VITAMIN B6 (PYRIDOXINE) AND CHRONIC PAIN

Is chronic pain a symptom or a disease? Primary chronic pain is considered a disease in its own right and not just an epiphenomenon of a specific disease. And what are the underlying mechanisms of primary chronic pain? Research is far from complete, new insights are still being gained on this topic. In this paper, I will discuss the surprising link between vitamin B6, pyridoxine, and chronic pain, and speculate on whether vitamin B6 plays a role in the mechanisms of primary chronic pain.

Before I continue, I must make a revelation. The mechanisms of chronic primary pain are complex and can by no means be reduced to a simple explanation or a single cause. The role of a particular vitamin in an individual's health may be more or less important, so taking certain vitamins in higher doses must always be discussed with a physician.

Chronic primary pain conditions such as chronic nonspecific low back or neck pain, fibromyalgia, chronic widespread pain, or multisite pain are very common and not well understood mechanistically. My interest in nutrients having role in the maintenance of pathological pain was piqued when reading case reports on vitamin b1 or larger cohort studies on b12, folic acid, and others in fibromyalgia. In a study aimed at finding useful biomarkers for any type of chronic pain a biomarker testing panel was used in chronic pain patients to analyse essential micronutrients critical for nerve health, chronic inflammation, oxidative stress/damage, and neurotransmitter turnover. The main finding was that 77% of patients had at least one abnormal biomarker value. Elevated xanthurenic acid, a hallmark of vitamin B6 deficiency, was found in 17% of the study participants. Thus, a subset of people with chronic pain (primary chronic pain not excluded) may have a vitamin B6 problem.

Vitamin B6 is a cofactor for more than 100 enzymes. It plays a critical role in tryptophan metabolism. Tryptophan is an amino acid that is very important for the synthesis of serotonin. When not used for this purpose, tryptophan is diverted into a metabolic pathway called the kynurenine pathway, which eventually leads to the synthesis of nicotinamide or NAD+. This is not a bad thing because a deficiency of NAD + is implicated in sleep problems in chronic pain. Normally, about 90-95% of tryptophan is converted to kynurenine and the rest is used for serotonin and protein production. The problem is not the activation of the metabolic pathway per se, but how it is activated (there are different types of activation) and the problems that can occur along the way that are related to various micronutrient deficiencies. In addition, tissue-specific disorders play a role; it is not the same whether the problematic activation of the kynurenine pathway occurs in the liver, in fat cells (adypocytes), in white blood cells such as lymphocytes, or in microglia in the brain. In any case, vitamin B6 is very important for this pathway throughout the body, and when it is not sufficiently present, intermediates such as kynurenine, hydroxy L kynurenine and xanthurenic acid are formed.

How can this happen? Kynurenine is an endogenous activator of AhR (aryl hydrocarbon receptor), which is involved in inflammation and obesity, among others. Expression of the enzyme IDO1, which converts even more tryptophan to kynurenine, is indicative of increased AhR activity. This creates a positive feedback loop between kynurenine, AhR, and IDO1, which results in more and more tryptophan being channelled into the kynurenine pathway while more and more vitamin B6 is consumed, eventually leading to vitamin B6 deficiency. Deficiency of vitamin B6 blocks the metabolic pathway and leads to accumulation of kynurenine pathway intermediates such as hydroxy-L-kinurenine or quinolinic acid, which has been shown to play a role in neuropathic pain in an animal model. When combined with magnesium deficiency, quinolinic acid does not lead to the production of NAD +, the cofactor that we would like to see increased in chronic pain. Thus, it could be speculated that impaired tryptophan metabolism per se contributes to the patophysiological mechanisms in chronic primary pain or at least enhances pre-existing pain sensitization, with vitamin B6 playing an important role.

The case for connection between obesity, inflammmation, chronic pain and depression

Obesity is associated with lower vitamin B6 status and also with risks for chronic low back pain and severity of fibromyalgia symptoms. One study found that elevated C-reactive protein (CRP) levels were associated with lower B-6 levels in morbidly obese patients, among others. On the other hand, increased CRP concentration was associated with more pain symptoms and greater disability in obese patients with fibromyalgia. Unfortunately, there are no studies on the interaction of pain, obesity, and vitamin B6. The association between inflammation, obesity, and chronic pain could be mediated by vitamin B6 status. Up-regulated inflammation plays a role in fibromyalgia. The kynurenine pathway is markedly upregulated in response to inflammation by proinflammatory cytokines such as TNF alpha and interferon gamma. Activation of the kynurenine pathway has been shown to play a role in comorbidity of pain and depression. Decreased serotonin production due to the positive feedback loop described above could lead to anxiety and depression and disruption of the descending inhibitory pain control system, which acts to inhibit pain under normal serotonin supply. Recently, a study found an important link between the peripheral kynurenine pathway and central nervous system metabolites, revealing a link between depression and inflammation.

Vitamin B6 also has a downside. Too much of it can lead to problems such as polyneuropathy, which in turn causes pain sensations. There are also reports of higher vitamin B6 levels in obese patients awaiting bariatric surgery. This suggests that there is a "sweet spot" for vitamin B6. It may be that patients with significantly lower serum levels of vitamin B6 and high serum or urinary metabolites of the kynurenine pathway such as xanthurenic acid could benefit most from supplementation in terms of weight and pain regulation. It is important to emphasise that vitamin B6 does not act alone, and other vitamins and micro/macro elements must be considered. As for other measures, physical inactivity activates AhRs via the IDO1 kynurenine AhR pathway. Therefore, exercise is very important in the treatment of obesity and chronic pain. Vitamin supplementation is a supportive measure to enable better physical functioning.