Low-Dose Naltrexone

Low-Dose Naltrexone: A Magic Bullet or a Long Shot to Aid Patients with Chronic Pain

By: Dr. Amy S Donnelly, PharmD, RPh

The current opioid epidemic in America has left the healthcare community searching for alternative therapies that are effective for chronic pain while minimizing the risk of harm. According to the CDC, more than 168 million opioid prescriptions were dispensed in 2018. (1) While this number has significantly decreased in recent years, there are still many patients using opioid medications that could benefit from other treatment options if available. Furthermore, because of the increased scrutiny surrounding the use of opioids, many patients struggle to obtain opioid medication access because of the potential misuse, abuse, and accidental overdose. Unfortunately, in some cases, patients who feel like they have no other options turn to illicit drugs and are at even higher risk of overdose; therefore, safer alternative therapies are needed. Low-dose naltrexone (LDN) is a potential therapy that is non-habit forming and has a low side-effect profile.

History and Mechanism of Action

Naltrexone, synthesized in 1963, is an opioid receptor antagonist. (2) The FDA approved it in 1984 to treat opioid addiction. (2) Available in many formulations, oral naltrexone is commercially available as 50 mg tablets. Compared to the traditional dosing of naltrexone, LDN, usually 4.5 mg, has been studied as a potential analgesic agent. When taken in doses this small, naltrexone displays paradoxical results to those seen in 50 mg or higher daily dosing, as indicated for opioid addiction. (2) The observed analgesic effects most likely result from increased endogenous opioid production. (2) Similarly, the observed anti-inflammatory effects from naltrexone are likely due to antagonism on non-opioid Tolllike receptor 4 (TLR4), located on microglia immune cells of the central nervous system. (2) In doing so, naltrexone acts as a glial modulator/inhibitor, resulting in neuroprotective effects by inhibiting cellular pathways that normally result in pro-inflammatory cytokines. (3)

The Utility of LDN in Chronic Pain

The efficacy of LDN has been examined in chronic pain and inflammation-related diseases such as multiple sclerosis (MS), fibromyalgia, and Crohn’s disease. (4) Collectively, these disease states affect over 47 million Americans, all of whom struggle with pain, significantly impacting their quality of life. (4) A retrospective chart review of 215 patients with MS who received LDN showed 75% of participants reported an increase or stable quality of life and 60% of participants reported a reduction in fatigue; however, no disease-modification effects have been seen in patients with MS taking LDN. (4) In patients with fibromyalgia, a single-blind

trial that included eight weeks of LDN therapy showed reduced pro-inflammatory markers and fewer pain symptoms. (4) In another study, over 90 days, 50% of patients reported a 40% improvement in symptoms and functioning. (4) Similarly, in Crohn’s disease, one study showed an 88% decrease in the severity of symptoms. (4) Interestingly, this study completed an endoscopic examination, showing that 48% of those treated with LDN had improved disease from baseline. (4) This study highlights the need for continued examination of possible disease-modification potential of LDN in patients with Crohn’s disease. LDN may also play an important role in patients requiring palliative care. For example, pain management is imperative in caring for patients dying from heart failure, lung disease, and diabetes. Although more studies are needed in palliative care, the potential exists to improve quality of life measurements in this patient population.

Safety

A low incidence of adverse side effects and drug-drug interactions were reported with the use of LDN. (2) Among those treated with LDN, the most common side effect reported was vivid dreams (37%). (2) Headaches were more common than placebo but are also notable in some disease states for which LDN is used. (2) Anecdotal physician reports of anxiety and tachycardia have also been noted with the use of LDN. (2) No significant effects on hepatic enzymes have been observed. (2) Importantly, no cases of misuse, abuse, dependence, or tolerance have been reported with LDN. (2) The favorable side-effect profile is reassuring as there are known health risks even when using non-opioids such as non-steroidal anti-inflammatory drugs. (2)

Potential Impact on Clinical Practice

In clinical practice, we must pursue therapies that will provide effective pain relief and do so with as minimal harm as possible. Presently, the choice to use LDN for the treatment of chronic pain should be made on a case-by-case basis in patients that desire an alternative to opioid therapy. LDN is not commercially available and must be compounded. However, compounded LDN is inexpensive and easily prepared, making it an affordable option regardless of insurance coverage. (5) Quality of life measurements, an important patient-centered outcome, have the potential to be enhanced using this emerging and novel approach with a low risk of patient harm.

Conclusion

LDN is a low-cost, minimal-side-effect alternative therapy for treating chronic pain. (2) While several studies across multiple high-burden disease states have shown clinical benefits, the positive benefits observed in some patients appear indistinguishable from placebo until at least one to two months after therapy is initiated. (2) High-quality and rigorous studies are required to elucidate the role of LDN in treating chronic pain. A call to action is needed to complete randomized, double-blind, placebo-controlled trials and determine the efficacy and safety of LDN in the care of patients with chronic pain. LDN has the potential to be a magic bullet amid America’s fight against the opioid epidemic. Hopefully, time and high-quality trials will offer additional supportive evidence, and its use for this indication will increase while keeping patients safe from the known hazards associated with opioids.

Author: Amy S Donnelly, PharmD, RPh, is a Staff Pharmacist at UNC Healthcare’s Rex Outpatient Pharmacy of Raleigh; asdpharmd@hotmail.com.

References

1. Opioid Overdose: U.S. Prescribing Rate Maps. Accessed June 30, 2020. cdc.gov 2. Younger J, Parkitny L, McLain D.

The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumato. 2014;33:451-9. 3. Trofimovitch D and Baumrucker

SJ. Pharmacology update: Lowdose naltrexone as a possible nonopioid modality for some chronic, nonmalignant pain syndromes. American Journal of Hospice & Palliative Medicine. 2019;36(10):90712. 4. Patten DK, Schultz BG, Berlau

DJ. The safety and efficacy of low-dose naltrexone in the management of chronic pain and inflammation in multiple sclerosis, fibromyalgia, Crohn’s disease, and other chronic pain disorders. Pharmacotherapy. 2018;38(3):382-9. 5. Bronfenbrener R. Inexpensive compounding of low-dose naltrexone (LDN) with orange juice. J Am Acad Dermatol, 2021

Sep;85(3):e139.