In 2017, Americans filled more than 191 million prescriptions for opioid analgesics despite skyrocketing rates of addiction and rapidly changing prescribing guidelines. 1 For many, opioid medications are life-changing in the best of ways, providing relief from debilitating pain that strips patients of functionality and quality of life. However, it is no secret that these painkillers have significant drawbacks and as the opioid epidemic continues to spread, a growing number of patients with neuropathic pain are seeking out alternatives to opioids.
Notoriously, opioids can cause tolerance, dependence, and addiction even when used for relatively short periods and at low doses. However, patients who use opioids to treat chronic neuropathic pain are particularly vulnerable. The tolerance that builds with habitual use means that patients will need to take increasingly larger doses of opioid medications to find relief, increasing the severity of side effects, the risk of overdose, and the likelihood that patients will turn to more dangerous administration methods, opioid variants, and drug sources. Additionally, the risk of addiction grows with time and dosage, potentially creating devastating physical and psychological harm. Meanwhile, abrupt discontinuation from opioid analgesics may cause a host of painful and distressing withdrawal symptoms.
For patients with neuropathic pain, whose pain may persist even when taking opioids, better, safer solutions are urgently needed. Now, emerging research suggests that butyric acid could be one of those solutions. As a natural analgesic, butyric acid may be capable of delivering potent pain relief on its own as well as improving the efficacy of other pain medications, including those to which patients have developed a high level of tolerance. By taking a butyric acid supplement, patients may be able to reduce the dose of opioid analgesics that they use or potentially eliminate them entirely, allowing patients with neuropathic pain to safely recapture their quality of life.
Evidence for Butyric Acid as an Alternative to OpioidsButyric acid is a natural chemical the human body produces in the gastrointestinal tract for the purpose of regulating the immune system of the intestines. While it is used to relieve the symptoms of gastrointestinal conditions, but it also has analgesic effects which may be helpful for patients with neuropathic pain. Patients seeking an alternative or adjunct to opioids may find that taking a butyric acid supplement is helpful for several reasons.
First, butyric acid can alleviate pain on account of its ability to regulate the genome of the nerve cells which transmit pain. When nerve cells encounter butyric acid, they undergo a cascade of genetic changes. These changes lead to the cells becoming less capable of transmitting pain signals while leaving them otherwise intact. As a result, when nerve cells encounter butyric acid, they transmit fewer pain signals, and the patient experiences less pain. However, butyric acid isn’t the only chemical which can reduce pain using this mechanism; butyric acid is but one member of a class of chemicals called the histone deacetylase inhibitors (HDAC inhibitors) that have similar effects on the genome of nerve cells. While the genome-regulating effect of these chemicals has only been described experimentally in mice so far, the results have been stunning.
In 2017 study using mouse models of neuropathic pain, a chemical with an identical genetic effect as butyric acid was found to have an analgesic effect which was on par with opioid medications. 2 The researchers found that mice with chronic neuropathic pain as the result of spinal injury exhibited a profound reduction in their pain level after treatment with an HDAC inhibitor. In fact, their post-treatment behavioral profile was comparable to that of mice without neuropathic pain. This total reduction in pain behaviors was then compared to mice treated with morphine. The results were surprising: researchers observed that the mice who were treated with the HDAC inhibitor expressed the same absence of pain behaviors as the mice which had been given morphine. Critically, the researchers found that this effect persisted for at least two hours before starting to ebb, and the mice who had been given the HDAC inhibitor appeared to behave normally the entire time.
A similarly constructed study published in 2013 also found that HDAC inhibitors have a significant impact on pain. In this study, rats treated with an HDAC inhibitor were able to tolerate mild pain 31% longer than rats who had received a placebo.3 Furthermore, the researchers observed that the rats treated with an HDAC inhibitor winced between 40% and 50% fewer times when exposed to a constant mild pain, suggesting that their nerves were less reactive after being medicated. These results confirm that HDAC inhibitors like butyric acid have enormous potential to relieve pain.
Butyric Acid May Increase Efficacy of Opioid Painkillers
While multiple studies indicate that butyric acid exhibits analgesic effects when used in isolation, butyric acid and other HDAC inhibitors may also enhance the efficacy of opioid painkillers. Though these effects have only been demonstrated in animal models of opioid tolerance so far, they have profound implications for patients with chronic neuropathic pain.
In a study conducted using morphine-resistant mice who no longer experienced the analgesic effects of morphine, researchers found that exposing the mice to an HDAC inhibitor restored the ability to experience analgesia from opioids.4 The study examined two groups of mice: one group with morphine resistance, and one group that had never been exposed to opioids. The mice in each group were divided into three subgroups, one of which was given morphine and saline, another of which was given morphine and an HDAC inhibitor, and the last of which was given only saline. Then, researchers measured how long it took the mice to withdraw their paws from a mild pain source. The morphine-resistant mice withdrew their paws from the pain source after an average of six seconds, which was identical to mice which hadn’t been given any morphine. In other words, the morphine-resistant mice were deriving no analgesia from the morphine as a result of their tolerance to its effects. When morphine-resistant mice were treated with an HDAC inhibitor alongside a dose of morphine, however, they took as long as 12 seconds to withdraw their paw from the pain source. This means that the dose of morphine they received was nearly as effective as in mice which had never been exposed to morphine before, who waited 14 seconds before withdrawing their paw.
These results suggest that patients with neuropathic pain can supplement their opioid therapies with an HDAC inhibitor like butyric acid to reduce the impact of acquired tolerance, thereby allowing them to lower their dose and achieve comparable analgesia to what they experienced on a higher dose. Significantly, even patients who no longer respond to their prescribed opioid medication due to tolerance may once again be able to achieve pain relief using safer dosages and lower-risk opioid variants.
The Benefits of Integrating Butyric Acid in Pain Managementfewer uncomfortable effects like constipation, which means they may be able to reduce reliance on laxative medications. More importantly, smaller doses mean a reduced risk of drowsiness, mood changes, and overdose. While overdose is not typically an immediate concern for most patients taking opioids as prescribed, patients with impaired liver function, high rates of alcohol consumption, or those using medications like benzodiazepines face a significantly higher risk of accidental overdose.
Critically, overdose and abuse risk grow with tolerance. As such, if HDAC inhibitors can help prevent patients from experiencing diminishing returns as they become tolerant to opioid effects, they could decrease the chances that a patient will abuse their prescription drugs and graduate to unsafe dosages, unsafe administration methods, more potent opioids, and black market drug sources. This is of particular concern at a time when a growing number of patients are shifting from monitored, prescribed opioid use to illicit use when they find they are no longer able to achieve the pain relief they need using their prescribed medication as directed. Ultimately, adding butyric acid and other HDAC inhibitors to opioid-based pain management strategies could making safe, responsible opioid use more therapeutically beneficial, diminishing the risk of addiction and helping patients protect both their physical and psychological health.
Exploring the potential of HDAC inhibitors like butyric acid is a work in progress, but patients should be encouraged by butyric acid’s lack of dependence and tolerance-forming effects. At present, there is no evidence that the effectiveness of butyric acid reduces the longer that it is used to treat any kind of pain. While clinical trials describing the strategies that patients can use to implement butyric acid and other HDAC inhibitors into opioid-reduction or replacement regimens, butyric acid is currently ready for patients to use as a nutritional supplement thanks to pioneering nutritional supplement providers.
- CDC. 2018. Prescription opioids: the problem. Center for Disease Control and Prevention, US Department of Health and Human Services. https://www.cdc.gov/drugoverdose/opioids/prescribed.html
- Sanna MD, Guandalini L, Romanelli MN, and Galeotti N. 2017. The new HDAC inhibitor LG325 ameliorates neuropathic pain in a mouse model. Pharmacology Biochemistry and Behavior. 160:70-75. https://www.sciencedirect.com/science/article/pii/S0091305717301740?via%3Dihub
- Denk F, Huang W, Sidders B, Bithell A, Crow M, et al. 2013. HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain. Pain. 154(9):1668-1679. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763368/
- Uchida H, Matsushita Y, Araki K, Mukae T, and Ueda H. Histone deacetylase inhibitors relieve morphine resistance in neuropathic pain after peripheral nerve injury. Journal of Pharmacological Sciences. 128(4):208-211. https://www.sciencedirect.com/science/article/pii/S1347861315001693?via%3Dihub