Central Sensitisation

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

Top Contributors - Alberto Bertaggia, Nathan Benson, Laura Ritchie, Jo Etherton, Shaimaa Eldib, Jess Bell, Bruno Serra, Uchechukwu Chukwuemeka, Kim Jackson, Lucinda hampton, Michelle Lee, Admin, Evan Thomas, WikiSysop, Claire Knott and Melissa Coetsee

Central Sensitisation

Illustration of action potential formation.

Nociception is described by IASP as the neural process of encoding noxious stimuli.

Central sensitisation is defined as an increased responsiveness of nociceptors in the central nervous system to either normal or sub-threshold afferent input resulting in:

1. Hypersensitivity to stimuli.
2. Responsiveness to non-noxious stimuli.
3. Increased pain response evoked by stimuli outside the area of injury, an expanded receptive field..

Watch the 2 minute video below on central sensitisation.

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

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

Neural plasticity plays a role in cellular changes with a demonstrable increase in both membrane excitability and synaptic efficacy.

Closer view of a neuromuscular junction: 1.presynaptic terminal; 2.sarcolemma; 3.synaptic vesicles; 4.Acetylcholine receptors; 5.mitchondrion.

The effect of this process is:

• Recruitment of additional, sub-threshold synaptic inputs to nociception resulting in a greater field of receptivity
• 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.
• Thought to play a role in affecting: pain facilitation and inhibition; inhibiting descending pathways; over-activation of the ascending, and, pain facilitatory pathways.
• Simplified, it means too many messages going in and not enough coming out.

The use of the term "central sensitisation" varies referring

• Sometimes solely to the neural plastic changes
• Sometimes to the the complex and multiple processes and systems which contribute to changes in the elicitation and perception of pain.
• Term was first used in a study of pain hypersensitivity in rats following repeated noxious stimuli to describe the use dependent neural plasticity demonstrated. These central changes due to peripheral noxious stimuli have been referred to as "activity-dependent central sensitisation".

A discussion about the various descriptions and definitions can be found on the Body in MInd website. 

Activity Dependent Central Sensitisation

Latremoliere and Woolf describe the changes demonstrated in their group's 1983 study as "activity dependent central sensitisation".

• Describes the mechanism of functional synaptic plasticity evoked in the dorsal horn neurons by input from nociceptors .
• Found that to invoke sensitisation, 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-dependent/transcription-independent; a longer lasting transcription-dependent phase (transcription is the process in which a gene's DNA sequence is copied (transcribed) to make an RNA molecule).
  

Activation of the NMDA receptor is an essential step in initiating and maintaining the sensitisation (N-Methyl-D-Aspartate is a glutamate receptor. Glutamate is a widespread excitatory neurotransmitter in the nervous system).

• Under normal circumstances this receptor channel is blocked by Mg²⁺ ions.
• Sustained release by nociceptors of glutamate, substance P and CGRP leads to membrane de-polarization, forcing the Mg²⁺ from the NMDA receptor.
• This rapidly boosts synaptic efficacy and allows Ca²⁺ in to the neuron, activating intracellular pathways and maintaining central sensitisation.
  

Central vs Peripheral Sensitisation

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

1. 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." 

• 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 an increase in responsiveness of nociceptors .
• Generally requires on going  peripheral pathology for the sensitisation to be maintained
• Generally localised to the site of injury.
• Has a role in altered heat sensation, but not in mechanical sensitivity.

2. Central sensitisation

• Novel inputs are recruited to the nociceptive pathways such as large, low-threshold mechanoreceptors classified as Aß fibres.
• Resulting in hypersensitivity in non-inflamed tissue and to touch.
   

Features of Central sensitisation

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

Artistic depiction of pain.

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. 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 , 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 sensitisation in their classification algorithm.

In 2010 Nijs et al. provided guidelines to aid the recognition of central sensitisation 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 sensitisation (fig 1) and this in conjunction with observable features (fig 2) can inform the therapist as to the presence of central sensitisation.

fig 1. Table of Medical diagnoses likely to suggest presence of central sensitsation reproduced from Nijs et al.

Medical Diagnosis	Central sensitisation 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

Symptom	Characteristic of central sensitisation	Might be related to Central sensitisation
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. proposed the Central Sensitisation 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 categorzsation, 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 Sensitisation

Central sensitisation 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.

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.

Non-Pharmacological Approaches

1.Patient Education

In cases of central sensitisation it is important to:

• change maladaptive illness perceptions,
• alter maladaptive pain cognitions,
• re-conceptualise pain.

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

1. the clinical picture is characterized and dominated by central sensitisation;
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).

Check out the following video from Lorimer Moseley to see his approach to educating patients about managing pain.

2. Manual Therapy

Usually Manual Therapy is used for its peripheral effects, however it also produces central analgesic effects activating descending anti-nociceptive pathways for a short period of time (30 - 35 mins.). This limits its clinical use in the management of central sensitisation.

• 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.
• On the contrary, Manual Therapy could also add peripheral nociceptive inputs, thus worsening the condition .
• Therefore, Manual Therapy should be delivered carefully.
  

3.Transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation is more effective in suppressing centrally than peripherally originated pain states. It provides short-term analgesic effects by stimulating the motor cortex or dorsolateral prefrontal cortex in various type of chronic pain patients. However, the precise mechanism of action is 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).

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 anti-inflammatory drugs and coxibs have peripheral effects, and are therefore inappropriate for the treatment of central sensitisation in patients with chronic pain.

Often used drugs to treat central sensitisation include:

• 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 sensitisation and in consequence, NMDA-receptor antagonists may be seen preferentially as anti-hyperalgesic 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 anti-nociception 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.