Acute pain and development of chronic pain

Differentiating acute and chronic pain

Compared to acute pain with its distinct warning and protective function, chronic pain has lost its direct relationship to the triggering event and has become a disease in its own right.

  • Acute pain (such as that following trauma or surgery, burns pain, headache, pain of trigeminal neuralgia, pain of major cardiac events, colic pain) often signals tissue damage and serves a protective function.

Pain can however persist long after its usefulness as an alarm system and after tissue damage has healed.

  • Chronic pain can be subdivided into chronic cancer and chronic non-cancer pain.

Such chronic pain is probably not directly related to initial injury or disease but is secondary to physiological changes in pain signalling and detection.1,2

(1)
Woolf CJ, Costigan M. Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci U S A. 1999;96:7723-30.
(2)
Woolf CJ, Max MB. Mechanism-based pain diagnosis: issues for analgesic drug development. Anesthesiology. 2001;95:241-9.

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Importance of early and effective treatment of pain

Chronic pain - a special therapeutic challenge

Poorly managed acute pain can lead to chronic pain states.
If pain is not treated adequately at an early stage, it often becomes more difficult to treat.

Pain lasting longer than 6 months is a burden for the patient and is not to be underestimated; it represents a special therapeutic challenge for the physician.

Chronic pain, a history of pain-associated surgeries and low social support are negative predictors for treatment outcome1.

Over time, chronic pain leads to morphological changes in the central nervous system2,3.

A number of mechanisms are involved in the sensitisation of pain:

  • Peripheral and central sensitisation
  • Endogenous pain modulation
  • Inflammation
(1)
Schulte E, Hermann K, Berghöfer A, et al. Referral practices in patients suffering from non-malignant chronic pain. Eur J Pain. 2010;14(3):308.e1-308.e10.
(2)
Tracey I, Bushnell MC. How neuroimaging studies have challenged us to rethink: is chronic pain a disease? J Pain. 2009;10:1113-20.
(3)
Apkarian AV, Sosa Y, Sonty S, et al. Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J Neurosci. 2004;24(46):10410-10415.

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Peripheral sensitisation – increased response at nociceptor level

Increased stimulation of first afferent neuron

During peripheral sensitisation1-4:

  • Nerve fibres react to damaging influences by producing action potentials which are transmitted to the central nervous system.
  • Release of inflammatory mediators activates “silentneurons and sensitizes the nociceptors.
  • The afferent C fibres react to the stimulus by peripherally releasing neuropeptides → neurogenic inflammation.
  • H+ plays a role in the inflammatory response

Sensitisation, activation of silent neurons and neurogenic inflammation amplify the effects of nociceptive stimuli.

A tangible results is, for example, hyperalgesia, i.e. painful stimuli are perceived more intensely. Allodynia, i.e. normally non-painful stimuli, such as pressure stimuli, are experienced as pain.

(1)
Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1-32.
(2)
Latremoliere A, Woolf CJ. Central sensitisation: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009 ;10:895-926.
(3)
Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765-8.
(4)
Woolf CJ; American College of Physicians; American Physiological Society. Pain: moving from symptom control toward mechanism-specific pharmacological management. Ann Intern Med. 2004;140:441-51.

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Central sensitisation – increased neuron excitability in the CNS

Increased spontaneous activity and stimulus response

Persistently, painful stimuli cause excessive excitation of spinal and supraspinal neurons (central sensitisation).1-3

  • Activation of the NMDA-receptors and plastic changes in the central neurons play a significant role in this central sensitisation
  • Excitatory neurotransmitters (e.g. glutamate, substance P, neurokinin A or CGRP) stimulate the dorsal horn neurons
  • Repeated pain stimuli activate the NMDA receptors (“wind-up”), which induce prolonged postsynaptic action potentials
  • Activation of the NMDA receptors raises intracellular Ca++, which is responsible for the expression of immediate early genes (e.g. c-fos and c-jun) leading to increased protein synthesis
  • Because of the associated rise in receptor density, neuronal sensitivity is also increased

These sensitisation processes increase the spontaneous activity and stimulus responses of the central neurons.

(1)
Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1-32.
(2)
Latremoliere A, Woolf CJ. Central sensitisation: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009 ;10:895-926.
(3)
Woolf CJ; American College of Physicians; American Physiological Society. Pain: moving from symptom control toward mechanism-specific pharmacological management. Ann Intern Med. 2004;140:441-51.

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The process of endogenous pain modulation

Modulation of pain

The μ-opioid receptor system and the monoaminergic system are highly relevant in the modulation of pain. Both play a key role in ascending and descending pain pathways.

μ-opioid receptor system
μ-opioid receptor agonists influence and directly inhibit the transmission of pain signals via the ascending pathway. In addition, μ-opioid receptor agonists are also involved in the modulation of pain signals on a supraspinal level with modulating impact on the descending pathways.

Monoaminergic systems
Key players of the monoaminergic systems are noradrenaline (NA) and serotonin (5-HT):

  • NA is involved in mediating descending inhibitory pain control (descending inhibition)
  • 5-HT can mediate either pain inhibitory or facilitatory responses (descending inhibition, facilitation), i.e. it can be either antinociceptive or pronociceptive
  • 5-HT is also associated with pro-emetic effects.
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Modulation in acute and chronic pain

Relative contribution in pain modulation

In acute nociceptive pain, pain modulation is to a large extend regulated by the opioidergic system (A).

In chronic pain (often associated with neuropathic components) modulations to the opiodergic system can lead to a reduction of opioid responsiveness (e.g. analgesic tolerance and/or opioid-induced hyperalgesia).1,2

A reduced activity of the opioidergic system means that the relative contribution of the two pain inhibiting systems changes towards the monoaminergic system (B), with noradrenaline mediated pain inhibition being of particular relevance.3

(1)
JC Ballantyne, JM Mao. Medical Progress. Opioid therapy for chronic pain. N Engl J Med (2003) 349,20:1943 - 1953.
(2)
DT Joo. Mechanisms of opioid tolerance: emerging evidence and therapeutic implications. Can J Anesth (2007)54,12:969 - 976.
(3)
ME Lynch. Antidepressants as analgesics: a review of randomized controlled trials. J Psychiatry Neurosci (2001) 26,1:30 - 36.

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Quick check

Identify the characteristics of acute pain. Please chose the correct statement:
Acute pain is not related to initial injury or disease
Acute pain constitutes a signal to a conscious brain about the presence of noxious stimuli and/or ongoing tissue damage
Acute pain is a disease on its own right
Acute pain is associated with the emergence of a complex set of physical and psychological changes
Please, select the correct statement
Peripheral sensitisation involves spinal and supra-spinal mechanisms of stimulus intensification
In chronification of pain, central sensitisation plays only a marginal role
Genetic and iatrogenic factors may also play a role in chronification of pain
The term sensitisation means the development of a smaller response to a stimulus on repeated contact
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Congratulations

Thank you for participating in the third basic module “Chronification of pain”. We hope you enjoyed it. The PAIN EDUCATION platform provides more eModules concerning pain therapy. If you like to, please continue with these eModules and check your knowledge.
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