Pain and inflammation are related: systemic inflammation may lead to a variety of pain states, and, in turn, persistent pain causes an upward adjustment of proinflammatory mediators that sometimes elicit a prolonged low-grade immune response, leading to long-lasting, subclinical inflammation.
The cytokines that are produced during inflammatory responses are the main stimulators of the production of acute-phase proteins, specifically C-reactive protein (CRP).
C-reactive protein is a nonspecific systemic marker of infection, inflammation, tissue damage, malignancy, and autoimmune disease.
In addition, CRP has a physiological role in inflammatory homeostasis maintenance.
As an acute-phase reactant, CRP is synthesized very rapidly and achieves very high levels in conditions with acute inflammatory response.
High levels of CRP are associated with the induction of interleukin (IL)-10 and perhaps IL-1RA, which have immediate anti-inflammatory effects.
However, in various conditions with low-grade inflammation, such as obesity, coronary heart disease, and depression, subclinical levels of CRP may activate the complement system and the induction in monocytes of proinflammatory cytokines, such as IL-1β, IL-6, and tumor necrosis factor alpha, having the opposite effect of acute-phase levels of CRP.
New insights into the role of low-level CRP elevation as a biomarker of various diseases in clinical practice have turned the research focus towards determining CRP levels in otherwise healthy individuals.
Although CRP and IL-6 are biomarkers of pain in conditions linked to low-grade inflammation, the association between inflammatory mediators and pain appears to be ambiguous:
not all persons experience pain in the presence of inflammation, and the occurrence and severity of pain are associated with changes in both proinflammatory and anti-inflammatory cytokines.
Increased experimental pain sensitivity (hyperalgesia) has been found in a number of chronic pain conditions.
Compared with healthy subjects, patients with chronic pain have lower pain thresholds, reduced pain tolerance, and report higher pain ratings when tested with standardized experimental pain stimuli.
These findings also hold true when experimental pain stimuli are delivered to body areas that are remote from the location of clinical pain.
Furthermore, generalized hyperalgesia appears to be particularly pronounced in widespread pain conditions, possibly because of inflammatory impact on brain circuits involved in descending pain inhibition, rendering individuals more sensitive.
we hypothesized that the following causal paths connecting subclinical inflammation, hyperalgesia, and chronic pain are possible:
(inflammation → hyperalgesia → chronic pain) or (inflammation → chronic pain → hyperalgesia), adjusted for all relevant confounders.
One possible scenario is therefore that subclinical inflammation leads to hyperalgesia, independent of the chronic pain condition itself.
The aim of this study was to examine whether increases in severity of subclinical inflammation, measured by hs-CRP, are related to increased experimental pain sensitivity, measured by cold-pressor tolerance, and to test whether this relationship is independent of the report of having chronic pain
I’ve only included excerpts talking about the meaning of what was found and you’ll have to check the full article to see more about the specific results.
Additionally, a post hoc analysis was performed in the study population without chronic pain. In this analysis, the relationship between hs-CRP levels and cold-pressor tolerance remained statistically significant (HR = 1.22, 95% confidence interval, 1.08-1.36, P = 0.001), which confirms that the relationship between subclinical inflammation and cold-pressor tolerance is independent of the presence of chronic pain.
the relationship between hs-CRP levels and experimental pain is independent of chronic pain, and independent of a number of possible confounding factors that are associated with both pain and inflammation (eg, sex, obesity, and depression
Taken together, these 2 studies provide strong evidence that there is a link between pain sensitivity and inflammation which is independent of chronic pain and of obvious confounders.
High-sensitivity C-reactive protein and cold-pressor tolerance
The relationship between hs-CRP levels, divided into Low, Average, Slightly elevated, and High hs-CRP groups,
We observed an overall negative relationship between hs-CRP levels and cold-pressor tolerance.
Taking into consideration the different possible causal paths connecting subclinical inflammation, hyperalgesia, and chronic pain, the model (inflammation → chronic pain → hyperalgesia) is not consistent with our findings.
With regard to the relationship between hyperalgesia and chronic pain, the cross-sectional association is well documented in both clinical and epidemiological studies
Several lines of evidence suggest that pain sensitivity may be of importance for the development of clinical pain.
Particularly, persons with increased pain sensitivity may experience higher levels of acute postoperative pain and may have increased risk of chronic pain development
However, the longitudinal evidence for the relationship between hyperalgesia and chronic pain is not conclusive, and large cohort studies are needed to elucidate the hypothesis that hyperalgesia leads to chronic pain.
Widespread hyperalgesia (ie, hyperalgesia across body sites) is commonly thought to be a result of altered central nervous processing. However, this is not necessarily true.
If hyperalgesia is a secondary effect of systemic inflammation, these effects could reflect sensitization of primary afferents.
The CPT induces pain by activating perivenous nociceptors, resulting in a deep aching pain.
The stimulus also produces a marked increase in blood pressure, through sympathetic activation and vasoconstriction
Acute hypertension is, in turn, known to elicit pain inhibition through a mechanism known as blood pressure–mediated hypoalgesia. This is possibly the reason why the CPT is particularly efficient in conditioned pain modulation paradigms, where a tonic stimulus (eg, cold pressor) reduces pain in a subsequent brief phasic stimulus (eg, heat stimulus)
This characteristic of the CPT suggests that the level of pain elicited will depend both on primary afferent drive and on later pain-modulating mechanisms. Moreover, because the hemodynamic response takes some time to develop, one would expect the level of pain inhibition to be of increasing importance at later stages of the stimulus
This is consistent with the typical stimulus–response function in our sample, in which pain intensity follows growth to limit function, reaching maximum levels around 60 seconds or so.
In fact, some subjects experience a decrease in pain towards the end of the stimulus
This analysis shows decreasing hs-CRP with increasing pain tolerance also in the early phase of the stimulus, which suggests that association may be related to primary afferent drive
Therefore, sensitization of primary afferents due to low-grade peripheral inflammation should be considered as a putative mechanism.
In addition to the main finding, this study showed lower pain tolerance among
- participants with low education level,
- current and former smokers, and
- participants with emotional distress and current statins usage.
Our study confirms and extends this finding, demonstrating that even former smoking was associated with lower pain tolerance
Current statin usage, according to our data, is associated with lower pain tolerance.
There was no significant relationship of age, BMI, or alcohol intake with cold-pressor tolerance.