Department of Internal Medicine, East Tennessee State University James H Quillen College of Medicine, Johnson City, Hospice and Palliative Medicine, Ballad Health System, Kingsport
Pharmacology Update: Low-Dose Naltrexone as a Possible Nonopioid Modality for Some Chronic, Nonmalignant Pain Syndromes
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.
A Retrospective Chart Review of Safety and Tolerability
Dr. Anthony P Turel, Penn State
LETTER TO THE EDITORS—RESEARCH REPORT
Journal of Clinical Psychopharmacology • Volume 35, Number 5, October 2015 www.psychopharmacology.com 609
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
To the Editors:
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that afflicts 400,000 people in the United States and more than 4 million individuals worldwide.1,2 The most common form of MS is relapsing remitting multiple sclerosis (RRMS), characterized by alternating relapses and remissions for a period of 10 to 15 years followed by steadily progressive deterioration transitioning into secondary progressiveMS.1,3 Multiple sclerosis is characterized by neurodegeneration of the spinal cord and brain, resulting in a reduction in mobility, reduced quality of life, and increased medical expenditures.4–6 Of the Food and Drug Administration approved therapies, many such as interferon beta-1a, interferon beta-1b, glatiramer acetate, and natalizumab require daily or weekly injections,5,6 whereas some of the oral medications such as fingolimod have unproven long-term efficacy. Nearly all of the therapies are costly and have side effects that reduce compliance.1,2 There remains an unmet medical need for safe, inexpensive therapies that delay MS progression and improve its clinical course.
A potential alternative or adjunctive therapy for MS is related to knowledge about the endogenous opioid system and its ability to modulate autoimmune diseases using animal models of MS.7–10 This novel biological pathway involves an endogenous opioid growth factor, chemically termed methionine enkephalin, and its nuclear-associated receptor, Opioid growth factor receptor.11 Modulation of this pathway by exogenous administration of opioid antagonists such as naltrexone (NTX) has been shown to mediate cell replication including T lymphocytes, astrocytes, and other glia that are associated with MS inflammation and degeneration.9 The magnitude and direction of change in cell proliferation is dependent on the duration of opioid receptor blockade.12 Low dosages of NTX (LDN), given once daily, block the receptor intermittently and result in inhibited cell replication. The LDN treatment of mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS, improves the course of progressive EAE.8,9 Mice immunized with myelin oligodendrocytic glycoprotein to establish EAE and treated daily with 0.1 mg/kg NTX (LDN) beginning at the time of disease induction show delayed onset of clinical disease and reduced behavioral deficits.8,9 Pathology of the spinal cord from these mice revealed significant reductions in the number of activated astrocytes and area of demyelination.8,9 The LDN treatment of mice with established relapsing-remitting EAE revealed that endogenous opioids inhibited progression of the disease as well.10
Three clinical trials of LDN in MS have been conducted and report that LDN increases the quality of life of MS patients.13–15 Cree et al14 concluded from a trial of 8 weeks that 4.5 mg LDN daily was a safe therapy that improved quality of life, whereas Sharafaddinzadeh et al13 reported safety after 17 weeks of treatment and recommended that longer trials be conducted to evaluate efficacy. Gironi et al15 studied primary progressive MS patients treated with LDN for 6 months and reported increased endogenous opioid levels in the patients and improved MS. The LDN treatment of patients with other autoimmune diseases including Crohn's disease and fibromyalgia has demonstrated safety and efficacy of the therapy.16,17 A major symptom of MS is fatigue,18 which is one of the many characteristics that patients seek to alleviate. Improvement in fatigue was cited in these clinical studies after LDN therapy, which suggests that there is a potential link between upregulated endogenous opioid systems and fatigue. Gironi et al15 reported elevated β-endorphin levels at 1, 3, and6 months after the onset of treatment, with β-endorphin levels remaining elevated for an additional month after LDN was discontinued. A return to pretreatment levels was not reported.15
To determine the safety, tolerability, and effectiveness of LDN on fatigue, a retrospective analysis of MS patients prescribed LDN (3.5 mg orally, once daily) by physicians in the Department of Neurology at The Penn State Hershey Medical Center was undertaken. The study was approved by the Human Subjects Protection Office of the Penn State College of Medicine and Hershey Medical Center and assigned an Institutional Review Board protocol number. Prescriptions were offered to MS patients who complained of 1 or more of the following: significant fatigue, needle phobia, refusal of injection therapy for other reasons, or refractory to other modes of therapy. Because of the potential of inducing acute withdrawal symptoms, LDN was not prescribed to patients receiving daily chronic opioid medications. All patients were given the option of receiving LDN with the understanding that medication could be stopped if they experienced side effects. Some patients already receiving disease-modifying therapy (DMT) when started on LDN continued the standard DMT along with adjunctive LDN. Evidence of major drug interactions was monitored but no interactions were reported.
The medical records of 215 MS patients, aged 18 to 65 years, seen in the MS clinic for a 7-year period (January 01, 2005 to May 31, 2012) and prescribed 3.5 mg LDN, orally, once daily, served as the study group. The LDN was provided by a licensed compounding pharmacy and cost the patients between US $30 to $50 monthly.
Information on LDN safety, tolerance, side effects, reasons for discontinuation, and hospitalizations while taking LDN were evaluated. Study data were collected and managed using REDCap (Research Electronic Data Capture), which is a secure web application designed to support data capture for research studies, providing user friendly web-based case report forms, real time data entry validation, audit trails, and deidentified data export mechanism to common statistical packages. Information regarding the self-reported potential effect of LDN on MS as collected by the physicians was also collated. The number of documented flares after LDN treatment was initiated was recorded, with a clinical flare defined as the appearance of new symptoms/signs or worsening of old symptoms/signs. Finally, in a retrospective manner, information regarding possible LDN effects on fatigue, quality of life, and the effect on MS was obtained from the patient's visit history and a review of symptoms.
Prescriptions for LDN were provided to 152 female (71%) and 63 male (29%) patients. The female to male ratio was 2.4:1 and more than 3 quarters of all patients had RRMS, a ratio similar to the prevalence cited in the United States.1,2 Clinically, 87% of the patients had RRMS and 10% had secondary progressive MS, with a mean disease duration of 10 years. The mean (SD) duration of exposure to LDN was 817(512) days; the median period of LDN treatment was 804 days. Individuals continuing on LDN for the course of this study were on the drug for a mean (SD) of 1217 (414) days, and a median of 1254 days. Patients (n = 111) who discontinued LDN received the drug for a mean of 526 days and cited insomnia, nightmares, no change in fatigue levels, cost, and recurrence of MS flares as causes to cease taking LDN. Because LDN treatment was not rigorously monitored as for a prospective study, side effects were based on the patients “perceived” and real changes. Seventy seven percent (n = 166) of patients taking LDN for any period of time did not report any side effects. Six percent of the patients had insomnia, whereas 5% of the patients had excessive dreams. There was no evidence of increased side effects related to other immunomodulators when combined with LDN. No abnormal laboratory results were noted. Of the 215 patients receiving LDN, 57 patients (26%) were hospitalized during the duration of this study; 48 of these patients were hospitalized for non-MS–related events such as infections. No patient was admitted to the hospital because of side effects of LDN.
Most of the MS patients began LDN therapy because of fatigue. Nearly 60% (n = 128) of patients receiving LDN for any period of time reported a reduction in fatigue with LDN therapy. Fifty of the 215 patients commented that LDN produced no relief from fatigue and 4 patients stated that LDN increased their fatigue levels. Regarding their quality of life and the perception of LDN's effects on MS, 130 patients (60%) stated that LDN stabilized or improved their disease and 75% of the patients reported improved or stabilized quality of life. Nine patients reported that LDN reduced the quality of life, and 8% of the patients had the perception that their disease increased while on LDN but provided no details.
In conclusion, this chart review focused on 215 MS patients who were provided a prescription for oral LDN. The study reports that a significant number of patients found combination therapy of an immunomodulating agent and LDN to be tolerable and possibly beneficial. Some patients preferred to take LDN as a monotherapy. The LDN did not cause any unexpected side effects, and those reported were previously noted in the literature. The LDN did not potentiate the side effects of the immunomodulating therapies that the patients were receiving. Any hospitalizations in this study were related to reasons other than MS, and there were no hospitalizations due to LDN.
Some limitations of this study are inherent in a retrospective chart review and include dependence on patient recollection and perception, the inability to determine specific indications for LDN, reasons for discontinuation, and proportion of patients who declined LDN because insurance did not pay for the treatment. Interactions between DMT and LDN were not elaborated, and a comparison with standard fatigue treatments such as amantadine or modafinil was not assessed.
Future studies comparing magnetic resonance imaging data before the onset of LDN therapy and periodically performed as standard of care will provide an assessment of the efficacy of daily LDN therapy. However, data from this retrospective study support future prospective double-blind investigations comparing a combination of LDN plus DMT and DMT alone.
The authors thank Marcus Magister, MD, Class of 2015, Penn State University College of Medicine, for the assistance in chart review, data acquisition, and data entry into REDCap.
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