Central sensitization and visceral hypersensitivity: Facts and fictions

A timely and well-focused review by Farmer and Aziz [1] in this issue of the Scandinavian Journal of Pain draws attention to the relative contribution of peripheral and central mechanisms to the so-called “Functional Gastro-Intestinal Disorders” (FGID) [2]. These are diseases whose main, and sometimes only, symptom is pain hypersensitivity not explained by structural or biochemical abnormalities. As such, these disorders are part of a larger group of pain conditions, both somatic and visceral, whose pathophysiology is obscure and which are believed – and the key word is belief – to be the result of CNS hyperexcitability generated by central sensitization.

It may seem presumptuous to start this commentary by reminding a Scandinavian audience that Vikings never wore horned helmets. This most enduring icon – who does not think of horned helmets when hearing the word Viking? – is a historical fabrication, a product of XIXth century romanticism, invented by the imaginative producers of Wagnerian operas who added this cumbersome and useless appendix to the Norsemen’s theatrical costumes [3]. Yet, it stuck firmly in everyone’s mind to the point that horned helmets and Vikings have become inseparable. But just because something is repeated many times it does not make it true. Which brings us to the relationship between pain hypersensitivity and central sensitization.

In their comprehensive review, Farmer and Aziz [1] describe the pathways that carry sensory signals from the internal organs to the brain and discuss the key molecular protagonists of this traffic. They attribute the visceral pain caused by acute and chronic inflammation to the well-documented sensitization of peripheral nociceptors and suggest that peripheral factors may also be responsible for the pain of FGIDs. They identify some new potential players in the physiopathology of FGIDs, like alterations of the microbiota ecosystem – an essential element of GI function – or disorders of the connective tissue or of the smooth muscle of the gut. They also call attention to genetic factors that may determine pain sensitivity and to the well known fact that many sufferers of FGIDs show psychological comorbidity and personality disorders. Their review leaves us with the feeling that if we look carefully we can always find a peripheral drive for the pain hypersensitivity of FGIDs and that most forms of visceral pain – or of somatic pain for that matter – are the consequence of a peripheral injury, an inflammatory process or a tissue alteration.

Yet, the prevailing belief is that unexplained pain is due to CNS hypersensitivity caused by “central sensitization”, an interpretation that lacks direct experimental or clinical evidence. The excuse for such explanation is that it gives comfort to the patients, by reassuring them that they have a real disease and that they are not making their symptoms up. This approach has been criticized as spurious diagnostic authority [4] because it misleads the patients, may generate inadequate therapies and prevents further investigations.

Central sensitization is a concept that has become very vague [5] and that means very different things to basic scientists and to clinicians. From a basic science point of view, central sensitization is a synaptic and cellular process shown by some neurons as a result of intense or persistent peripheral input. Interestingly, central sensitization of putative nociceptive neurons has always been shown as a consequence of intense peripheral stimulation, i.e. always driven by a peripheral input. It is likely that central sensitization is an expression of a general process of synaptic plasticity, not uniquely or immediately related to pain processing [5]. Such processes are essential components of the CNS mechanisms of memory, learning and reward. In animal experiments central sensitization is often documented as an increased activity of motor reflexes in the spinal cord, yet we know that motor and sensory processes can be dissociated and that pain perception involves many complex CNS circuits beyond a simple motor or sensory relay in the spinal cord [6].

It is impossible to translate the relationship between pain hypersensitivity and CNS hyperexcitability – as well as any supporting data – from animal experiments to the human pain experience. We can measure the increased excitability of CNS neurons in animal preparations but we cannot tell what contribution these neurons make to the pain experience of the intact animal. On the other hand, we can assess an increased pain sensitivity in a patient but we cannot be certain that it is due, and only due, to the enhanced synaptic excitability of the patient’s CNS neurons. The failure in clinical trials of putative analgesic compounds that were developed because of their strong profile as inhibitors of central sensitization in animal experiments – the best example are NK1 antagonists [7] – is a decisive proof of the disconnect between the clinical and the basic science concepts of central sensitization.

In addition, clinical data does not always support that pain hypersensitivity is a consequence of CNS hyperexcitability [8]. For instance, well-documented studies show that not all patients with chronic pain show generalized pain hypersensitivity [9]. Also, it has been reported that there is no correlation between pain hypersensitivity and the time course of chronic pain, which makes it difficult to use hypersensitivity as an outcome predictor of chronic pain [10]. Even the idea of pre-emptive analgesia for post-surgical pain, which was one of the first derivatives of the expected relationship between CNS hyperexcitability and pain hypersensitivity, has been substantially revised because the evidence for the beneficial effects of pre-emptive analgesia was controversial [11].

Farmer and Aziz [1] draw attention to potential peripheral factors in the pathophysiology of FGIDs, including alterations in the microbiota ecosystem and disorders of the connective tissue or of the smooth muscle. This opens the debate as to whether central sensitization is always driven by peripheral inputs and therefore a natural consequence of an enhanced sensory drive. But in addition to a peripheral generator, there are also potential pathophysiological mechanisms for pain hypersensitivity that do not require a hyperexcitable CNS. Hormonal imbalances [12], structural brain alterations [13] and genetic and cognitive factors are known to play an important role in the generation of chronic pain states. It is appropriate to point out that other functional pain disorders that were thought to be the consequence of pure CNS hyperexcitability – for instance fibromyalgia – are now being reinterpreted as the evidence accumulates in favour of disturbances of the peripheral nervous system [14,15]. It is likely that as more evidence is gathered and these new interpretations develop we will see an increasing role of peripheral drives and structural alterations in the generation of chronic pain states.

We should always question prevailing dogmas, examine the strength of the evidence and not take for granted what looks like a handy explanation just because it has been said many times. It is the only way to make progress in the understanding of complex pain disorders and, as a bonus, it is also a good way to find out that Vikings never wore horned helmets.