Can we measure the relative contributions of peripheral and central mechanisms of painful conditions, and how can it guide therapy?

In this issue of the Scandinavian Journal of Pain, Dagfinn Matre and Stein Knardahl publish an interesting study on how clinical pain intensity in neck and shoulder patients and concomitant “secondary hyperalgesia” or area of static mechanical hyperalgesia around a skin burn, varied within and between patients [1]. All 27 patients were sedentary workers with neck/shoulder pain that varied between days. They all had pain at least 2–3 days/week, but an important inclusion criterium was the variation in pain intensity; the subjects had to experience pain-free days. The authors wanted to test whether “central sensitization” measured as the area of secondary hyperalgesia around a skin burn would vary within individuals between the painful and the less painful days. Therefore, all subjects were tested twice. The authors were quite successful in finding days with different levels of clinical pain in the subjects, with a mean VAS score of 1.7 and 4.3 on weak pain days and strong pain days respectively. However, they found no difference between painful and less painful days for the main outcome; the area of secondary hyperalgesia around a burn injury on the forearmes. They interpret their main findings as an indication that variation in nociceptive input from the periphery may be the most likely explanation for the between-days variation in clinical neck/shoulder pain in the present study.

Studying peripheral and central components of pain is highly relevant. A better understanding is needed for guiding therapy and research. During the last years the importance of central nervous mechanisms for several different pain conditions, previously thought of as peripherally driven only, has been highlighted [2,3,4,5]. Central sensitization is one important such mechanism. The concept was introduced by Clifford Woolf in 1983 when he described how a thermal injury to the paw of an animal induced segmental plastic changes in the spinal cord [6]. This would explain reduced thresholds, increased receptive fields, and augmented synaptic output [6].

The task force for taxonomy of the International Association for the Study of Pain (IASP) define “central sensitization” as “an enhanced responsiveness of nociceptive neurons in the CNS to their normal afferent input”.

An important question is whether there are individuals with a higher risk for developing central sensitization than others, and if so, whether these subjects have an increased risk for developing conditions with a general pain hypersensitivity. Some interesting findings on genetics of sensory function are emerging [7]

Moreover, studies of shoulder impingement syndrome found that patients with hypersensitivity in the area of pain or referred pain had a poorer outcome after surgery [8].

Learning the mechanisms of central sensitization offered new targets for novel analgesics. Drugs that do not effectively stop a noxious stimulus (nociceptive pain) but instead normalize a hypersensitive pain system are important tools. Drugs like ketamine, some antidepressants, alfa-2-agonists, and anticonvulsants such as gabapentin and pregabalin, reduce central sensitization. We also need clinical tools to identify patients where central sensitization is a major treatment target.

The burn injury model used by the Matre and Knardahl tested the sensitization around a burn injury remote from the painful location. The results may have been different if the same stimulus was applied in the field of pain distribution. Other less painful methods than the burn injury are needed for use in the clinic. Despite the negative findings of the present study, the search for a better understanding of the peripheral versus the central nervous contributions to pain conditions should continue. That will eventually help us choosing the correct treatment for each individual patient.