assumes no insurance coverage. The price is lower than what would be paid for current on-patent medications for fibromyalgia, which can cost over US$100 per month.
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]. However, the complete sample size of all LDN trials combined is still quite small and thus clinically useful data and experience are limited.
Side effects of LDN treatment are mild. In our research, participants have rated LDN as slightly more tolerable than placebo (91.0 versus 89.5 %, not significant). The most common side effect we have observed is the reporting of more vivid dreams, which is seen in approximately 37 % of the participants. In a minority of cases, patients report nightmares. As a side effect, vivid dreams develop rapidly (as soon as the first dosing) and decrease over time. It is unclear what mechanism may drive increased vividness of dreams. Individuals generally self-report increased effectiveness of sleep, so it is unlikely that the vivid dreams represent an adverse disruption of normal sleep patterns. It is important to note that increased vividness of dreams is also the most commonly reported side effect during placebo administration, so some cases may be driven by expectancy.
The frequency of headaches when taking LDN was slightly higher than during placebo administration, though more participants will need to be assessed in order to determine the statistical significance of the difference. Spontaneous headaches are common in individuals with fibromyalgia and frequently appeared in all stages of the clinical trials.
While not observed in research studies, some physicians have anecdotally reported anxiety and tachycardia as adverse reactions to LDN. As anxiety is a known symptom of opioid withdrawal, it is possible that some individuals would experience anxiety due to blockade of endogenous opioids. Further observation will need to be carried out to determine how common this adverse event is and how to best manage it.
For individuals without severe hepatic disease, there does not appear to be any need to frequently monitor hepatic function. Even at much larger dosages, naltrexone does not significantly change hepatic enzyme activity [47]. We have not observed any toxicity issues with chronic use.
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. In our studies, the cessation of LDN is generally followed by a slow return of symptoms to baseline levels.
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. As such, many individuals may try to create their own dosing by subdividing 50-mg tablets. Internet resources that explain the process of splitting 50-mg tablets or creating a solution and dividing out liquid doses have been found. Such approaches will likely lead to unintended variability in the day-to-day dosing. The harm of such inconsistency is mitigated by the fact that it is very unlikely that someone could dangerously overdose on naltrexone. Still, patients taking responsibility for creating doses is far from optimal.
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. For now, the once daily 4.5-mg dosing schedule appears to be used without much critical analysis, as there are no published reports of even basic dose-ranging in human participants. Proper dosing studies need to be performed to determine the therapeutic range of the drug and to identify a process for determining an individual’s optimal dosage. The importance of determining proper dosing strategies is highlighted by animal research that suggests, for example, that while LDN may suppress tumors when used in the typical fashion, it may actually enhance tumor growth when administered more frequently [48].
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. The low dosage is often cited as a reason for clinicians and patients to not be concerned about safety. However, we must be open to the possibility that the unique clinical effects possible with the low dosage could also present new health risks. There are no reported serious concerns to date. While inhibition of immune system parameters could theoretically raise the risk of infections or cancer due to decreased immunosurveillance, there have been no reports of such a side effect at any dosage of naltrexone.
Not recognized by insurance companies
As an off-label, nonmainstream treatment, LDN may not be covered by insurance plans. As noted previously, the low overall cost of LDN may make it accessible even to patients who do not have it covered by insurance. Still, there will undoubtedly be a significant number of individuals who will find even a monthly cost of approximately US$35 to be prohibitively expensive. Therefore, the potential lack of insurance coverage is a downside of LDN.
Beyond LDN
As a glial cell modulator, LDN is considered a medication of convenience. Naltrexone was not created as a microglia modulator. It is unlikely, therefore, that LDN represents the full promise of glial cell modulation in the treatment of chronic pain and inflammatory conditions. We now discuss some of the most promising compounds that may be tested in the near future.
Dextro-naltrexone
While commercially available naltrexone is usually referred to simply as naltrexone HCl, it is actually the levo (also known as “left” or “−“) enantiomer of naltrexone. The levo form of naltrexone carries largely opioid antagonistic effects. The dextro (“right” or “+”) form of naltrexone was likely jettisoned during development because there was no known anti-abuse properties of the enantiomer.
Dextro-naltrexone, however, may be far more interesting in terms of anti-inflammatory and microglia-modulating properties. Preliminary data in animal models have already suggested that dextro-naltrexone may have a role in reducing pain and inflammation [22]. Not only does it appear to potently suppress microglia but it also exerts little activity on opioid receptors, which could translate into reduced risk of side effects related to systemic opioid blockade. Therefore, dextro-naltrexone might be administered at higher dosages, yielding greater microglia-suppressing activities while minimizing side effects. It is also possible that dextro-naltrexone, co-administered with opioid analgesics, might allow patients to realize the full benefits of opioid analgesia while simultaneously blocking many of the adverse effects.
Currently, dextro-naltrexone is not available for human use, and we are not aware of any studies of the compound tested in human subjects. There is also no source for obtaining dextro-naltrexone for human consumption. Getting dextro-naltrexone to clinical trials would require a great deal of time and money to navigate the necessary FDA and other regulations to ensure patient safety. It is unclear if any groups are progressing on this front (though the medication is referenced in a 2013 US patent application filing—US 13/799,287). We suggest that this line of research be adopted and dextro-naltrexone be tested on at least a small group of chronic pain patients to look at potential applications.
Other compounds
LDN is not unique in receiving FDA approval for one purpose and then subsequently being discovered to also act as a glial cell modulator. Such compounds being tested in clinical trials include compounds such as minocycline [49] and dextromethorphan [50]. Further research will likely discover other compounds to have glial cell modulating properties, and opioid antagonists similar to naltrexone, such as nalmefene [51], may be good targets for further study.
Many other agents are currently being tested in animal models, such as fluorocitrate and 3-hydroxymorphinan, and it is likely that compounds are now being developed specifically for their TLR4-modulating properties. Other Toll-like targets are of interest as well, such as TLR-7 and TLR-9 blockage by hydroxychloroquine, which has been used successfully in inflammatory disorders such as systemic lupus erythematosus [52] and post-Lyme’s arthritis [53]. We expect glial cells modulators to be a central theme in future drug development efforts.
The potential of agents to suppress microglia extends beyond existing pharmaceuticals and includes botanicals. Several botanicals, such as stinging nettle, reishi mushroom, and curcumin, possess many key characteristics of potent glial cell modulators [54]. Most of these compounds and extracts are currently available for human use as supplements. However, research in this area has been confined to in vitro and animal in vivo work. Future clinical trials may test several of these botanicals for treating fibromyalgia and other conditions.
Public opinion
LDN has garnered a public reputation that is not commonly seen with pharmaceutical treatments. There is a considerable grassroots effort in the UK to have the medication recognized by the National Health Service (NHS). In the USA, a book has been published specifically on LDN [55]. Considerable information and misinformation is disseminated via the internet. Some sources recommend LDN for a vast range of medical conditions, the majority of which have not been subjected to any scientific study. To date, we are aware of initial clinical evidence of efficacy only in fibromyalgia, Crohn’s disease, multiple sclerosis, and complex regional pain syndrome. Whatever uses LDN may ultimately be found to have, it is clear that there is presently a great gap between the claims and the scientific evidence.
Individuals who are normally resistant to consuming mainstream pharmaceuticals are nonetheless often willing to trial LDN. Patient affinity for LDN may be driven somewhat by the “low-dose” preface, which can be agreeable to individuals who have experienced negative side effects from other medications. Clinicians prescribing LDN should be aware that many patients will come into the treatment with considerable expectations which could drive placebo effects. Patients may even approach a clinician with a specific request to be prescribed LDN.
Next steps
Throughout this review, we have raised several suggestions for future research projects, including dose ranging studies for LDN, development and clinical testing of dextro-naltrexone, clinical testing of other available microglia modulators, and clinical trials of LDN administered concomitantly with opioid analgesics. We will now highlight a few additional research directions:
Test LDN in other inflammatory conditions
Our findings that baseline ESR may be associated with LDN response suggest that other inflammatory conditions, such as rheumatoid arthritis, polymyalgia rheumatica, and lupus, may benefit from LDN. LDN may serve as a concomitant medication when immunomodulatory therapies are not effective or not well tolerated by the patient. We propose that pilot trials could be carried out to test LDN in inflammatory and autoimmune conditions.
Better tracking of inflammatory markers during LDN treatment
Future studies examining LDN should determine if positive response is associated with a reduction of ESR or other measures of inflammation (high sensitivity C-reactive protein, secreted cytokines in blood plasma, growth factors, matrix metalloproteinases, etc.). Such information would help provide mechanistic information about the treatment. Examination of intracellular immune processes may further shed light on the mechanism of LDN treatment. Measurements of immune activity should be collected at least immediately before and after treatment or when the primary outcomes are assessed.
Conclusions
The totality of the basic and clinical research to date suggests that LDN is a promising treatment approach for chronic pain conditions thought to involve inflammatory processes. The clinical data supporting its use are very preliminary, and more research is needed before the treatment approach can be widely recommended. Critical parameters such as dosing still need to be refined. LDN may emerge as the first of many glial cell modulators that could be used to treat chronic conditions, with more specifically targeted medications developed in the future. As conventional anti-inflammatories have poor blood brain-barrier permeability, we expect centrally active immune modulators to be an area of interest in the future.
Acknowledgments
Financial support was provided by the American Fibromyalgia Syndrome Association and the Binns Family Foundation.
Conflict of interest: The authors declare none.
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Letter to the Editor
Ghai B, Bansal D, Hota D, Shah CS. Off-label, low-dose naltrexone for refractory chronic low back pain. Pain Med. 2014;15(5):883‐884. doi:10.1111/pme.12345.
Chopra P, Cooper MS. Treatment of Complex Regional Pain Syndrome (CRPS) using low dose naltrexone (LDN). J Neuroimmune Pharmacol. 2013;8(3):470‐476. doi:10.1007/s11481-013-9451-y.
Abstract
Complex Regional Pain Syndrome (CRPS) is a neuropathic pain syndrome, which involves glial activation and central sensitization in the central nervous system. Here, we describe positive outcomes of two CRPS patients, after they were treated with low-dose naltrexone (a glial attenuator), in combination with other CRPS therapies. Prominent CRPS symptoms remitted in these two patients, including dystonic spasms and fixed dystonia (respectively), following treatment with low-dose naltrexone (LDN). LDN, which is known to antagonize the Toll-like Receptor 4 pathway and attenuate activated microglia, was utilized in these patients after conventional CRPS pharmacotherapy failed to suppress their recalcitrant CRPS symptoms.
Santos CM, Francischi JN, Lima-Paiva P, Sluka KA, Resende MA. Effect of transcutaneous electrical stimulation on nociception and edema induced by peripheral serotonin. Int J Neurosci. 2013;123(7):507‐515. doi:10.3109/00207454.2013.768244
Abstract
Transcutaneous electrical nerve stimulation (TENS) is defined as the application of an electrical current to the skin through surface electrodes for pain relief. Various theories have been proposed in order to explain the analgesic mechanism of TENS. Recent studies have demonstrated that part of this analgesia is mediated through neurotransmitters acting at peripheral sites. The aim of this study was to investigate the effects of low frequency (LF: 10 HZ) TENS and high frequency (HF: 130 HZ) TENS on hyperalgesia and edema when applied before the serotonin (5-HT) administered into the rat paw. LF and HF TENS were applied to the right paw for 20 min, and 5-HT was administered immediately after TENS. The Hargreaves method was used to measure nociception, while the hydroplethysmometer (Ugo Basile®) was used to measure edema. Neither HF nor LF TENS inhibited 5-HT-induced edema. However, LF TENS, but not HF TENS, completely reduced 5-HT-induced hyperalgesia. Pre-treatment of the paw with naltrexone, prior to application of TENS, (Nx: 50 μg; I.pl.) showed a complete blockade of the analgesic effect induced by low frequency TENS. Thus, our results confirmed the lack of an anti-inflammatory effect through the use of TENS as well as the participation of peripheral endogenous opioid receptors in LF TENS analgesia in addition to its central action.
Frech T, Novak K, Revelo MP, et al. Low-dose naltrexone for pruritus in systemic sclerosis. Int J Rheumatol. 2011;2011:804296. doi:10.1155/2011/804296 https://www.ncbi.nlm.nih.gov/pubmed/21918649
Abstract
Pruritus is a common symptom in systemic sclerosis (SSc), an autoimmune disease which causes fibrosis and vasculopathy in skin, lung, and gastrointestinal tract (GIT). Unfortunately, pruritus has limited treatment options in this disease. Pilot trials of low-dose naltrexone hydrochloride (LDN) for pruritus, pain, and quality of life (QOL) in other GIT diseases have been successful. In this case series we report three patients that had significant improvement in pruritus and total GIT symptoms as measured by the 10-point faces scale and the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) questionnaire. This small case series suggests LDN may be an effective, highly tolerable, and inexpensive treatment for pruritus and GIT symptoms in Ssc.
Hesselink JM, Kopsky DJ. Enhancing acupuncture by low dose naltrexone. Acupunct Med. 2011;29(2):127‐130. doi:10.1136/aim.2010.003566
Abstract
To find appropriate and effective treatment options for chronic pain syndromes is a challenging task. Multimodal treatment approach has been gaining acceptance for chronic pain. However, combining treatments, such as acupuncture, with rational pharmacology is still in its infancy. Acupuncture influences the opioid and cannabinoid system through releasing endogenous receptor ligands. Low dose naltrexone also acts on both these systems, and upregulates the opioid and cannabinoid receptors. The authors hypothesise that low dose naltrexone could enhance the pain-relieving effect of acupuncture.
Hay JL, La Vincente SF, Somogyi AA, Chapleo CB, White JM. Potentiation of buprenorphine antinociception with ultra-low dose naltrexone in healthy subjects. Eur J Pain. 2011;15(3):293‐298. doi:10.1016/j.ejpain.2010.07.009
Abstract
Previous reports have demonstrated greater antinociception following administration of a buprenorphine/naloxone combination compared to buprenorphine alone among healthy volunteers. The aim of the current investigation was to determine whether buprenorphine antinociception could be enhanced with the addition of ultra-low dose naltrexone, using a range of dose ratios. A repeated-measures, double-blind, cross-over trial was undertaken with 10 healthy participants. The effects of each buprenorphine:naltrexone ratio (100:1, 133:1, 166:1, and 200:1) on cold pressor tolerance time and respiration were compared to the effects of buprenorphine only. The 166:1 ratio was associated with significantly greater tolerance time to cold pressor pain than buprenorphine alone. Minimal respiratory depression and few adverse events were observed in all conditions. These findings suggest that, as previously described with naloxone, the addition of ultra-low dose naltrexone can enhance the antinociceptive effect of buprenorphine in humans. This potentiation is dose-ratio dependent and occurs without a concomitant increase in adverse effects.
Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.
Largent-Milnes TM, Guo W, Wang HY, Burns LH, Vanderah TW. Oxycodone plus ultra-low-dose naltrexone attenuates neuropathic pain and associated mu-opioid receptor-Gs coupling. J Pain. 2008;9(8):700‐713. doi:10.1016/j.jpain.2008.03.005
Abstract
Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in mu-opioid receptor (MOR)-G protein coupling from G(i/o) to G(s) that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L(5)/L(6) spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to G(s) in the damaged (ipsilateral) spinal dorsal horn. This MOR-G(s) coupling occurred without changing G(i/o) coupling levels and without changing the expression of MOR or Galpha proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-G(s) coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-G(s) coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this G(s) coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-G(s) coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain.
PERSPECTIVE:
The current study investigates whether Oxytrex (oxycodone with an ultra-low dose of naltrexone) alleviates mechanical and thermal hypersensitivities in an animal model of neuropathic pain over a period of 7 days, given locally or systemically. In this report, we first describe an injury-induced shift in mu-opioid receptor coupling from G(i/o) to G(s), suggesting why a mu-opioid agonist may have reduced efficacy in the nerve-injured state. These data present a novel approach to neuropathic pain therapy
Hamann S, Sloan P. Oral naltrexone to enhance analgesia in patients receiving continuous intrathecal morphine for chronic pain: a randomized, double-blind, prospective pilot study. J Opioid Manag. 2007;3(3):137‐144. doi:10.5055/jom.2007.0051
Abstract
BACKGROUND: Years worth of observations suggest that morphine has both inhibitory and excitatory actions, and that selective blockade of excitatory effects by low doses of opioid antagonists (e.g., naltrexone) may paradoxically enhance morphine analgesia. The purpose of this pilot study was to evaluate and compare the analgesic efficacy and safety of two different low doses of oral naltrexone given in addition to chronic intrathecal morphine infusions in patients with chronic nonmalignant pain (CNMP).
METHODS: After institutional review board approval, 15 patients with CNMP receiving continuous intrathecal morphine were admitted into a prospective, randomized, double-blind, placebo-controlled, seven-day pilot study. Patients were randomized into three treatment groups based on oral naltrexone dose: 100 microg (Group A, n = 3), 10 microg (Group B, n = 7), or placebo (Group C, n = 5). All patients continued with their constant intrathecal morphine infusion, and in addition they received one capsule of study medication every 12 hours for seven days. Other analgesics or coanalgesics were kept at a constant dose level throughout the study. Patients rated pain scores (visual analogue score [VAS]; 0 = no pain, 10 = worst pain imaginable) and side effects three times daily throughout the study period. Efficacy measures included pain intensity difference (PID) scores, constructed so that positive scores indicate a reduction in pain intensity and negative scores indicate a worsening of pain.
RESULTS: Fifteen patients (six male, nine female) with a mean (SD) age of 55 (10) years and weight of 81 (21) kg completed the study. The mean (SD) baseline VAS pain intensity rating was similar in all three groups (6.8 [1.5]). Baseline pain VAS score minus the lowest daily pain VAS score yielded the peak PID score. The peak PID score from Day 1 was statistically (p < 0.05) highest (median PID score: 5.9) in Group A compared with Group C. There was a trend in PID scores across Days 2 through 7, with median PID scores higher (i.e., greater pain relief p = 0.07) in Group A. In the daily global pain assessments, the pain scores across Days 2 through 7 approached significance (least pain) in Group A compared to Group C (p = 0.07) or B (p = 0.08). Side effects were common (93 percent of patients), minor (headache, nausea, sedation, dry mouth), and similar across treatment groups. No serious adverse events were observed, and no evidence of opioid withdrawal was seen.
CONCLUSIONS: 1) Patients with chronic pain who received oral naltrexone 100 microg BID in addition to their chronic intrathecal morphine infusions demonstrated the greatest improvement (p = 0.07) in their daily pain scores. Because of the small sample size, the results did not reach traditional levels of significance. 2) Side effects were common, minor, and similar across treatment groups. 3) No serious adverse events were recorded. 4) No evidence of opioid antagonist toxicity or opioid withdrawal was observed.
Webster LR. Oxytrex: an oxycodone and ultra-low-dose naltrexone formulation. Expert Opin Investig Drugs. 2007;16(8):1277‐1283. doi:10.1517/13543784.16.8.1277
Abstract
Oxytrex (Pain Therapeutics, Inc.) is an oral opioid that combines a therapeutic amount of oxycodone with an ultra-low dose of the antagonist naltrexone. Animal data indicate that this combination minimizes the development of physical dependence and analgesic tolerance while prolonging analgesia. Oxytrex is in late-stage clinical development by Pain Therapeutics for the treatment of moderate-to-severe chronic pain. To evaluate the safety and efficacy of the oxycodone/naltrexone combination, three clinical studies have been conducted, one in healthy volunteers and the other two in patients with chronic pain. The putative mechanism of ultra-low-dose naltrexone is to prevent an alteration in G-protein coupling by opioid receptors that is associated with opioid tolerance and dependence. Opioid agonists are initially inhibitory but become excitatory through constant opioid receptor activity. The agonist/antagonist combination of Oxytrex may reduce the conversion from an inhibitory to an excitatory receptor, thereby decreasing the development of tolerance and physical dependence.
Abul-Husn NS, Sutak M, Milne B, Jhamandas K. Augmentation of spinal morphine analgesia and inhibition of tolerance by low doses of mu- and delta-opioid receptor antagonists. Br J Pharmacol. 2007;151(6):877‐887. doi:10.1038/sj.bjp.0707277
Abstract
BACKGROUND & PURPOSE: Ultralow doses of naltrexone, a non-selective opioid antagonist, have previously been found to augment acute morphine analgesia and block the development of tolerance to this effect. Since morphine tolerance is dependent on the activity of micro and delta receptors, the present study investigated the effects of ultralow doses of antagonists selective for these receptor types on morphine analgesia and tolerance in tests of thermal and mechanical nociception.
EXPERIMENTAL APPROACH: Effects of intrathecal administration of mu-receptor antagonists, CTOP (0.01 ng) or CTAP (0.001 ng), or a delta-receptor antagonist, naltrindole (0.01 ng), on spinal morphine analgesia and tolerance were evaluated using the tail-flick and paw-pressure tests in rats.
KEY RESULTS: Both micro and delta antagonists augmented analgesia produced by a sub-maximal (5 microg) or maximal (15 microg) dose of morphine. Administration of the antagonists with morphine (15 microg) for 5 days inhibited the progressive decline of analgesia and prevented the loss of morphine potency. In animals exhibiting tolerance to morphine, administration of the antagonists with morphine produced a recovery of the analgesic response and restored morphine potency.
CONCLUSIONS & IMPLICATIONS: Combining ultralow doses of micro- or delta-receptor antagonists with spinal morphine augmented the acute analgesic effects, inhibited the induction of chronic tolerance and reversed established tolerance. The remarkably similar effects of micro- and delta-opioid receptor antagonists on morphine analgesia and tolerance are interpreted in terms of blockade of the latent excitatory effects of the agonist that limit expression of its full activity.