Research

The objective of this study was to evaluate the effect of low-dose naltrexone (LDN) as a carboplatin chemotherapy-associated drug in female dogs with mammary carcinoma in benign mixed tumors (MC-BMT) after mastectomy and to assess its association with quality of life and survival rates. Sixty female dogs were included in this study, all of which had histopathological diagnosis of MC-BMT and were divided into three groups: G1 (control), consisting of animals submitted only to mastectomy with or without regional metastasis; G2, composed of treated animals that did not present with metastasis; and G3, treated dogs that presented with metastasis. G2 and G3 were also subdivided according to the treatment administered: chemotherapy alone (MC-BMT(-) C/MC-BMT(+) C) or LDN and chemotherapy (MC-BMT(-) C+LDN/MC-BMT(+) C+LDN). All animals were subjected to clinical evaluation, mastectomy, peripheral blood lymphocyte immunophenotyping, beta-endorphin and met-enkephalin quantification, and evaluation of survival rates and quality of life scores. The results showed 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 (P < 0.05). Evaluation of clinical and pathological parameters indicated a significant association between the use of LDN and both prolonged survival and enhanced quality of life. These results indicate that LDN is a viable chemotherapy-associated treatment in female dogs with MC-BMT, maintaining their quality of life and prolonging survival rates.

Low-dose naltrexone has been shown to treat autoimmune conditions, such as multiple sclerosis, fibromyalgia, and Crohn's disease. We present two cases in which low-dose naltrexone proved an effective therapy for dermatomyositis (DM), an idiopathic inflammatory myopathy. A search of PubMed for “low dose naltrexone” and “dermatomyositis” did not reveal any reported cases of the use of low-dose naltrexone in DM. We suspect that low-dose naltrexone produces an antiinflammatory effect via inhibition of toll-like receptor 4 (TLR4) and augmentation of endogenous opioid production. Low-dose naltrexone as treatment for DM is promising, as the cost of the medication is low, and its adverse effects are minimal.

Naltrexone and naloxone are classical opioid antagonists. In substantially lower than standard doses, they exert different pharmacodynamics. Low-dose naltrexone (LDN), considered in a daily dose of 1 to 5 mg, has been shown to reduce glial inflammatory response by modulating Toll-like receptor 4 signaling in addition to systemically upregulating endogenous opioid signaling by transient opioid-receptor blockade. Clinical reports of LDN have demonstrated possible benefits in diseases such as fibromyalgia, Crohn's disease, multiple sclerosis, complex-regional pain syndrome, Hailey-Hailey disease, and cancer. In a dosing range at less than 1 μg per day, oral naltrexone or intravenous naloxone potentiate opioid analgesia by acting on filamin A, a scaffolding protein involved in μ-opioid receptor signaling. This dose is termed ultra low-dose naltrexone/naloxone (ULDN). It has been of use in postoperative control of analgesia by reducing the need for the total amount of opioids following surgery, as well as ameliorating certain side-effects of opioid-related treatment. A dosing range between 1 μg and 1 mg comprises very low-dose naltrexone (VLDN), which has primarily been used as an experimental adjunct treatment for boosting tolerability of opioid-weaning methadone taper. In general, all of the low-dose features regarding naltrexone and naloxone have been only recently and still scarcely scientifically evaluated. This review aims to present an overview of the current knowledge on these topics and summarize the key findings published in peer-review sources. The existing potential of LDN, VLDN, and ULDN for various areas of biomedicine has still not been thoroughly and comprehensively addressed.

A 60-year-old white woman presented with a history of moderate, generalized plaque psoriasis covering 10% of her body surface area (BSA). The patient began low-dose naltrexone, 4.5 mg daily. The patient's psoriatic lesions were significantly improved at 3 months, and the affected BSA had decreased from 10% to 1% after 6 months of treatment. The calculated PASI (psoriasis area severity index) score decreased from 7.2 to 0.9 after 6 months of treatment. Symptoms of pruritus also improved with naltrexone. No other adjuvant medications were used during this period. No side effects from the treatment were reported. As of this writing, the patient has continued therapy with low-dose naltrexone without any adverse effects and with continued success. Treatment of psoriasis with low-dose naltrexone may be appealing because of its low side-effect profile, low cost, and its efficacy in patients with chronic inflammatory conditions.

Hailey-Hailey disease, otherwise known as familial benign chronic pemphigus, is a genetic intraepidermal blistering disorder. In nongeneralized HHD, there have been a few published case reports of HHD treated successfully with low-dose naltrexone (LDN). The exact mechanism by which naltrexone works for HHD is unclear.

The phenotypic expression of HHD can be quite variable. Although at times minimal, in rare cases, this disorder cannot only become generalized but result in systemic sequelae due to fluid and protein loss, with lesions providing an ideal media for bacterial colonization and infection. The use of antibiotics to cover significant pathogens or colonization should be used in combination with other primary treatment modalities. It is unclear how much the antibiotics contributed to resolution of our patient's disease initially; however, the patient clearly showed improvement with only use of naltrexone during weeks 5 through 8. Furthermore, the patient has maintained clearance of his disease using LDN at variable doses and has not used any additional antibiotics. There is a clear correlation between the lowering of the dose and flare of his disease. Because the patient has had no significant side effects from the medication, it has been continued per patient preference.

Until this point, treatments have only modified the disease, as they have not clearly targeted the pathophysiologic components. Despite the uncertainty of mechanism of action, LDN in this patient as well as a few other documented case reports of HHD treated with LDN, led to dramatic clinical improvement, with minimal side effects. Overall, this intriguing topic needs future investigation, as there are limited published data. Based on recent literature and experience with LDN, it would appear to be the treatment of choice for HHD when more conventional treatment modalities fail. Moreover, its use provides a powerful addition to the therapeutic armamentarium for generalized HHD.

The ancient autoimmune skin condition psoriasis is still ubiquitous worldwide, produces the same, often-intolerable effects noted in its earliest recorded descriptions, and remains without cure. Management options designed to resolve the itchy, scaly, weeping, erythematous, and often widespread lesions of that disorder are now available, but they vary in efficacy, most are associated with the development of severe adverse effects, and many are prohibitively expensive. In this article, we describe the successful use of a compounded formulation of oral low-dose naltrexone to manage guttate psoriasis in a 75-year-old white male patient. That therapy produced only 1 adverse effect (dry skin near the lesions on the patient's arms and legs) and was relatively inexpensive. The formulation for that preparation and comments from the patient, the pharmacist who suggested its use, the prescriber, and the compounder who prepared it are included. Many clinicians are unaware of the benefits of compounded low-dose naltrexone in treating autoimmune diseases. We hope that this case report will encourage compounding pharmacists to consider and suggest it as an alternative therapy for patients who cannot tolerate or afford manufactured medications to treat psoriasis.

Low dose naltrexone (LDN) has been promising as a complementary medication for patients with a broad range of medical disorders. Although not a proven cure, evidence from clinical trials supports LDN as being a valuable adjunct for disorders in which the immune system plays a centralized role. Additionally, clinical trials have proposed a unique mechanism(s) allowing LDN to affect tumors including non-small cell lung cancer (NSCLC) at the cellular level by augmenting the immune system. We present a case of a 50-year-old male with a prolonged survival and a past medical history of prostate and lung cancer.

BACKGROUND: 30% of Gulf War veterans developed Gulf War Illness (GWI) with chronic fatigue, pain, and neuropsychological disabilities.

PURPOSE: To assess the efficacy of low-dose naltrexone to treat GWI. Methods: A double-blinded, placebo-controlled crossover trial of naltrexone 4.5 mg/day was conducted. The Clinical global impression scale (CGIS), visual analogue scales (VAS), SF-36 Health Survey, and the Connors Continuous Performance Test assessed treatment response. ClinicalTrials.gov registry Identifier is NCT02206490.

RESULTS: Thirty-seven participants completed the protocol. 100% had upper airway inflammation on examination. 88% were overweight or obese. The CGIS detected improvement in 38% of patients (n = 14) (responders), with 6 of these patients reporting much improvement. Non-responders were rated as showing no change from baseline (n = 18; 49%), or were rated minimally worse (n = 5; 13%). On the SF-36 Health Survey, responders showed significantly less disability than non-responders with respect to emotional limitations (p = 0.01) as well as greater improvement on VAS scales for confusion (p < 0.01), vertigo (p = 0.03) and depression (p = 0.05). All enrolled participants had detectable levels of naltrexone in their serum at the end of the treatment period, with values ranging from 1.5to 18 ng/ml. Anecdotally, some subjects and their spouses felt that naltrexone should be continued after the study ended.

CONCLUSION: This pilot trial suggests low-dose naltrexone may be effective for some with GWI. Further study and consideration of other doses is needed.

Naltrexone, a non-selective antagonist of opioid receptors, is mainly used as rehabilitation therapy for discharged opiate addicts to eliminate addiction in order to maintain a normal life and prevent or reduce relapse. In recent years, there have been some novel and significant findings on the off-label usage of naltrexone. Within a specific dosage window, LDN can act as an immunomodulator in multiple autoimmune diseases and malignant tumors as well as alleviate the symptoms of some mental disorders. The results of increasing studies indicate that LDN exerts its immunoregulatory activity by binding to opioid receptors in or on immune cells and tumor cells. These new discoveries indicate that LDN may become a promising immunomodulatory agent in the therapy for cancer and many immune-related diseases. In this article, we review the pharmacological functions and mechanisms of LDN as well as its clinical therapeutic potential as revealed by our team and other researchers.

Fibromyalgia is a syndrome associated with chronic, widespread musculoskeletal pain, fatigue, depression, and cognitive dysfunction. With few U.S. Food and Drug Administration-approved treatment options, there is evidence that low-dose naltrexone, an opioid antagonist approved for opioid and alcohol dependence at high doses, may have efficacy in the treatment of fibromyalgia and chronic pain.

At the doses required for fibromyalgia treatment, naltrexone needs to be compounded, and no data currently exists regarding the long-term stability of low-dose naltrexone capsules. This limits pharmacies to a maximum beyond-use date of 180 days. Our study examined the stability of compounded capsules of low-dose naltrexone in Avicel over 360 days. Naltrexone was extracted from compounded capsules and assessed using reversed-phase high-performance liquid chromatography validated to differentiate between the degraded and undegraded naltrexone. United States Pharmacopeia guidelines state that compounded medications must remain within 10% of the labeled potency at all times during the assigned expiration date for a preparation. Our results show that low-dose naltrexone is stable for 360 days when stored at room temperature and away from light remaining within 90% to 110% of the labeled potency throughout the study period. Based on our study results, the beyond-use date for compounded low-dose naltrexone formulations stored at room temperature and protected from light can be extended to 1 year. The longer beyond-use dating allows patients greater flexibility in using these capsules during the flare-ups associated with fibromyalgia without needing a refill immediately at the onset of symptoms. In addition, it may help compounding pharmacies reduce waste associated with small-batch preparation of these capsules.