Neurobiological basis for pain vulnerability

Neurobiological basis for pain vulnerability: why me? – Franziska Denk; Stephen McMahon – Apr 2017


A great deal of mechanistic work conducted in pain research is concerned with answering the question of why a certain stimulus should be perceived as painful or how the nervous system in a chronic pain state differs from the healthy norm.

In these kinds of studies, individual differences in perception are usually seen as a nuisancea distraction from any “real signal.”

Yet, these differences are very significant to the individuals, even if they aren’t near the average. These”distractions”

And indeed, there is a large amount of noise to contend with: pain experiences are extremely variable, both in health and disease.

In the following, we are going to make this variability the focus of our review. We will outline the evidence for its existence, discuss the various biological mechanisms that might underpin it, and finally, deliberate on potential implications such variability might have for the concept of personalised medicine.

Pain experience is variable

I cannot stress this enough: everyone’s pain is different and findings applicable to one kind of pain may be utterly ineffective for others.

Like many biological phenomena, pain perception differs widely between individuals, be they humans,59,61 rats,76 or mice55,56 (Fig. 1).

Pain is a subjective experience that can be reported upon by an individual, but cannot yet be measured objectively in that person.

This subjectivity is likely to be the result of a variety of factors, many of which are unrelated to differences in pain perception per se.

For instance, a person’s mental or motivational state on the day of testing can introduce variation, as can their level of attention.

Nonetheless, quantitative measures reveal a degree of spread in pain responsiveness that suggests underlying biological differences in nociception itself.

For instance, the normal range for heat pain thresholds encompasses anything from 35 to 50°C, whereas mechanical pain thresholds range from almost 0 to 250 mN.

This is in contrast to nonpainful measures that are just as sensitive to state variance, but have much tighter population distributions; for instance, warmth and mechanical detection thresholds have 95% confidence intervals of 33 to 36°C and a few milli-Newtons, respectively.

The same variability can be observed in a clinical context, where pain and pathology are often only weakly correlated.

The field of arthritis provides some good examples of this. The degree of osteoarthritis in a joint is quantified with the help of X-rays, which are scored according to the so-called Kellgren/Lawrence scale (K/L).

  • A score of 0 indicates that the X-ray ostensibly looks normal, whereas a
  • score of 4 indicates a maximum degree of bone erosion and damage.

Clearly, a degree of correlation exists between the amount of damage and the degree pain experienced, but it is surprisingly weak.

  • Some patients with a K/L of 0 still experience pain, with mean visual analogue scale (VAS) scores of 36 ± 30 in one study.5
  • Conversely, patients who have minor to no pain can still have visible signs of osteoarthritis according to K/L, eg, in that same study, people with VAS scores of less than 10 had an average K/L score of 1.49.

These surprisingly weak or even absent correlations between levels of pain and the different pathological features of osteoarthritis have been identified time and again.

Finally, resolution of pathology does not always go hand in hand with cessation of pain.

Perhaps the most recent striking illustration of this is the dawning realisation that while anti–tumour necrosis factor α treatment can provide an almost magical cure for the inflammatory symptoms of rheumatoid arthritis, it frequently does not eliminate the pain that patients experience.

What mechanisms underlie our divergent pain perceptions and varying vulnerability for pathological or long-lasting pain?

On a macrolevel, individual differences have to be either driven by genetic or environmental factors.

Other thoughts?

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