Key clinical highlights
- Sensitisation may play a role in the underlying pathophysiology of nociceptive, neuropathic and mixed pain.1,2
- Sensitisation can occur at the level of peripheral nerves and dorsal root ganglion (peripheral sensitisation), and in the spinal cord, descending pain pathways and brain (central sensitisation).2
- During sensitisation, a reduction in the activation threshold of neurons can result in an exaggerated pain and altered sensitivity response including altered sensations.1,3,4
- Diagnosis and understanding of the mechanisms underlying a patient’s pain are crucial when developing management strategies.5
- Sensory alterations such as allodynia and hyperalgesia may be useful surrogate markers of sensitisation.6
What is sensitisation?
Sensitisation can play a role in the pathophysiology of both nociceptive pain and neuropathic pain (Figure 1).1,2
In nociception, sensitisation typically develops as a consequence of tissue damage and inflammation.1
Inflammatory mediators activate intracellular signal transduction pathways in nociceptor terminals. This increases the production, transport, and membrane insertion of transducer channels and voltage-gated ion channels.4
This is caused by a reduction in activation threshold and an increase in the magnitude of response to a noxious stimulus. As a result, nociceptors become increasingly sensitive to painful stimuli.1
Sensitisation in neuropathic pain
The pathophysiology of neuropathic pain may involve the peripheral and central nervous systems.
Peripheral sensitisation involves changes in the excitability of peripheral nerves or dorsal root ganglion.2
Some patients with peripheral nerve lesions develop reduced thermal and mechanical pain thresholds. This may reflect peripheral nociceptor sensitisation, resulting from increased membrane excitability without inflammation.4
Central sensitisation involves changes in the spinal cord neurons, the descending pain controlling pathway and the brain.2
Central sensitisation resembles activity-dependent synaptic plasticity in the cortex with involvement of various synaptic modulators and excitatory amino acids, changes in ion channel activity and properties, increased density of ionotropic receptors, and the activation of pre- and post-synaptic kinases.4
In both cases, the threshold for generating pain signals is reduced and the duration, amplitude and spatial distribution of the pain increases.3,4
Clinical significance of sensitisation
Sensitisation can affect the way in which subsequent noxious and non-noxious stimuli are perceived – noxious stimuli can elicit a greater pain response (hyperalgesia), and non-noxious stimuli may be interpreted as pain (allodynia; Figure 2).6
Central and peripheral sensitisation may contribute to some of the symptoms associated with neuropathic pain as outlined in Table 1.6
Implications for pain diagnosis and management
Obtaining a correct diagnosis through identifying the type and origin of a patient’s pain and instituting appropriate early management is crucial as it may improve health outcomes.5
The changes that occur in the nervous system as a result of nerve injury or disease can be profound. The manner in which this affects a patient’s experience of pain is poorly understood at present. However, the aim of clinical examination remains to correctly identify the type of pain the patient is experiencing – nociceptive, neuropathic or mixed pain.5
By analogy, if pain were a fire alarm, nociceptive pain would be activated appropriately only by the presence of fire, high temperatures would activate inflammatory pain, and pathological pain would be a false alarm caused by malfunction of the system itself.3
Allodynia and hyperalgesia may be useful surrogate markers of sensitisation.6 Table 2 briefly describes some sensory tests, which may be of use when performing a physical examination to determine the presence of positive and negative signs of neuropathic pain.2
Currently, clinical diagnostic tests are limited. For example quantitative sensory testing can quantify positive and negative signs associated with neuropathic pain. However it is time-consuming and is only available in a few centres.2
- Gold MS & Gebhart GF. Nat Med. 2010; 16: 1248-1257.
- Magrinelli F, et al. Pract Neurol. 2013; 13: 292–307.
- Woolf CJ. J Clin Invest. 2010; 120: 3742-3744.
- Costigan M, et al. Annu Rev Neurosci. 2009; 32: 1-32.
- Haanpää ML, et al. Am J Med. 2009; 122 (10 Suppl): S13-21.
- Woolf CJ & Mannion RJ. Lancet. 1999; 353: 1959-1964.
- Gottschalk A, Smith DS. Am Fam Physician. 2001; 63: 1979-1984.
- Neurology Expert Group. Therapeutic Guidelines: Neurology, 2011 Version 3. Melbourne: Therapeutic Guidelines Limited; 2011.