Low Dose Naltrexone (LDN)
Naltrexone is a long-acting oral opiate antagonist which is approved for the treatment of alcohol addiction(50mg tablettakendaily). The mechanismofactionis complete opiate blockade, which removes the pleasure sensation derived from drinking alcohol (created by endorphins). Low Dose Naltrexone (LDN) in the range of 3-4.5 mg per day has been shown to have the opposite effect – brief opiatereceptorblockadewithresulting . Throughthe work of Bihari and Zagon, it has beendetermined that the levelofthe endogenous opiate met- enkephalin is increased byLDN. Met-enkephalin is involved in regulating cellproliferation and can inhibit cancer cell growth inmultiple celllines. Increased met-enkephalinlevels created byLDN thus have the potential to inhibit cancer growth in humans. Phase II human trials of met-enkephalin, and published case reports confirmed the potentialrole ofLDN intreating pancreatic and other cancers.
Accumulating evidence suggests that LDN 3.0-4.5 mg orally, taken once daily at bedtime supports immune-modulation which may reduce various oncogenic and inflammatory autoimmune processes. Since LDN can upregulate endogenous opioid activity, LDN may promote stress resilience, social bonding, and emotional well-being. Unfortunately, large scale trials are lacking and are unlikely to be funded giventhe currentnon-proprietarystatus of naltrexone.
Fibromyalgia – Pain Reduction
Fibromyalgia is a chronic paindisorder characterized bydiffuse musculoskeletalpain, fatigue, sleep disturbanceand cognitiveimpairment. A significant number of fibromyalgia patients do not respond adequately to the current drugs (pregabalin, milnacipran, duloxetine) approved for fibromyalgia treatment bythe Food and Drug Administration (FDA). Thus, there is a need foradditional therapeutic options.
Fibromyalgia is a mitochondrial disorder and also a thyroid disorder. The prevalence ofFM is approximately 2-7% in the general globalpopulationand is 30-40% in the populationofHashimoto
thyroiditis (HT) with a structural pathology. For this reason, researchers and doctors at Stanford University have been studying the benefits of using thyroid hormone to treat patients with fibromyalgia.
Many neurodegenerative disorders, diabetes, cancer, fibromyalgia, muscularand cardiovascular diseases have been associated with low CoQ10 levels. CoQ10 deficiencies are due to autosomal recessive mutations, mitochondrialdiseases, age-related oxidativestressand carcinogenesisprocesses, and also a secondary effect of statin treatment. Oral CoQ10 treatment is a frequent mitochondrial energizer and antioxidant strategy in many diseases that may provide a significant symptomatic benefit. CoQ10 treatmentdoesnotcauseseriousadverseeffectsinhumans and newformulationshavebeen developed thatincrease CoQ10 absorptionand tissue distribution.
LDN has also been found to be a beneficial, highly tolerable, and inexpensive treatment to reduce daily pain in patients with fibromyalgia. In a single-blind, crossover pilot clinical trial at the Division ofPain Management, Stanford University, LDN reduced fibromyalgia symptoms in ten womenmeeting criteria for fibromyalgia, with a greater than 30% reduction of symptoms over placebo. Inaddition, laboratory tests showed that mechanical and heat pain thresholds were improved by LDN. Individuals withhighersedimentationrates (indicating generalinflammatoryprocesses) had the greatest reduction of symptoms in response to LDN. It is hypothesized that LDN causes transient blockade of opioid receptors centrally resulting in a rebound of endorphin function which may attenuate pain in fibromyalgia. At lowdoses (4.5mg), naltrexone may inhibit the activity ofmicroglia and reverse centraland peripheralinflammation. Sideeffects(including insomniaand vivid dreams) wererare, and described asminorand transient.
A placebo-controlled, double-blind trial was sponsored by the American Fibromyalgia Syndrome Associationand reported atthe AmericanAcademyofPainMedicine’s 28thAnnualMeeting in February, 2012. In the new trial, Jarred Younger, PhD, and colleagues from Stanford University, PaloAlto, California, evaluated 30 women with fibromyalgia (average age, 43years), completing 2weeks of baseline measurements, 12 weeks of LDN treatment (4.5 mg each day), 4 weeks of placebo, and 4 weeks offollow up.
The primary outcome for all patients was reduction of daily pain, reported through patient symptom severity reports via handheld computer. At the end of the trial, patients reported a 43% reductionin pain during the LDN treatment when compared to the placebo treatment. The only major side effects reported more frequentlyduring theLDNphaseoftreatmentwerevivid dreams (37% inLDNvs 13% inplacebo) and headache(16% inLDNvs 3% inplacebo). During bothtreatmentphases, patients reported similartolerability (89.2vs 89.4 out of100). Furtherstudy is warranted.
FrontBiosci(LandmarkEd). 2014Jan1;19:619-3 3 . Exp Biol Med (Maywood). 2017 Jan 1:153 53 70217724791. Pain Med. 2009 May-Jun; 10(4):663 -72.
Nal tr exon e i s n ot com m er ci al l y avai l abl e i n a 4.5 m g dose, bu t ou r ph ar m acy can com pou n d LDN by pr escr i pti on .
Low-dose naltrexone is a widely used off-labeltherapeutic prescribed fora variety ofimmune- related disorders. The mechanism underlying LDN’s efficacy for fatigue, Crohn’s disease, fibromyalgia, and multiple sclerosis is, in part, intermittent blockade of opioid receptors followed by upregulation of endogenous opioids. Serum[Met5]-enkephalinlevels are lowerinhumans withmultiple sclerosis relative to non-multiple sclerosispatients, and LDNhas restored their levels.
A retrospective studywas conducted onpatientsatPennStateHersheyMedicalCenterdiagnosed with relapsing-remitting multiple sclerosis between 2006 and 2015. Two cohorts ofpatients were established based ontheirmultiple sclerosis therapyatthe time oftheirfirstvisit. One group of patients (n=23) was initially prescribed LDN due to symptoms of fatigue or refusal to take an available disease-modifying therapy. The second group of patients (n=31) was treated with glatiramer acetate (Copaxone®) and offered LDN as anadjunct therapy to theirdisease-modifying therapy.
Patient data from visits occurring 1-50 months post-diagnosis was evaluated in a retrospective manner. Statistical analyses between the groups and for eachpatientindicated no significant differences in clinical laboratory values, timed walking, orchanges in magnetic resonance imaging.
A six month phase II multicenter-pilot trial with LDN was carried out in 40 patients with primary progressive multiple sclerosis (PPMS). The primary end points were safety and tolerability. Secondary outcomes were efficacy on spasticity, pain, fatigue, depression, and quality oflife. Clinical and biochemical evaluations were serially performed. Neurological disability progressed in only one patient. Beta-endorphins concentration increased during the trial and a significant reduction of spasticity was measured atthe end ofthe trial.
A single center, double-masked, placebo-controlled, cross over study at the Multiple Sclerosis Center at UCSF evaluated eight weeks of treatment with LDN 4.5 mg nightly on self-reported quality of life in patients with clinically definite multiple sclerosis. 80 patients were enrolled and 60 subjects completed the trial. 10 withdrew before completing the first trial period: 8 for personal reasons, 1 fora non-MS related adverse event and 1 for perceived benefit. LDN was well tolerated and serious adverse events did not occur. LDN was associated with significant improvement on mental health quality of life indices.
Although sleep disturbances are rare, some patients using LDN have reported vivid dreams. To avoid this, therapy canbe started with a lowerdose (1.5mg) and increased slowly overtwo months.
Health and Healing. May 2010. Vol. 20, No. 5
Pharmacists of The Month
Sahar Swidan, Pharm.D., BCPS, ABAAHP, FAARFM, FACA has been named Pharmacist of the Month by the Professional Compounding Centers of America (PCCA) for September 2017. PCCA provides pharmacy compounding training and continuing education programs, fine chemicals, devices and technical consulting. Pharmacists are chosenforthis honorbased on theirdedicationtoqualitystandardsinpharmacy compounding, and for theircommitmentto theircommunity and patients.