|Year : 2022 | Volume
| Issue : 4 | Page : 211-215
Naltrexone beyond psychiatric domain
Ashutosh Garg, Khyati Thapliyal, Vivek Pal Singh
Department of Internal Medicine, BLK-Max Super Speciality Hospital, New Delhi, India
|Date of Submission||24-Mar-2022|
|Date of Decision||27-Apr-2022|
|Date of Acceptance||16-May-2022|
|Date of Web Publication||18-Oct-2022|
Dr. Vivek Pal Singh
Department of Internal Medicine, BLK-Max Super Speciality Hospital, New Delhi
Source of Support: None, Conflict of Interest: None
Naltrexone, an opioid receptor (OR) antagonist, at its standard doses, is a United States Federal Drug Administration-approved drug for opioid and alcohol use disorders. However, with the discovery of nonneuropsychiatric effects of OR signaling with low-dose naltrexone, it has found novel applications in inflammatory, malignant, insulin sensitivity-related, and chronic pain conditions. Lower doses also ameliorate its adverse effects. Its off-label use in the abovementioned situations has proven to be cost-effective against costly immunomodulating and antineoplastic drugs. Its lower cost and miniscule margin of interest have precluded in-depth analysis by the pharmaceutical industry. So far, only animal studies, cell culture studies, and case reports have been conducted, some of which exhibit promising benefits. There is a dearth of much-needed quality trials.
Keywords: Alcohol, inflammatiov, insulin, malignancy, opioid
|How to cite this article:|
Garg A, Thapliyal K, Singh VP. Naltrexone beyond psychiatric domain. Indian J Med Spec 2022;13:211-5
| Introduction|| |
Naltrexone was first synthesized in 1963. It is a competitive opioid receptor (OR) antagonist, which unlike its predecessors – nalorphine, naloxone, and cyclazocine – can be taken orally and has a longer duration of action permitting once-daily dosing. Its sole United States Federal Drug Administration (USFDA)-approved use continues for alcohol and opioid use disorders at standard doses of 50 mg to 100 mg/day. It has been shown to prevent relapse and to minimize alcohol consumption. Naltrexone is hepatotoxic, so its use entails follow-up with liver chemistries.
In the 1980s, during the acquired immunodeficiency syndrome (AIDS) epidemic, Dr. Bernard Bihari, Deputy Medical Commissioner for New York City, noted that naltrexone at its standard doses, when given to heroin addicts, made them more irritable and depressed. Concomitantly, at low doses, it raised endorphin levels which, in turn, boosted immunity. He titrated doses that minimize adverse effects but keep up endorphin levels. These doses of 1–5 mg came to be known as low-dose naltrexone (LDN) and were successfully used as adjuncts in AIDS. The discovery of LDN kick-started research into the nonneuropsychiatric underpinnings of OR down signaling.
This is a narrative review highlighting the areas in which LDN has been shown to have substantive benefits. Its role in modulating insulin resistance (IR), altering the immune system, delaying cancer progression, and utility in chronic pain conditions has been discussed in detail, with emphasis on its intracellular mechanisms of action.
| Insulin Resistance|| |
Insulin Resistance (IR) is a pro-inflammatory state., Traditional teaching in type 2 diabetes mellitus models has been that IR antedates hyperinsulinemia. However, recent studies have shown that hyperinsulinemia itself is a pro-inflammatory state which alters adipose tissue macrophage (ATM) phenotype culminating in IR. Thus, it seems that IR and hyperinsulinemia set up a vicious cycle.
Choubey et al. employed high-fat diet (HFD) mouse models to study the effect of LDN in hyperinsulinemia-challenged ATMs. HFD-induced hyperinsulinemia orients ATMs to their M1 (pro-inflammatory) phenotype characterized by higher levels of interleukin-1β, tumor necrosis factor-alpha, and interleukin-6. LDN, however, resisted change from M2 (anti-inflammatory) to M1 phenotype [Figure 1].
|Figure 1: Low dose naltrexone inhibits the pro-inflammatory conversion of adipose tissue macrophages challenged with hyperinsulinemia|
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Toll-like receptor-4 (TLR-4) is a salient mediator of inflammation and IR., TLR-4, once stimulated, breaks the bond between the nuclear factor kappa-light-chain-enhancer of beta-cells (NF-ĸB) and nuclear factor kappa-light-chain-gene enhancer in B-cells inhibitor α (IĸBα), resulting in nuclear translocation of NF-ĸB cascading into a pro-inflammatory state. Mice models have shown that hyperinsulinemia promotes this translocation and LDN has a suppressive effect here [Figure 2].
|Figure 2: SIRT-1 gene tends to improve insulin sensitivity but is repressed in adipose tissue macrophages challenged with hyperinsulinemia. Low dose naltrexone reverses this repression|
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A crucial piece of the above puzzle is the intranuclear enzyme, SIRT-1 or sirtuin-1 (mammalian ortholog of yeast silent mating type information regulator 2) which is known to improve insulin sensitivity. Choubey et al. exhibited that hyperinsulinemia-challenged macrophages tend to repress nuclear SIRT-1 levels, but on administering LDN, the repression is reversed. LDN and SIRT-1 overexpression also attenuated hyperinsulinemia-induced NF-ĸB activity. Interestingly, LDN was unable to attenuate NF-ĸB activity if the SIRT-1 gene was silenced [Figure 2].
In patients with polycystic ovary syndrome (characterized by a state of IR), there appears to be a potential role of standard-dose naltrexone. However, it is contraindicated in hepatic insufficiency and in those using opioids chronically. It is considered a pregnancy category C drug.
| Inflammatory Conditions|| |
Before the 1980s, endogenous opioids – endorphins, enkephalins, and dynorphins – were considered mainly neuromodulators. However, subsequently, it was found that a specific enkephalin, called (Met5)-enkephalin, modulated growth as well. Later on, referred to as the opioid growth factor (OGF), it was shown to act on the-OR (zeta-OR or OGF receptor [OGFr]). Further studies showed that OGFr did not share sequence homology with the other OR. OGF-OGFr axis regulates cell cycle in the G0-S phase modulating normal and cancer cell proliferation [Figure 3]. Modulation of this axis in animal models of MS with LDN has shown delayed onset of symptoms. In a 2015 retrospective review by Turel et al., they summarized, through animal and human studies, that LDN improved fatigue in relapsing-remitting MS, improved quality of life, and delayed disease progression. There were no newly reported adverse effects (other than those already present in literature). Notwithstanding the costly immunomodulating therapies that are staple for MS patients, LDN could be their magic bullet.
|Figure 3: Opioid growth factor via the opioid growth factor receptor promotes proliferation while low dose naltrexone has been shown to have antagonistic and therefore anti-proliferating effect on both normal and cancer cells|
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In a 2006 case–control French study on inflammatory bowel disease patients, Philippe et al. showed that diseased enterocytes and T-cells overexpressed μ-ORs. This led to research into the potential role of drugs acting on opioid receptors for auto-inflammatory conditions.
In a 2018 database review by Parker et al., they did an intention-to-treat analysis on two randomized controlled trials (RCTs) – one adult and other pediatric – involving Crohn's disease patients and found that the studies could not substantively conclude that LDN can induce remission in Crohn's disease.
A double-blind placebo-controlled study is currently ongoing in The Netherlands since January 2021 to assess if LDN can induce remission in mild-to-moderate Crohn's disease. The study has kept endoscopic remission as their primary outcome criterion and secondary outcomes include patient-reported outcomes, among others.
Similar to MS patients, the modulation of OGF-OGFr axis has been postulated to offer benefit to psoriasis patients. In two separate clinical case reports on patients with psoriasis vulgaris and erythrodermic psoriasis, long-term treatment (3 months) with LDN showed clearance of skin lesions with no recurrence of flare during 6-month follow-up.,
In a 2019 reported pharmacoepidemiological study from Norway, using the Norwegian Prescription Database, the authors reported that LDN use in patients with rheumatoid arthritis resulted in reduction in the use of disease-modifying antirheumatic drugs, steroids, and analgesics. The outcome was statistically significant. However, this was a quasi-experimental study. Thus, there is an unmet need for blinded RCTs in rheumatoid arthritis patients.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)
The acute respiratory distress syndrome and other multi-organ dysfunction in Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have been shown to be secondary to “cytokine storm.” In this regard, the mitogen-activated protein kinase (MAPK) pathway (also known as extracellular signal-regulated kinase [ERK]) assumes special significance. The phosphorylation status of MAPK/ERK is closely related to viral load. Choubey et al. (2022) have shown that the effect of LDN has an inhibitory effect on ERK in murine models. LDN, being already US-FDA certified as free of clinical toxicity, can be employed for human RCTs to give potential unequivocal evidence of benefit in SARS-CoV-2.
| Malignancy|| |
Naltrexone's action through the OGF-OGFr axis on cell cycle regulation appears to be the main mechanism of action on preventing cancer progression. LDN use in the cancers of the skin, lung, bladder, liver, colon, and rectum has shown that there could be mortality benefit. In a wide-ranging systematic review by Liubchenko et al., including human, animal, and cell culture studies, they concluded that low doses (vs. standard dose) naltrexone when given in intermittent dosing had beneficial effect on tumor progression.
| Chronic Pain Conditions|| |
Naltrexone is an OR antagonist, therefore its use as an analgesic seems counterintuitive. This paradoxical effect is relevant only for LDN and not for its standard doses. Various theories have been propounded, but two of these stand out i.e. the effect of LDN on TLR-4 found on the microglia cells (the macrophages of the central nervous system) and the up-regulation of endogenous opioids' levels and OR.
First, the seemingly paradoxical effect of naltrexone in reducing pain, appears to be mediated by a non-OR mechanism, i.e., through TLR-4 found on the microglial cells, among others. As described for IR (see above), TLR-4 acts downstream to NF-ĸB to modulate inflammatory activity. LDN suppresses this cascading mechanism, thus acting as an anti-inflammatory agent. However, LDN has shown to be of benefit in disorders like fibromyalgia which is not considered an inflammatory disorder per se. Instead, fibromyalgia is more likely to heighten response to pain stimuli. Thus, LDN could be said to modulate pain response in addition to its anti-inflammatory activity.
Second, in vivo models using a chronic combination of opioid agonists and LDN have shown that there is an increase in the levels of endogenous opioids and upregulation of OR.
Similar questionnaire-based and pilot studies have shown that LDN may have a substantial role to play in the treatment of irritable bowel syndrome and complex regional pain syndrome.,, However, data from these studies cannot be extrapolated to justify use in clinical settings. RCTs are needed to substantiate (or refute) said statements.
| Strengths|| |
In contrast to the usual monthly cost of fibromyalgia treatment (United States) of $100, LDN costs about $35. As of now, naltrexone is not available for nonpsychiatric indications in India. Kumar et al. in their 2020 study comparing naltrexone with acamprosate in the management of alcohol dependence procured the former drug free of cost from government supply. The United States cost can be taken as a proxy for the Indian market until indigenous data are available.
Minimal adverse effects
Turel et al. (2015) reported that in patients with MS on LDN, over 77% did not report any adverse effects. Immune thrombocytopenic purpura was reported in this study, but whether it was the outcome of the disease or the intervention, it could not be made clear. Hepatotoxicity is reported only for doses 300 mg/day or above in a placebo-controlled study. No interference with other medications like warfarin has been seen. LDN use in the nonpsychiatric domain is predicated on the premise that only standard doses of naltrexone can be potentially toxic while LDN has not shown any adverse effects till date except for vivid dreaming and insomnia., However, adequately powered controlled studies are lacking.
Minimal abuse liability
Unlike standard dose naltrexone, there appears to be no abuse liability for LDN. However, patients are advised not to take opioids in conjunction with LDN, since the combination may result in opioid overdose and abuse.
| Weaknesses|| |
There are reports of development of immune thrombocytopenic purpura in patients on MS who were inducted with LDN; however, the confounding factors seem to be the use of other immunomodulating drugs and of the disease effect itself. Other issues such as insomnia (6%) and nightmares (5%) have also been reported.
Nonavailability of low-dose tablets
Since the only USFDA-approved use of naltrexone seems to be for alcohol and opioid use disorders and that too for standard dose naltrexone, LDN needs to be procured from special issue pharmacies as of now.
Beyond the scope of insurance
Apropos to the USFDA approval limitation, insurance companies do not cover LDN and it continues to be an off-label drug. Even though the long-term cost of LDN versus standard therapies is arguably miniscule, given LDN use in most chronic conditions, the cost per capita assumes significance.
| Conclusion|| |
OR antagonism – through LDN – has brought OR signaling outside the confined domain of neuropsychiatry. Its role in modulating insulin sensitivity, regulation of normal cellular growth, restriction of cancer cell progression, tempering pain sensitivity, and reducing inflammation has heralded the drug into hitherto uncharted territories. Animal and cell culture models have provided insight into its effect on TLRs, ATMs, microglial cells, NF-ĸB, SIRT-1, OGF-OGFr axis, and MAPK/ERK pathway, among others. Case reports have shown clinical benefits over long-term use.
However, there are sizable gaps in research: there is a paucity of quality studies and long-term follow-up. The unavailability of low-dose tablets in the market is a limiting factor in itself.
Given the unraveling of novel cascading mechanisms in the action of naltrexone, it is imperative that superior and comprehensive studies must be undertaken to welcome this economical drug to needy patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]