Hello, it's been awhile since I posted. I thought I would give you an update on managing my Fibro & arthritis pain. I have a new Rheumatologist and she put me on a low dose of Naltrexone after a study she gave me. ncbi.nlm.nih.gov/pmc/articl...
LDN is a compound that is not covered under my insurance. I did go to my local pharmacy which charged my $79 for 30 days. The following month, I came across a pharmacy who tailors to cancer patients and they only charge me $35 which is very reasonable. I must say this is an excellent drug which has muzzled the majority of my chronic fibro pain which ranges from moderate to severe and that is not counting the stormy days. The only problem I had with the LDN was horrible insomnia on top of my insomnia. It was a nightly battle to fall asleep. So I did some research and decided to take half the dosage in the morning and I found that it was just as effective if I had taken it at night time plus I was able to fall asleep with the help of some OTC drugs. Eventually, I took the whole dose in the morning. I must say my pain was reduced nearly 75% until the stormy weather came into season but I am still doing much better. I also have been taking Hydroxychloroquine for my arthritis joint pain for years. I am told that this drug has the lowest number of side effects but the eyes and my field of vision needs to be checked every 6 months. On a side note, my new insurance speciality care company wanted to provide me a 90 day mailing supply of the Hydroxychloroquine. However, after taking the new pill, within a week I had extreme joint pain throughout my body like I have never experienced before and a very active vacation was fast approaching. I called my doctor and asked about the quality of the mail order drug as opposed to the drug I get from my local pharmacy and to me, there clearly was a difference. I filed a complaint with the speciality drug company who said they would reverse the order and file their own complaint preventing further purchasing from that drug company/provider. I refilled the drug at my local pharmacy and in a matter of days my joint pain faded. So there is a difference of the quality of drugs to consider. I won't receive another mail drug order. There's a reason they are cheaper! I hope this helps. Take care all. DG
PS. For part time work, I teach the 6 week Stanford University's Chronic Pain Self Management Program which is very good program. One I wish I could have attended that program 17 years ago after my career ending injury. It would have saved me from all the blood, sweat, tears, depression and Hell I went through for many of those 17 years! It does provide you a number of tools to help you manage chronic pain but you have to make the effort! Unfortunately, I see many of my participants unwilling to make the effort to learn to manage their pain. I'm sorry to say but it seems they just want a pill and be able to sit and watch TV day and night.
Keep in mind, nearly everyone has a chronic condition or chronic pain. Don't stop living! After you go through all your therapies, injections, PT... then learn how to accept your pain and learn how to manage it. Live life! The International Association for the Study of Pain's widely used definition states: "Pain is an unpleasant sensory and emotional experience...." For me, I see that my chronic pain is a false signal, a dysfunction of the central nervous system or similar. So, I accept my pain, viewing it as my second shadow, even my friend, for it has taught me much about me, about others and about life. You learn deep outer lessons and deep inner lessons when you are in pain because pain has your undivided attention! If you are not willing to learn them, then more pain will appear. Don't focus on the pain itself or you will feed it and more pain will come. The same goes with depression. So, as you can see it is a time for self reflection and for changes--small changes or major changes. It's also about simplifying your life. These are my personal observations.
For tools to help learn how to manage your pain see if CPSMP is taught in your community. I also teach a "modified," senior friendly, Yang style 12 week Tai Chi (Taijiquan: Moving for Better Balance) program for fall prevention and minor balance problems. I have many people in my class with fibro, arthritis, lupus, depression, diabetes, cancer, back pain, heart problems, PD, MS, knee/hip replacements, strokes....the list goes on. Tai Chi or Taijiquan is an excellent low impact, safe exercise. My participants had wonderful results while they are practicing. There is also another program, Tai Chi for Arthritis, which I teach and this program is global. Check to see if someone is teaching it in your community. Finally, there is a very inspiring video I wish to share. Despite chronic conditions, depression, chronic pain, you still can live and enjoy life. I'm a great example! Enjoy life, yes, even in pain!
Yeah, I love it too. I came across it on TV while flipping channels and I was stunned when I watched it. I was meant to see it and even pass it on. I think everyone can relate to it. What an inspiration. I would imagine I would regret the things I didn't get a chance to do or experience. Sometimes, I get so wrapped up in my work and other home activities. I love gardening but I found myself, when I worked and when I didn't, passing up opportunities to travel, take vacations, to try and experience new things because it is out of my comfort zone. Others sit in front of the tv all day and don't want to do anything. I think people miss out on so much.
I have a parent who sits all day and night glued to the darn TV and I hate it because she no longer wishes to do anything. She is getting weaker and is about to lose her independence. I remember in the first Harry Potter movie and the Mirror of Erised which I can accuse the TV as doing the same thing. I loved what Professor Dumbledore said, "It shows us nothing more or less than the deepest, most desperate desire of our hearts.... However, this mirror will give us neither knowledge or truth. Men (and women) have wasted away before it, entranced by what they have seen, or been driven mad, not knowing if what it shows is real or even possible.
The Mirror will be moved to a new home tomorrow, Harry, and I ask you not to go looking for it again. If you ever do run across it, you will now be prepared. It does not do to dwell on dreams and forget to live, remember that. Now, why don't you put that admirable cloak back on and get off to bed.”
I wish my Mom would understand that but for her it is an escape from reality, an addiction of a different kind which causes her to be a shut in. Live life regardless what condition you have! Having arthritis isn't the end or chronic pain.... Live life and do things, only in a different way.
There are people who listen to a particular song each morning to give them encouragement for the day. Some read passages or readings, practice yoga, qigong, tai chi.... Perhaps, watching the video every morning may help you get through the day and motivate you to keep moving forward and look for ways to ignite a spark towards starting a new project or take small steps to fulfill a wish or a dream you might have.
Take care all. DG
DebbieG49 I.m not sure we can access things like this unless we use the internet-that is a bit iffy since we are not sure what we are buying- I assume you live ousisde UK hun?
Hi NurseGlady123, yes, I live in the USA. Here's the study on LDN. Check to see if your doc can prescribe LDN. It is a good drug for Fibro. I've never felt better in my 17 years after my injury. I still have pain but it is muzzled. It looks like LDN is available in the UK. Check out: prescribe4me.co.uk/lowdosen...drmyhill.co.uk/wiki/Low_dos...
The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain
Jarred Younger,corresponding author Luke Parkitny, and David McLain
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This article has been cited by other articles in PMC.
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.
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.
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
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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.
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, non mainstream 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 on
It didn't work for me. Kept me awake and did nothing for pain. Plus I had brain stabs which was odd. It obviously works for some but it's not a magic pill/liquid.
Hi, yeah, not every drug will work for everyone. Like every other drug and chronic condition, it is all about trial and error which takes time. Some will benefit and some will experience side effects. Sometimes the minor side effects for most drugs are tolerable and will lessen in weeks as it did for me. I experienced an immediate benefit and was willing to work with the drug's side effects of sleepless nights. I worked on improving my sleep hygiene as it is called. I tried teas, sleep mediations & soft meditative music I found on Youtube. It wasn't easy but I'm glad I hung in there. As for me, I do well with LDN with another drug for my joint pain. It's not a perfect, magical drug that relieves all pain. I don't think one exists even with opiates which I used conservatively for many, many years. Even then I only found minor relief. I have never heard of brain stabs until now. I think one searches for meds, therapies...to help tolerate the pain especially if the cause is unknown. We hope to find a drug or therapy to help us live a more comfortable and enjoyable life if possible. Also to improve our current quality of life. Again, there are other tools you can use to help lessen your pain and to help tolerate the minor side effects. I'm been to hell and back with my pain so any level of benefit I receive from a drug is well appreciated. Keep trying what becomes available and is sometimes used off label. Something will help even if it is minor. Take care.
Hi I tried it for about 2 weeks I think. Might have been a little more. Anyway, I was a bit scared because I've had a cva or stroke. Went to rheumatologist at that time and he gave me a steroid shot. My hands were really sore and the tendons in my fingers were pulling ☹
I'm sorry to hear that. A lot of meds can have some really bad side effects. I've had bad ones but not that bad. I hope you made a full recovery. I have participants in my classes who had strokes and had amazing accounts on how they struggled to learn how to talk, walk... All drugs have a risk of creating horrible complications. My thought is, cautiously try a med with an open mind. It may help improve your current quality of life for the moment. No use being sick, laying in bed when you have a family and kids wanting desperately to go places and experience life. There may be a med that can help you live life and enjoy life in the moment. Get off if the problem becomes serious. If I end up with complications down the road because of the med, I'll deal with it then but at least I had a number of good years with the family & life and I was able to be active, doing the things I enjoy. When you think about it, everyone is going to encounter a serious medical condition regardless if they are on meds or not. It simply is the nature of life. But there are always things you can do to improve your situation.
Like you, I too have tendons in my hand pulling at my fingers. I stretch my hands out many times during the day to stretch those tendons out before they start curling my fingers in. My grandmother and mom have very bad R.A. and both could/can not write, can barely hold a coffee cup or eat. There are things you can do to help prevent it from getting that bad. In my Tai Chi classes, I practice and teach my participants to stretch all 10 fingers way out, hold the stretch for a minute. You will notice that the tendons will want to resist the stretch, even fight and tense up but still hold the stretch. Focus on your tendons, breath deeply a few times and whisper "relax", "stretch out," "relax." If you maintain the stretch the tendons will eventually start to give, stretch and relax. Mine feel like thick rubber bands, like those on asparagus. They resist & fight but I breath deeply and tell them to just relax & stretch and they do. This is called mindful stretching where there is a mental component with the physical stretching. It's friendlier and more effective.
The body does things, painful things to get our attention. For years, we have ignore it, forced it to do things without much consideration. Now, the wear and tear has caught up to us and now it is time to give our bodies so attention, care and kindness but not couch sitting. Remember, "if you don't use it, you will lose it." Also, one of my favorites is: "Inactivity may seem like your best friend but it is your worse enemy." It causes muscle weakness, poor posture, back pain, poor flexibility, poor balance and poor health along with limited mobility, balance issues, an increase in falls and the lose of your personal independence!
Do the stretch a number of times, different times of the day. Keep practicing the stretch when you are in the car, watch tv, in the morning... This will help you maintain your finger dexterity so you will be able to continue to dress yourself, care for yourself, eat, bath... I visited a care facility years ago to teach a class. I saw many people who lost their ability to use their fingers to eat, bath, dress, get up and go to the bathroom... It was an eye opening experience. One that motivated me to stay active regardless how I feel, how tired I am and how much pain I have! Fresh air, sun and activity does wonders mentally and physically. You can use exercises daily to strengthen the muscles in your fingers... along with your flexibility and dexterity. Some people do finger exercises, paint, even knit to help maintain dexterity so they can maintain through independence. Squeeze a foam ball 10-20xs, stretch out 5-7x... WebMD has "10 Ways to Exercise Hands and Fingers" you may be interested in. webmd.com/osteoarthritis/ss...
I do feel quite broken. Stroke is the gift that keeps giving. Because I've had a carotid dissection, I have headaches on the left side. Also the sympathetic nerve is damaged. The flight or fight mechanism. So now I have more anxiety too. Plus body temp it's like a stuck thermostat. And pain...
Please can you elaborate on how your stroke is a gift...? Or were your referring to the hardships. Truly, there are true gifts one may receive following a tragedy or a time of great difficulty. Gifts of character, wisdom, knowledge, courage, empathy, compassion, persistence, endurance, patience, understanding...the list is endless. They are all opportunities to learn things you would be able to without going through such trying times. It's like being in a crucible physically, mentally & spiritually. Please share.
Hi, I'm sorry your having a difficult time. Are you seeing a doc and trying depression meds? Is there a program you can participate in? Have a hobby or an interest to learn a new one... wood work, wood burning...something creative? I have had a number of people in my classes who had strokes. They continued with their therapies and learned Tai Chi. They/we saw improvements in their attitudes and their mobility. They had better hand and eye coordination and mobility. I saw one start my class with a walker then a cane then without both, walking as the rest of us did. She continue with her therapies and attended my classes. Please find something that interests you. Check out programs & activities at your library or community and senior center. Anything positive and creative you can do will improve your emotional and mental outlook. Even if you have to go through the motions dry as the desert, just do it. More feelings and energy will follow. Hang in there. Dont give up. There is always something you can do to improve your quality of life. There are books out there written by people who had strokes and persevered. Check your library. Take care.
I'm going to my doctor later. Problem is, I can't seem to tolerate with meds. Because I have the left side headache, it gives me issues with side effects. Or flushing/sweating. Could make the pain worse, giving a flare. I've tried various nerve drugs. A few of anti depressant drugs. Again just have to stop...
I have a cat and occasionally go to the stables. Just hacking now, though I used to compete. A lot of motivation has gone now though. I feel as if I'm just going through the motions. Waiting to go 😣
Hi. Debbie, this site said I live about 110 miles from you... wish it were closer because I could use a Rheumatologist who will prescribe LDN. I just asked mine, but she said no. I was put on it many, many years ago by an integrative doc, so maybe I'll have to find another one of those (that was in the Chicago area... I've since moved to Florida).
I've used both LDN (past) & hydroxychloroquine (last 4 years). I was just taken off hydroxychloroquine due to issues with my eyes (not necessarily related to the drug but as extra precaution, I went off).
I'm happy you're getting good results with the LDN. That is definitely my drug of choice, although I'd definitely prefer not being on any. LDN should only cost $35/month, so you're in the right place now. Also I've read not to take slow release.
I had FMS & CFS about 20 years ago. I guess I still do, but I went at it with alternative therapy, LDN, no toxins in my home, etc. It all helped. At times I still feel like I have some FMS pain, especially after exercising. My main issues now are more on the Mixed Connective Tissue end and I'm still trying to figure out what that actually means.
I've always wanted to do Tai Chi. The one for arthritis sounds perfect. I'm trying to get back into gentle yoga. If you ever do classes near DeLand, FL, pls let me know. Thank you.
Hi, I'm glad you found other ways to manage your FMS & CFS outside of medications. Stress also plays a huge role in illnesses as well. Right now, my Mom is moving into a care facility. I'm hoping once she settles in, I will be able to settle down. Both meds are working well for me. I have my eyes checked every 6 months. So far, so good. I do have joint pain and was taking Cimzia injections. My doctor wants me to get off the drug and I have been noticing quite a lot of joint pain. I'll try to gut it out to see how bad it gets. I'm not a fan of injections.
I too have more pain, muscle & joint, after exercising, even after practicing Tai Chi. It's more of a flare up but that is the way life is and has been for 17 years. I must keep moving or else my joints will lock up and I will have more muscle pain. I don't let the pain stop me from doing what I enjoy. Gentle yoga is good as well as Tai Chi. Just remember, you can always "Modify" the Yoga pose as well as the forms in Tai Chi.
There are a lot of different Tai Chi programs out there--both instructed and on video. I always recommend taking classes with an instructor because I have seen people doing crazy things in class which will only cause more back, neck, hip and knee pain. One needs an instructor to make appropriate instructions on proper posture, alignment, form, movement.... You can work with a video but it too has it's limitations as to what you are actually doing, and why... If you do go to a class, make sure you start out with warm up exercises for the neck, shoulder, hip, knees, ankles... If they don't do any warm up exercises prior to performing a sequence of forms, make sure you go early and do some warm ups. Some Tai Chi programs (108) are physically demanding and can aggravate back & joint problems if the instructor doesn't take the time to warm people up and to build up muscle tone. Some sequences have high risk forms such as heel kicks, low snake crawl, lotus sweeps...which can cause problems if not taught correctly and worked into gently.
Check your county's Area Agency on Aging Office to see what Tai Chi programs are offered in your area. Check out n4a.org/ These are Evidence Based Tai Chi programs funded by the government for Health & Wellness along with Fall Prevention. There are for seniors 60+. You may also want to check your local YMCA, Senior Center, & Community Center. Your Tai Chi by the Sea has an instructor who is certified to teach Tai Chi for Arthritis. Make sure you start with a beginner program. People who jump into a continuing class will just get confused and overwhelmed. Start from the beginning. Also, don't let the fees prevent you from learning and practicing Tai Chi or Yoga. Seniors tend to be very cheap and that isn't wise because that class, those exercises, can and will prevent falls, help improve your core & leg muscle strength, flexibility, balance, mobility and health in addition to helping you maintain your independence! A fall can drastically change your health and life even if you didn't break a bone. It starts a downward spiral. I can say enough about how Tai Chi has helped me and many of my participants.
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