Home Medicine CNS–mechanisms contribute to chronification of pain
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CNS–mechanisms contribute to chronification of pain

  • Harald Breivik EMAIL logo , Audun Stubhaug and Stephen Butler
Published/Copyright: April 1, 2017
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Scandinavian Journal of Pain
From the journal Scandinavian Journal of Pain Volume 15 Issue 1

In this issue of the Scandinavian Journal of Pain, Per Brodal, professor of neurobiology at the Institute of Basic Medical Sciences, University of Oslo, Norway, publishes a topical review of how our central nervous system (CNS) handles sensory impulses from the peripheral nervous system [1]. Per Brodal is highly qualified to write such a review: he is the author of the outstanding textbook The Central Nervous System, now in its 5th Edition [2].

1 What is pain?

The IASP definition of pain from 1994:

“An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”

Amanda C. de C. Williams and Kenneth D. Craig recently proposed a new definition, mainly because they feel it is necessary to emphasize the psychosocial aspects of the experience of pain [3]:

“Pain is a distressing experience associated with actual or potential tissue damage with sensory, emotional, cognitive, and social components.”

Per Brodal emphasizes that.. .”pain is a sensation, an experience, and common with other sensations, e.g. itching, it has a bodily location”. Pain felt in an arthritic knee joint exists only when the person experiences it. The MRI image of the knee joint can give the observer an impression of a badly pathological knee, but the person imaged can be pain-free.

The burden of suffering caused by a pain condition depends critically on how the person or patient perceives the situation that brought on the pain experience and the perceived disruption of their life due to the pain. This is why Amanda Williams and Kenneth Craig want to emphasize the cognitive and psychosocial aspects of the pain experience [3].

Nociceptors are sensors that can identify tissue injury, a noxious event, can send impulses via peripheral nerves, rapidly through Adelta, and more slowly via C-fibres, to the CNS, where appropriate reactions occur to motivate the body/person to react to maintain homeostasis. A pain experience can be initiated by processes that are still not an actual tissue injury, but homeostasis is disturbed and there is potential tissue damage. Per Brodal therefore proposes to use homeoceptors for such sensors that can initiate a CNS-process when homeostasis is being disturbed, a process that eventually leads to a pain experience [1].

2 A salience network in our brain monitors and reacts to homeostatic disturbances that can be potential tissue-injury

A pain network in CNS with interconnected nodes (the anterior cingular gyrus, the insula, the second somatosensory area, and the thalamus) is active when a person feels pain, see Fig. 1 in Per Brodal’s article [1,4,5]. By “node” Brodal means a locus that potentially connects to a variety of other brain structures. But this network can be activated by non-painful stimuli. Depending on the importance for homeostasis, this salience network is there to enable the person to react appropriately and optimally to a stimulus from several possible different modalities. Because a pain stimulus, at least from an acute pain evoking tissue injury, normally is a highly salient alarm signal, this network may most often serve and react to impulses from sensors that detect early changes that can develop to a tissue injury [1].

3 A sensitive pain network insures that all harmful events are detected and reacted to appropriately.

Per Brodal emphasises the wise arrangement with a very sensitive sensor system that rapidly reacts to any potential tissue injury so that homeostasis is protected and well preserved. However, it is conceivable that such a sensitive, even hypersensitive, system can be overloaded by false alarms, malfunctions and causes pain experiences when no tissue damage has happened, or it keeps reacting to impulses that are not initiated by potential tissue damage [1]. This could explain how a patient can experience pain where the medical doctor or nurse cannot find any tissue damage, i.e. the patient will be diagnosed with having a pain condition without any obvious somatic cause, referred to as primary pain, or even “functional pain”, almost implying malingering. This can also be the case when aggravating a minor pain condition can provoke severe pain.

4 Pain and pleasure – our two most powerful teachers of behaviour

From a young age, we rapidly learn to avoid painful and potentially pain-provoking situations. This is life-protecting knowledge. However, this can be overdone; the patient can develop “fear-avoidance”, avoiding behaviours that they feel may be damaging. The patient may stop using an injured limb, something that makes sense immediately after an injury or after surgery [6], and even a few weeks after a fractured wrist or ankle. However, when this continues long after the injury has healed completely, then all the negative effects of a passive, inactive limb, will appear. Eventually the patient develops a neglect-like phenomenon; the inactive limb loses the normal sensorimotor signalling between CNS and muscles and joints in the limb. The patient will gradually feel that this painful and useless limb does not belong to the patient; the patient neglects the limb: “That foot does not belong to me anymore”. This is similar to what hemiplegic post-stroke patients experience.

This behaviour is typical of an injury where appropriate teaching about reactivation is neglected and, in extreme cases, gradually leading to disuse atrophy of muscles, contractures of joints, painful allodynia to touch and to cold. This produces a painful, useless limb with the symptoms and signs of Complex Regional Pain Syndrome (CRPS) [7]. In a young patient, this is a sad and tragic sight, and fate. This is a difficult-to-treat pain condition.

Effective prevention and treatment are so simple: Inform, motivate, instruct to activate the patient – early on it is not so difficult but delays make it more difficult. Fortunately, this situation is very rare but once it develops, most frequently in young people, treatment becomes complicated. This is an example of what Brodal calls “network locking” [1].

5 Pain-prone personality? Or personality coloured by pain?

Why is there such a very wide difference in pain sensitivity and pain tolerance between persons of the same ethnicity and living in apparently similar conditions? Christopher S. Nielsen documented in his twin-studies how genes determine about 50% of sensitivity to pain [8]. This means that there is a lot the health care providers can do to motivate patients who appear to be on the slippery road to chronic pain [8].

It is therefore not difficult to imagine that our complex pain modulating, pain experience regulating mechanisms can vary tremendously between persons, leaving some of us at higher risk of CNS network malfunctioning, or at least having such highly sensitive sensors and salience networks that the normal pain hypersensitive state after surgery or injury [6] does not return to the pre-operative/preinjury state but keeps on accepting and reacting to peripheral innocuous stimuli (= false alarms) as if they are real tissue-injury-signals. This creates a persistent pain experience, Brodal’s “network locking” [1].

And an ongoing, never ending, persistent pain experience is highly stressful, causing all the well-known somatic, mental, psychosocial and economic miseries of a chronic pain state.

6 The role of peripheral input in maintenance of chronic pain

The debate on the importance of peripheral input is far from settled. Recently Harutinian and colleagues in Aarhus, Denmark, documented how a peripheral nerve block can relieve chronic neuropathic pain [9]. It is a pity they did not cite one of the important research reports published in PAIN 27 years ago [10]. The famous “Karolinska Pain Troika”, Staffan Arnér, Bjørn Meyerson, Ulf Lindblom published an observational study in 1990 documenting that peripheral blocks with a local anaesthetic could relieve chronic pain [10]. Not only that, but after repeated blocks, the relief could last for a considerable, and for the patient with chronic pain, clinically meaningful time. Pat Wall’s editorial comment to their paper was supportive and he recommended strongly “more research on peripheral nerve blocks for chronic pain” [11].

7 Is there hope for prevention of persistent pain?

Some time ago we thought that we could predict who is at higher risk of developing persistent postsurgical pain (PPP) by looking for certain risk factors [12]. By taking extra care of patients with risk factors when they have to undergo an elective operation, such as treating their pain optimally during and after surgery as well as continuing to give such patients continued pain relief after discharge from the hospital, and by bringing them to the chronic pain clinic early on, rather than waiting till they have developed a difficult to treat PPP [1213, 14-15]. The results have not been too encouraging to date and we need to learn much more about the phenomenon of “network locking” [1]. No doubt, there is more we all can do here and, hopefully further research will show the way.

8 Conclusions

The eminently experienced brain neurobiologist, Professor Per Brodal, in this topical review of pain modulating systems in our CNS, has increased our knowledge and understanding of these fantastically complex [1] neurobiological systems that regulate our pain experiences. He points out that nociception and pain optimally function as the most important salience stimulus in the homeostatic systems in the CNS. However, the system can “go awry” and understanding that phenomenon is difficult [1]. We are beginning to understand why some persons are more prone to develope persistent pain than others are. In due time we should be able to take advantage of this deeper knowledge and take better care of those who are at higher risk of developing persistent pain, rather than trying to relieve it once persistent pain has fastened its claws in our sensitive CNS.

DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2017.03.001.

Department of Pain Management and Research, Oslo University Hospital, Box 4956, Nydalen, 0424 Oslo, Norway. Fax: +47 23073690.

  1. Conflicts of interest: None declared

References

[1] Brodal P. A neurobiologist’s attempt to understand persistent pain. Scand J Pain 2017;15:140–7.Search in Google Scholar

[2] Brodal P. The central nervous system(t). 5th ed. New York: Oxford University Press; 2016.Search in Google Scholar

[3] Williams ADeC, Craig KD. Updating the definition of pain. Pain 2016;157:2420–3.Search in Google Scholar

[4] Butler S. Important new insight in pain and pain-treatment induced changes in functional connectivity between the Pain Matrix and the Salience-, Central Executive-, and Sensorimotor-networks. Scand J Pain 2017;16:64–5.Search in Google Scholar

[5] Kolesar TA, Bilevicius E, Kornelsen J. Salience, central executive, and sensorimotor network functional connectivity alterations in failed back surgery syndrome. Scand J Pain 2017;15:10–4.Search in Google Scholar

[6] Stubhaug A, Breivik H, Eide PK, Kreunen M, Foss A. Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiol Scand 1997;41:1124–32.Search in Google Scholar

[7] Breivik H. Compolex Regional Pain Syndrome (CRPS): high risk of CRPS after trauma in another limb in patients who already have CRPS in one hand or foot: lasting changes in neural pain modulating systems. Scand J Pain 2017;14:82–3.Search in Google Scholar

[8] Nielsen CS, Stubhaug A, Price DD, Vassend O, Czajkowski N, Harris JR. Individual differences in pain sensitivity: genetic and environmental contributions. Pain 2008;136:21–9.Search in Google Scholar

[9] Haroutounian S, Nikolajsen L, Bendtsen TF, Finnerup NB, Kristensen AD, Hasselstrøm JB, Jensen TS. Primary afferent input critical for maintaining spontaneous pain in peripheral neuropathy. Pain 2014;155:1272–9.Search in Google Scholar

[10] Arnér S, Lindblom U, Meyerson BA, Molander C. Prolonged relief of neuralgia after regional anesthetic blocks. A call for further experimental and systematic clinical studies. Pain 1990;43:287–97.Search in Google Scholar

[11] Wall P. Neuropathic pain. Pain 1990;43:267–8.Search in Google Scholar

[12] Breivik H. Persistent post-surgical pain (PPP) reduced by high-quality management of acute pain extended to sub-acute pain at home. Scand J Pain 2014;5:237–9.Search in Google Scholar

[13] Tiippana E, Nelskylä K, Nilsson E, Sihvo E, Kataja M, Kalso E. Managing post-thoracotomy pain: epidural or systemic analgesia and extended care – a randomized study with an as usual control group. Scand J Pain 2014;5:240–7.Search in Google Scholar

[14] Tiippana E, Hamunen K, Heiskanen T, Nieminen T, Kalso E, Kontinen VK. New approach for treatment of prolonged postoperative pain: APS Out-Patient Clinic. Scand J Pain 2016;12:19–24, http://dx.doi.org/10.1016/j.sjpain.2016.02.008.Search in Google Scholar

[15] Jensen TS, Stubhaug A, Breivik H. Important development: extended acute pain service for patients at high risk of chronic pain after surgery. Scand J Pain 2016;12:58–9.Search in Google Scholar
Published Online: 2017-04-01
Published in Print: 2017-04-01

© 2017 Scandinavian Association for the Study of Pain

Articles in the same Issue

  2. Scandinavian Journal of Pain
  3. Editorial comment
  4. Cardiovascular risk reduction as a population strategy for preventing pain?
  5. Observational study
  6. Diabetes mellitus and hyperlipidaemia as risk factors for frequent pain in the back, neck and/or shoulders/arms among adults in Stockholm 2006 to 2010 – Results from the Stockholm Public Health Cohort
  7. Editorial comment
  8. Exercising non-painful muscles can induce hypoalgesia in individuals with chronic pain
  9. Clinical pain research
  10. Exercise induced hypoalgesia is elicited by isometric, but not aerobic exercise in individuals with chronic whiplash associated disorders
  11. Editorial comment
  12. Education of nurses and medical doctors is a sine qua non for improving pain management of hospitalized patients, but not enough
  13. Observational study
  14. Acute pain in the emergency department: Effect of an educational intervention
  15. Editorial comment
  16. Home training in sensorimotor discrimination reduces pain in complex regional pain syndrome (CRPS)
  17. Original experimental
  18. Pain reduction due to novel sensory-motor training in Complex Regional Pain Syndrome I – A pilot study
  19. Editorial comment
  20. How can pain management be improved in hospitalized patients?
  21. Original experimental
  22. Pain and pain management in hospitalized patients before and after an intervention
  23. Editorial comment
  24. Is musculoskeletal pain associated with work engagement?
  25. Clinical pain research
  26. Relationship of musculoskeletal pain and well-being at work – Does pain matter?
  27. Editorial comment
  28. Preoperative quantitative sensory testing (QST) predicting postoperative pain: Image or mirage?
  29. Systematic review
  30. Are preoperative experimental pain assessments correlated with clinical pain outcomes after surgery? A systematic review
  31. Editorial comment
  32. A possible biomarker of low back pain: 18F-FDeoxyGlucose uptake in PETscan and CT of the spinal cord
  33. Observational study
  34. Detection of nociceptive-related metabolic activity in the spinal cord of low back pain patients using 18F-FDG PET/CT
  35. Editorial comment
  36. Patients’ subjective acute pain rating scales (VAS, NRS) are fine; more elaborate evaluations needed for chronic pain, especially in the elderly and demented patients
  37. Clinical pain research
  38. How do medical students use and understand pain rating scales?
  39. Editorial comment
  40. Opioids and the gut; not only constipation and laxatives
  41. Observational study
  42. Healthcare resource use and costs of opioid-induced constipation among non-cancer and cancer patients on opioid therapy: A nationwide register-based cohort study in Denmark
  43. Editorial comment
  44. Relief of phantom limb pain using mirror therapy: A bit more optimism from retrospective analysis of two studies
  45. Clinical pain research
  46. Trajectory of phantom limb pain relief using mirror therapy: Retrospective analysis of two studies
  47. Editorial comment
  48. Qualitative pain research emphasizes that patients need true information and physicians and nurses need more knowledge of complex regional pain syndrome (CRPS)
  49. Clinical pain research
  50. Adolescents’ experience of complex persistent pain
  51. Editorial comment
  52. New knowledge reduces risk of damage to spinal cord from spinal haematoma after epidural- or spinal-analgesia and from spinal cord stimulator leads
  53. Review
  54. Neuraxial blocks and spinal haematoma: Review of 166 case reports published 1994–2015. Part 1: Demographics and risk-factors
  55. Review
  56. Neuraxial blocks and spinal haematoma: Review of 166 cases published 1994 – 2015. Part 2: diagnosis, treatment, and outcome
  57. Editorial comment
  58. CNS–mechanisms contribute to chronification of pain
  59. Topical review
  60. A neurobiologist’s attempt to understand persistent pain
  61. Editorial Comment
  62. The triumvirate of co-morbid chronic pain, depression, and cognitive impairment: Attacking this “chicken-and-egg” in novel ways
  63. Observational study
  64. Pain and major depressive disorder: Associations with cognitive impairment as measured by the THINC-integrated tool (THINC-it)
https://doi.org/10.1016/j.sjpain.2017.03.002

Articles in the same Issue

  2. Scandinavian Journal of Pain
  3. Editorial comment
  4. Cardiovascular risk reduction as a population strategy for preventing pain?
  5. Observational study
  6. Diabetes mellitus and hyperlipidaemia as risk factors for frequent pain in the back, neck and/or shoulders/arms among adults in Stockholm 2006 to 2010 – Results from the Stockholm Public Health Cohort
  7. Editorial comment
  8. Exercising non-painful muscles can induce hypoalgesia in individuals with chronic pain
  9. Clinical pain research
  10. Exercise induced hypoalgesia is elicited by isometric, but not aerobic exercise in individuals with chronic whiplash associated disorders
  11. Editorial comment
  12. Education of nurses and medical doctors is a sine qua non for improving pain management of hospitalized patients, but not enough
  13. Observational study
  14. Acute pain in the emergency department: Effect of an educational intervention
  15. Editorial comment
  16. Home training in sensorimotor discrimination reduces pain in complex regional pain syndrome (CRPS)
  17. Original experimental
  18. Pain reduction due to novel sensory-motor training in Complex Regional Pain Syndrome I – A pilot study
  19. Editorial comment
  20. How can pain management be improved in hospitalized patients?
  21. Original experimental
  22. Pain and pain management in hospitalized patients before and after an intervention
  23. Editorial comment
  24. Is musculoskeletal pain associated with work engagement?
  25. Clinical pain research
  26. Relationship of musculoskeletal pain and well-being at work – Does pain matter?
  27. Editorial comment
  28. Preoperative quantitative sensory testing (QST) predicting postoperative pain: Image or mirage?
  29. Systematic review
  30. Are preoperative experimental pain assessments correlated with clinical pain outcomes after surgery? A systematic review
  31. Editorial comment
  32. A possible biomarker of low back pain: 18F-FDeoxyGlucose uptake in PETscan and CT of the spinal cord
  33. Observational study
  34. Detection of nociceptive-related metabolic activity in the spinal cord of low back pain patients using 18F-FDG PET/CT
  35. Editorial comment
  36. Patients’ subjective acute pain rating scales (VAS, NRS) are fine; more elaborate evaluations needed for chronic pain, especially in the elderly and demented patients
  37. Clinical pain research
  38. How do medical students use and understand pain rating scales?
  39. Editorial comment
  40. Opioids and the gut; not only constipation and laxatives
  41. Observational study
  42. Healthcare resource use and costs of opioid-induced constipation among non-cancer and cancer patients on opioid therapy: A nationwide register-based cohort study in Denmark
  43. Editorial comment
  44. Relief of phantom limb pain using mirror therapy: A bit more optimism from retrospective analysis of two studies
  45. Clinical pain research
  46. Trajectory of phantom limb pain relief using mirror therapy: Retrospective analysis of two studies
  47. Editorial comment
  48. Qualitative pain research emphasizes that patients need true information and physicians and nurses need more knowledge of complex regional pain syndrome (CRPS)
  49. Clinical pain research
  50. Adolescents’ experience of complex persistent pain
  51. Editorial comment
  52. New knowledge reduces risk of damage to spinal cord from spinal haematoma after epidural- or spinal-analgesia and from spinal cord stimulator leads
  53. Review
  54. Neuraxial blocks and spinal haematoma: Review of 166 case reports published 1994–2015. Part 1: Demographics and risk-factors
  55. Review
  56. Neuraxial blocks and spinal haematoma: Review of 166 cases published 1994 – 2015. Part 2: diagnosis, treatment, and outcome
  57. Editorial comment
  58. CNS–mechanisms contribute to chronification of pain
  59. Topical review
  60. A neurobiologist’s attempt to understand persistent pain
  61. Editorial Comment
  62. The triumvirate of co-morbid chronic pain, depression, and cognitive impairment: Attacking this “chicken-and-egg” in novel ways
  63. Observational study
  64. Pain and major depressive disorder: Associations with cognitive impairment as measured by the THINC-integrated tool (THINC-it)
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