The interactions between cutaneous and deep pain

In the present issue of the Scandinavian Journal of Pain Silvia Lo Vecchio and co-workers in Thomas Graven-Nielsen’s and Lars Arendt-Nielsen’s research group publish an investigation that studied the relations between cutaneous and deep pain in healthy volunteers [1]. Skin inflammation was induced by ultraviolet irradiation (UV); different measurements of cutaneous and deep pain were made, both at the site of inflammation and at surrounding areas. After UV-induced inflammation, all pain thresholds were reduced compared to baseline. This suggested that the UV-induced inflammation led to hyperalgesia at both non-inflamed cutaneous areas and deep tissues, likely the muscles.

The relations between inflammation at one tissue and hyperalgesia at other tissues or body sites have clinical relevance. Clinicians are frequently confronted with the observation that a painful lesion is associated with hyperalgesia at distant body areas. Those who are little familiar with pain physiology may be confused by these observations. However, spread of pain and hyperalgesia to other tissues and body sites has been extensively investigated in pre-clinical models. These studies have revealed profound changes in central nociceptive pathways that can be responsible for this phenomenon. Changes include (but are not limited to) increase in neuronal connections within the spinal cord [2], reduction in endogenous inhibitory control [3], release of sensitizing mediators in the spinal cord [4] and widespread central sensitization via humoral mechanisms [5].

Experimental studies using quantitative sensory tests have been invaluable tools to investigate spreading hyperalgesia in humans [6]. The research group that performed this study [1] has already provided substantial work in describing the patterns of referred pain with different human experimental models [7]. Spread of hyperalgesia has been confirmed by electro physiological studies that assessed the size of reflex receptive fields in patients [8]. Hyperalgesia caneven spread to the contralateral side, as shown for instance in a study on unilateral epicondylalgia [9]. Interestingly, a pilot study found positive correlations between concentration of locally released inflammatory cytokines and the size of reflex receptive fields in endometriosis patients [10]. This confirms the potential importance of inflammatory processes in the determination of generalized hyperalgesia.

These works, together with other ones in the field, have shed light on clinical phenomena that had been poorly understood. They are giving clinicians tools to better understand their patients, and patients the possibility to better understand their symptoms.

Lo Vecchio et al. [1] found that skin inflammation induced by UV facilitated deep pain, as assessed by pressure stimulation. This finding is relevant and provides experimental support for clinical observations of deep tissue hyperalgesia in different inflammatory conditions. Clinicians should be aware of the fact that hyperalgesia at non injured tissues is common and can be explained, at least in part, by changes in central nociceptive pathways. Interestingly, this phenomenon can be observed also in acute pain models, like the one presented in this study, and in healthy volunteers. This challenges the common belief that spread of pain and hyperalgesia occurs only in chronic pain.

One limitation of the study is the lack of a control condition. Therefore, it cannot be ruled out that the observed changes in the thresholds are not specifically the result of the induced inflammation of the skin.

An additional important question is whether muscle hyper-algesia can become independent of the primary source of nociception: can hyperalgesia and spontaneous pain persist after resolution of the primary site of inflammation? This is an essential question that has been only marginally addressed in human research. Again, experimental models of human pain are invaluable tools to study such issues. For instance, in a previous study, experimental muscle pain was induced by injecting hypertonic saline; lidocaine subsequently injected into the same muscle substantially reduced the local and referred pain in a majority of subjects [11]. This suggested that the referred pain and hyperalgesia depended on the presence of a nociceptive stimulus arising from the muscle where the hypertonic saline had been injected. However, a later study using nerve growth factor (NGF) instead of hypertonic saline came to another conclusion: muscle pain and spreading hyperalgesia induced by NGF was maintained despite subsequent anaesthesia of the primary nociceptive locus [12]. This different finding may be the result of the use of NGF, which, unlike hypertonic saline, induces central sensitization that might persist even after blocking the neural pathways arising from the primary nociceptive source [13].

In line with this research, the study by Lo Vecchio et al. [1] added a second experiment to address the question whether local anaesthesia of the skin would lead to attenuation of spreading hyperalgesia. Topical anaesthesia of the inflamed skin was performed in 5 subjects. An increase only in pin-prick thresholds outside the irradiated area was observed. I believe that the administration 24h after inflammation is a strength and not a limitation of the study; inclinical conditions it is frequently impossible to predict the time of injury and treatment are performed after inflammation has already taken place. The results provide some evidence that, at least with this model, blocking the primary painful stimulus may reduce spread of hyperalgesia. However, the study with only 5 participants was likely underpowered for this question and the results have to be taken with caution.

In summary, the study by Lo Vecchio et al. [1] has shown that localized inflammation may lead to deep tissue hyperalgesia, adding knowledge on our current understanding of the manifestations of inflammatory pain syndromes. The result has to be confirmed by studies that include a control condition. Furthermore, modulation of deep hyperalgesia by interventions applied at the primary site of inflammation remains an important field of future research.