Ketogenic Diet's Potential Effects on Opioid Use
Breakdown on 2023 study to determine whether a Ketogenic Diet enhances the antinociceptive beneficial effects of oxycodone in mice, its impact on opioid sensitivity and withdrawals, and more.
Here’s a little something different than usual; I wrote this piece to break down an interesting study, from the Department of Psychiatry at Yale University School of Medicine, determining whether or not a ketogenic diet can enhance the beneficial effects of oxycodone, its impact on pain from inflammation, and as they said they ultimately, "sought to identify the potential effects of a KD [ketogenic diet] on a range of oxycodone responses in mice," which in turn results in a better understanding of its potential effects on humans.
Being someone who has lived with multiple chronic pain disorders and autoimmune diseases that cause chronic inflammation and pain for decades, I find this to be full of very intriguing information in a rather neglected part of pain management that doesn't really get discussed much in relation to your pain levels, if it all—your diet!
It has often gotten to the point where I felt like doctors didn’t have anymore better ideas to help me fix the source of my pains, that they opted to simply throw more pills at me instead of tapering me off of the ones that didn’t work—more pain medicine, more thyroid medicine, more psych medicine, more inflammation medicine, more acid reflux medicine, etc., until I found myself pushing 20 daily medicines, many redundant [i.e. 3 antidepressants, 3 antipsychotics, and anti-anxiety meds, all at once] and way too many conflicting with one another [not meant to be taken together], almost all on the maximum doses except for my oxycodone and muscle relaxer [which I keep on relatively low doses for my problems because I don’t want to be all drugged up on opioids all the time; I just want enough of a dose to have a manageable, liveable amount of daily pains.
They kept adding more medications to the plethora of daily medications I took until a year ago when I finally put my foot down and demanded I be taken off everything that clearly wasn’t working to help my health improve, or that was redundant, and refused to again stack pills upon pills when they aren’t working in the first place! I am currently on less daily medications than I have been on in at least a decade!
I explain that to help you, as my reader, to better understand why this information is so exciting and promising sounding to me. I don’t want to one day find myself upping my pain medicine every so often, due to building a tolerance, until I wake up one day, years from now, to discover I am on some wicked high dosage of opioids and that I became the Oxycontin Cookie Monster shown above!
So, no, this is not exactly my usual politically charged breakdown of new controversial legislation or my vaccine and other COVID-related deep dives, but I hope at least some of my more nerdy readers, or perhaps even readers who also deal with chronic pain, can enjoy this piece and find something in it useful knowledge.
Opioid Epidemic
Opioid overdose deaths have been on the rapid incline for the past 25 years, with no end in sight; it increased 519% between 1999 and 2019, with 49,860 deaths reported in 2020 and 81,806 in 2022
Unfortunately, commonly prescribed for unmanageable pain, prescription opioids, such as oxycodone, play a major role in the ongoing, tragic opioid epidemic rocking our nation, contributing to 32% of all overdose deaths.
According to the National Institute on Drug Abuse [NIDA], "drug overdose deaths specifically involving prescription opioids rose from 3,442 in 1999 to 17,029 in 2017. From 2017 to 2019, the number of deaths declined to 14,139. This was followed by a slight increase in 2020, with 16,416 reported deaths. In 2022, the number of deaths declined to 14,716.”
Oxycodone is still one of the most effective for pain management, therefore, it is also one of the most prescribed medications despite the well-known risk of abuse associated with the narcotic.
Ketogenic Diet’s Effects on Oxycodone
The opioid epidemic's widespread effect on families nationwide has forced much more attention to be focused on investigating effective treatments for those fighting addiction with Opioid Use Disorder [OUD], and also finding ways of maximizing the therapeutic benefit of oxycodone and simultaneously minimizing negative consequences in a pain management setting.
Surprisingly, opiates aside, there is published preliminary evidence showing that living with a Ketogenic Diet has what are called antinociceptive benefits, or ability to "block the detection of a painful or injurious stimulus by sensory neurons" [in preclinical as well clinical settings], or in layman's terms—relief describing or relating to any factor that increases tolerance for, or reduces sensitivity to, harmful stimuli, usually stimuli that cause pain.
Amazingly, the pain relieving benefits of a Ketogenic diet prompted scientists at the Department of Psychiatry at Yale University School of Medicine to wonder about the possibility of using a ketogenic diet to modulate and possibly amplify and enhance the body's oxycodone response.
Being that the effects of the role of Ketogenic dieting on oxycodone is unknown, they "sought to identify the potential effects of a KD [ketogenic diet] on a range of oxycodone responses in mice," to better understand its effect on humans.
You may be wondering what the Ketogenic Diet is! The Ketogenic Diet is described in the study as, "a high fat, low/moderate protein, low carbohydrate diet, best known for its efficacy in treating pediatric epilepsy."
Their specific Ketogenic Diet [AIN-76A Modified (Bio-Serv #F3666)] had, “a caloric value of 7.24 kcal/g, with a composition of 93.4% fat, 4.7% protein, and 1.8% carbs. The control food group was labeled as "Standard Chow," and the standard chow [(Teklad Global #2018)] consisted of a caloric value of 3.1 kcal/g, with a composition of 18% fat, 24% protein, and 58% carbs.”
The scientists tested for many outcomes in attempts to determine whether a Ketogenic Diet is capable of causing weightloss, reducing overall pain, reducing amount of opioids when self-administering, lessening severity of opioid withdrawal, latency of pain relief after medicating, and its impact on oipoid sensitivity; all done on both males and females separately.
They first have to put the mice on either ketogenic or chow diet groups, test for ketosis, and run the various tests [I explain in more detail below] to determine if the aforementioned qualities are impacted by the ketosis, including but not limited to allowing self-administration of oxycodone and inducing withdrawals of oxycodone.
First, Male and female mice were trained to "operantly self-administer oral oxycodone while maintained on standard chow," meaning the mice were taught to self-administer oxycodone with the purpose of controlling pain levels while all mice still eat the control food, Standard Chow.
The study explained, "after their Day 6 self-administration session, the dietary intervention experiment was started by replacing the standard chow with ketogenic diet for the KD group." They went on to say, "we observed a significant reduction in oxycodone consumed by KD males, and a trend reduction by KD females."
Then, they introduced the Ketogenic and Chow Diets to the mice and tested tail blood for ketosis. The study noted, "while both male and female mice on a ketogenic diet rapidly develop ketosis, we observed sex differences in bodyweight loss in KD male mice only. This persisted throughout locomotor and hot plate testing. This sex-specific bodyweight response to the ketogenic diet in mice has not been reported in the literature, however it is consistent with clinical data evaluating patients with obesity on a ketogenic diet, where it was reported that male subjects lost more weight than females.”
They noted, "unlike male mice, female mice showed no differences in the relative change in bodyweight percentage from the start of dietary intervention to the time of locomotor testing." However, "similar to the males, female KD mice displayed an enhanced locomotor response to oxycodone compared to Chow as evaluated across time bins, as well as cumulative activity per phase. The female Chow mice displayed slightly higher activity than Ketogenic Diet mice during the Baseline phase.
Next, the "hot plate assay was used to assess changes in the antinociceptive effects of oxycodone in males and female mice."
The study conducted testing to determine the pain-relieving qualities by recording the, "time to nociceptive behavior," which was "recorded at five time points: baseline (BL) prior to 2 mg/kg oxycodone injection, and 10, 20, 30, and 45 min after injection."
They claim the hot plate assay showed, "no difference between male dietary groups was observed at baseline (BL), however latency to show discomfort was significantly increased in the KD mice with a main effect of diet after oxycodone injection."
Similar to the males, "the female mice had no difference at BL between groups, however latency was significantly increased in the KD mice with a main effect of diet after oxycodone. There were no differences in bodyweight loss among the Pair-fed Chow vs KD males, and with Chow vs KD females."
Unfortunately for the mice, the next quality to assess the Ketogenic Diet's effects on are opioid withdrawal symptoms. According to the study, they measured withdrawal severity by assessing the mice's jumping behavior after inducing opoid withdrawals by administering naloxone [the drug in Narcan thats given to save the lives overdosing opioid addicts]
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After the mice had completed three days of continuous oxycodone delivery via osmotic minipumps [miniature infusion pumps used to give specific doses of the drug being studied at specific times], then, "jumps were quantified over twenty minutes immediately after naloxone injection (1 mg/kg i.p.)."
The results of the withdrawal section showed, "male mice in the KD group had significantly more jumps than Chow mice," yet oddly showed that, "no difference was observed with female mice comparing KD vs Chow."
Oxycodone-induced locomotor activity was next tested; this was meant to screen for general changes in opioid sensitivity on the ketogenic diet.
Amazingly, the oxycodone-induced locomotor activity tests showed a likely impact the Ketogenic Diet has through antinociceptive benefits; they claim, "male and female Ketogenic Diet mice displayed robust increases in activity after oxycodone treatment compared to Chow mice, indicating that the ketogenic diet may enhance the effects of the opioid.”
The female Ketogenic Diet mice displayed significantly less activity during baseline and saline phases than Chow before showing a complete reversal from lower to higher oxycodone-induced locomotor activity. This strengthens the finding that the ketogenic dietary manipulation enhanced their opioid sensitivity.
Summary:
While the Ketogenic Diet, "induced substantial weight loss in male mice, this was not the case in female mice despite effective induction of ketosis in both sexes."
Strikingly, they found that the Ketogenic Diet, "augmented antinociceptive and locomotor effects of oxycodone in both sexes,“ [Ketogenic Diet expanded the pain relieving of pain caused by normal stimuli and the way in which the physical characteristics or components of oxycodone influences the locomotion neuromechanics of both sexes of mice].
While according to the study, the Ketogenic Diet, "exacerbated oxycodone withdrawal in males, this effect was absent in female mice.
The Ketogenic Diet also, "reduced oxycodone self-administration, especially in early sessions following the Ketogenic Diet diet administration, and with a more pronounced effect in male than female mice."
"Male and female mice showed no difference in rewards earned between KD and Chow groups over the test session," which was noted to mean there was no change in opioid-induced behavioral motivation such as pleasure, pain, and reward for the mice.
Ultimately, it appears that the Ketogenic Diet mice, both male and female, showed that the Ketogenic Diet likely 1) has antinociceptive benefits alone, 2) enhances the antinociceptive benefits of concurrently taken opioid medications, 3) increases activity levels for opioid users, and 4) enhances opioid sensitivity.
The Ketogenic Diet also 1) causes the males to lose more weight, but not the females, 2) exacerbated opioid withdrawal in males, but not in females, and 3) latency to show discomfort drastically increased right away from the basline in males, but not in females.
My Final Thoughts
It would be extremely interesting to know how this translates into how a ketogenic diet effects humans who use opioids for pain management
It sounds like ultimately, it has the potential to do things like assist in increasing the effectiveness of the pain relieving properties of opioids without the need to increase the dosage of the opioids, helping reduce the length and severity of opioid withdrawals without the need to be on different types of opioids [i.e. methadone or suboxone], and increasing activity levels of opioid patients without having to take the patient's working pain reliever away.
If a ketogenic diet really could impact humans the way it does mice—it could really help people who live their entire life in pain, and are willing to try practically anything to be in less pain, and want to get the most beneficial results from their pain management.
Living a life of daily pain for as long as you can remember is exhausting. Out of pure desperation, we will relentlessly try anything and everything that can possibly tamper down the constant agony, and more often than not, it does nothing to improve our quality of life! It is discouraging, but if the pain is bad enough, we'll give the next new thing a shot
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If a lifestyle change to a ketogenic diet can make a chronically pained person less pained for more time, less tired and more active, and give relief with less negative side effects—we're always willing to give it a try!
Other studies are available that look into the connection between the ketogenic diet and a reduction in inflammation and chronic pain, but I found this one to be very thorough and especially helpful in discovering the possible widespread beneficial effects of adding a ketogenic diet to the pain management protocols for oxycodone patients.
Original Yale study “Ketogenic diet enhances the effects of oxycodone in mice”: