Re-wiring the brain and chronic pain

Pain is a deceptively simple experience. If you hit your thumb with a hammer you feel instant pain, which peaks rapidly and then gradually resolves over a few days as the damaged tissues repair themselves.


In theory a painful crisis is just the same; the conventional wisdom is that the flow of blood inside the blood vessels within bones is blocked by sickled red cells, the tissues downstream are starved of blood and oxygen, and the resulting tissue death leads to an acute inflammatory response and severe pain. In the normal course of events, the pain resolves over a period of a week to ten days as the damage caused by the lack of oxygen is made good.

Of course, this is a gross over-simplification in so many ways. For example, the perception of pain, what you actually feel, is altered by many different factors. The classic example is of soldiers in the midst of battle, who may suffer horrific injuries but report feeling no pain until they are well away from the scene of the fighting. The stress and excitement of battle seems to be able, temporarily, to switch off pain sensation. Many other factors act in the opposite direction and will heighten pain experiences, including sleep deprivation, depression, lack of control, fear and many others. Clearly, what goes on in the brain is able to dramatically alter how we feel and respond to pain.


Pain messages are transmitted from the damaged area to the brain via nerve fibres in the spinal cord. The brain not only modifies our perception of pain but can also block or reduce upwards transmission of pain impulses via descending, modulatory pathways in the spinal cord. This is the so called “gate mechanism”.; the brain is able to control how wide or narrow the pain gate is.

One of the important ways in which pain perception is modified is known as central sensitisation. In this condition the pain circuits in the brain are fundamentally altered, usually in response to repeated, severe, poorly controlled pain experiences. Central sensitisation affects different people in different ways, but all have in common the fact that more pain is felt over longer periods of time. The pain may be experienced more intensely (hyperalgesia) or sensations which are not normally painful may be experienced as pain (allodynia); the area over which pain is felt may expand way beyond the damaged area or painful sensations may continue long after the initial cause of the pain has resolved.

Graph illustrating the concepts of hyperalgesia and allodynia

This graph illustrates the concepts of hyperalgesia and allodynia. In the normal course of events, as the intensity of the pain stimulus increases the pain experienced also increases (blue line). No surprise there!  However, repeated painful experiences, can result in central sensitisation which shifts the graph to the left (red line). The perception of pain is heightened at all levels of pain stimulus and non-painful sensations are now experienced as pain. 

Maybe as many as a one third of patients with sickle cell disease are said to have “chronic pain”; pain is experienced on a more or less continuous basis, with little if any pain free periods. It has always been difficult to understand this in terms of the simplistic notions of a painful crisis discussed above, but it is looking increasingly likely that the explanation lies in the concept of central sensitisation. When you think about it, patients with sickle cell disease are a high risk group for this complication of pain; they experience repeated episodes of severe pain throughout life and the pain is often poorly managed and ineffectively controlled. In a proportion of patients, this results in changes in pain wiring in the brain, which alters the disease from a condition characterised by intermittent episodes of pain, with long pain free intervals in-between, to one where the experience of pain is virtually continuous.

Some of the best evidence for this view comes from patients whose sickle cell has been “cured” by a successful bone marrow transplant, or where the disease activity has been effectively suppressed by regular automated exchange transfusions. In both circumstances, patients may, paradoxically, continue to experience severe pain, often requiring treatment with powerful, opiate pain killers, a situation which can persist for several years. Re-setting of the aberrant wiring in the brain, and neutralisation of the central sensitisation, eventually leads to a gradual cessation of these pain experiences.

The importance of central sensitisation, as a process which significantly adds to the misery of life for some people with sickle cell, has been highlighted in a study from John Hopkins Medical College, which is due to be published shortly in the Journal of Pain. The researchers studied 83 adult patients with sickle cell disease, testing their responses to a standard heat pain stimulus in a variety of different contexts. The subjects were then given a variety of psychological questionnaires to complete and kept a daily pain and sleep diary for the next 18 months.

From the results of the pain experiments the researchers identified two sub-groups; one, a group of 21 individuals, who scored high for central sensitisation markers and another, of 17 individuals, who had low scores. When the two groups were compared the patients with high scores for central sensitisation experienced more frequent crises and had more pain in-between crisis days, as a result they also had more contact with hospitals and doctors. Psychologically, they had an increased tendency to catastrophise, in other words they always assumed the worst was going to happen, and they had profound disturbances of sleep.

None of this may seem particularly surprising but, in terms of quality of life, it indicates that central sensitisation is a very damaging condition and demonstrates, importantly, that it is a major factor driving patients to seek repeated medical help. The authors make the point that addressing the underlying problem either by preventing the development of central sensitisation in the first place, by providing effective, rapid pain relief at all times, or diagnosing and treating the established condition, should be key therapeutic aims. Short circuiting central sensitisation would go a long way to improve the quality of life of a subset of sickle cell patients and potentially save the health service significant amounts of money. A win win situation!

An evaluation of central sensitization in patients with sickle cell disease. C C Campbell, G Moscou-Jackson, P Carroll, K Kiley, C Haywood, S Lanzkrom, M Hand, R R Edwards & J A Haythornthwaite. Journal of Pain (accepted for publication) DOI: 10.1016/j.pain.2016.01.475

For more on chronic pain see:

Cannabis, sickle cell and new concepts in chronic pain: 15th October 2015

Chronic pain conference: 14th and 17th December 2014


About rogerjamos

I am a consultant haematologist who has worked in Hackney, London, UK with patients who have sickle cell disease for many years. Knowledge is power; the hope is that this blog will empower patients by putting them in touch with contemporary research into sickle cell disease and facilitating informed discussion on the issues raised. Dr Roger Amos MA, MD, FRCPath
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