IASP describes nociception as a neural process that encodes noxious stimuli.
Central sensitization is defined as increased activation of nociceptors in the central nervous system on normal or inferior afferent input resulting in:
- Hypersensitivity to stimuli.
- Responses to non-noxious stimuli.
- Enhanced pain response evoked by extensive uptake of stimulation outside the injured area..
The diagram on the right is a possible programming event.
Watch the 2 minute video below on central sensitization
The International Association for the Study of Pain (IASP) describes central sensitization as
“Increased response of nociceptive neurons in the central nervous system to their normal or low levels of afferent input”
Neural plasticity plays a role in cellular adaptation characterized by increases in both membrane excitability and synaptic efficacy.
The effect of this process is:
- Recruitment foforo sub-threshold synaptic inputs to nociception a ɛde kɛse field of receptivity ba
- Increased output of nociception.
- The effects of this process can persist beyond the initial exposure period resulting in hypersensitivity to pain on normally harmless substances.
- It was thought to play a role in affecting: pain relief and inhibition; preventing slopes; ascending pathways and hyperactive pain.
- Keeping it simple means more messages will get in and less will go out.
[The nerve synapse pictured on the right is a Neuromuscular junction (close view): 1.presynaptic terminal; 2.the sarcolemma; 3.synaptic weakness; 4.Acetylcholine receptor; 5.mitchondrion}
The use of the term central sensitization varies in definition
- Sometimes it is only a change of the tissue plastic
- Sometimes to complex and numerous mechanisms and systems that contribute to changes in pain stimulation and perception.
- The term was first used in a study of hyperalgesia in rats following repetitive noxious stimuli to describe the activity-dependent neuroplasticity demonstrated. This central change induced by peripheral noxious stimuli has been termed activity-dependent central sensitisation.
A discussion of the various definitions and definitions can be found on the Body in MInd website.
Activity Dependent Central sensitisation
Latremoliere and Woolf described the changes shown in their group’s 1983 study as activity-dependent central sensitization.
- described the mechanism of functional synaptic plasticity induced in dorsal horn neurons by input from nociceptors .
- It was found that for sensitization to occur, noxious stimuli must be persistently intense and repeated.
- These 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 duplication (transcription) of the DNA sequence of a gene so that its becoming an RNA molecule). 
Activation of NMDA receptors is an important step in initiating and maintaining sensitization (N-methyl-D-aspartate is a glutamate receptor. Glutamate is an excitatory neurotransmitter ubiquitous in the nervous system ).
- Under normal conditions, this receptor channel is blocked by Mg2+ ions .
- Sustained release of glutamate substances P and CGRP by nociceptors leads to membrane depolarization, forcing Mg2+ from NMDA receptors .
- This rapidly increases synaptic efficiency and allows Ca2+ entry into neurons to activate intracellular pathways and maintain central sensitization .
Central vs Peripheral Sensitisation
Although the described central and peripheral sensitization appear to be comparable processes, they represent distinct processes and clinical features .
1. The IASP describes peripheral sensitization as
Peripheral pain sensory neurons increase their responsiveness to stimuli in their receptive fields, and their thresholds decrease. 
- Nociceptors are activated when their peripheral ends are exposed to noxious stimuli, such as inflammatory mediators in damaged tissue. Sustained stimulation results in a lowered activation threshold, which increases nociceptor reactivity .
- Peripheral pathology often required to maintain sensitization
- Usually confined to the site of injury .
- Plays a role in altering thermal sensation but not mechanical sensitivity .
2. Central sensitisation
- New inputs are recruited to nociceptive pathways, such as large low-threshold mechanoreceptors classified as Aß fibers.
- Causes non-inflamed tissue and touch allergies.
Features of Central Sensitization
A survey of expert clinicians in a Delphi-derived survey found the following characteristics to describe central sensitization in a clinical setting .
- Disproportionate non-mechanical unpredictable pain excitation pattern in response to multiple/non-specific aggravating/relieving factors.
- Pain persists beyond expected tissue healing/pathological recovery time.
- Pain that is out of proportion to the nature and extent of the injury or lesion.
- Wide non-anatomic distribution of pain.
- History of failed interventions (medical/surgical/therapeutic).
- Strong association with maladaptive psychosocial factors (eg, negative emotions, poor self-efficacy, maladaptive beliefs, and pain behaviors alter family/work/social life-medical conflict).
- Unresponsive to NSAIDs and/or more responsive to antiepileptic (eg Lyrica) / antidepressant (eg amitriptyline) medications.
- Reports of spontaneous (i.e. stimulus independent) and/or paroxysmal pain (i.e. sudden recurrence and severity of pain).
- Pain associated with increased functional disability.
- More constant/unremitting pain.
- Night pain/disturbed sleep.
- Pain associated with other dysesthesias (e.g. cold burning crawling).
- Hyperpathia or pain that is more intense and irritating (i.e. easily irritated that takes longer to resolve).
- Disproportionate inconsistent non-mechanical/non-anatomic patterns of pain stimulation in response to movement/mechanical testing.
- Positive findings of hyperalgesia (primary secondary) and/or allodynia and/or hyperpathia in pain distribution.
- Pain/tenderness in diffuse/non-anatomic areas.
- Actively identify various psychosocial factors (eg, catastrophizing fear-avoidant behavioral distress).
Identification in the Clinical Setting
In 2009 Schäfer et al.  proposed the classification of low back-related leg pain using an examination protocol that first included a subjective assessment, including the Leeds Assessment of Neuropathy Signs and Symptoms (LANSS) scale , followed by a physical examination (Neuroscience Examination evaluation of active motor nerve tissue provocation test). Based on this composite assessment, a LANSS score ≥ 12 indicates central sensitivity in its classification algorithm.
In 2010 Nijs et al  provided guidelines to help identify central sensitization in musculoskeletal patients.
In their paper, they suggest that a patient’s medical diagnosis can provide insight into the likelihood that central sensitization is present (Figure 1), and that, combined with observable features (Figure 2), can inform the therapist of the presence of central sensitization.
Figure 1. Medical diagnostic chart that may indicate central sensitivity Adapted from Nijs et al. . Medical diagnosis Central sensitivity is a feature of this disorder Central sensitivity exists as a subgroup: Chronic low back pain X Chronic whiplash associated Disease X (sub)acute whiplash-related disorder X temporomandibular joint disorder X myofascial pain syndrome X osteoarthritis X rheumatoid arthritis X fibromyalgia X chronic fatigue syndrome X chronic headache X irritable bowel syndrome X
Symptoms and characteristics of central sensitivity may be related to central sensitivity Allergy to strong light X allergy to touch X allergy to noise X allergy to pesticides X allergy to mechanical pressure X allergy to drugs X allergy to drugs Temperature (high or low) X Fatigue X Sleep disturbance X Lack of sleep X Poor concentration X Swelling sensation (eg extremities) X Tingling X Numbness X
In 2012, Mayer et al.  proposed the Central Sensitivity Inventory (CSI). The clinical goal of this screening tool is to help better assess symptoms considered associated with CS to aid physicians and other clinicians in syndrome classification sensitivity severity Identification and treatment planning to help reduce or possibly avoid unnecessary diagnostic and therapeutic procedures. CSI has shown good psychometric strength, clinical utility, and initial construct validity.
Management of Central Sensitisation
Central sensitization is characterized by the absence of peripheral sources of nociceptive input, so it seems more appropriate to use top-down mechanisms to activate downstream nociceptive processing and reduce downstream nociceptive facilitation .
In the video below, Professor Peter O’Sullivan discusses some of the myths about back pain that are widely accepted and negatively impact the perception and treatment of back pain.
In cases of central sensitization, it is important to:
- change maladaptive illness perceptions,
- alter maladaptive pain cognitions,
- re-conceptualise pain.
This can be achieved through education in the physiology of pain, which demonstrates when:
- The clinical manifestations are characterized and dominated by central sensitization;
- There is a maladaptive notion of illness.
Face-to-face education on the physiology of pain combined with written educational materials can be effective in modifying the chronic fatigue syndrome) .
Watch Lorimer Moseley’s video below to learn about his approach to educating patients about pain management. 
2. Manual Therapy
Usually manual therapy is used for its peripheral effects, but it also produces central analgesic effects and activates descending antinociceptive pathways for a short period of time (30 – 35 minutes). This limitation Its clinical application in the management of central sensitization.
- Some think that repeated Manual Therapy can activate descending anti-seizure pathways over time there is no evidence for this mechanism yet.
- Conversely, manual therapy may also increase peripheral pain input, thereby exacerbating the condition .
- Therefore, manual therapy should be performed with care.
3.Transcranial magnetic stimulation
Repetitive transcranial magnetic stimulation is more effective in inhibiting centrally originating pain states than peripherally originating pain states . It provides short-term analgesia by stimulating the motor cortex or the dorsolateral prefrontal cortex in patients with various types of chronic pain . However, the exact mechanism of action remains unclear, and the clinical application of this technique is limited by practical barriers (the analgesic effect of the device is too short-lived and limited to a few specialized centers) .
A variety of pharmacological treatments have been tested in patients with neuropathic pain, including conditions known to involve central sensitization. However, some of these treatments are still under investigation and not widely used clinically.
- Drugs such as NSAIDs and coxibs have peripheral effects and are therefore not suitable for treating central sensitization in patients with chronic pain .
Drugs commonly used to treat central sensitization include :
- Acetaminophen (paracetamol) – The main effect is to centralize the potentiation of descending inhibitory pathways. In addition, it may have an inhibitory effect on cyclooxygenase in the central nervous system
- Serotonin and norepinephrine reuptake inhibitors – activate norepinephrine descending and serotonergic pathways
- Opioid-activation of opioid receptors has an inhibitory effect, including presynaptic inhibition of primary nociceptive afferents and postsynaptic inhibition of projection neurons
- N-methyl-D-aspartate receptor blockers (i.e., ketamine) – blocking excitation with NMDA receptor antagonists may limit or reduce the spread of hyperalgesia and allodynia due to sensitization, NMDA receptor antagonists may therefore be preferentially considered as antihyperalgesic agents either Antiallodynic agents instead of traditional analgesics
- Gabapentin/Pregabalin (calcium channel alpha(2)delta ligand) – binds to the alpha(2)delta (a2d) subunit of voltage-sensitive Ca2+ channels and maintains synapses between primary and secondary afferent fibers Enhanced release of pain transmitters at Sequencing sensory neurons chronic pain
- Tramadol – a centrally acting drug that induces antinociception in animals and analgesia in humans.
- How to explain central sensitization to patients with ‘unexplained’ chronic musculoskeletal pain: a practical guide – open access article available here.
- Louw A, Nijs J, Puentedura EJ. A clinical perspective on a pain neuroscience education approach to manual therapy. J Man Manip Ther. 2017; 25(3): 160-168.
- Woolf CJ, Latremoliere A. Central Sensitization: A generator of pain hypersensitivity by central neural plasticity. The Journal of Pain 2009; 10(9):895-926
- Loeser JD, Treede RD. The Kyoto protocol of IASP basic pain terminology. Pain 2008;137: 473–7.
- Dhal JB, Kehlet H. Postoperative pain and its management. In:McMahon SB, Koltzenburg M, editors. Wall and Melzack’s Textbook of pain. Elsevier Churchill Livingstone;2006. p635-51.
- International Association for the Study of Pain. IASP Terminology. Available from: https://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698#Sensitization. [Accessed 19 July 2020]
- Meeus M, Nijs J, Van der Wauwer N, Toeback L, Truijen S. Diffuse noxious inhibitory control is delayed in chronic fatigue syndrome: an experimental study. Pain 2008;139:439-48
- Meeus M, Nijs J. Central Sensitization: a biopyschosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome. Clinical Rheumatology 2007; 26:465-73
- Woolf CJ. What to call the amplification of nociceptive signals in the central nervous system that contribute to widespread pain? Pain 2014. Article in Press.
- Hansson P. PAIN 2014. http://dx.doi.org/10.1016/j.pain.2014.07.016. pii: S0304-3959(14)00335-2
- Body in Mind. Everything you wanted to know about CENTRAL SENSITISATION http://www.bodyinmind.org/central-sensitisation/ (accessed 10 June 2014)
- Woolf CJ.Evidence of a central component of post-injury pain hypersensitivity. Nature 1983;306;686-688.
- Woolf CJ, Saltar MW. Neuronal plasticity:increasing the gain in pain. Science 2000;288:1765-69.
- Khan academy stages of transcription Available from:https://www.khanacademy.org/science/biology/gene-expression-central-dogma/transcription-of-dna-into-rna/a/stages-of-transcription (last accessed 1.6.2020)
- Mayer ML, Westbroke GL, Guthrie, PB. Voltage-dependant block by Mg2+ of NMDA responses in spinal cord neurones. Nature 1984;309:261-263.
- International Association for the Study of Pain. Pain Terms: A Current List with Definitions and Notes on Usage. http://iasp.files.cms-plus.com/Content/ContentFolders/Publications2/ClassificationofChronicPain/Part_III-PainTerms.pdf(accessed 12 July 2014
- Hucho T, Levine JD. Signalling pathways in sensitization: Towards a nociceptor cell biology. Neuron 2007;55:365-376
- Danny Orchard. Peripheral and central sensitisation. Available from: http://www.youtube.com/watch?v=YwDMmSwUOOU [last accessed 22/11/15]
- Smart KM, Blake C,Staines A, Doody C. Clinical Indicators of “Nociceptive”, “peripheral neuropathic”, and “central sensitisation” as mechanisms based classifications of musculoskeletal pain. A Delphi survey of expert clinicians. Manual Therapy 2010;15:80-7
- Schäfer A, Hall T, Briffa K. Classification of low back-related leg pain—A proposed patho-mechanism-based approach. Manual Therapy. 2009 Apr 1;14(2):222–30.
- Bennett M. The LANSS Pain Scale: the Leeds assessment of neuropathic symptoms and signs. Pain. 2001 May;92(1-2):147–57.
- Nijs J, Van Houdenhove B, Oostendorp RAB. Recognition of central sensitization in patients with musculoskeletal pain: application of pain neurophysiology in manual therapy practice. Manual Therapy 2010;15:135-41
- Mayer TG, Neblett R, Cohen H, Howard KJ, Choi YH, Williams MJ, et al. The Development and Psychometric Validation of the Central Sensitization Inventory (CSI). Pain Pract. 2012 Apr;12(4):276–85.
- Nijs J, Meeus M, Van Oosterwijck J, Roussel N, De Kooning M, Ickmans K, et al. Treatment of central sensitization in patients with ‘unexplained’ chronic pain: what options do we have? Expert Opin Pharmacother. 2011 May;12(7):1087–98.
- Pain-Ed.com. Prof Peter O’Sullivan – Back pain – separating fact from fiction. Available from: http://www.youtube.com/watch?v=dlSQLUE4brQ[last accessed 22/11/15]
- Nijs J, Wilgen CP van, Oosterwijck JV, Ittersum M van, Meeus M. How to explain central sensitization to patients with ‘unexplained’ chronic musculoskeletal pain: Practice guidelines. Manual Therapy. 2011 Oct 1;16(5):413–8.
- Moseley L. Tame the Beast. Available at https://www.tamethebeast.org/#tame-the-beast (accessed 2 Mar 2020).
- Lorimer Moseley. Tame the Beast. Available from https://www.youtube.com/watch?time_continue=295&v=ikUzvSph7Z4&feature=emb_logo [last accessed 09/03/2020]
- Vicenzino B, Collins D, Wright A. The initial effects of a cervical spine manipulative physiotherapy treatment on the pain and dysfunction of lateral epicondylalgia. Pain. 1996 Nov;68(1):69–74.
- Bialosky JE, Bishop MD, Robinson ME, Zeppieri G, George SZ. Spinal manipulative therapy has an immediate effect on thermal pain sensitivity in people with low back pain: a randomized controlled trial. Phys Ther. 2009 Dec;89(12):1292–303.
- Bialosky JE, Bishop MD, Robinson ME, Barabas JA, George SZ. The influence of expectation on spinal manipulation induced hypoalgesia: an experimental study in normal subjects. BMC Musculoskelet Disord. 2008;9:19.
- Moss P, Sluka K, Wright A. The initial effects of knee joint mobilization on osteoarthritic hyperalgesia. Man Ther. 2007 May;12(2):109–18.
- Sluka KA, Skyba DA, Radhakrishnan R, Leeper BJ, Wright A. Joint mobilization reduces hyperalgesia associated with chronic muscle and joint inflammation in rats. J Pain. 2006 Aug;7(8):602–7.
- Leung A, Donohue M, Xu R, Lee R, Lefaucheur J-P, Khedr EM, et al. rTMS for suppressing neuropathic pain: a meta-analysis. J Pain. 2009 Dec;10(12):1205–16.
- Leo RJ, Latif T. Repetitive transcranial magnetic stimulation (rTMS) in experimentally induced and chronic neuropathic pain: a review. J Pain. 2007 Jun;8(6):453–9.
- Lefaucheur JP. The use of repetitive transcranial magnetic stimulation (rTMS) in chronic neuropathic pain. Neurophysiol Clin. 2006 Jun;36(3):117–24.
- Kosek E. Medical management of pain.Chapter 12. In: Sluka K. Mechanisms And management of pain for the physical therapist. IASP press, Seattle;2009. p. 231-55