Nociceptive pain evaluation - "My everything hurt."

Body ache, flu like all-over puffiness and pain. Inflammation => swelling => pressure => nociceptive & neuropathic pain.

I went to bed early last night and woke up feeling more normal and alert, three am, I will accept that. As I was laying there yesterday after dinner, I thought about what hurt? Where was the pain, what was the pain? Answer - everywhere. Everything hurt, every inch of my arms and body didn’t want to move or be touched. My scalp hurt - my hair follicles. It hurt to chew - the teeth in the gumline can feel bruising when inflamed. It all hurt, ached, low level body ache. What is wrong with me?

*Addition added from the emailed version.

This is fibromyalgia like pain. My worst years with Puffy-achy-can’t move, was age 38. I creaked down the stairs one morning thinking this feels like age 88. What is wrong with me?

Turns out over activation of carotenoids to Retinoic Acid seems to be what is wrong with me and peaches and carrots are my kryptonite, not beneficial for me individually — and potentially many other people. But who? How to screen for them?

Checking Retinoic Acid (RA) levels can be more informative than screening used for histamine excess, but the problem of excess RA can be localized as seen in the changes in alcoholism. Low levels of RA were found in the liver and eyes and elevated levels elsewhere.

Liver biopsy? Or just try eliminating vitamin A and carotenoid rich foods? See if it works? Since the treatment would be to eliminate vitamin A and carotenoid rich foods anyway - it would just save time to try. Therapeutic Trial - guidance would be needed. If too many sources of vitamin A and carotenoids were missed, then the symptoms might improve but still continue, and then the person might think that the strategy was not the solution to stick with and work harder at. Check mixed supplements also, and vit A or carotenoids would be in a one-a-day vitamin.

Tracking symptoms and diet in a daily log and other lifestyle notes can help while trying to identify problems and work on solutions.

Fibromyalgia is not well understood and is thought to involve mitochondrial dysfunction. A study in a Nursing journal looked at gene expression differences between fibromyalgia patients who were identified as more “catastrophizing” of their pain. (1)

“Psychological factors, such as negative personality traits, are also suspected to play a role in FM pathogenesis (Clauw, 2009). Catastrophizing has been well-established as a predictor of the severity of a pain experience (Aaron, 1999; Buenaver, Edwards, & Haythornthwaite, 2007; Buitenhuis, De Jong, Jaspers, & Groothoff, 2008; Burckhardt, Clark, & Bennett, 2001; Burckhardt, Clark, O'Reilly, & Bennett, 1997). In addition, pain catastrophizing is thought to influence the experience of FM symptoms (Burgmer et al., 2011). Being able to distinguish the biological mechanisms responsible for these known physiologic and psychological contributors to FM symptoms would be a major advance in the field, because identification of physiologic pathways related to specific symptoms defining FM will provide a foundation for new interventions. This study report is on a preliminary finding from a subset analysis of an ongoing study that seeks to differentiate the gene expression profiles between women who are healthy and those with fibromyalgia.” (Lukkahatai, et al, 2014) (1)

I was hearing a lot about psychosomatic pain and talk therapy from my “medical doctor” at that time. Too often the attitude women are greeted with is: “Pain? (Women don’t feel pain, honey) you must be crazy.” Add an expensive pharmaceutical to a diagnosis and suddenly the diagnosis becomes popularized in the media and at the medical offices (aka Bipolar disorder) - CAUTION label on the drugs that may be suggested. *I am on no prescription meds currently but was put on several at different times and they can be very dangerous.

What is considered catastrophizing? “rumination, magnification, and helplessness.”

“Catastrophizing was measured using the Pain Catastrophizing Scale (PCS), a 13-item, self-report questionnaire consisting of three subscales: rumination, magnification, and helplessness. Participants were asked to rate their thoughts and feelings on a 0 (not at all) to 4 (all the time) numeric scale. The PCS total score had acceptable internal consistency in past research (Cronbach’s alpha = 0.87) (Osman et al., 2000; Osman et al., 1997). A PCS score of 16 or higher has been considered to be the cutoff for high catastrophizing (Riddle, Wade, Jiranek, & Kong, 2010).” (Lukkahatai, et al, 2014) (1)

It is empowering to learn that avoiding peaches and carrots can allow me to live a more normal life with energy, no headache, and no all-over body ache where even your hair follicles and teeth and gumline hurts. It is not empowering to be told that while your problem is not well understood, it is probably because you are worrying about it too much. Thanks, so helpful.

It is true that added emotional stress will just make the inflammation and pain worse. The deep breathing exercises and self-injury distraction tactics are more helpful than being told that maybe you are a hypochondriac and should go talk about your problems more in therapy (aka “rumination”).

Back to the study - while of the nine women about half were scored as low pain versus high pain based on their feedback, measurable parameters showed all of the fibromyalgia n = 9 group had about equal pain with widespread tenderness. The catastrophizing was also about half and the women who scored higher on that survey did seem to have more mental fatigue and reported worse symptoms.

“Subjects in the high catastrophizing group (n = 5) reported higher scores in almost all of the symptoms reported and had significantly higher mental fatigue than the low catastrophizing group (n = 4) t (7) = −2.447, p = 0.044 (table 2).” (Lukkahatai, et al, 2014) (1)

Were some of the women in worse pain and the lab test measurements just didn’t perceive the difference? Or were some of the women making themselves sicker by worrying about it and focusing on it more?

The gene expression differences between the “high pain” and “low” included some genes that were up regulated and some that were downregulated. SCO2, a gene for a copper ion binding protein was downregulated. (Table 3, 1) From the schizophrenia series we know that decreased copper transport in the brain can be a causal factor for the condition. Over-thinking is part of “schizophrenia” or histamine excess.

Mystery clue in Table 4 - the gene expression difference between the “high catastrophizing” and “low”:

“TMTC1 — transmembrane and tetratricopeptide repeat containing 1 — function is yet unknown”. (Table 4, 1)

We have a clue about its function now, it was up regulated in the “high catastrophizers”.

Pathway analysis of the various gene differences between the high and low pain groups found:

“Further Ingenuity Pathway analysis of the differentially expressed probesets, revealed distinct canonical pathways between the high and low pain groups to include: […] role of retinoic acid-inducible 1 (RIG1)-like receptors in antiviral innate immunity, […] (figure 1B).” (1)

“To confirm that physiologic pathways were not influenced by outlying conditions (e.g., acute viral infection from one of the study subjects), especially between the pain groups, a Monte Carlo stimulation method was performed by randomly excluding one subject at a time and re-running the differential gene expression analysis and determining if physiologic pathways remain consistently the same during the analyses. The Monte Carlo simulation method confirmed that the top 5 canonical pathways (role of pattern recognition of bacteria and viruses, activation of interferon regulatory factor [IRF] cytosolic pattern recognition receptors, interferon signaling, role of retinoic acid-inducible 1 [RIG1]-like receptors in antiviral innate immunity, and the role of hypercytokinemia / hyperchemokinemia in the pathogenesis of influenza) remain consistently observed in the high pain group.” (Lukkahatai, et al, 2014) (1)

The “high catastrophizing” versus “low” also were found to have gene pathway differences:

“The 139 differentially expressed probesets between the high and low castratrophizing groups were analyzed by IPA and revealed four common physiologic networks to include: cellular movement / hematological system development and function / immune cell trafficking; amino acid metabolism / small molecular biochemistry / cellular movement; cell death / cancer / hereditary disorder; and cellular development/ gene expression (figure 2A). Top canonical pathways associated with the differentially expressed probesets between the two catastrophizing groups included type 2 diabetes signaling; valine, leucine, and isoleucine biosynthesis; pantothenate and coenzyme A (CoA) biosynthesis; role of Janus kinases (JAK2) in hormone-like cytokine signaling; and inhibition of angiogenesis by thrombospondin-1 (TSP1) (figure 2B). Overlay of the physiologic networks and canonical pathways revealed pathways related to dendritic cell maturation and glucocorticoid receptor signaling as common networks that were associated with the differentially expressed genes between the catastrophizing groups (figure 2C).” (Lukkahatai, et al, 2014) (1)

Dendritic cell problems are seen in schizophrenia and a lack of vitamin B5 (pantothenate) and Coenzyme A (CoA) would affect mitochondrial function. I did add a high dose B5 to my routine many years ago. Inhibition of angiogenesis would be a loss of blood vessel repair or growth which would mean less nutrient delivery and toxin removal = puffy and toxic/acidic and triggering TRP channels from a more acid environment. That would increase calcium entry into cells and lead to more pain.

“Ca 2+ entry across membranes is mediated by different channels, including transient receptor potential (TRP) channels, some of which (e.g., TRPA1, TRPM2, TRPV1, and TRPV4) can be activated by oxidative stress and have a role in the induction of peripheral pain.” (2)

So, from this point forward I am relabeling these women as genetically impaired rather than “high catastrophizing”.

Wouldn’t a B5 supplement be cheaper and more effective than years of talking about your (not) imaginary pain with a talk therapist? (~ $12-15 for 100-250 capsules of 500 mg)

We need to make our own CoenzymeA, so an inability to make that is kind of a big negative for mitochondrial health. Supplements sold for CoA support are a precursor blend typically.

What do valine, leucine and isoleucine do?

• “Valine. This is one of three branched-chain amino acids (BCAAs) on this list. That means it has a chain branching off from one side of its molecular structure. Valine helps stimulate muscle growth and regeneration and is involved in energy production (8).”

• Leucine. Like valine, leucine is a BCAA that is critical for protein synthesis and muscle repair. It also helps regulate blood sugar levels, stimulates wound healing, and produces growth hormones (12).

• Isoleucine: The last of the three branched-chain amino acids, isoleucine is involved in muscle metabolism and is heavily concentrated in muscle tissue. It’s also important for immune function, hemoglobin production and energy regulation (10).” (3)

These changes in CoA production or branch chain amino acids (very important) might be temporary - I feel better today, fairly normal for me. Taking notes or thinking of words to label your types of feelings can help to cope with them better next time. Later in the post I include some supplements that I used to help reduce the inflammatory response. The upset gut was helped by organic tofu. I have found that easiest to digest when eating causes colitis like pain. When I was eating a carrot every day, the influx of carotenoids being converted to Retinoic Acid would be every day. The pain and fatigue and low stress tolerance would be daily.

The thing about Retinoic Acid is — the receptor it activates controls gene transcription - which genes produce proteins or don’t — as many as 10,000-15,000 genes directly and many more indirectly through its effects on the Vitamin D and Thyroid Receptors and the PPAR receptors.

So, a temporary influx of peach carotenoids turned into active Retinoic Acid, could then in turn up or down regulate a bunch of other genes.

If the peach influx is a daily event, then the up and down regulation would also be occurring daily.

Let today be peach free, for me.

A gene allele is a permanent difference, whether it is transcribed into a protein or not involves the regulatory or signaling systems which include the Retinoic Acid Receptors. I take Dimethylglycine and methionine as free amino acid supplements due to a double gene allele in the BHMT enzyme that makes it a dysfunctional protein. I might make some of it but it doesn’t work. I can’t digest proteins to the free methionine or DMG permanently - something is flawed in the version of the protein that I make, and it is dysfunctional, leaving me uncheerful and headachy when I forget to take my amino acid drink, Cheerful juice, tm, see below.* The difference in gene expression is the transcription of the protein - is a gene actively being used to make mRNA for protein transcription or is it inactive?

Clearly, these women are metabolically disrupted, and therefore they do have something to worry about → Why are they metabolically disrupted? Why are they in constant pain?

And why is the medical industry focused on rating their “Catastrophizing” instead of on restoring function and quality of life? On the other hand, the study proved that the women did have underlying differences, they were complaining for a reason - but complaining still doesn’t help if no action is taken. It does add to oxidative stress and would worsen symptoms further.

But so might peaches or carrots, mangoes, papaya, tomatoes, kale, or Moringa leaves.

Knock me over with a feather - carrots are not good for me after all. They may be good for you, but I don’t know anymore, you may need to be screened for overactivation of carotenoids to Retinoic Acid. Are you in chronic mystery pain? Maybe its Retinoid Toxicity simply being called a mystery.

Addition (from emailed version): The various pathways made it seem as if a viral infection might be present. Reanalyzing the results with each woman’s data excluded for one, a re-analysis x 8, provided no change in the results, which the research team took to suggest that no single woman had a significant viral infection that was skewing the group’s average results.

The Retinoic acid inducible gene-1 has a role in sensing viral infection, but it also is involved in inflammation, apoptosis, senescence, and the group of receptors have regulatory control over Type 1 interferon production (a type of cytokine that increases with viral infection or inflammation). The Retinoic acid inducible gene-1 is activated by the activated form of vit A: all-trans Retinoic acid (ATRA). (6)

What if the group of women with fibromyalgia, as a whole, had a history of over-activation of Retinoic acid after an Epstein-Barr viral infection (like me) and their bodies all were busily still trying to fight a virus, that is generally present in most of us without causing illness. Our microbiome includes virus that are benign and may even provide some anti-inflammatory benefits. An over-reaction by the body can be deadly too and seems to be occurring on an ongoing basis for more people than just me (my mom doesn’t seem to get worse from vitamin A foods or carotenoids - she worsens with use of the histamine trigger foods which can include anything that has been a leftover for several days - microbial fermentation to free amino acids continues in the fridge, but slower than at room temperature).

Additional addition - man-splainers have volunteered the information that vitamin A is beneficial for health and important for reducing measles severity. True. Thank you. And that therefore my problem must be something else - not true. I would be willing to do a repeat peach experiment with someone else funding inflammatory lab test bio markers before and after and the gene expression screening used by (Lukkahatai, et al, 2014). (1)

As Alzheimer’s and other issues are the direct risk for me getting it wrong, I will continue to do my own research and trial and error learning without lab testing funds.

For normal health it is very true that vitamin A and carotenoids are very beneficial for immune health and eyesight. I do recommend vitamin A and carotenoid sources and prepare them for others.

Related posts:

This post has the breakdown on how much goat liver curry would be too much for normal health - as it contains active Retinoic acid and inactive forms. Answer not as much as you might think, a few ounces may reach toxic levels, but the bigger risk would be with regular, daily, weekly use of the few ounces, rather than a monthly generous serving. Retinoic acid & toxicity - dosing - how much is too much for normal health?

This post has the solutions and risks of modern life that add to Hyperinflammation - a positive feedback loop that may lead to Alzheimer’s dementia.

Why focus on Retinoid Toxicity - answer, it can lead to Alzheimer’s dementia. Also linked in the last post: Symptoms of Retinoid Toxicity - some are odd, so a questionnaire screening may help suggest whether it might be a problem or probably not. Time doesn’t help. I got worse over the years.

“There’s simply no polite way to tell people they’ve dedicated their lives to an illusion.” - Daniel Dennett

We don’t know what we don’t know, until we learn it.

To share more on fibromyalgia - the catastrophizing in part, is part of the diagnostic process or was at the time I was not diagnosed. There was a body map with 13 points typical of pain points and a patient had to have 8 of them to be diagnosed. This was early in the phases of fibromyalgia becoming an accepted condition. I hadn’t mentioned those specific zones, or only a few that matched. I had fibromyalgia-like symptoms for many years and weekly migraines.

How do you say: “My everything hurts!”?

Every point on the body map. It hurts.

It is better to know what to avoid, and work to avoid it, than to live in daily pain.

I feel better today.

I took artemisinin, black seed oil, an extra high dose niacin, made sure to get my Bs and more of the other daily boxes.

The high dose niacin did throw off my routine. All the various solute loads - 200 mg, 500 mg this, 1000 mg that, add up to gut load and too much at any one time can lead to dumping it all suddenly. Solute load for free amino acids, or supplements or sugar all need to be spaced out over the day to be absorbed well rather than making a sudden exit in the bathroom.

I am forgetful and my routine is complex. There are also too many other tasks now besides my own care. Being a high need patient is time consuming and maintaining autoimmune disease in remission may look like “health,” but it is more of a prevention of relapse” phase of life rather than normal health. Pacing oneself and avoiding emotional upheaval or disruption of self-care routines are all important.

Strenuous exercise and ongoing over-doing it causes myokines formed by muscle action. (4) They are inflammatory like cytokines and would add to the hyperinflammation positive feedback loop.

Oleate helped reduce inflammation from myokines in participants with Type 2 Diabetes. (4) Oleate is a fat which improves insulin resistance for unknown reasons and was also found to reduce inflammation in a study on palmitate-induced insulin resistance. (5)

“However, the mechanisms by which oleate may improve insulin resistance are unknown. Here we report that oleate prevents palmitate-induced insulin resistance and inflammation in skeletal muscle cells.” (5)

*My Cheerful Juice tm - about a half spoonful of Dimethylglycine (DMG) and methionine powder, and I added a half spoon of lysine because I have a vegan diet and tend towards low lysine (need more beans and tofu, less nuts and seeds which are richer in arginine). The amino acids are acidic, the beverage is too acidic, I add a little Baking soda to modify it, just a smidge. Cardamom, a sprinkle for flavor and phospholipids. Some sweetener, Pure Maple Syrup, a spoonful, or stevia powder, an ounce or two of pomegranate juice or cherry or blueberry, and/or a couple ounces of aloe vera gel. More acidic juices make it worse, even more acidic. The total is in a 12-ounce water glass, and I drink it slowly, or in two halves.

DMG acts as an inhibitory, or calming neurotransmitter within the brain. When I go without too long, it seems a migraine is a result and having a Cheerful juice can help resolve the headache. When I first tried DMG in the large amount I was astounded by feeling noticeably more cheerful and energetic within about 20 minutes. I had first tried a capsule and noticed no difference. The half spoonful may be 2.5 to 5 grams. Up to ten grams a day may be the amount humans need but it is not really known and there is no officially recommended intake.

Photo by Lital Levy on Unsplash

Disclaimer: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

1. Lukkahatai N, Majors B, Reddy S, Walitt B, Saligan LN. Gene expression profiles of fatigued fibromyalgia patients with different categories of pain and catastrophizing: a preliminary report. Nurs Outlook. 2013 Jul-Aug;61(4):216-224.e2. doi: 10.1016/j.outlook.2013.03.007. Epub 2013 May 16. PMID: 23684314; PMCID: PMC3720238. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720238/

2. Nazıroğlu M, Öz A, Yıldızhan K. Selenium and Neurological Diseases: Focus on Peripheral Pain and TRP Channels. Curr Neuropharmacol. 2020;18(6):501-517. doi: 10.2174/1570159X18666200106152631. PMID: 31903884; PMCID: PMC7457405. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457405/

3. Essential Amino Acids: Definition, Benefits, and Food Sources, healthline.com, https://www.healthline.com/nutrition/essential-amino-acids

4. Ciaraldi TP, Ryan AJ, Mudaliar SR, Henry RR, Altered Myokine Secretion Is an Intrinsic Property of Skeletal Muscle in Type 2 Diabetes, PLOS, July 25, 2016

   https://doi.org/10.1371/journal.pone.0158209 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158209

5. Coll T, Eyre E, Rodríguez-Calvo R, et al., Oleate Reverses Palmitate-induced Insulin Resistance and Inflammation in Skeletal Muscle Cells*, J Biological Chemistry, 283;17, 2008, pp 11107-11116, ISSN 0021-9258, https://doi.org/10.1074/jbc.M708700200.

   https://www.sciencedirect.com/science/article/pii/S0021925820619019

6. Liu F, Gu J. Retinoic acid inducible gene-I, more than a virus sensor. Protein Cell. 2011 May;2(5):351-7. doi: 10.1007/s13238-011-1045-y. Epub 2011 May 28. PMID: 21626268; PMCID: PMC4875335. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4875335/pdf/13238_2011_Article_1045.pdf