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Thank you for entrusting in the compounding services at MD Custom Rx to help meet the unique medication needs of your patients. We are excited to share with you our monthly newsletter and look forward to continuing to be your medication problem solvers. Please don't ever hesitate to let us know how we can be of further assistance to you and your practice.
Sincerely,
John, Dan and Monica |
Low Dose Naltrexone (LDN)
Harnessing Inherent Physiology to Fight Cancer
Naltrexone HCl was approved by the FDA in 1984 for the treatment of opioid addiction. Only 50 mg tablets are commercially available. LDN refers to daily dosages of naltrexone that are approximately 1/10th of the typical opioid addiction treatment dosage. In most published research, the daily dosage is 4.5 mg, though the dosage can vary. At the low dosage level, naltrexone exhibits paradoxical properties, including analgesia and anti-inflammatory actions, which have not been reported at larger dosages.
LDN antagonizes the effect of opioids on the immune cell opioid receptors, essentially releasing the immune cells from their immunosuppressed state. This, in turn, allows these immune cells to recognize and destroy malignant cells. Naltrexone does not appear to have any bone marrow stimulatory effects, thus proliferation of the malignant cell line will likely not be increased if used in hematological malignancies (leukemia, lymphoma, myeloma, etc). Opioid growth factor (OGF), also known as [met5]-enkephalin, has been the subject of several preclinical and Phase I and II clinical trials in pancreatic and hepatocellular cancers (and published case reports in neuroblastoma and hepatoblastoma). Preclinical research has also established ovarian cancer as a viable alternative treatment consideration. Ovarian cancer cells express OGF receptors (OGFr), albeit less abundantly than healthy cells.
OGF reduces cell hyperproliferation by upregulating cyclin-dependent inhibitory kinase pathways. Exogenous OGF stimulates this cell cycle delay, inhibits DNA synthesis and triggers immune-mediated cytotoxicity. Prior blockade of OGF and OGF receptor with the nonselective opioid receptor antagonist, low dose naltrexone (LDN), upregulates the expression of OGF and OGFr. Oral administration of LDN (3mg) 4 hours prior to injection of OGF enhances the upregulated OGFr activity. The OGF-OGFr axis may be a feasible target for treatment of cancer of the ovary following cytoreduction or in conjunction with standard chemotherapy for additive effectiveness.
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Low Dose Naltrexone for Induction of Remission in Crohn's Disease
The condition with the most scientific support for LDN efficacy is Crohn's disease (CD). CD is an inflammatory bowel disease that exerts gastrointestinal tract and systemic effects. Opioid signaling, long known to affect secretion and motility in the gut, has been implicated in the inflammatory cascade of Crohn's disease. LDN has been reported to reduce not only self-reported pain of CD but also objective markers of inflammation and disease severity (including the severity scores from endoscopic evaluation). Over 80% of the study participants exhibited significant improvement.
To evaluate the efficacy and safety of LDN for induction of remission in Crohn's disease, a systematic search of MEDLINE, EMBASE, CENTRAL, and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Review Group Specialized Register was performed and identified two relevant studies. One study assessed the efficacy and safety of 12 weeks of LDN (4.5 mg/day) treatment compared to placebo in adult patients (N = 34). The other study assessed eight weeks of LDN (0.1 mg/kg, maximum 4.5 mg/day) treatment compared to placebo in pediatric patients (N = 12). The primary purpose of the pediatric study was to assess safety and tolerability. Both studies were rated as having a low risk of bias. The study in adult patients reported that 30% (5/18) of LDN treated patients achieved clinical remission at 12 weeks compared to 18% (3/16) of placebo patients. The study in children reported that 25% of LDN treated patients achieved clinical remission compared to none of the patients in the placebo group. The proportion of patients who achieved endoscopic response (CDEIS decline > 5 from baseline) was significantly higher in the LDN group compared to placebo. Seventy-two percent (13/18) of LDN patients achieved an endoscopic response compared to 25% (4/16) of placebo patients. Endoscopic remission (CDEIS < 3) was achieved in 22% (4/18) of the LDN group compared to 0% (0/16) of the placebo group. No serious adverse events were reported in either study.
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The Use of Low Dose Naltrexone (LDN) as a Novel Anti-inflammatory Treatment for Chronic Pain
Younger and Parkitny of the Department of Anesthesia, Pain and Perioperative Medicine, Stanford University, Palo Alto, CA and McClain of McLain Medical Associates, Birmingham, AL note that LDN has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, multiple sclerosis, and complex regional pain syndrome. The researchers report that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone's better-known activity on opioid receptors. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.
"LDN has been tested experimentally in a small number of chronic pain conditions. One such condition is fibromyalgia (FM). FM is a chronic pain disorder that is characterized by diffuse musculoskeletal pain and sensitivity to mechanical stimulation as well as profound fatigue, cognitive disruption, and sleep difficulty. Although FM does not respond to common anti-inflammatories and does not seem to be an inflammatory disorder in the classic sense, inflammatory processes may still be involved. Two separate, small clinical trials have shown that LDN may be an effective treatment for FM. In both trials, LDN was administered at 4.5 mg daily, once at night before bedtime. In the first crossover trial, published in 2009, LDN reduced fibromyalgia pain significantly greater than placebo in 6 out of the 10 women. While the pilot study was encouraging, it had limitations such as a single-blind design. To help validate the findings, a second study in 30 women with fibromyalgia was conducted. In that double-blind, crossover, counterbalanced study, 57% of the participants were observed to exhibit a significant (1/3) reduction of pain during LDN. At the end of the LDN treatment, half of the participants reported feeling 'much improved' or 'very much improved' from LDN. Together, these two studies suggest that LDN is superior to placebo in reducing the pain associated with fibromyalgia."
"Naltrexone, however, exerts its effects on humans via at least two distinct receptor mechanisms. In addition to the antagonist effect on mu-opioid and other opioid receptors, naltrexone simultaneously has an antagonist effect on nonopioid receptors (Toll-like receptor 4 or TLR4) that are found on macrophages such as microglia. It is via the nonopioidantagonist path that LDN is thought to exert its anti-inflammatory effects. Microglia are central nervous system immune cells that are activated by a wide range of triggers. Once activated, microglia produce inflammatory and excitatory factors that can cause sickness behaviors such as pain sensitivity, fatigue, cognitive disruption, sleep disorders, mood disorders, and general malaise. When chronically activated, the resulting proinflammatory cascade may become neurotoxic, causing several deleterious effects. Given the wide variety of inflammatory factors produced by activated microglia (e.g., proinflammatory cytokines, substance P, nitric oxide, and excitatory amino acids), a range of symptoms and medical outcomes could share the pathophysiological mechanism of central inflammation. Conditions such as fibromyalgia may involve chronic glial cell activation and subsequent production of proinflammatory factors."
Naltrexone has also shown some promise in reducing the severity of multiple sclerosis. Also, limited case evidence suggests that LDN may also be effective in controlling symptoms of complex regional pain syndrome (CRPS), a disease that often shows evidence of both local and low-level systemic inflammation.
The typical dosage of LDN in published research is 4.5 mg. The medication is commonly given approximately an hour before bedtime, although some individuals reporting insomnia as a side effect are moved to a morning dosing. If side effects are reported, the dosage can be reduced to 3.0 mg. Because there is no commercial formulation of LDN, research studies obtain Low Dose Naltrexone from compounding pharmacies.
Advantages of LDN include:
* Low cost
* Low side effects
* No known abuse potential
Contact our compounding pharmacist for more information.
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