mini review

Can Chronic Pain be considered a Disease of Civilization?

Paul Clayton*

Chief Scientific Advisor, Gencor Pacific, Hong Kong

*Corresponding author: Paul Clayton, Chief Scientific Advisor, Gencor Pacific, Hong Kong

Received Date: 17 October 2022

Accepted Date: 31 October 2022

Published Date: 04 November 2022

Citation: Clayton P (2022) Can Chronic Pain be considered a Disease of Civilization? Chron Pain Manag 6: 146. DOI: https://doi.org/10.29011/2576-957X.100046

Abstract

The increasing incidence of chronic neuropathic, neurogenic and nociplastic pain, together with decreasing latency and the role of neuroinflammation in pain perception, all suggest that the modern diet and lifestyle is adding considerably to the overall burden of pain and the growing need for adequate pain management. These same factors dysregulate the body’s endogenous pain modulating endocannabinoid and immune systems. Novel dispersant technology now allows the use of certain endogenous agonists as therapeutic tools with uniquely high therapeutic indices.

Keywords: Pain management; Pain matrix; Neuropathic; Nociplastic; Nociceptive; Neuroinflammation; Palmitoylethanolamide; Autacoid

Access to pain management is considered a fundamental human right [1], but safe and effective pain management is still, for many, little more than an aspiration. In the United States over one in four adults suffers from chronic pain [2], and the drugs used to treat pain leave much to be desired. The peptic ulcer and cardio problems linked to NSAID’s [3], and the public health crisis caused by the over-zealous marketing of opioids, have damaged confidence in the prevailing medical model.

Has Life Always Been so Painful? [4]

AActually, no. The prevalence of chronic pain has increased significantly during the last two decades [5,6], currently affecting 20% of US adults [7] and a significantly higher percentage of older adults [8]. This Janus finding shows that external factors are affecting the neurological and immunological substrate of pain, and that their identification could lead to new treatment and prophylactic strategies. The fact that even among children the incidence of chronic pain is now, startlingly, over 10% [9], makes this quest all the more urgent.

Might our diet be causing this? Is the fleeting pleasure of ultra-processed food making our lives more painful? And if so, would restoring pre-transitional nutritional values help?

Within the USA there is evidence suggesting that chronic pain is more likely to affect folk who eat a more ultra-processed and pro-inflammatory diet [10-12], and those with lower socioeconomic status [13,14], linked to poorer diet. When one examines global patterns of ultra-processed food consumption [15], however, it is hard to make out any broader trend.

Europeans eat a more traditional diet, and their chronic pain figures are lower than in the USA [16]. The British and Japanese also consume less ultra-processed food than Americans, yet their recorded chronic pain figures appear to be somewhat higher [17,18].

The fact that the data are not particularly coherent is unsurprising. The studies used different survey methods and different pain criteria. None of them attempt to distinguish between the three main sub-types of chronic pain (neuropathic, nociceptive and nociplastic), which respond differently to dietary inputs. And pain does not occur in a neurological vacuum; its perceived intensity is affected by interwoven social and psychological factors which differ in different individuals, families and cultures.

For example, individuals with chronic pain typically have higher psychological distress scores [i.e. [17]]. It is a bi-directional relationship. Chronic pain is stressful and may reduce opportunities for social interaction. Conversely, social pain [loneliness, social defeat, anger] tends to exacerbate physical pain, especially nociplastic pain [19, 20], probably by activating a shared neural network known as the pain matrix [20-22].

The pain matrix is sensitized by early life trauma [23] and amplified by neuroinflammation [24], which is affected by multiple lifestyle factors.

Transient low-level neuroinflammation is physiologically normal, and entirely positive. It is involved in immune surveillance and signaling, together with aspects of brain development, memory and learning [25,26]. At higher levels, it is a crucial element in injury repair.

If neuroinflammation is excessive and/or chronic, however, triggered by a pro-inflammatory diet and/or substantial peripheral inflammation, or by repeated social defeat, it gives rise to sickness behaviors including loss of appetite, lethargy, apathy, demotivation, reduced activity and reduced sociability [27]. It also drives depression, brain ageing and neurodegenerative disease [27,28]. (28 is a fascinating and comprehensive read).

Our rising intakes of pro-inflammatory, ultra-processed foods, which drive inflammatory disease, will therefore contribute to increasing reports of chronic pain [27,28]. Progressive damage to our social networks and repeated social defeat will add to those numbers [29,30].

There are rare individuals with genetic factors that leave them unable to feel pain [31]. This raises the question of whether such individuals might also be immune to solitude and social defeat [22,23], but this appears not to be the case [32]. We are more complex than that [33] … and being pain-free comes with its own set of problems. It would be better to have a more moderately skewed genetic makeup, which reduces but does not abolish the likelihood of chronic pain, and depression [34,35].

Interestingly, two UK Biobank studies [34,35] found significant genetic differences in male and female pain-associated SNP’s. This may be one of the reasons why women generally experience more recurrent pain, and likely experience more severe pain and longer-lasting pain than men do [i.e. 36,37].

An increasingly pained society provides a healthy market for painkillers, but this is not a healthy response. Already well known to cause health issues, evidence is accumulating that they may actually be counter-productive.

Pain, inflammation, the immune system, nutrition and healing are all intimately connected. Inflammation following injury is an essential part of the process of tissue remodeling and repair [38], and there is some evidence that if drugs are used to suppress inflammation after injury, healing may in some cases be slowed [39]. New research suggests that inflammation also re-sets local neural networks so that the acute pain of injury fades as the wound resolves; and that anti-inflammatory drugs may disrupt this too.

A research team out of McGill University [40] examined 98 patients with acute injury and found that when innate immune cells known as neutrophils were inhibited by NSAID’s or steroids, pain was almost twice as likely to become chronic, and last up to 10 times longer than in controls. Acetaminophen and lidocaine, which reduce pain without damping neutrophil activity, did not have this effect.

To add insult to the original injury, the Cochrane Collaboration finds that the NSAID’s are only marginally effective in the management of acute [41] pain, and barely effective at all in chronic [42] pain. Overall, therefore, the case for antiinflammatory analgesics in the management of chronic pain is looking very shaky.

There is a compound produced in the body in response to injury, which may be a more appropriate therapeutic tool. This is the autacoid palmitoylethanolamine (PEA), a quasi-endocannabinoid which acts as the body’s first response to tissue damage, pain and inflammation.

PEA is formed locally where and when needed, and modulates the neuronal transmission and sensation of pain [43]. It is effective in many models of neuropathic pain including surgical [44], diabetic [45] chemotherapeutic [46], and compression [47]; and in nociceptive [inflammatory] pain also [44].

The Montreal group found that neutrophils exerted analgesic effects where and when needed, and PEA operates in precisely this manner. Neutrophils appear to act in conjunction with local PEA synthesis whenever the body responds to injury, but the collaboration is a complex one.

PEA’s anti-inflammatory effects include inhibiting neutrophil migration into areas of tissue damage [45-47]. Theoretically, therefore, PEA should slow recovery from pain. This seems counter-intuitive, and the available evidence suggests that it does not happen. PEA appears to accelerate the repair of micro-damaged tissue (i.e. [48-50]).

We need to think in subtler terms, and re-thinking neutrophils could be the key. Neutrophils, once thought of as simple phagocytic cells that drive inflammation, are now known to play many other roles including a final interaction with macrophages which enables the resolution of inflammation [51]. There appear to be multiple sub-types of neutrophil which are induced and/or transformed in different tissues as and when required [52].

The fact that PEA reduces neutrophil infiltration after injury, and yet does not delay pain or damage resolution, suggests that it acts selectively on neutrophil sub-types in a functional and adaptive manner.

PEA’s evolutionary complexity and fitness for task is confirmed by its ability to shift macrophages into anti-inflammatory and pro-resolving mode [53], which dying neutrophils also do [51]; and to prevent mast cell degranulation [54-56] by blocking Substance P [57], a neuropeptide produced by tissue damage, which modulates pain perception. It exerts additional antiinflammatory and anti-nociceptive actions via selective activation of PPAR-alpha [58] and CB1 [59] receptors; and may play a pivotal role in preventing the transition from acute to chronic pain [58,60]. Finally, by reducing neuroinflammation, PEA alleviates [pre-clinical] anxiety [i.e. 61], and [clinical] depression [62].

The above data suggest that PEA synthesis might be usefully considered as a component in the cell danger response. How does this relate to the recorded increase in cases of chronic pain?

Pain and inflammation after injury is normal and desirable. Our bodies need to learn what is harmful, and to defend against intruders. Neutrophils are involved in pain and inflammation, and under ‘normal’ metabolic circumstances (i.e. when we were still eating a pre-transitional diet), presumably appropriate numbers of the right neutrophils were engaged.

The industrial, pro-inflammatory diet likely skews cellular and autacoidal responses to injury (i.e. 63-65), increasing the chances of progressing to chronic inflammation and pain - which is what the epidemiology shows is happening [5,6]. And when pain and inflammation are protracted, as they are by the modern diet [63-65], PEA ‘exhaustion’ may develop: chronic inflammatory conditions eventually reduce the body’s ability to generate PEA [55,56].

Even this is not the end of the story, because the modern diet also causes dysbiosis. The gut microbiome is involved in pain sensing, and in inflammatory, neuropathic and nociplastic pain sensitization [66-72]. The enteric nervous system probably evolved before the CNS [73], there is considerable cross-talk between the two and the dysbiosis that is so common today is likely contributing to the increasing numbers of individuals who reportedly graduate from acute to chronic pain [5-7].

Chronic pain appears to lead to increased connectivity in the pain matrix [74] via a learning or kindling effect which may well be exacerbated by neuroinflammation [24]. The pain matrix communicates with the default network, which is functionally altered during the experience of pain, may be structurally altered by chronic pain [75] and is also degraded by the modern diet [76].

Chronic pain also affects the salience network [77], which overlaps with the default network in the cingulate, potentially explaining how the intensity of perceived pain can be modified by distraction; and why pain is worsened by loneliness [19,20].

Here is a neurological substrate that links social emotions, emotional processing, self-image and pain perception. It implies that as Western society continues to fragment, our self-worth continues to be attacked and our diet continues to deteriorate, chronic pain will become an unwanted guest in ever more homes. We will tend to focus more on the negative aspects of our lives and experiences, driving isolation, depression and anxiety [78-81] and immune dysfunction [82-84] in a descending spiral.

What are the Implications for Medical Practice?

The pain matrix appears to be down-regulated by antidepressant drugs such as duloxetine [85], which has some ability to reduce neuroinflammation [86,87] and relieves physical pain more rapidly and more effectively than it does mental distress. Duloxetine’s withdrawal effects, unfortunately, can be seriously problematic.

I revert to the body’s endogenous analgesic, PEA. With excellent safety data [88,89] and efficacy in numerous models of pain [43,45-48,89-91], it has recently been found to reduce inflammatory markers and stress in athletes [50] and in Covid patients [92]. Non-addictive and free from withdrawal effects, it attenuates cocaine cravings in pre-clinical models [93] and is currently being trailed for opioid reduction in below knee fracture fixation [94].

Due to its ability to reduce neuroinflammation [56,61,95], palmitoylethanolamide has also found uses as a sleep aid [96] and mood enhancer [97].

PEA’s main barrier to use has been its poor oral bioavailability. Micronised preparations made some progress in this direction but the issue has recently been resolved by Lipisperse, a novel delivery system that uses cold water dispersion technology to dramatically enhance the bioavailability of hydrophobic agents [98]. When given as a supplement, PEA- Lipisperse likely acts not only at the site of injury but also within the pain matrix, in a non-autacoidal manner.

This old / new analgesic should now be reconsidered as a physiologically appropriate first line intervention in pain management.

References

  1. International Pain Summit of the International Association for the Study of Pain (2011) Declaration of Montréal: declaration that access to pain management is a fundamental human right. J Pain Palliat Care Pharmacother 25: 29-31.
  2. Dahlhamer J, Lucas J, Zelaya C, Nahin R, Mackey S, et al. (2018) Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults - United States, 2016. MMWR Morb Mortal Wkly Rep 67: 1001
  3. Drini M (2017) Peptic ulcer disease and non-steroidal anti-inflammatory Aust Prescr 40: 91-93.
  4. https://www.youtube.com/watch?v=KS_f6O8mWsk
  5. Zimmer Z, Zajacova A (2020) Persistent, Consistent, and Extensive: The Trend of Increasing Pain Prevalence in Older Americans. J Gerontol B Psychol Sci Soc Sci 75: 436-447.
  6. Zajacova A, Grol-Prokopczyk H, Zimmer Z (2021) Pain Trends Among American Adults, 2002-2018: Patterns, Disparities, and Correlates. Demography 58: 711-738.
  7. Jason YR, Mullins PM, Bhattacharya N (2022) Prevalence of chronic pain among adults in the United States. Pain 163: e328-332.
  8. Domenichiello AF, Ramsden CE (2019) The silent epidemic of chronic pain in older adults. Prog Neuropsychopharmacol Biol Psychiatry 93: 284-290.
  9. Murray CB, de la Vega R, Murphy LK, Kashikar-Zuck S, Palermo TM (2021) The prevalence of chronic pain in young adults: a systematic review and meta-analysis. Pain 163: e972-e984.
  10. Du C, Smith A, Avalos M, South S, Crabtree K, et al. (2019) Blueberries improve pain, gait performance, and inflammation in individuals with symptomatic knee osteoarthritis. Nutrients 11: 290.
  11. Strath LJ, Jones CD, Philip George A, Lukens SL, Morrison SA, et (2019) The effect of low-carbohydrate and low-fat diets on pain in individuals with knee osteoarthritis. Pain Med 21: 150-160.
  12. Bañuls-Mirete M, Ogdie A, Guma M (2020) Micronutrients: Essential Treatment for Inflammatory Arthritis? Curr Rheumatol Rep 22: 87.
  13. Green CR, Anderson KO, Baker TA, Campbell LC, Decker S, et al. (2003) The unequal burden of pain: confronting racial and ethnic disparities in pain. Pain Med 4: 277-294.
  14. Williams DR, Mohammed SA, Leavell J, Collins C (2010) Race, socioeconomic status, and health: complexities, ongoing challenges, and research opportunities. Ann N Y Acad Sci 1186: 69-101.
  15. Marino M, Puppo F, Del Bo’ C, Vinelli V, Riso P, et al. (2021) A Systematic Review of Worldwide Consumption of Ultra-Processed Foods: Findings and Criticisms. Nutrients 13: 2778.
  16. Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D (2006) Survey of chronic pain in Europe: prevalence, impact on daily life, and Eur J Pain 10: 287-333.
  17. Fayaz A, Croft P, Langford RM, Donaldson LJ, Jones GT (2016) Prevalence of chronic pain in the UK: a systematic review and metaanalysis of population studies. BMJ Open 6: e010364.
  18. Inoue S, Kobayashi F, Nishihara M, Arai YC, Ikemoto T, et al. (2015) Chronic Pain in the Japanese Community--Prevalence, Characteristics and Impact on Quality of Life. PLoS One 10: e0129262.
  19. Allen SF, Gilbody S, Atkin K, van der Feltz-Cornelis C (2020) The associations between loneliness, social exclusion and pain in the general population: A N=502,528 cross-sectional UK Biobank study. J Psychiatr Res 130: 68-74.
  20. Yarns BC, Cassidy JT, Jimenez AM (2022) At the intersection of anger, chronic pain, and the brain: A mini-review. Neurosci Biobehav Rev 135: 104558.
  21. Kross E, Berman MG, Mischel W, Smith EE, Wager TD (2011) Social rejection shares somatosensory representations with physical pain. Proc Natl Acad Sci U S A 108: 6270-6275.
  22. Eisenberger NI (2012) The neural bases of social pain: evidence for shared representations with physical pain. Psychosom Med 74: 126
  23. Burke NN, Finn DP, McGuire BE, Roche M (2017) Psychological stress in early life as a predisposing factor for the development of chronic pain: Clinical and preclinical evidence and neurobiological J Neurosci Res 95: 1257-1270.
  24. Ji RR, Nackley A, Huh Y, Terrando N, Maixner W (2018) Neuroinflammation and Central Sensitization in Chronic and Widespread Pain. Anesthesiology 129: 343-366.
  25. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, et al. (2011) Synaptic pruning by microglia is necessary for normal brain Science 333: 1456-1458.
  26. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, et (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131: 1164-1178.
  27. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9: 46-56.
  28. DiSabato DJ, Quan N, Godbout JP (2016) Neuroinflammation: the devil is in the details. J Neurochem 139: 136-153.
  29. https://drpaulclayton.eu/blog/social-defeat/
  30. Weissbourd R, Batanova M, Lovison V, Torres E (2021) How the Pandemic Has Deepened an Epidemic of Loneliness and What We Can Do About It. Harvard Graduate School.
  31. Salomons TV, Iannetti GD, Liang M, Wood JN (2016) The “Pain Matrix” in Pain-Free Individuals. JAMA Neurol 73: 755-756.
  32. Danziger N, Faillenot I, Peyron R (2009) Can we share a pain we never felt? Neural correlates of empathy in patients with congenital insensitivity to pain. Neuron 61: 203-212.
  33. Cohen LD, Kipnis D, Kunkle EC, Kubzansky PE (1955) Observations of a person with congenital insensitivity to pain. J Abnorm Soc Psychol 51: 333-338.
  34. Johnston KJA, Adams MJ, Nicholl BI, Ward J, Strawbridge RJ, et al. (2019) Genome-wide association study of multisite chronic pain in UK PLoS Genet 15: e1008164.
  35. Johnston KJA, Ward J, Ray PR, Adams MJ, McIntosh AM, et al. (2021) Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank. PLoS Genet 17: e1009428.
  36. Bartley EJ, Fillingim RB (2013) Sex differences in pain: a brief review of clinical and experimental findings. Br J Anaesth 111: 52-58.
  37. Umeda M, Kim Y (2019) Gender Differences in the Prevalence of Chronic Pain and Leisure Time Physical Activity Among US Adults: A NHANES Study. Int J Environ Res Public Health 16: 988.
  38. Landén NX, Li D, Ståhle M (2016) Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci 73: 3861-3885.
  39. Schug SA (2021) Do NSAIDs Really Interfere with Healing after Surgery? J Clin Med 10: 2359.
  40. Parisien M, Lima LV, Dagostino C, El-Hachem N, Drury GL, et al. (2022) Acute inflammatory response via neutrophil activation protects against the development of chronic pain. Sci Transl Med 14: eabj9954.
  41. van der Gaag WH, Roelofs PD, Enthoven WT, van Tulder MW, Koes BW (2020) Non-steroidal anti-inflammatory drugs for acute low back Cochrane Database Syst Rev 4: CD013581.
  42. Enthoven WT, Roelofs PD, Deyo RA, van Tulder MW, Koes BW (2016) Non-steroidal anti-inflammatory drugs for chronic low back pain. Cochrane Database Syst Rev 2: CD012087.
  43. Seol TK, Lee W, Park S, Kim KN, Kim TY, et al. (2017) Effect of palmitoylethanolamide on inflammatory and neuropathic pain in rats. Korean J Anesthesiol 70: 561-566.
  44. Clayton P, Hill M, Bogoda N, Subah S, Venkatesh R (2021) Palmitoylethanolamide: A Natural Compound for Health Management. Int J Mol Sci 22: 5305.
  45. Impellizzeri D, Peritore AF, Cordaro M, Gugliandolo E, Siracusa R, et al. (2019) The neuroprotective effects of micronized PEA (PEA-m) formulation on diabetic peripheral neuropathy in mice. FASEB J 33: 11364-11380.
  46. Campolo M, Lanza M, Paterniti I, Filippone A, Ardizzone A, et al. (2021) PEA-OXA Mitigates Oxaliplatin-Induced Painful Neuropathy through NF-κB/Nrf-2 Axis. Int J Mol Sci 22: 3927.
  47. Hesselink JMK, Kopsky DJ (2015) Palmitoylethanolamide, a neutraceutical, in nerve compression syndromes: efficacy and safety in sciatic pain and carpal tunnel syndrome. J Pain Res 8: 729-734.
  48. Petrosino S, Cordaro M, Verde R, Moriello AS, Marcolongo G, et (2018) Oral Ultramicronized Palmitoylethanolamide: Plasma and Tissue Levels and Spinal Anti-hyperalgesic Effect. Front Pharmacol 9: 249.
  49. Genovese T, Esposito E, Mazzon E, Di Paola R, Meli R, et al. (2008) Effects of palmitoylethanolamide on signaling pathways implicated in the development of spinal cord injury. J Pharmacol Exp Ther 326: 12
  50. Mallard A, Briskey D, Richards A, Mills D, Rao A (2020) The Effect of Orally Dosed Levagen+® (palmitoylethanolamide) on Exercise Recovery in Healthy Males-A Double-Blind, Randomized, PlaceboControlled Study. Nutrients 12: 596.
  51. Greenlee-Wacker MC (2016) Clearance of apoptotic neutrophils and resolution of inflammation. Immunol Rev 273: 357-370.
  52. Rosales C (2018) Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types? Front Physiol 9: 113.
  53. Rinne P, Guillamat-Prats R, Rami M, Bindila L, Ring L, et al. (2018) Palmitoylethanolamide Promotes a Proresolving Macrophage Phenotype and Attenuates Atherosclerotic Plaque Formation. Arterioscler Thromb Vasc Biol 38: 2562-2575.
  54. De Filippis D, Luongo L, Cipriano M, Palazzo E, Cinelli MP, et al. (2011) Palmitoylethanolamide reduces granuloma-induced hyperalgesia by modulation of mast cell activation in rats. Mol Pain 7: 3.
  55. Skaper SD, Facci L, Giusti P (2014) Mast cells, glia and neuroinflammation: Partners in crime? Immunology 141: 314-327.
  56. Skaper SD, Facci L (2012) Mast cell-glia axis in neuroinflammation and therapeutic potential of the anandamide congener palmitoylethanolamide. Philos Trans R Soc Lond B Biol Sci 367: 33123325.
  1. Petrosino S, Moriello AS, Verde R, Allarà M, Imperatore R, et al. (2019) Palmitoylethanolamide counteracts substance P-induced mast cell activation in vitro by stimulating diacylglycerol lipase activity. J Neuroinflammation 16: 274.
  2. Solorzano C, Zhu C, Battista N, Astarita G, Lodola A, et al. (2009) Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in Proc Natl Acad Sci U S A 106: 20966-20971.
  3. Capasso R, Orlando P, Pagano E, Aveta T, Buono L, et al. (2014) Palmitoylethanolamide normalizes intestinal motility in a model of post-inflammatory accelerated transit: involvement of CB₁ receptors and TRPV1 channels. Br J Pharmacol 171: 4026-4037.
  4. Fotio Y, Jung KM, Palese F, Obenaus A, Tagne AM, et al. (2021) NAAA-regulated lipid signaling governs the transition from acute to chronic pain. Sci Adv 7: eabi8834.
  5. Lama A, Pirozzi C, Severi I, Morgese MG, Senzacqua M, et al. (2022) Palmitoylethanolamide dampens neuroinflammation and anxiety-like behavior in obese mice. Brain Behav Immun 102: 110-123.
  6. Ghazizadeh-Hashemi M, Ghajar A, Shalbafan M-R, GhazizadehHashemi F, Afarideh M, et al. (2018) Palmitoylethanolamide as Adjunctive Therapy in Major Depressive Disorder: A Double-Blind, 501 Randomized and Placebo-Controlled Trial. J Affect Disord 232: 127
  7. Martins GMDS, França AKTDC, Viola PCAF, Carvalho CA, Marques KDS, et al. (2022) Intake of ultra-processed foods is associated with inflammatory markers in Brazilian adolescents. Public Health Nutr 25: 591-599.
  8. Silva CA, Santos IDS, Shivappa N, Hebert JR, Crivellenti LC, et al. (2019) The role of food processing in the inflammatory potential of diet during pregnancy. Rev Saude Publica 53: 113.
  9. Mignogna C, Costanzo S, Di Castelnuovo A, Ruggiero E, Shivappa N, et al. (2022) The inflammatory potential of the diet as a link between food processing and low-grade inflammation: An analysis on 21,315 participants to the Moli-sani study. Clin Nutr 41: 2226-2234.
  10. Lagomarsino VN, Kostic AD, Chiu IM (2020) Mechanisms of microbialneuronal interactions in pain and nociception. Neurobiol Pain 9:
  11. Dworsky-Fried Z, Kerr BJ, Taylor AMW (2020) Microbes, microglia, and pain. Neurobiol Pain 7: 100045.
  12. Lin B, Wang Y, Zhang P, Yuan Y, Zhang Y, et al. (2020) Gut microbiota regulates neuropathic pain: potential mechanisms and therapeutic J Headache Pain 21: 103.
  13. Guo R, Chen LH, Xing C, Liu T (2019) Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential. Br J Anaesth 123: 637-654.
  14. Boer CG, Radjabzadeh D, Medina-Gomez C, Garmaeva S, Schiphof D, et al. (2019) Intestinal microbiome composition and its relation to joint pain and inflammation. Nat Commun 10: 4881.
  15. Minerbi A, Gonzalez E, Brereton N, Fitzcharles MA, Chevalier S, et al. (2019) Altered serum bile acid profile in fibromyalgia is associated with specific gut microbiome changes and symptom severity. Pain.
  16. Li S, Hua D, Wang Q, Yang L, Wang X, et al. (2020) The Role of Bacteria and Its Derived Metabolites in Chronic Pain and Depression: Recent Findings and Research Progress. Int J Neuropsychopharmacol 23: 26-41.
  17. Furness JB, Stebbing MJ (2018) The first brain: Species comparisons and evolutionary implications for the enteric and central nervous Neurogastroenterol Motil 30: e13234.
  18. Lee MJ, Park BY, Cho S, Kim ST, Park H, et al. (2019) Increased connectivity of pain matrix in chronic migraine: a resting-state functional MRI study. J Headache Pain 20: 29.
  19. Čeko M, Frangos E, Gracely J, Richards E, Wang B, et al. (2020) Default mode network changes in fibromyalgia patients are largely dependent on current clinical pain. Neuroimage 216: 116877.
  20. https://drpaulclayton.eu/blog/the-shadow-of-your-smile/
  21. Jahn P, Deak B, Stankewitz A, Keeser D, Griffanti L, et al. (2021) Intrinsic network activity reflects the ongoing experience of chronic Sci Rep 11: 21870.
  22. Benson S, Brinkhoff A, Lueg L, Roderigo T, Kribben A, et al. (2017) Effects of acute systemic inflammation on the interplay between sad mood and affective cognition. Transl Psychiatry 7: 1281.
  23. Muscatell KA, Dedovic K, Slavich GM, Jarcho MR, Breen EC, et (2015) Greater amygdala activity and dorsomedial prefrontalamygdala coupling are associated with enhanced inflammatory responses to stress. Brain Behav Immun 43: 46-53.
  24. Inagaki TK, Muscatell KA, Irwin MR, Cole SW, Eisenberger NI (2012) Inflammation selectively enhances amygdala activity to socially threatening images. Neuroimage 59: 3222-3226.
  25. Muscatell KA, Moieni M, Inagaki TK, Dutcher JM, Jevtic I, et al. (2016) Exposure to an inflammatory challenge enhances neural sensitivity to negative and positive social feedback. Brain Behav Immun 57: 21-29.
  1. Maydych V (2019) The Interplay Between Stress, Inflammation, and Emotional Attention: Relevance for Depression. Front. Neurosci 13:
  2. Hadamitzky M, Lückemann L, Pacheco-López G, Schedlowski M (2020) Pavlovian conditioning of immunological and neuroendocrine Physiol Rev 100: 357-405.
  3. Ramírez-Amaya V, Alvarez-Borda B, Bermúdez-Rattoni F (1998) Differential effects of NMDA-induced lesions into the insular cortex and amygdala on the acquisition and evocation of conditioned Brain Behav Immun 12: 149-160.
  4. Skljarevski V, Zhang S, Iyengar S, D’Souza D, Alaka K, et al. (2011) Efficacy of Duloxetine in Patients with Chronic Pain Conditions. Curr Drug Ther 6: 296-303.
  5. Choi HS, Park JH, Ahn JH, Hong S, Cho JH, et al. (2015) The antiinflammatory activity of duloxetine, a serotonin/norepinephrine reuptake inhibitor, prevents kainic acid-induced hippocampal neuronal death in mice. J Neurol Sci 358: 390-397.
  6. Park JA, Lee CH (2018) Neuroprotective Effect of Duloxetine on Chronic Cerebral Hypoperfusion-Induced Hippocampal Neuronal Biomol Ther (Seoul) 26: 115-120.
  7. Pickering E, Steels EL, Steadman KJ, Rao A, Vitetta L (2022) A randomized controlled trial assessing the safety and efficacy of palmitoylethanolamide for treating diabetic-related peripheral neuropathic pain. Inflammopharmacology.
  8. Steels E, Venkatesh R, Steels E, Vitetta G, Vitetta L (2019) A double-blind randomized placebo controlled study assessing safety, tolerability and efficacy of palmitoylethanolamide for symptoms of knee osteoarthritis. Inflammopharmacology 27: 475-485.
  9. Briskey D, Ebelt P, Steels E, Subah S, Bogoda N, et al. (2022) Efficacy of Palmitoylethanolamide (Levagen+TM) Compared to Ibuprofen for Reducing Headache Pain Severity and Duration in Healthy Adults: A Double-Blind, Randomized Clinical Trial. Food & Nut Sci 13: 690-701.
  10. Briskey D, Roche G, Rao A (2021) The Effect of a Dispersible Palmitoylethanolamide (Levagen+) Compared to a Placebo for Reducing Joint Pain in an Adult Population – A Randomised, DoubleBlind Study. Int J Nut Food Sci 10: 9-13.
  11. Fessler SN, Liu L, Chang Y, Yip T, Johnston CS (2022) Palmitoylethanolamide Reduces Proinflammatory Markers in Unvaccinated Adults Recently Diagnosed with COVID-19: A Randomized Controlled Trial. J Nutr 152: 2218-2226.
  12. Zambrana-Infantes E, Rosell Del Valle C, Ladrón de Guevara-Miranda D, Galeano P, Castilla-Ortega E, et al. (2018) Palmitoylethanolamide attenuates cocaine-induced behavioral sensitization and conditioned place preference in mice. Pharmacol Biochem Behav 166: 1-12.
  13. https://clinicaltrials.gov/ct2/show/NCT05317676
  14. Petrosino S, Schiano Moriello A (2020) Palmitoylethanolamide: A Nutritional Approach to Keep Neuroinflammation within Physiological Boundaries-A Systematic Review. Int J Mol Sci 21: 9526.
  15. Rao A, Ebelt P, Mallard A, Briskey D (2021) Palmitoylethanolamide for sleep disturbance. A double-blind, randomised, placebo-controlled interventional study. Sleep Sci Pract 5: 12.
  16. De Gregorio D, Manchia M, Carpiniello B, Valtorta F, Nobile M, et al. (2019) Role of palmitoylethanolamide (PEA) in depression: Translational evidence: Special Section on “Translational and Neuroscience Studies in Affective Disorders”. J Affect Disord 255: S0165-0327(18)31599-4.
  17. Briskey D, Mallard AR, Rao A (2020) Increased Absorption of Palmitoylethanolamide Using a Novel Dispersion Technology System (LipiSperse®). J Nutr Food Sci 5: 3.

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Chronic Pain & Management