Pharmacology Update: Low-Dose Naltrexone as a Possible Nonopioid Modality for Some Chronic,Nonmalignant Pain Syndromes

Abstract

Pain can have a devastating effect on the quality of life of patients in palliative medicine. Thus far, majority of research has been centered on opioid-based pain management, with a limited empirical evidence for the use of nonopioid medications in palliative care. However, opioid and nonopioid medications such as nonsteroidal anti-inflammatory drugs have their limitations in the clinical use due to risk of adverse effects, therefore, there is a need for more research to be directed to finding an alternative approach to pain management in comfort care setting. The purpose of this article is to discuss a potential new drug that would adequately alleviate pain and enhance quality of life without significant risks of adverse effects that would limit its use. Naltrexone is a reversible competitive antagonist at μ-opioid and κ-opioid receptors, which when used at standard doses of 50 to 150 mg was initially intended for use in opioid and alcohol use disorders. However, it was discovered that its use in low doses follows alternate pharmacodynamic pathways with various effects. When used in doses of 1 to 5 mg it acts as a glial modulator with a neuroprotective effect via inhibition of microglial activation. It binds to Toll-like receptor 4 and acts as an antagonist, therefore inhibiting the downstream cellular signaling pathways that ultimately lead to pro-inflammatory cytokines, therefore reducing inflammatory response. Its other mode of action involves transient opioid receptor blockade ensuing from low-dose use which upregulates opioid signaling resulting in increased levels of endogenous opioid production, known as opioid rebound effect. Low dose naltrexone has gained popularity as an off-label treatment of several autoimmune diseases including multiple sclerosis and inflammatory bowel disease, as well as chronic pain disorders including fibromyalgia, complex regional pain syndrome, and diabetic neuropathy. Low-dose naltrexone (LDN) may also have utility in improving mood disorders and the potential to enhance the quality of life. This article will therefore propose the potential off-label use of LDN in management of nonmalignant pain in the palliative medicine setting.

Keywords

naltrexone chronic pain nonmalignant palliative treatment fibromyalgia

Introduction

Management of pain is crucial in palliative care, as it can lead to suffering and a devastating impact on the quality of life. Patients dying from cardiac failure, chronic lung disease, diabetes, and other terminal illnesses account for two-thirds of patients in need of palliative care, and can experience comparable pain to that of patients with cancer. Adequate assessment and management of pain is therefore a major challenge in palliative medicine. Majority of research has been focused on optimizing opioid analgesic therapy; however, use of opioid-based medications is not without constraints, given gastrointestinal (GI) side effects such as nausea and constipation, mental status change, hemodynamic disturbance, and the risk of respiratory depression. There is also concern with regard to their long-term use, given the potential for addiction and abuse, as well as the possibility of opioid-induced hyperalgesia.¹ Therefore, although opioids have been the leading and most effective agents for pain management in palliative care, they have a limited utility for optimal pain control, and their use for chronic, nonmalignant pain is controversial.¹

Current evidence on the efficacy of nonopioids, primarily nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, is not adequately reflected in clinical practice. Although nonopioid analgesics are thought to be beneficial in the management of palliative patients, their use also has their limitations due to GI, cardiovascular, and renal adverse effects.²

In search of a drug that would adequately control pain and limit the risks of adverse effects, as well as improve the quality of life, naltrexone, used at a significantly lower than standard dose, has recently surfaced as a potential agent for such a purpose. This review article will therefore discuss the off-label use of low-dose naltrexone (LDN) as a novel agent for primarily nonmalignant pain management in palliative care setting.

Low-Dose Naltrexone

Naltrexone, 17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-one, is a long-acting opioid receptor antagonist that was initially approved by Food and Drug Administration (FDA) in 1984 for the treatment of opioid dependence, and is currently also FDA-approved for treatment of alcohol dependence.^3
-5 Naltrexone has a great oral absorption, however it undergoes significant first-pass metabolism; it is metabolized by a noncytochrome dehydrogenase enzyme to its active metabolite, 6-β-naltrexol. Naltrexone is primarily renally excreted; however, dose adjustment is not needed with mild-renal impairment; dose adjustments in moderate to severe renal impairment have not been studied.⁶ Naltrexone and its active metabolite are reversible competitive antagonists at μ-opioid and κ-opioid receptors, with the highest affinity for µ-opioid receptors.^7,3 The standard dose of naltrexone at 50 to 150 mg also prevents inhibition of gamma-aminobutyric acid receptor as well as inhibition of dopamine release.⁵

Initial off-label use of naltrexone in doses ranging from 1.5 mg to 3 mg appeared to have an immune-modulating effect in patients with acquired immune deficiency syndrome in 1990s.^8,3 Subsequently, it had gained popularity as an off-label treatment for pain and inflammation in several autoimmune diseases including multiple sclerosis (MS) and Crohn disease, as well as fibromyalgia.⁶ In 2007, the first trial was published on the use of LDN in Crohn disease, which demonstrated remission in 67% of patients as well as improvement in quality of life.⁹

In 2013, there was an immense increase in the use of LDN for various clinical indications in Norway, following a documentary of patients with severe MS who were treated with LDN with subsequent remission of disease. Following the documentary, there was increased awareness and use of LDN at mean dose of 5.3 mg in the Norwegian population, for a wide range of diagnoses. A search of the Norwegian Prescription Database revealed that the number of naltrexone users increased from 14 in 2012 to more than 11 000 in 2013.¹⁰ Low-dose naltrexone continued to be used off-label with continued recruitment of new consumers.¹⁰

Mechanisms of Action

The premise behind using LDN stems from the fact that its kinetics do not follow a linear dose–effect curve, rather, it follows multiple dose–dependent pharmacological pathways with different end-results. In low-doses ranging from 1 to 5 mg, naltrexone acts as a glial modulator with a neuroprotective effect via inhibition of microglial activation in the central nervous system (CNS), thereby reducing the production of potentially neurotoxic chemical.^4,3 Microglia are CNS immune cells that are activated by various stressors. Once activated, microglia produce inflammatory and excitatory molecules resulting in pro-inflammatory cascade leading to neurotoxicity.^11,4 Naltrexone specifically binds to Toll-like receptor 4 (TLR4), where it acts as an antagonist. Toll-like receptor 4 downstream cellular signaling pathways ultimately lead to pro-inflammatory cytokines such as interleukin-1, tumor necrosis factor-α, interferon-β, excitatory amino acids, substance P, and nitric oxide, which result in neuroinflammation. This serves as a pathophysiological mechanism of central inflammation with a consequent range of symptoms and clinical outcomes, including increased pain sensitivity, fatigue, cognitive disruption, as well as sleep and mood disorders.⁴ Low-dose naltrexone disrupts this signaling cascade with reduced synthesis of the pro-inflammatory cytokines, consequently attenuating the activated microglial cells and resulting in analgesic and anti-inflammatory effect.^3,11

Low dose naltrexone has another mode of action; instead of producing a permanent opioid receptor blockade, using lower dose results in transient opioid receptor blockade which upregulates opioid signaling. It has been demonstrated in both animal and human cell studies that administration of naltrexone in low doses (ie, 0.1 mg/kg) results in a blockade lasting 4 to 6 hours, during which time there is increased endogenous opioid production—known as opioid rebound effect.⁴ Evidence suggests that this rebound effect also prompts increased production of opioid receptors, thereby increasing the sensitivity of signaling in addition to increasing the production of endorphins, to compensate for the transient deficit.⁵ Furthermore, increased production of endogenous opioids could inhibit the proliferation of B lymphocytes and T lymphocytes, thereby modulating the immune system.⁶

Furthermore, intermittent blockade by naltrexone blocks the opioid growth factor (OGF) receptor resulting in biofeedback response that increases production of endogenous OGF, also known as [Met5]-enkephalin, with concomitant increase in μ-opioid, delta-opioid, and OGF receptor expression, thereby facilitating interactions between OGF and opioid growth factor receptor (OGFr).^12,3 Some studies also indicate that LDN acts as an immunomodulating agent by directly binding to the OGF receptor within immune cells. Binding of OGF-OGFr and increased endogenous opioid signaling has been shown to play an important role in supporting growth and development of tissues and organs. Opioid growth factor and naltrexone can therefore promote cell proliferation and wound healing, as well as reduce inflammation.¹¹

In an animal model study using experimental autoimmune encephalomyelitis mice to investigate the pathomechanism of MS, an inflammatory disorder of the CNS, [Met5]-enkephalin levels were shown to be depressed prior to the onset of disease symptoms and were restored with LDN therapy.¹² Moreover, it was demonstrated that serum [Met5]-enkephalin levels were lower in humans with MS relative to non-MS patients, and LDN restored their levels. This therefore demonstrates the potential of LDN as a modulator of the neuroimmune axis.¹²

Furthermore, upregulated endorphins were demonstrated to produce neuropsychological benefits.^2,3 Retrospective study evaluated patients with MS with a mean disease duration of 10 years, who took LDN with a median therapy period of 804 days. Three quarters of patients endorsed an improvement in quality of life.³ Cree et al investigated the efficacy of 8 weeks of treatment with 4.5 mg LDN on self-reported quality of life of patients with MS. Eight weeks of treatment with LDN was associated with improvement in mental health outcome measures such as mental health, pain, and cognitive function, which could be attributed to upregulation of mood enhancing beta-endorphins and possibly augmented dopamine activity.¹³ It is further hypothesized that LDN may enhance the quality of life through increased energy and reward feedback via the connection between μ-opioid receptors and central dopamine neurons in the mesencephalon.¹⁴

Because of naltrexone’s activity as an opioid receptor agonist, it would be expected to have no efficacy in chronic pain for patients already on opioids, and, in fact, would likely cause uncomfortable and undesirable effects on such patients.¹⁵

Immune Modulation

In a study investigating the effect of LDN in inflammatory bowel disease (IBD), administration of low-dose naltrexone (LDN) was postulated to result in up-regulation of endogenous encephalin and endorphin levels and to have a positive modulatory effect on the m-opioid receptors.¹⁶ In both mouse and rat models of IBD, LDN alleviated inflammation, in part by reducing pro-inflammatory cytokine production.^17,18 In another study, it was demonstrated that pro-inflammatory Th1 and Th17 cells produce enhanced levels of endogenous opioids during colitis in mice, which suppress pain signals during chronic mucosal inflammation.¹⁹ The study by Lie et al demonstrated an increased expression of µ-opioid receptor in mucosal immune cells (T lymphocytes and monocytes), and one possible reason for this upregulation may be compensatory pain management. It is thus plausible that remission of disease in patients treated with LDN is in part attributed to a general improvement in well-being.¹⁷

It has been demonstrated that peripheral nerve injury activates spinal cord microglial cells via TLR4. Activated spinal cord microglia modulate pain processing at both spinal and supraspinal levels and result in signaling cascades with products such as proinflammatory cytokines chemokines, calcitonin gene-related peptide, substance P, and glutamate which have been demonstrated to be involved in neuropathic pain.²⁰ A series of studies by Hutchinson et al using animal rat models used pharmacological approaches for reversing neuropathic pain via blockade of TLR4; it was demonstrated that neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagonists such as naloxone and naltrexone.²¹

Uses in Chronic Pain

Fibromyalgia

Human data for the use of LDN is preliminary. A PubMed search using the keywords “low dose naltrexone [and] fibromyalgia,” yielded 19 articles, many of them selective reviews of the literature. Two separate, small clinical trials demonstrated LDN administered at 4.5 mg daily reduced fibromyalgia (FM) pain significantly greater than placebo.^22,23 Of these, the Younger et al, trial was randomized, double blinded, placebo-controlled and crossover, but the results were described as “preliminary.”

Fibromyalgia is a multisymptom condition, with widespread musculoskeletal pain as well as cognitive problems, fatigue, insomnia, GI problems, and mood disorder.⁴ Fibromyalgia is not a classical inflammatory or immune-mediated condition; however, the immune system is thought to play a role its complex pathophysiology. The pathophysiology of FM may involve proalgesic sensitization of the CNS in response to various stimuli. Another study by Parkitny and Younger demonstrated a 15% reduction of FM-associated pain and an 18% reduction in overall symptoms after an 8-week period. Furthermore, it was shown that individual’s baseline erythrocyte sedimentation rate, a marker of inflammation, was strongly correlated with their response to LDN. The findings of this trial suggested that LDN treatment in fibromyalgia is associated with a decrease in pro-inflammatory cytokines with significant improvement of symptoms.²⁴

Complex Regional Pain Syndrome

Data on low-dose naltrexone is similarly sparse in regard to complex regional pain syndrome (CRPS). A PubMed search on the keywords “low dose naltrexone and complex regional pain syndrome” produced 5 articles 1 of which was a case study of 2 patients²⁵ and none were placebo-controlled.

Complex regional pain syndrome is a neuropathic pain syndrome involving glial activation and sensitization of the CNS as a result of peripheral nerve injury. It is a neuroinflammatory condition characterized by a sensory, motor, autonomic, and vasomotor dysfunction, as well as pain that is out of proportion to the inciting event. Postmortem analyses have demonstrated activation of microglial cells via TLR4 receptor within the CNS which have been implicated in the generation of CRPS symptoms; furthermore, sustained TLR4 stimulation in microglial cells can also lead to neuronal injury and death. Pro-inflammatory cytokines, as well as brain-derived neurotrophic factor, induce enhanced excitatory tone and diminished inhibitory tone in the nociceptive networks leading to allodynia. In rodents, naltrexone was demonstrated to cross the blood–brain barrier, suppress glial cell activation, and reverse neuropathic pain arising from chronic constrictive nerve injury.²² In a case report of 2 patients with CRPS who were treated with LDN after conventional CRPS pharmacotherapy failed to suppress their symptoms demonstrated remission of pain and dystonic spasms in one patient and remission of all CRPS symptoms in the second patient.²⁵

Chronic Low-Back Pain

In another case report of a patient with chronic paraspinal low back pain that was ineffectively treated with short-acting opioids, NSAIDs, tricyclic antidepressant, antiepileptics, and physical therapy and corticosteroid injections, treatment with LDN was shown to result in a dramatic improvement in pain. Treatment was started with 2 mg of LDN for 2 weeks followed by 4 mg, which resulted in 30% to 40% reduction in pain after 2 weeks.¹⁸ No adverse events were noted during or after the drug administration, and no other treatments were used. The patient was experiencing minimal pain after 6 months of drug initiation and was able to participate in all daily physical activities.²⁶

Diabetic Neuropathy

In yet another case report, LDN was used off-label for the treatment of painful diabetic neuropathic pain refractory to most available therapy. The patient had a 30-year history of type-2 diabetes with 7 years of diabetic neuropathy that failed therapy with amitriptyline, pregabalin, duloxetine, lamotrigine, NSAIDs, as well as lumbar paravertebral nerve block.²⁷ He was initiated on naltrexone 2 mg daily with partial improvement in pain; the dose was subsequently increased to 4 mg with significant improvement in pain after 2 weeks. He continued the same dose without experiencing any significant side effect. This was a first report demonstrating the efficacy of LDN in relieving the pain of diabetic neuropathy; however, it will need to be followed by large randomized, double-blind, clinical trials to establish the possible mechanism, efficacy, and safety of LDN in painful diabetic neuropathy.²⁶

Malignant Pain

The purpose of this article was to primarily focus on nonmalignant pain, however LDN may also have utility in cancer-related pain and even improve quality of life in patients unable to tolerate chemotherapy given its immune enhancing effects.⁵ An animal study involving female dogs with histopathological diagnosis of mammary carcinoma in benign mixed tumors (MC-BMT) with or without regional metastasis, who underwent treatment with chemotherapy alone or LDN and chemotherapy demonstrated higher serum concentrations of beta-endorphin and met-enkephalin, fewer chemotherapy-related side effects, and better quality of life and survival rates in the LDN-treated groups than in LDN-untreated groups. Evaluation of clinical and pathological parameters indicated a significant association between the use of LDN and both prolonged survival and enhanced quality of life.²⁸

Emotional Well-Being and Quality of Life

Naltrexone may also have a role in promoting resilience and emotional well-being, as well as improvement of psychiatric problems such as anxiety and depression.¹⁵ Evidence from animal research reveal that opioid receptors play rather specified roles in mood-related processes, and therefore have a promising antidepressant potential.²⁹ Naltrexone at doses of 3 to 4.5 mg was shown to increase the expression of mu, delta, and epsilon opioid receptors as well as central and circulating met-enkephalin and beta endorphin, which presumably enhances psychological well-being.¹⁵ Efficacy of LDN was also investigated in augmentation of breakthrough depression in patients on prodopaminergic antidepressants. Low-dose naltrexone augmentation showed some benefit for major depressive disorder relapse in these patients. There is a demonstrated link between μ-opioid receptors and dopaminergic neurons in the mesencephalon. Naltrexone binds to the scaffolding protein Flamin A, which prevents G protein signaling in G-coupled receptor systems of the μ-opioid receptor. Filamin A is also found in dopaminergic D2 and D3 receptors. It is proposed that LDN might reverse desensitization to D2 and D3 agonists. It is therefore hypothesized that LDN may have potential dopaminergic mechanisms, however confirmation in larger studies is needed.³⁰

Discussion

Naltrexone is an inexpensive medication with a low side effect profile, with some reported incidences of vivid dreams, nightmares, headaches, and anecdotal reports of anxiety and tachycardia. Even at much larger dosages, naltrexone does not significantly affect liver function, and there has not been any observed toxicity or withdrawal symptoms with chronic use.⁴ Therefore, current evidence supports the safety and tolerability of LDN in several chronic pain and inflammatory disorders; however, there are few studies demonstrating the efficacy of LDN, with most studies relying on subjective measures such as quality of life and self-reported pain. Evidence for objective data is limited.⁶

No large-scale clinical trials or standardized experimental studies have described patients receiving long-term LDN therapy, discontinuation rates, or proportion of chronic users. There are currently no guidelines for the clinical use of LDN and no FDA-approved use for naltrexone at any dosage for the treatment of chronic pain, inflammatory diseases, or any other medical condition. In addition, LDN is not commercially available and must be produced in a compounding pharmacy.

While there have been numerous modalities developed for the use of LDN, none have been empirically validated. Therefore, naltrexone has remained as an off-label option. Further clinical research with randomized controlled trials is warranted before any treatment approach can be implemented.⁴

Conclusion

Based on the limited evidence that exists thus far, LDN is a promising subject for further research, and may, in the future, offer a nonopioid approach for chronic pain, including in palliative care. Low-dose naltrexone targets multiple and varied sites and exhibits significant pharmacologic activity against pain of various origins including central, neuropathic, and inflammatory. Low-dose naltrexone appears to act, at least partially, by enhancing endogenous opioid production and modulating pain sensitivity without the peripheral adverse effects of opioid medications. Given its concomitant anti-inflammatory effect there may be efficacy associated with chronic inflammatory, autoimmune, and neuropathic disorders.

Naltrexone has a rather benign adverse effect profile, with no evidence of long-term adverse drug effects. Furthermore, upregulated endorphins may produce neuropsychological as well as antidepressant effects, giving it the potential to enhance the quality of life, making it a future potential candidate for use in palliative medicine. Further research, including randomized, double blind, placebo-controlled trials is warranted.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Steven J. Baumrucker

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