Rights of Man

Although access to pain management is considered a fundamental human right (ie 1), safe and effective pain management is still, for many, an aspiration. In the United States over one in four adults suffers from chronic pain (2), largely because the drugs used to treat pain are so imperfect. The NSAID’s are linked to well-known GI and cardio problems (3), and following the public health crisis caused by the Sacklers’ unscrupulous marketing of opioids, many doctors now deliberately under-treat pain (4). 

Has life always been so painful? (5)

Actually, no. The prevalence of chronic pain has increased significantly during the last two decades in adults (6, 7).

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% (8), 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? Almost certainly, yes. 

In pre-clinical models, ultra-processed high fat foods make sensory nerves malfunction (9, 10); and this appears to reflect the human condition. 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 (11-13), and those with lower socioeconomic status (14, 15), which is linked to poorer diet (16, 17). 

If you look at global patterns of ultra-processed food consumption (18), 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 (19). The British and Japanese also consume less ultra-processed food than Americans, yet their recorded chronic pain figures appear to be somewhat higher (20, 21).

The fact that the data are not particularly coherent, however, 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, nociplastic and nociceptive, which is largely inflammatory), 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 (ie 22). It is a bi-directional relationship. Chronic pain is stressful and may reduce opportunities for social interaction. Social pain (loneliness, social defeat, anger) tends to exacerbate physical pain, especially nociplastic pain (22, 23), probably by activating a shared neural network known as the pain matrix (23-25). 

The pain matrix is sensitized by early life trauma (26) and amplified by neuroinflammation (27), which is affected by multiple lifestyle factors.

Transient low-level neuroinflammation is ‘normal’ and entirely positive. It is involved in immune surveillance and signalling, together with aspects of brain development, memory and learning (28, 29), and at higher levels 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 behaviours including loss of appetite, lethargy, apathy, demotivation, reduced activity and reduced sociability (30). It also drives depression, brain ageing and neurodegenerative disease (31, 32). (31) 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 (31, 32). Progressive damage to our social networks and repeated social defeat will add to those numbers (33, 34). 

There are rare individuals with genetic factors that leave them unable to feel pain (35). I wondered if those individuals might also be immune to solitude and social defeat (25, 26), but this appears not to be the case (36). We are more complex than that (37) … 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 (37- 39). 

Incidentally, the two UK Biobank studies (38, 39) 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 (ie 40, 41).

An increasingly pained society provides a healthy market for painkillers, but this is not a healthy response. Those drugs are well known to cause health issues, and now we are beginning to understand that they may actually be counter-productive.

Pain, inflammation, the immune system, the microbiome, nutrition and healing are all intimately connected. Inflammation following injury is an essential part of the process of tissue remodeling and repair (42), and there is some evidence that if drugs are used to suppress inflammation after injury, healing is slowed (43). New research suggests that inflammation also re-sets local neural networks so that the acute pain of injury fades as the wound resolves; and anti-inflammatory drugs may disrupt this too. 

A research team out of McGill University (44) 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. In line with these findings, two different 2022 RSNA reports found that long-term use of either NSAID’s (45) or steroids (46) worsened inflammation and tissue damage in clinical arthritis.

This may be why the Cochrane Collaboration finds that the NSAID’s are only marginally effective in the management of acute (47) pain, and barely effective at all in chronic (48) pain. Overall, therefore, the case for anti-inflammatory analgesics 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 (49). It is effective in many models of neuropathic pain including surgical (50), diabetic (51) chemotherapeutic (52), and compression (53), and in nociceptive (inflammatory) pain also (49). 

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 (55). 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 (ie 56).

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 (57). There appear to be multiple sub-types of neutrophil which are induced and/or transformed in different tissues as and when required (58).

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 (59), which dying neutrophils also do (57); and to prevent mast cell degranulation by blocking Substance P (60, 66-68), a neuropeptide produced by tissue damage which modulates pain perception. PEA also reduces (pre-clinical) neuroinflammation and anxiety (ie 61), and depression (62).   

The above data suggest that PEA synthesis might be considered as a component in the cell danger response, and that PEA may act within the pain matrix, perhaps via glial modification (68, 69), as well as at the site of injury. Maybe it’s more than an autacoid …

How does all of 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 (ie when we were still eating a pre-transitional diet), presumably the right amount of the right neutrophils were engaged and an appropriate amount of PEA was formed.

The industrial, pro-inflammatory diet likely skews cellular and autacoidal responses to injury (ie 64, 65), increasing the chances of progressing to chronic inflammation and pain – which is what the epidemiology shows is happening (6-8). But that 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 (70-75); (70 is particularly good). The enteric nervous system probably evolved before the CNS (76), 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 graduate from acute to chronic pain, and suffer from depression (77).

Chronic pain appears to lead to increased connectivity in the pain matrix (78) via a learning or kindling effect which may well be exacerbated by neuroinflammation (27). The pain matrix communicates with the default network, which is functionally altered during the experience of pain, may be structurally altered by chronic pain (79) and is also degraded by the modern diet (78). 

Chronic pain also affects the salience network (80), 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 (21, 22).

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 (80-86), driving isolation, depression, anxiety (83-86) and immune dysfunction (87, 88) in a descending spiral. As corporations continue to brainwash us we become more predisposed to believe in sugar pills (89) and the many sugar-coated lies our governments tell us.

How can we reverse this?

The pain matrix appears to be down-regulated by ‘antidepressant’ drugs such as duloxetine (90), which has some ability to reduce neuroinflammation (91, 92) and relieves physical pain more rapidly and more effectively than it does mental distress. Duloxetine’s withdrawal effects, however, are vicious. 

A better and more sustainable solution is better nutrition, social renewal and the reimagining of Thom Paine’s democratic republic. In an age of hypernormalisation and spavined political correctness, an antidote from the house of Paine: “He who dares not offend cannot be honest” (93).

• An amended version of this post was published as a scientific paper. ‘Is chronic pain a disease of civilisation?’ Clayton P. Chron Pain Manag 6: 146. (2022)

Next week: The theory of medical evolution. How evolved is your doctor?

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