Authors: Rowena Field, M. Physio, Fereshteh Pourkazemi, Ph.D., Kieron Rooney, Ph.D.
Journal: Pain Medicine, Volume 23, Issue 2, February 2022, Pages 326-338 (Pub:9-12-2021)

DOI: https://doi.org/10.1093/pm/pnab278

Scientific journal articles provide valuable information about a specific topic. These articles are usually littered with scientific jargon and incomplete methodology, making them extremely hard to read for the average person. Due to these shortcomings, even scientists in similar fields have trouble digesting papers from other fields. In this series, I aim to extract important and practical information from these journal articles and provide criticism regarding their methodology and ideology. Along with this, readers will gain an understanding of how to read scientific articles and draw conclusions about their validity on their own.

The first journal article in this series focuses on how dietary intervention may alleviate symptoms of medical problems. Specifically, this article refers to a low-carbohydrate diet and its impact on patients with chronic pain. Chronic pain is a serious medical condition that results from intermittent or sustainable pain for more than three months. Since pain is a symptom, and many underlying conditions can cause chronic pain, a physician is needed to make a formal diagnosis. The subjects (N = 27) were screened and deemed ineligible if they (1) took medication for any metabolic disorder, (2) had a history of an eating disorder, or (3) had bariatric surgery. All subjects were over the age of 18, with a mean of 53 years old, eating a standard western diet (average BMI = 29.5), and had been experiencing chronic pain for equal to or greater than three months (VAS > 30 mm). A study that takes place over the course of 12 weeks is tough on any individual, let alone someone suffering from chronic pain, and three subjects dropped out between weeks one and three. For personal reasons, two patients withdrew from the study during weeks four through twelve. This left the study with 22 subjects at the end of the twelve-week study. An important item to consider is that this is a pilot study, which means it is a small-scale preliminary test that can be used to fine-tune and conduct a larger study in the future. For any conclusive data, comprehensive studies are preferred. However, these pilot studies are crucial for understanding why certain clinical trials receive funding and where the clinical trials are headed in the future.

This group of researchers got the idea that a very low-calorie ketogenic diet (VLCKD) may reduce pain in subjects suffering from chronic pain from earlier studies that involved using a ketogenic diet to alleviate certain symptoms of diseases. Some of these diseases or disorders include Alzheimer’s, psoriasis, Parkinson’s, autism, and attention-deficit/hyperactivity disorder. A VLCKD is also known to benefit obese and diabetic subjects. The VLCKD is correlated with increased weight loss, better sleep quality, improved quality of life, a reduction in pro-inflammatory molecules, and better glucose regulation.

This study further split the experimental treatment group into a well-formulated ketogenic diet (WFKD) and a whole-food diet (WFD). There was no control group, and the researchers decided to use the subject’s baseline levels or reported scores at week zero and compare them to week thirteen. The researchers note that the subjects were well educated on each of the diets, although, in my opinion, this is hard to gauge without proper supplementary information. Information regarding how the subjects were educated can help improve the reproducibility of the experiment. The importance of this revolves around the ability of these individuals to learn, if they weren’t given adequate time to understand the diet model and which foods are essential etc., then their self-reported adherence scores can be widely variable. Another important note is that self-rated daily adherence to the diet model was 82% for the WFKD group and 87% for the WFD group. These self-reported scores can be attributed to many problems. First, if a subject is eating on a diet 70% of the day, what are they doing for the remaining 30%? How deviant are these subjects behaving around the 30% they are not eating on the plan? Also, this is a self-reported score, so a subject can report a higher adherence score if they do not want to appear "weak" or "undisciplined" to the research team. The use of a food journal with timestamps along with a self-reported adherence score should be the standard in a pilot study. Future comprehensive studies should combine a food journal, self-reported adherence score, and bi-hourly text messages in real-time during waking hours. These text messages can be laid out in several different formats, such as “please report your breakfast foods” or even provide motivation for the subjects. These simple, cost-effective, and time-efficient methods for accurately calculating adherence can drastically increase the reproducibility of an experiment.

The results of the paper are rather underwhelming when looking at the broad picture. However, when keeping in mind that this is a pilot study, the results are very promising. For those readers who are not familiar with statistics, anytime I state the word "significant" in a results section, it means that the p-value is less than 0.05 (P < 0.05). The p-value is simply a calculated probability that tells the analyzer how likely the data is to be categorized under the null hypothesis. In other words, it refers to the probability that the data occurred by chance. Therefore, a low p-value would indicate the data is so different from the controlled data that it would be extremely unlikely to occur by random chance. When putting certain variables into layman’s terms, a message can be taken incorrectly, so if you would like to gain a more complete understanding of this value, please feel free to watch YouTube videos on the subject to gain a better understanding of this concept. To start, there was a significant reduction in measured (VAS) pain at week thirteen compared to measured pain at week zero. Interestingly, a significant decrease in high sensitivity C-reactive protein (a marker for inflammation) was found in the ketogenic group, while no significant change (a slight increase) was observed for the whole-foods group. The Quality of Life (QOL) questionnaire is a commonly used tool in clinical trials because it is easy to use, cost-effective, and efficient. Both groups demonstrated a significantly improved QOL assessment score at the end of the study when compared to before the study. Moreover, depression, anxiety, and mood scores were significantly improved amongst the WFKD but not in the WFD group. The WFKD group also had a significant reduction in body weight, body mass index (see earlier post), and waist-to-hip ratio, whereas the WFD group did not. The results thus far have pointed in a very clear direction: a ketogenic diet is an effective tool in managing pain, regulating mental status, and possibly improving metabolic conditions.

However, these results do not tell the whole story. Numerous studies over the last decade have shown that caloric restriction (30%) has a positive effect on longevity, metabolism, and inflammation. The study highlighted in this review uses no control group, that is, they do not have a group that simply did not reduce their caloric intake. The highlighted experiment uses a WFD group as the control and compares this diet with the VLCKD. The WFD group reduced their caloric intake by 300 calories, while the WFKD (VLCKD) group reduced their calories by nearly 800 calories. A more appropriate set-up would have been to include a third group that consisted of a very low-calorie whole food diet (VLCWFD). With the addition of this group, the researchers can compare the effects of the ketogenic diet and not the effects of heavy caloric restriction.

When it comes to managing pain, diet can play a crucial role. In previous blog posts, I have discussed the link between diet, gut health, inflammation, and overall well-being. A poor diet can lead to inflammation, thus exacerbating symptoms of pain, while a well-balanced diet may help shield the patient from this exacerbating pain. This research article focuses on a diet that can go further than shielding. This article proposes a diet that has the potential to help alleviate the symptoms of chronic pain when compared to other "healthy" diets. The very low-calorie ketogenic diet has been used to treat an array of medical disorders, including diabetes and Alzheimer’s. One proposed mechanism by which VLCKD may alleviate symptoms of many medical disorders is that VLCKD leads to improved glucose and insulin homeostasis. Glucose, at normal physiological serum concentrations, is beneficial. It can be used as a quick fuel source and can act as a messenger molecule by stimulating the release of hormones such as insulin and GLP-1. However, in many disorders, such as obesity, glucose is at a supraphysiological serum concentration, thus triggering excess insulin release, which leads to insulin resistance and inflammation. This inflammation causes long-term damage to our cells, which can cause them to develop a disease phenotype. The VLCKD is a diet that has less than 50 g of carbohydrates (glucose), which means there is no excess glucose floating around our body. When glucose becomes low from exercising or just from existing, our body breaks down glycogen and turns it into glucose, thus raising blood glucose levels to a healthy and normal level. During ketosis, our body runs out of glycogen and is forced to break apart triglycerides, or stored fat, into ketones. Ketones are a molecule derived primarily from lipids and can be used as fuel to replace blood glucose as a source of fuel. Of course, our body doesn’t totally rid itself of glucose. It can use amino acids and other molecules to build up a glucose molecule that can circulate in the body. This way, blood glucose levels remain relatively stable and low but not dangerously low.

In conclusion, this article highlights the potential of a combination diet for the treatment of chronic pain. The diet is a combination of a very low-calorie diet and a ketogenic diet, which consists of a caloric reduction of about 800 Cals. And less than 50 grams of net carbs. This combination promotes a state of deep ketosis, or burning of fats, for fuel. This diet has been shown to be beneficial in a variety of medical disorders and continues to be included in a variety of clinical trials. The VLCKD group in this experiment demonstrated significant reductions in reported pain, inflammatory markers, and significant improvements in QOL, anxiety, and depression. It is evident that a VLCKD can alleviate symptoms of pain in patients with chronic pain disorders. This pilot study manages to progress the understanding of interactions between diet and medical disorders and pave the way for future clinical trials. These future trials must include larger sample sizes, better regulation of diet, and a diverse set of markers to validate the use of specific dietary interventions as treatments for serious medical problems.