Learning Objectives: After participating in this continuing professional development activity, the provider should be better able to:
1. Identify recent studies examining the beneficial effects of low-dose naltrexone in some inflammatory diseases.
2. Describe the safety profile of low-dose naltrexone and how it compares to customary dosages.
3. List the advantages of naltrexone over earlier opioid antagonists.
Naltrexone was first synthesized in 1963 and later researched by Blumberg, Dayton, and Wolf in 1965 and found to be an orally active, long-acting, and very potent opioid antagonist (Figure 1).1-4 Advantages of naltrexone over earlier opioid antagonists such as cyclazocine, nalorphine, and naloxone include its oral activity and long duration of action, which permit once-daily administration. In addition, a lack of dysphoria was observed in patients taking naltrexone, although that aspect was later brought into debate.5-7
Patented in 1967, naltrexone later underwent clinical trials in collaboration with the National Institute on Drug Abuse for use in treatment of opioid dependence. In 1984, naltrexone was approved by the FDA for oral treatment of opioid dependence.
In 1995, naltrexone was approved by the FDA for oral management of alcohol dependence. An intramuscular formulation for alcohol and opioid dependence was approved by the FDA in 2010.6
Unlike methadone and buprenorphine, naltrexone is not a controlled substance.8
Naltrexone Versus Naloxone
Naltrexone should not be confused with naloxone (Narcan), which is used to reverse the effects of opioids, to counter hypoventilation in overdose cases, and for emergence from anesthesia when narcotics have been given. In some states, naloxone is also liberally prescribed as a potential emergency dose that family members can administer in the case of unintended overdose by someone who is taking prescribed opioids or illicitly abusing opioids or heroin.
In contrast to naloxone, naltrexone is indicated for long-term care.
More recent research has suggested that naltrexone, when given in smaller amounts, might have a useful anti-inflammatory effect because of the varying actions of the drug at different dosages.
Low-Dose Naltrexone for Pain and Inflammation
"Low-dose naltrexone" (LDN) describes the off-label use of naltrexone at low doses for diseases other than those related to chemical dependency or intoxication. Among the diseases for which LDN might be used is multiple sclerosis.
Evidence for recommending such use is still incomplete, and the use of LDN for conditions such as multiple sclerosis is still undergoing research.9 Naltrexone inhibits opiate receptors, the main function of which is to bind endogenous opiates (endorphins and enkephalins) and reduce pain. Thus, the primary use of naltrexone is to rapidly reverse opioid toxicity, or in the chronic treatment of opioid addiction.
However, receptors and hormones have been frequently co-opted for other uses over evolutionary history, thus causing side effects. Moreover, opiate receptors exist on other cell types, including cells involved in immune function. Hence, activating or inhibiting these receptors may modulate immune function or other biological functions. Also, changing the dosage can exert different effects.
LDN indicates doses that are 1/10th or less of the standard dose of naltrexone. Most research studies have used 4.5 mg per day. Doses range from 0.001 to 16 mg in clinical practice.
LDN binds to the endorphin receptors for about 90 minutes, and the blockade lasts about 4 to 6 hours. Naltrexone also binds to and acts as an antagonist of the opioid growth factor receptor (OGFR) and toll-like receptor 4 (TLR4) and interacts with high- and low-affinity binding sites in filamin-A (FLNA).10
LDN (daily dose of 1-5 mg) appears to reduce glial inflammatory response by modulating TLR4 signaling, with systematic upregulation of endogenous opioid signaling by transient opioid receptor blockade. Very low doses of naltrexone (<0.001 to 1 mg/day) interact with FLNA to produce TLR4 antagonism, whereas standard clinical doses (50 to 100 mg/day) exert opioid receptor and OGFR antagonism. The interactions of naltrexone with FLNA and TLR4 are what is involved in the therapeutic effects of LDN.10 Thus, in a dosing range at less than 1 [mu]g per day, oral naltrexone can potentiate opioid analgesia by acting on FLNA, which is essentially a scaffolding protein involved in [mu]-opioid receptor signaling.
Recent studies have examined the use of LDN in the treatment of chronic pain.11,12 Some evidence suggests reduction of symptoms related to chronic pain conditions such as fibromyalgia, inflammatory bowel conditions, and multiple sclerosis by modulation of neuroinflammation-specifically, of the glial cells with release of inflammatory chemicals in the central nervous system. These effects seem to be unique to low dosage, compared with the dosage approved by the FDA for alcohol and opioid dependence.
In this review, we look at how LDN may be used as a new anti-inflammatory drug for chronic pain problems that are known to be caused by inflammatory processes. Opioid antagonists, such as naltrexone, may have a paradoxical analgesic effect within this narrow dosage window. Be aware that studies are preliminary and approval for pain management with LDN has not yet been received from the FDA.
Evidence of LDN as Effective Treatment for Fibromyalgia
Experiments with LDN have been carried out in a narrow spectrum of chronic pain syndromes. One such condition is fibromyalgia (FM). Affecting more than 3 million people a year in the United States, FM is a disorder that affects muscle and soft tissue and is characterized by severe, chronic muscle pain, tenderness, fatigue, and sleep disturbances.
Musculoskeletal discomfort and sensitivity to mechanical stimulation are characteristics of FM and can cause extreme weariness, cognitive impairment, and sleep issues. Although FM does not appear to be an inflammatory condition in the conventional sense and does not respond to widely used anti-inflammatory medicines, there is a possibility that inflammatory processes are still active.13,14
In 2 small clinical investigations, LDN was demonstrated to be an effective treatment for FM. Published in 2009, the first crossover experiment demonstrated that LDN reduced FM pain significantly in 6 of 10 women when compared with placebo.15 However, several limitations to this pilot study were identified, including a single-blind design.
In the second follow-up study, 30 women with FM were surveyed to ensure the accuracy of the initial findings.16 A significant reduction in pain was observed in 57% of those taking LDN in this double-blind, crossover, counterbalanced experiment.
At the end of the treatment, half of the respondents reported feeling "far better" or "very much improved." There is strong evidence from these 2 studies that LDN is superior to placebo in the treatment of the pain symptoms of FM (Figure 2).17
A third, larger study is currently underway in 120 patients to examine the effects of LDN on FM.18
In all investigations, LDN was administered orally once daily at a dosage of 4.5 mg before bedtime.
Evidence of Involvement With Inflammatory Markers in General
In the early phases of clinical research on LDN, no human studies were available to replicate the results observed in animal models. Indirect data, however, suggested that LDN may be a novel anti-inflammatory agent.
One of the most reliable predictors of LDN's clinical response is the baseline erythrocyte sedimentation rate (ESR). ESR is frequently used as a clinical test that may identify both long-term and short-term inflammation.19 In FM, ESR levels were generally in the normal to high-normal range and a greater reduction in pain was observed in patients with higher baseline ESRs, even though FM is not traditionally classified as an inflammatory disorder.
Evidence of Efficacy in the Treatment of Well-Characterized Inflammatory Diseases
The nature of the chronic illnesses that respond to LDN therapy suggests that LDN may have anti-inflammatory capabilities in humans. LDN has also been found in studies to be effective in the treatment of Crohn's disease (CD).20 CD is a transmural, relapsing inflammatory condition that affects the digestive tract and much of the body. Opioid signaling, which affects secretion and motility in the gut, is most likely a part of the inflammatory cascade of CD. Evidence shows that LDN may assist with self-reported pain and objective markers of inflammation and disease severity in this illness (including the severity scores from endoscopic evaluation). However, a Cochrane review concluded there was insufficient evidence to allow for any firm conclusions regarding the efficacy and safety of LDN used to treat patients with active CD.21
Naltrexone has shown some promise in lowering the severity of multiple sclerosis.22 It is not as clear that LDN is as successful in this condition as it was in other disease states. Although some clinical endpoints and one study failed to show a difference from the placebo, there is some evidence of reduced stiffness and improved mental well-being. However, improvements in any of the clinical outcomes were not found.23
Different Mode of Action in Low Versus Higher Doses for Inflammation and Pain
Although LDN's distinct anti-inflammatory pathways are supported by a large body of data, there are other compelling explanations for the beneficial effect of LDN.
Zagon and colleagues noted that the body will compensate by upregulating both endogenous opioids and opioid receptors if an opioid blockade is moderate and temporary.24,25 In the past, blockade with naltrexone or naloxone has been shown to have an opioid upregulation effect. It is possible that the "opioid rebound" effect might have a variety of deleterious impacts on health and quality of life, including increased endogenous analgesia and the suppression of critical immunological components.6 Positron emission tomography scans of patients receiving low or normal doses of naltrexone show significant differences.26
Use of LDN in Research
It is important to remember that there are no clinical guidelines for the use of LDN at present. For the treatment of chronic pain or inflammatory diseases, naltrexone has not been authorized by the FDA for use at any dosage. In addition, the FDA has not approved LDN for use in treating any medical condition. In order to perform LDN research, an FDA Investigational New Drug application must be submitted. Several means have been suggested by researchers to administer LDN, but none have been empirically proven. Rather than offering therapeutic advice, we have considered how LDN has been used in previous studies.
Published research shows that 4.5 mg or less of LDN is the most often used dosage. Most individuals take this medication an hour or so before going to bed. However, some people with insomnia are advised to take it in the morning. Those experiencing adverse effects should cut their dose to 3 mg.
Because a commercial formulation of LDN does not exist, a patient can obtain LDN only from compounding pharmacies across the country. The most common fillers are standard gelatin capsules and microcrystalline cellulose.
Adverse Drug Reactions
The low reported incidence of negative side effects is an intriguing feature of LDN. LDN is well tolerated and has been reported as safe in numerous studies.27 Naltrexone does not appear to accumulate with repeated once-daily oral administration and there is no change in time to peak concentrations with repeated administration.1
The adverse effects of LDN treatment are minimal. In approximately 37% of instances, participants reported experiencing more vivid dreams as a side effect. There are just a few occasions in which patients report having nightmares. Dreams become vivid as soon as the initial dosage is taken, and then the effect appears to fade away over time.
Naltrexone is metabolized in the liver, and earlier reports with large doses indicated hepatic damage. There is no evidence to date that LDN would have this adverse effect; nevertheless, a review of liver function before starting naltrexone at any dosage would be prudent.
More research is needed before conclusive evidence can be drawn about the statistical significance of the difference between LDN and placebo in the occurrence of headaches. Patients with FM are more likely to have unpredictable headaches, which have been documented in research studies at every stage.
Endogenous opioid blocking may produce anxiety in certain individuals, because it is a known sign of opioid withdrawal. Additional research will be needed to determine the prevalence of this adverse occurrence and how to effectively handle it.
Drug Interactions
Naltrexone is not metabolized by the cytochrome P450 system and has a low potential for drug interactions. There have been no reports of LDN interfering with the effects of any other medications. However, because the research populations were so small, many possible interactions may have gone unnoticed. Despite the absence of pharmacologic interactions, synergistic effects with anti-inflammatory and disease-modifying antirheumatic medications should be investigated. The use of LDN in combination with an opioid analgesic is an evident exception.
The most often asked question about LDN is whether it may be used with opiate medicines. Even at a low dosage, naltrexone may cause enough opioid receptor blockade to reduce the effectiveness of opioid analgesics. All patients who used opioid analgesics were excluded from the various research studies. Although there are data supporting the use of ultra-LDN in conjunction with opioid analgesics in humans, further research is indicated with larger study groups.28,29
Summary
LDN has been shown to be a potential treatment option for chronic pain issues that are thought to be caused by inflammatory processes, according to a large body of research. Evidence supports the safety and tolerability of LDN in multiple sclerosis, FM, and CD. However, fewer studies support the efficacy of LDN treatment.
Most studies have focused on subjective measures such as quality of life or self-reported pain. Additional research is needed to confirm the efficacy of LDN in clinical trials before it can be widely supported as a pain management therapy. Important aspects such as dose need to be fine-tuned.
For now, LDN may be the first in a series of glial cell modulators to be used to address a variety of long-term health conditions. To date, naltrexone at any dose is not approved for pain management.
References