Central Sensitisation / Sensitization

Original Editor - Nathan Benson as part of the PPA Pain Project.

Top Contributors - Alberto Bertaggia, Nathan Benson, Laura Ritchie, Jo Etherton and Michelle Lee

Central Sensitisation

Nociception is described by IASP as the neural process of encoding noxious stimuli. Central sensitisation describes the circumstances in which there is an enhancement of the function of neurons involved in nociception [1] resulting in

  1. hypersensitivity to stimuli[2],
  2. responsiveness to non-noxious stimuli[3]
  3. and an increased pain response evoked by stimuli outside the area of injury, an expanded receptive field[4].

The International Association for the Study of Pain (IASP) describes central sensitization as


“Increased responsiveness of nociceptive neurons in the central nervous system to their
normal or subthreshold afferent input.”[3]


Neural plasticity plays a role in cellular changes with a demonstrable increase in both membrane excitability and synaptic efficacy. The effect of this process is the recruitment of additional, sub-threshold synaptic inputs to nociception resulting in a greater field of receptivity and an increased output of nociception.The effects of this process may persist beyond the duration of the initial noxious input resulting in pain hypersensitivity to normally innocuous stimuli.


It is also thought to play a role in affecting pain facilitation and inhibition; inhibiting descending pathways[5] and over-activation of the ascending, pain facilitatory pathways[6]. Which, simplifed, means too many messages going in and not enough coming out.

The use of the term "central sensitisation" varies sometimes referring solely to the neural plastic changes only and sometimes to the the complex and multiple processes and systems which contribute to changes in the elicitation and perception of pain[7][8][9]. A discussion about the various descriptions and defintion s can be found on the Body in MInd website. The term was first used in a study of pain hypersensitivity in rats following repeated noxious stimuli to describe the use dependant neural plasticity demonstrated[10][7]. These central changes due to peripheral noxious stimuli have been referred to as "activity-dependant central sensitisation"[2].

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Activity Dependent Central sensitization

Latremoliere and Woolf describe the changes demonstrated in their group's 1983 study as "activity dependent central sensitization". This describes the mechanism of functional synaptic plasticity evoked by in the dorsal horn neurons by input from nociceptors [2]. They found to invoke sensitization the noxious stimuli had to be sustained, intense and repeated.  The changes can be divided into two, time dependent phases: an early, short duration phase which is phosphorylation-dependant/transcription-independent, and a longer lasting transcription-dependant phase[11].

Activation of the NMDA receptor is an essential step in initiating and maintaining the sensitization (N-Methyl-D-Aspartate is a glutamate receptor. Glutamate is a widespread excitatory neurotransmitter in aht enwevious system). Under normal circumstances this receptor channel is blocked by Mg2+ ions[12]. Sustained release by nociceptors of glutamate, substance P and CGRP leads to membrane de-polarization, forcing the Mg2+ from the NMDA receptor[12]. This rapidly boosts synaptic efficacy and allows Ca2+ in to the neuron, activating intracellular pathways and maintaining central sensitization[2].

Central vs Peripheral Sensitization

While descriptively central sensitization and Peripheral sensitisation may appear to be comparable processes, they represent quite distinct and processes and clinical features[2].


Peripheral sensitisation is described by the IASP as


"Increased responsiveness and reduced threshold of nociceptive neurons in the periphery to
the stimulation of their receptive fields.
"[13] 


 

It is initiated when the peripheral terminus of nociceptors are exposed to noxious stimulus, for example inflammatory mediators in damaged tissue. On going stimulation results in a lowering of the activation threshold and thus and increase in responsiveness of nociceptors [14].

As a result of this  it generally requires on going  peripheral pathology for the sensitization to be maintained and is generally localised to the site of injury[14]. It has a role in altered heat sensation, but not in mechanical sensitivity[2].

In the process of central sensitisation novel inputs are recruited to the nociceptive pathways such as large, low-threshold mechanoreceptors classified as Aß fibres. This results in hypersensitivity in non-inflamed tissue and to touch.
 

[15]
[16]

Features of Central Sensitization

A survey of expert clinicians in a Delphi-derived survey found the following characteristics to describe central sensitisation in the clinical setting [1].

Subjective features

  • Disproportionate, non-mechanical, unpredictable pattern of pain provocation in response to multiple/non-specific aggravating/easing factors.
  • Pain persisting beyond expected tissue healing/pathological recovery times.
  • Pain disproportionate to the nature and extent of injury or pathology.
  • Widespread, non-anatomical distribution of pain.
  • History of failed interventions (medical/surgical/therapeutic).
  • Strong association with maladaptive psychosocial factors (e.g. negative emotions, poor self-efficacy, maladaptive beliefs, and pain behaviours, altered family/work/social life, medical conflict).
  • Unresponsive to NSAIDs and/or more responsive to anti-epileptic (e.g. Lyrica) /anti-depressants (e.g. Amitriptyline) medication.
  • Reports of spontaneous (i.e. stimulus independent) pain and/or paroxysmal pain (i.e. sudden recurrences and intensification of pain).
  • Pain in association with high levels of functional disability.
  • More constant/unremitting pain.
  • Night pain/disturbed sleep.
  • Pain in association with other dysesthesias (e.g. burning, coldness, crawling).
  • Hyperpathia or pain of high severity and irritability (i.e. easily provoked, taking a long time to settle).


Clinical features

  • Disproportionate, inconsistent, non-mechanical/non-anatomical pattern of pain provocation in response to movement/mechanical testing.
  • Positive findings of hyperalgesia (primary, secondary) and/or allodynia and/or hyperpathia within the distribution of pain.
  • Diffuse/non-anatomical areas of pain/tenderness on palpation.
  • Positive identification of various psychosocial factors (e.g. catastrophisation, fear-avoidance behaviour, distress).

Identification in the Clinical Setting

In 2009 Schäfer et al.[17] proposed a classification of low back-related leg pain using an examination protocol which incorporates first the subjective assessment, including the Leeds Assessment of Neuropathic Symptoms and Sign (LANSS) scale [18], and second the physical examination (neurological examination, assessment of active movements, neural tissue provocation tests). Based on this comprehensive assessment, a LANSS score ≥ 12 is indicative of central sensitization in their classification algorithm.

In 2010 Nijs et al.[19] provided guidelines to aid the recognition of central sensitization on musculoskeletal patients.

In their paper, they suggest that a patient's medical diagnosis can offer insight into the likelihood of the presence of central sensitization (fig 1) and this in conjunction with observable features (fig 2) can inform the therapist as to the presence of central sensitization.


fig 1. Table of Medical diagnoses likely to suggest presence of central sensitization reproduced from Nijs et al[19].
Medical Diagnosis Central sensitization is a characteristic of this disorder Central Sensitisation is present as a subgroup
Chronic lower back pain
X
Chronic Whiplash associated disorders X
(Sub)acute whiplash associated disorders
X
Tempromandibular disorders
X
Myofascial pain syndrome
X
Osteoarthritis
X
Rheumatoid arthritis
X
Fibromyalgia X
Chronic fatigue syndrome X
Chronic headache
X
Irritable bowel syndrome X


Fig 2: table reproduced from Nijs et al[19] of symptoms related to central sensitization
Symptom Characteristic of central sensitization Might be related to Central sensitization
Hypersensitivity to bright light X
Hypersensitivity to touch X
Hypersensitivity to noise X
Hypersensitivity to pesticides X
Hypersensitivity to mechanical pressure X
Hypersensitivity to medication X
Hypersensitivity to temperature (high or low) X
Fatigue
X
Sleep disturbances
X
Unrefreshing sleep
X
Concentration difficulties
X
Swollen feeling (e.g. in limbs)
X
Tingling
X
Numbness
X


In 2012 Mayer et al.[20] proposed the Central Sensitization Inventory (CSI). The clinical goal of this screening instrument is to help better assess symptoms thought to be associated with CS in order to aid physicians and other clinicians in syndrome categorization, sensitivity, severity identification, and treatment planning, to help minimize, or possibly avoid, unnecessary diagnostics and treatment procedures. CSI has showed good psychometric strength, the clinical utility, and the initial construct validity.

Management of Central Sensitization

Central sensitization is characterized by the absence of peripheral sources of nociceptive input, therefore it seems more appropriate to use a treatment with a top-down mechanism, activating descending nociceptive processing together with decreasing descending nociceptive facilitation[21].

In the video below, Prof Peter O'Sullivan discusses some of the myths about back pain which are widely held and negatively impact on the perception and treatment of back pain.

[22]


Non-Pharmacological Approaches

Patient Education

In cases of central sensitization it is important to:

  • change maladaptive illness perceptions,
  • alter maladaptive pain cognitions,
  • reconceptualise pain.

This can be accomplished with pain physiology education, which is indicated when:

  1. the clinical picture is characterized and dominated by central sensitization;
  2. maladaptive illness perceptions are present.

Face-to-face sessions of pain physiology education, in conjunction with written educational material, are effective for changing pain cognitions and improving health status in patients with various chronic musculoskeletal pain disorders (i.e. chronic low back pain, chronic whiplash, fibromyalgia and chronic fatigue syndrome)[23].

Manual Therapy

Usually Manual Therapy is used for its perpheral effects, however it also produces central analgesic effects[24][25][26] activating descending anti-nociceptive pathways for a short period of time (30 - 35 mins.)[27][28]. This limits its clinical use in the management of central sensitization.

Although some speculate that repeated sessions of Manual Therapy may result in a long term activation of descending anti-nociceptive pathways, there is no evidence of this mechanism available yet[21]. On the contrary, Manual Therapy could also add peripheral nociceptive inputs, thus worsening the condition [21]. Therefore, Manual Therapy should be delivered carefully.

Transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation is more effective in suppressing centrally than peripherally originated pain states[29]. It provides short-term analgesic effects by stimulating the motor cortex or dorsolateral prefrontal cortex in various type of chronic pain patients[29][30][31]. However, the precise mechanism of actionis still not clear, and the clinical utility of the technique is limited by practical obstacles (too short analgesic effects, availability of the equipment limited to few specialized centers)[21].

Pharmacological Approaches

A variety of pharmacological treatments have been trialed in patients with neuropathic pain, including conditions that are known to involve central sensitisation. However, some of these treatments are still under investigation and are not in widespread clinical use.

Pharmacological agents such as non-steroidal antiinflammatory drugs and coxibs have peripheral effects, and are therefore inappropriate for the treatment of central sensitization in patients with chronic pain[32].

Often used drugs to treat central sensitization include[21]:

  • acetaminophen (paracetamol) - primarily acts centrally reinforcing descending inhibitory pathways. In addition, it may exert an inhibitory action on the enzyme cyclooxygenase in the CNS
  • serotonin- and norepinephrine-reuptake inhibitors - activate noradrenergic descending pathways together with serotonergic pathways
  • opioids - activation of opioid receptors has inhibitory effects, including presynaptic inhibition of primary nociceptive afferents and postsynaptic inhibition of projecting neurons
  • N-methyl-D-aspartate receptor blockers (i.e. ketamine) - blockade of excitation with NMDA-receptor antagonists may limit or reduce the spread of hyperalgesia and allodynia due to sensitization and in consequence, NMDA-receptor antagonists may be seen preferentially as antihyperalgesic or anti-allodynic agents rather than as traditional analgesics
  • gabapentin/pregabalin (calcium channel alpha(2)delta ligands) - bind to the alpha(2)delta (a2d) subunit of voltage-sensitive Ca2+ channels, which sustain the enhanced release of pain transmitters at the synapses between primary afferent fibres and second-order sensory neurons under conditions of chronic pain
  • tramadol - centrally acting drug that induces antinociception in animals and analgesia in humans.


Resources

  • "How to explain central sensitisation to patients with ‘unexplained’ chronic musculoskeletal pain: Practice guideline" - open access article can be found here.


References

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