key: cord-0301843-k4j9g1pm authors: Toledano, A. C. title: Low-Dose Naltrexone/Acetaminophen Combination in the Preventive Treatment of Migraine: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial with an Open-Label Extension for None-Responders date: 2021-03-26 journal: nan DOI: 10.1101/2021.03.23.21254186 sha: 81368f33702c8fa9e0ef34407f0df19d523fb800 doc_id: 301843 cord_uid: k4j9g1pm We tested low-dose naltrexone/acetaminophen combination for episodic migraine prevention. We randomly assigned patients to naltrexone/acetaminophen (n=6) or placebo (n=6) for a 12-week double-blind treatment. Non-responders continued into open-label treatment with naltrexone/acetaminophen (n=5) for additional 12 weeks. Patients were adults who experienced 5 to 17 (average 9.7) migraine days at baseline. The primary endpoint was the mean change in the monthly migraine days during the last 4 weeks of the double-blind treatment period. The key secondary endpoint was the mean change in the monthly migraine days from the 4-week double-blind follow-up (2nd baseline) to the last 4 weeks of the open-label treatment period. The magnitude of the treatment effect for naltrexone/acetaminophen observed in the double-blind period was 2.2 fewer monthly migraine days than placebo (p=0.43). Four out of 6 (66.7%) naltrexone/acetaminophen-treated patients experienced 75% reduction in migraine days compared to 1 out of 6 (16.7%) placebo-treated patients (p=0.09). In the open-label phase, treatment with naltrexone/acetaminophen (n=5) led to 8.2 fewer mean monthly migraine days (from 11.8 to 3.6), representing 69.5% improvement (p=0.03), and 100% of the patients experienced a 50% reduction in monthly migraine days. Adverse events were mild/moderate and transient, included dry mouth, fatigue, sedation, nausea, and feeling jittery. We postulate that naltrexone's toll-like receptor (TLR4) antagonism properties prevent pro-inflammatory cytokines' production in the trigeminal ganglion averting ''overactive nerves'' and migraine. Although this trial used low-dose naltrexone (defined as 1 - 5 mg/day), we postulate mid-dose naltrexone (MDN) (defined as 6 - 10 mg/day) may offer a greater migraine prevention control. The estimated global prevalence of migraine is 14.7% (that's around 1 in 7 people). 1 In the global burden of disease study, updated in 2013, migraine was the sixth highest cause worldwide of years lost due to disability (YLD). 2 In the United States, approximately 38 million Americans are afflicted by migraine, and available treatments do not adequately meet the needs of many. Hence, there is a need for new treatments for preventing migraine. Oral naltrexone/acetaminophen combination, if proven effective, may provide greater efficacy/tolerability ratio than existing migraine prevention treatments. Naltrexone, 3 an opioid antagonist approved for addiction treatment, is also an analgesic due to recently-discovered toll-like receptor 4 (TLR4) antagonism properties. Inhibiting the TLR4 with naltrexone in nerve cells of the dorsal root ganglia (DRG) and trigeminal ganglion led to reduction in pro-inflammatory cytokines' production and reversal of neuropathic pain and migraine in animal studies. [4] [5] [6] [7] [8] [9] [10] Naltrexone can prevent a "localized cytokine storm" (our term) in nerve cells averting pain. We postulate that naltrexone's toll-like receptor (TLR4) antagonism properties prevent pro-inflammatory cytokines' production in the trigeminal ganglion averting "overactive nerves" and migraine. The Interagency Pain Research Coordinating Committee (IPRCC) voted a study that used naloxone 5 (a opioid/TLR4 antagonist similar to naltrexone) as one of 2009-2013 pain research advances that represent significant progress in the field. "This research supports TLR4 as a potential therapeutic target for treating chronic pain in patients, and, as the establishment of a completely new class of pain-relieving medication, would be a remarkable advance in pain treatment." 11 TLR4 is an innate immune system receptor that usually detects invasion of foreign agents such as viruses and initiates a cascade leading to cytokines' production to eliminate them. However, the TLR4 can also be triggered by endogenous damage molecules originating from injured tissues (e.g., a herniated intervertebral disc) and lead . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted March 26, 2021. ; https://doi.org/10.1101/2021.03.23.21254186 doi: medRxiv preprint to cytokines' production and pain. 12 The inborn, innate immune system is distinct from the learned, adaptive immune system. Naltrexone blocks the production of pro-inflammatory cytokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon-β, calcitonin gene-related peptide (CGRP), nitric oxide (NO), and reactive oxygen species (ROS) in nerve cells, 5, 8, 13, 14 preventing a "localized cytokine storm" (our term) and pain generation. Naltrexone exerts its action at the beginning of the cascade leading to the production of many pro-inflammatory cytokines blocking their creation. Drugs that neutralize individual cytokines after their formation include adalimumab (Humira), a TNF-α blocker; anakinra (Kineret), an IL-1 blocker; Tocilizumab (Actemra), an IL-6 blocker; and rimegepant, (Nurtec), a CGRP blocker. Naltrexone can prevent the production of multiple cytokines eliminating the need to neutralize them. But once created, naltrexone, cannot stop these cytokines. We hypothesize that the pathophysiological event underlying migraine is the excessive production of pro-inflammatory cytokines in the trigeminal ganglion creating a neuroinflammatory response resulting in a "localized cytokine storm." Similarly, in the dorsal root ganglions, a "localized cytokine storm" results in neuropathic back pain. We postulate that a localized "cytokine storm" is the underlying event leading to "overactive nerves" (layman's term) and nerve pain. Pro-inflammatory cytokines exaggerate neuronal excitability, contributing to neuropathic pain and migraine. Activation of TLR4 has been implicated in the pathogenesis of migraine 9,15 and (+)-Naltrexone blocked the development of facial allodynia in modeled migraine in rats. 9 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) Dr. Bernard Bihari invented Low-Dose Naltrexone (LDN) (a daily dose of 1 to 5 mg) in the mid-1980s for "normalizing the immune system function." 16, 17 However, scientists discovered the innate immune system and TLRs in humans in the 1990s (a Nobel Prize was awarded in 2011). 18 The prevailing theory for LDN's mechanism of action was that it increases endorphin production, systemically upregulating endogenous opioid signaling by a transient opioid-receptor blockade. 19 later research attributed the analgesic properties of naltrexone to TLR4 antagonism leading to pro-inflammatory cytokines' production inhibition. Currently, LDN is widely accepted as an alternative medicine modality and is used by its proponents to treat various medical conditions. It is almost sold as an everyday supplement by certain pharmacies. 19, 20 Grassroots interest in off-label LDN sprang clinical trials for fibromyalgia, multiple sclerosis, Crohn's disease, and complex regional pain syndrome (CRPS). [21] [22] [23] [24] [25] Although LDN is reportedly used as an off-label treatment for various medical conditions, there are no confirmatory studies for these off-label uses. Addiction specialists are the primary prescribers of naltrexone. Acetaminophen potentially enhances the combination in several ways. Acetaminophen created synergy for analgesia in combination drugs such as Vicodin (hydrocodone/ acetaminophen). 26 Similarly, combining naltrexone with acetaminophen could attain synergy for analgesia. Acetaminophen 1000 mg was already established as an effective acute migraine medication and can therefore enhance the combination's treatment effect on migraine. 27, 28 Acetaminophen has the public's trust as the world's most used drug. Acetaminophen was found to be also an emotional pain reducer. Acetaminophen significantly reduced hurt feelings in human studies. 29, 30 Acetaminophen's emotional . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 26, 2021. ; https://doi.org/10.1101/2021.03.23.21254186 doi: medRxiv preprint pain reducing properties could potentially be augmented by naltrexone 31 and enhance the combination's effect on the overall sense of well-being. Naltrexone's established cytokine production inhibition properties in the trigeminal and dorsal root ganglia averting pain could theoretically reduce pain symptoms associated with COVID-19 and COVID-19 vaccination. Three experimental TLR4 antagonists FP7, Eritoran, and retrocyclin 101, were significantly better than placebo in treating lethal influenza. 32-34 TLR4 signaling is a key disease pathway controlling the severity of acute lung injury. 35 Naltrexone, a readily available TLR4 antagonist, needs to be evaluated for the treatment of pain symptoms in COVID-19. Interestingly, the innate immune system's pathway that mounts an initial response to viral infections is the same one that leads to neuropathic pain when triggered intrinsically by damage-molecules. Naltrexone/acetaminophen combines naltrexone's unutilized analgesic properties with the established and well-trusted analgesic properties of acetaminophen. Patients were recruited to our single site in Miami, Florida, through billboards and social media advertising. The study was conducted between August 25, 2017, and July 26, 2018. ANODYNE-3, (the study's name) enrolled patients 18 to 75 years of age with a history of migraine with or without aura for at least one year that was consistent with the diagnosis criteria of the International Classification of Headache Disorders (ICHD)-3rd edition (beta version) 36 and have experienced 5 to 17 migraine days in the 4-week . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 26, 2021. ; https://doi.org/10.1101/2021.03.23.21254186 doi: medRxiv preprint baseline. The study population included 11 patients with episodic migraine and one with chronic migraine. Patients needed to have at least 5 migraine days during the baseline. Patients using opioid medications or who had a history within the previous 3 years of drug abuse were excluded. Our goal was to enroll 48 patients, but we were unable to meet that goal due to hurricane Irma's (September 2017) impact on our community. The sponsor/investigator -Annette Toledano, M.D., was responsible for all the trial elements, including design, execution, data collection, analysis, and interpretation. The trial's protocol and informed consent were approved by the Schulman Associates IRB (now Advarra). All patients provided written informed consent before starting the study procedures. The informed consent informed the patients of the conflict of interest of the sponsor/investigator. The study patients were compensated for participation. This study was conducted under an Investigational New Drug (IND) application with the United States Food and Drug Administration (FDA). The ANODYNE-3 trial was a phase 2, single-site, randomized, double-blind, and placebo-controlled proof-of-concept study. We evaluated the patients in seven site visits during the double-blind phase and four visits during the open-label phase. The visits included: baseline (week -4), randomization (week 0), and double-blind treatment . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Patients recorded in a daily paper diary the duration and headache severity. They also recorded photophobia, phonophobia, nausea, vomiting, and any acute migraine medication use. The study pharmacist prepared the study medication from marketed tablets placed in two single-ingredient capsules backfilled with microcrystalline cellulose. The study pharmacist devised the randomization schedule using a block size of 12. The study medication kits were sequentially numbered, and the investigator assigned the kits to The efficacy and safety analyses included all randomized patients who received at least one dose of the study medication, recorded a baseline migraine severity rating, and reported at least one post-dose assessment. All statistical tests were 2-sided hypothesis tests performed at the 5% significance level. Statistical analyses were conducted using MedCalc statistical software. 37 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) We assessed 94 patients for eligibility; 12 patients met the inclusion criteria and were . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted March 26, 2021. ; https://doi.org/10.1101/2021.03.23.21254186 doi: medRxiv preprint Comparing the baseline to the last 4-weeks of the double-blind period, treatment with naltrexone/acetaminophen (n=6) led to 5.7 fewer monthly migraine days, whereas treatment with placebo led to 3.5 fewer monthly migraine days, both groups improving from a baseline rate of 9.7 monthly migraine days. The magnitude of the treatment effect observed in the double-blind period was 2.2 fewer monthly migraine days (p=0.43) (Table 2 and Figure 3 ). In the double-blind period, 66.7% of the naltrexone/acetaminophen patients experienced a 50% reduction in migraine headache days from baseline to the last 4 weeks of the double-blind period compared to 33.3% in placebo patients (p=0.27). 66.7% of naltrexone/acetaminophen patients experienced 75% reduction in migraine days compared to 16.7% of placebo patients, (p=0.09), and 50.0% of the naltrexone/acetaminophen-treated patients experienced 100% reduction in monthly migraine days compared to 16.7% of placebo patients, (p=0.27) ( Table 2 ). The magnitude of the treatment effect from baseline to the last 4 weeks of the doubleblind treatment for Headache Impact Test (HIT) score was -9.8 points (p=0.29), and for Pittsburgh Insomnia Rating Scale-20, it was -11.7 (p=0.27). The magnitude of the treatment effect in monthly migraine hours in the double-blind period was a 28.8 hours reduction (p=0. 35) . In the open-label period, treatment with naltrexone/acetaminophen (n=5) led to 8.20 fewer monthly migraine days (from 11.80 to 3.60), amounting to 69.5% improvement, (p=0.03) (Figure 4) . Also, 100% of the patients experienced a 50% reduction in the monthly migraine days ( Table 3 ). The treatment effect from the double-blind follow-up to . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Acetaminophen-overuse head could be expected in patients having more than 15 headaches per month who consume acetaminophen more than 15 days per month for more than 3 months. 36 Since the study administered acetaminophen 650 mg daily, we were concerned that acetaminophen may induce medication overuse headaches. The study provided data on 11 three-month treatment courses with naltrexone/acetaminophen for nine unique patients and two patients who received two consecutive courses separated by 4 weeks. During each of these courses, migraine days were lower than the baseline ( Figure 5 and Figure 6 ). This study provided preliminary evidence that a daily dose of naltrexone 4.5 mg/acetaminophen 650 mg did not induce medication overuse headache after three months of treatment. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted March 26, 2021 The analysis included all the 12 patients who were randomized (all of them completed the study). § A migraine day was defined as a calendar day in which a patient reported a headache of ≥ 30-minute duration and met criteria for migraine with or without aura. ¶ Headache Impact Test (HIT-6). Scores range from 36 to 78, with a score of over 50 indicating disability. ** Pittsburgh Insomnia Rating Scale-20 (PIRS-20). Scores range from 0 to 60, with scores above 20 suggesting insomnia. ‡ Patient Global Impression of Change PGIC: 1=Very much worse. 2=Much worse. 3=minimally worse. 4=no change. 5=minimally improved 6=Much improved. 7=very much improved. p-value -95% confidence intervals . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted March 26, 2021 (Table 4 ). Dry mouth, fatigue, sedation, nausea, and feeling jittery were the most commonly reported events. All the adverse events were mild/moderate in severity and resolved within 1 to 3 days. No serious adverse events were reported. No deaths or discontinuations due to an adverse event were reported. No changes in monthly liver transaminases or bilirubin were observed. The open-label treatment phase, representing "real world" response, demonstrated statistically significant reductions in migraine days per month, days of any acute headache medications use, Headache Impact Test score, at least moderate migraine days, and severe headache days. The daily dose of naltrexone in this study was approximately 1/10th of the approved addiction treatment dose. The daily acetaminophen dose was 650 mg. Although this trial used low-dose naltrexone (defined as 1 -5 mg/day), we postulate mid-dose naltrexone (MDN) (defined as 6 -10 mg/day) may offer a greater migraine prevention control. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) Limitations of this trial included its tiny sample size and treatment periods of just 3 months. The treatment period needed to be longer than 3 months to assess the acetaminophen-overuse headache risk. Targeting the toll-like receptor-4 represents a novel approach to treating migraine. Adding acetaminophen, the world's most used drug, could enhance the combination's analgesic effect and boost the public's trust conferring an advantage over naltrexone alone. This trial provides preliminary evidence for the potential benefits of naltrexone as a migraine prevention treatment. This study was the first to assess a naltrexone product for migraine prevention. Adequately powered clinical trials are needed to confirm these findings. The study's sample size was too small to achieve statistical significance for the primary endpoint. The naltrexone/acetaminophen combination received two U.S. patents for treating pain and a U.S. patent for treating emotional pain. Author Contribution: Concept, design, statistical analysis, and data interpretation: Annette Toledano. Dr. Toledano had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conflict Of Interest Disclosures: Dr. Annette Toledano reports she is the founder/medical director of Allodynic Therapeutics, LLC and the inventor/patent holder . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Migraine: the seventh disabler Headache disorders REVIA® (naltrexone hydrochloride tablets USP) 50 mg Opioid Antagonist Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone Toll-like receptors in chronic pain Systemic Administration of Propentofylline, Ibudilast, and (+)-Naltrexone Each Reverses Mechanical Allodynia in a Novel Rat Model of Central Neuropathic Pain +)-naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4 Supradural inflammatory soup in awake and freely moving rats induces facial allodynia that is blocked by putative immune modulators Structure-Activity Relationships of (+)-Naltrexone-Inspired Toll-Like Receptor 4 (TLR4) Antagonists -2013 Pain Research Advances | Interagency Pain Research Coordinating Committee Role of extracellular damage-associated molecular pattern molecules (DAMPs) as mediators of persistent pain Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for Fibromyalgia Naltrexone Inhibits IL-6 and TNFα Production in Human Immune Cell Subsets following Stimulation with Ligands for Intracellular Toll-Like Receptors Inhibition of toll-like receptor 4 alleviates hyperalgesia induced by acute dural inflammation in experimental migraine Low Dose Naltrexone (LDN) Pioneer Dr. Bernard Bihari Talks About His Life MD: Low-dose Naltrexone for Normalizing Immune System Function The Nobel Prize in Physiology or Medicine Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization Low-dose naltrexone for disease prevention and quality of life Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis Low-dose naltrexone therapy improves active Crohn's disease Treatment of Complex Regional Pain Syndrome (CRPS) Using Low Dose Naltrexone (LDN) Combination Analgesics The acute treatment of migraine in adults: the american headache society evidence assessment of migraine pharmacotherapies Efficacy and Safety of Acetaminophen in the Treatment of Migraine: Results of a Randomized, Doubleblind, Placebo-Controlled, Population-Based Study Acetaminophen reduces social pain: behavioral and neural evidence A Social Analgesic? Acetaminophen (Paracetamol) Reduces Positive Empathy Naltrexone alters the processing of social and emotional stimuli in healthy adults TLR4 antagonist FP7 inhibits LPSinduced cytokine production and glycolytic reprogramming in dendritic cells, and protects mice from lethal influenza infection The TLR4 antagonist Eritoran protects mice from lethal influenza infection The θ-defensin retrocyclin 101 inhibits TLR4-and TLR2-dependent signaling and protects mice against influenza infection Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury Headache Classification Committee of the International Headache Society (IHS) MedCalc's Comparison of proportions calculator We acknowledge the immense contribution of the study patients, the study pharmacist, and the clinical research coordinators, whose hard work made this trial possible.