Low-Dose Naltrexone Use in Chronic Pain Patients

Low-Dose Naltrexone Use in Chronic Pain Patients

As a result of chronic pain becoming more prevalent, it is important to discuss how chronic pain impacts an individual’s life. Many think that patients who suffer from chronic pain, can find relief just by popping a pill, yet that isn’t always the case. On most occasions, chronic pain patients go through trial and error and numerous hospitalizations to find a treatment regimen. The pain impacts not only their quality of life, mentally and physically, but it also impacts their social lives and their self-confidence, and it impacts them financially. These are often things that people do not realize.

‍History of Naltrexone

Over the last sixty years, Naltrexone has been used for many things, one of the most common uses being to help with opioid addiction. Naltrexone was first synthesized and patented in 1961 by Dr. Jack Fischman and Dr. Mozez Lewenstein. From there, intravenous Naltrexone was approved by the Food and Drug Administration (FDA) for opioid overdose reversal in 1971, which was used for emergency treatments (Srivastava & Gold, 2018). LDN or low-dose Naltrexone was discovered in 1980 at Penn State University’s Hershey Medical Center by Dr. Ian Zagon and Dr. Patricia McLaughlin (Some history about ldn, n.d.). In 1984, the FDA approved Naltrexone for treating heroin addiction (Srivastava & Gold, 2018). In 1985, Dr. Bernard Bihari became interested in using low doses of Naltrexone due to the AIDS epidemic expanding. Dr. Bihari was the first doctor to start clinical use of LDN. He saw that the low doses of Naltrexone could regulate the immune system due to the increased production of endorphins at night that was due to the medication (Schopick, 2013). To help patients, he was looking for a medication that increased endorphins without completely blocking opioid receptors. It was not until 2007, that an LDN trial in humans was published and presented to the world (Srivastava & Gold, 2018). In 2014, a study came out stating that a combination of extended-release Naltrexone and Bupropion were linked to weight loss and then were approved for use in the United States (Naltrexone, n.d.). Despite the fact that Naltrexone has been around for quite a while, it is still gaining attention in the medical field due to all the different uses it has. Low doses of Naltrexone have become more popular in chronic pain management, instead of opioids.

How Naltrexone is Used and How it Works

Naltrexone is mainly used to help narcotic dependents who have stopped using narcotics stay drug-free, as well as help alcoholics stay sober. Naltrexone is available both as a pill and an injectable. The pill form of Naltrexone (ReVia, Depade) is typically dosed at fifty milligrams once a day, however; the injectable extended-release form is generally dosed at three hundred and eighty milligrams once a month. It is a synthetic opioid antagonist used in the prevention of relapse of opioid use disorder and alcohol use disorder (Naltrexone, n.d.). Naltrexone is not a narcotic. The medication works by blocking the euphoric and sedative effects of drugs. Naltrexone binds and then blocks opioid receptors, including mu-, kappa-, and gamma-, in the central nervous system, which then reduces opioid cravings one might have (What is naltrexone, n.d.).

Mechanisms of Action of Low-Dose Naltrexone

When Naltrexone is used at a lower dose than what is standard, fifty milligrams, it exerts different pharmacodynamics. In low doses that range from one to five milligrams, Naltrexone acts as a glial modulator with a neuroprotective effect through the inhibition of microglial activation in the central nervous system (Toljan & Vrooman, 2018). This then reduces the production of neurotoxic chemicals (Trofimovitch & Baumrucker, 2019). Microglia are important central nervous system immune cells because once they are activated by stressors, the cells produce inflammation and excitatory molecules, resulting in a pro-inflammatory cascade, which then leads to neurotoxicity (Trofimovitch & Baumrucker, 2019). Low dose Naltrexone then comes in and disrupts the signaling cascade with reduced synthesis of the pro-inflammatory cytokines. This then slows down the activated microglial cells and results in an analgesic and anti-inflammatory effect (Trofimovitch & Baumrucker, 2019).

Opioid Epidemic

Due to opioids being on the rise with the current opioid epidemic, Naltrexone has become quite popular in the last twenty years. Opioids are an easy and quick fix for many patients dealing with pain. Opioid abuse has risen dramatically in the United States due to physicians prescribing it for acute and chronic pain. From 1999 to 2018, almost 450,000 individuals have died due to an overdose involving prescription opioids (Understanding the epidemic, 2020). Around 128 people die each and every day in the in the United States due to an opioid overdose (Understanding the epidemic, 2020). As a result of these high numbers, the Centers for Disease Control and Prevention (CDC) has opioid guidelines to help improve the way that opioids are prescribed. As a result of opioids being so popular in the treatment of chronic pain patients, the CDC has published particular guidelines for how to prescribe opioids to chronic pain patients so individuals do not misuse them.

Chronic Pain

Chronic pain is an extensive health concern that affects one in three Americans and costs the United States economy more than $635 billion dollars each and every year (Ji et. al., 2018). Although there are millions of people who suffer from chronic pain, there are not a lot of options to help the patients who suffer from pain that is essentially described as treatment-resistant. The patients that suffer from this intense pain go through deep or transcranial brain stimulation and ketamine infusions (Borsook et. al., 2018). Yet often times, patients with this intense chronic pain cannot find a long-term solution, which unfortunately leaves doctors puzzled. Patients turn to alternative medicine and seek off-label medicines because of how desperate they are for relief (Patten, Schultz, & Berlau, 2018). Primary care physicians find chronic pain extremely challenging to treat and manage. The doctors often turn to opioids, which then leaves patients wondering about the long-term efficacy and the serious side effects they might have from the medication. In 2012, over 259 million prescriptions for opioids were written to help patients with acute and chronic pain (Patten, Schultz, & Berlau, 2018). Often times due to the severity of the situation, patients have to find a pain management specialist. It is believed that the cause of this chronic pain has to do with the neuronal plasticity in pain coding pathways and circuits. However, the perception of pain typically is associated with inflammation, which is a complex biological response of the somatosensory, immune, neuronal, autonomic, and vascular/circulatory system to tissue damage, pathogens, or irritants (Ji et. al., 2018). Researchers believe that even though the observable signs and symptoms of inflammation may have been resolved in a patient, the chronic pain can persist (Ji et. al., 2018).

Demographic and Socioeconomic Influences on Chronic Pain

Demographic and social factors, such as sex, gender, age, marital status, family relations, and socioeconomic status, are all essential parts of how people feel and deal with pain (Borsook et. al., 2018). Socioeconomic status plays a key role in how one might accept or deny treatment after a car accident. If one is in a lower socioeconomic class, the individual might not have health insurance to get the help they need or want. Individuals who live in poverty have a higher allostatic load and more stressors threatening their physiological homeostasis (Borsook et. al., 2018). This is due to the chronic stress and uncertainty that these individuals have in their lives. Allostasis can contribute to socioeconomic load as well as to disease comorbidity associated with chronic pain (Borsook et. al., 2018). The African American community has also reported that they receive less aggressive treatment and fewer newly prescribed medications to manage pain, as well as decreased access to primary care providers and pain management specialists (Maly & Vallerand, 2018). In some neighborhoods, African Americans and other minority groups lack a safe place to exercise and have decreased social support due to neighborhood violence, which has a cumulative effect on the experience of chronic pain (Maly & Vallerand, 2018). Socioeconomic status, medical access, as well as homelessness have been reported to contribute to a more negative experience of pain overall (Maly & Vallerand, 2018).

Management of Complex Regional Pain Syndrome with Low-Dose Naltrexone

With Complex Regional Pain Syndrome having little to no treatment options, low-dose Naltrexone is one of the few treatment options that has helped some manage their pain. Complex Regional Pain Syndrome, or CRPS, is a neuropathic pain syndrome that involves glial cell activation and central sensitization in the central nervous system (Chopra & Cooper, 2013). Itcan be classified as a neuroinflammatory condition characterized by a combination of sensory, autonomic, vasomotor, and motor dysfunctions. One of the characteristic symptoms that stands out is that the pain is out of proportion from the initial injury (Chopra & Cooper, 2013). If CRPS is caught early enough, effective treatments can be given to help reduce the spread of the regional pain, autonomic dysfunction, motor changes, and hypoalgesia. In a study published in early 2013, the researchers looked at two typical CRPS patients. Both patients had tried the conventional CRPS pharmacotherapy, which failed to suppress their CRPS symptoms in the end. One patient who had cardiac bypass surgery for coronary artery disease began to have widespread CRPS symptoms after surgery. The patient developed dystonic spasms in both upper and lower extremities; then the patient underwent multiple treatments with anticonvulsants, antidepressants, physical therapy, psychotherapy, topical and systemic analgesics, as well as opioids (Chopra & Cooper, 2013). The patient’s pain continued to the where they were receiving intravenous ketamine infusions. The patient then started LDN. Within two months, their dystonic spasms stopped, the patient was able to walk without a cane, their pain level dropped three to four points on the Numeric Rating Scale, and pain severity reduced significantly (Chopra & Cooper, 2013). The second patient in the study also showed significant improvement after they were prescribed LDN. Both patients had no side effects of the LDN.

Side Effects of Low-Dose Naltrexone

Due to low dose Naltrexone having little to no side effects this has made the drug more appealing to patients. At higher doses, however, there are more reported cases of adverse side effects due to Naltrexone being a water-soluble compound that can cross the blood-brain barrier, which increases the potential for neurological effects (Ploesser, Weinstock, & Thomas, 2010). Many often worry about the safety and toxicity of medications, but due to the Naltrexone being at such a low dose, there have not been any significant adverse laboratory abnormalities found in studies (Smith, 2019).

Why Low-Dose Naltrexone is not FDA Approved for Pain Management

Although low dose Naltrexone benefits many individuals who live with a chronic inflammatory disease and or chronic pain, the medication at a low dose is currently not approved by the United States Food and Drug Administration (FDA) for pain. However, the higher dosage of fifty milligrams to one-hundred-and-fifty milligrams a day is FDA-approved for patients who are in recovery from an opioid or alcoholism addiction. As a result of the medication being on the market for so long, many pharmaceutical companies do not want to waste their time and money on clinical trials to get the medication FDA approved at a lower dose. Another reason why many will not put their time and money into getting it approved is because the medication can be produced generically, which means no return on their investment. The drug maker, Alkermes, currently owns the exclusive rights to the extended-release version of Naltrexone, stated that as a company, they have no interest in pursuing low dose Naltrexone due to the lack of evidence that it can help chronic pain patients (Smith, 2019).

The Potential of Low-Dose Naltrexone in Chronic Pain Management

In summary, low dose Naltrexone has helpful off-label benefits for chronic pain patients even though it is not FDA-approved. From childhood experiences to the neighborhood one lives in, every aspect of an individual’s life impacts how they interpret and experience pain. Individuals must realize that there is a spectrum of pain and that each and every persons’ pain scale is different, some more severe than others. Although pharmaceutical companies currently view low-dose Naltrexone as a bad investment, maybe one day they will see it as a good investment and want to help millions. In the future, more clinical trials and double-blind studies need to be conducted on low-dose Naltrexone and the effects that it has on chronic pain and inflammation. Making doctors and medical professionals aware of LDN this could allow more traction for more research studies and essentially help millions of people. With little to no treatment for some chronic pain patients, knowledge of this medication may drastically change one’s life for the better. With how inexpensive LDN is and the wide array of treatment options, this drug has could increase in popularity very quickly. It could possibly be the next miracle medication that has been sitting in front of us for the last sixty years. Could it be the medication to cure obesity? With little to no side effects in such a small dose, will LDN become an over-the-counter medication to treat inflammation? Who knew that a drug developed to help opioid addicts and alcoholics would be used to treat patients with HIV, IBS, chronic pain, fibromyalgia, Crohn’s disease, multiple sclerosis, complex regional pain syndrome, and more? In conclusion, this treatment should be widely used in pain management clinics and should be standard protocol instead of nerve blocks and opioids.

References

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Chopra, P., & Cooper, M. S. (2013). Treatment of complex regional pain syndrome (crps) using

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