Table 3.

Definition used to describe human assumed central sensitisation and the reported prevalence of human assumed central sensitisation.

1st Author, Year	Definition of HACS or HACS Similar Definition	Reference Definition HACS (1st Author, Year)	Prevalence HACS in Patients with CLBP Stated in the Article	CSI
				Mean	Prevalence (Cut-Off CSI 40)
Ansuategui Echeita, 2020a [41] #	“Central Sensitisation was introduced as a possible pathophysiological mechanism in several chronic pain conditions, including a subgroup of patients with CBP.”	Woolf, 1983 [16] Roussel, 2013 [13]	NR	34.7 ± 13.1	22 out of 56 (39.3%)
Ansuategui Echeita, 2020b [42] #	“In a subgroup of patients with chronic pain, pain might not be direct reflection of the presence of a noxious peripheral stimulus (nociceptive pain) nor the nervous system (neuropathic pain), but could be the result of a condition in which the CNS is in a hypersensitive state; central sensitisation.”	Woolf, 2011 [18]
Aoyagi, 2019 [43]	“Defined as augmented central pain processing.”	Woolf, 2007 [77] Latremoliere, 2009 [78] Woolf, 2011 [18] Clauw, 2015 [79] Nijs, 2014 [80] Roussel, 2013 [13]	NR	NA	NA
Aoyagi, 2020 [44]	“Defined as amplified pain processing in the central nervous system.”	Clauw, 2015 [79] Nijs, 2015 [81] Roussel, 2013 [13]	NR	NA	NA
Ashina, 2018 [45] #	“Both back pain and primary headache disorders may play a role in the sensitisation of partially overlapping central nociceptive pathways.”	Yoon, 2013 [82]	NR	NA	NA
Bid, 2017 [46]	“CS is described by the International Association for the Study of Pain (IASP) as: "Increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input". CS is also defined as "an augmentation of responsiveness of central neurons to input from unimodal and polymodal receptors".”	Loeser, 2008 [7] Meyer, 1995 [83]	Experimental (n = 64): 78.1% Control (n = 64): 64,1% Based on the CSI	Baseline Experimental: 45.68 Control: 37.34 Week 4 Experimental: 23.42 Control: 28.21 Week 8 Experimental: 11.17 Control: 21.17	91 out of 128 (71.1%)
Bilika, 2020 [47] #	“A phenomenon of hypersensitivity of the central nervous system in patients with chronic pain.”	Roussel, 2013 [13] Woolf, 2011 [18]	NR	31.79 ± 12.19	CLBP only: 9 out of 28 (32.14%) CLBP+: 1 out of 23 (4.17%)
Chiarotto 2018 [48] #	“an amplification of neural signalling within the central nervous system that elicits pain hypersensitivity”	Woolf, 2011 [18]	NR	33.93 ± 11.88	NR
Clark, 2018 [49]	“Central sensitisation involves facilitation of peripheral stimulus processing and alterations in descending inhibitory control of nociceptive input to the brain.”	Woolf, 2011 [18] Nijs, 2010 [76] Mayer, 2012 [25]	NR	46.14 ± 19.39	16 out of 21 (76.2%)
Clark, 2019 [50] #	“A dysregulation of the central nervous system causing neuronal hyperexcitability, characterized by generalized hypersensitivity of the somatosensory system to both noxious and non-noxious stimuli.”	Nijs, 2010 [76] Mayer, 2012 [25] Neblett, 2013 [84]	NR	50.10 ± 13.86	125 out of 165 (75.8%)
Cuesta-Vargas, 2016 [51] #	“CS involves an abnormal increase of pain caused by neuronal hyperexcitability and dysfunction in descending and ascending pathways in the central nervous system.”	Kindler, 2011 [85] Heinricher, 2009 [86]	NR	CLBP only: 22.57 ± 11.37 CLBP+: 25.62 ± 12.22	CLBP only: 7 out of 107 (6.5%) CLBP+: 7 out of 73 (9.6%)
Defrin, 2014 [52]	“Current pain theory holds that sustained peripheral noxious input, whether due to sensitized sensory endings or ectopic pacemaker activity, may secondarily initiate a state of spinal central sensitisation. In this state, afferent input is amplified and activity in low threshold Ab mechanosensitive afferents is rendered painful (Ab pain). A well-known example is secondary hyperalgesia, a region of hypersensibility to light touch (tactile allodynia) on the skin that surrounds the location of a primary noxious input.”	Raja, 1984 [87] Torebjörk, 1992 [88] Woolf, 2011 [18]	CLBP+: 60.8%, based on the presence of tactile allodynia CLBP only: 13.3%	NA	NA
Dixon, 2016 [53]	“Central sensitisation is an amplified state of neural signalling in the central nervous system (CNS) that is implicated in the pathogenesis of several chronic conditions that primarily involve pain and complex, multisymptom illnesses. When in the sensitized state, the CNS amplifies the sensory processing of the peripheral inputs so that the experience of the individual no longer accurately reflects the information provided by peripheral inputs. This state has been described as an increase in signal gain in which low-level sensory inputs are amplified into stronger signals, or as a decrease in signal inhibition processes, or both.”	Kaya, 2013 [89] Lluch, 2014 [90] Wang, 2014 [91] Batheja, 2013 [92] Woolf, 2011 [18]	NR	NA	NA
Hubscher, 2014 [54]	“Parallel to this peripheral phenomenon, intense ongoing peripheral nociceptive input can lead to altered central mechanisms, such as, an immediate-onset and lasting increase in the excitability of dorsal horn pain transmission neurons, referred to as central sensitisation. Central sensitisation may manifest as pain hypersensitivity (eg, allodynia, hyperalgesia, temporal summation [TS]) that can spread to non-injured areas.”	Ji, 2003 [93] Salter, 2004 [94] Woolf, 2011 [18]	NR	NA	NA
Huysmans, 2018 [55]	“Central sensitisation can be defined as a process of abnormal and intense enhancement of pain caused by increased neuronal responses to stimuli in the central nervous system. This central hyperexcitability is associated with altered sensory processing in the brain, malfunctioning of endogenous pain inhibitory systems, increased activity of pain facilitatory pathways, and temporal summation of second pain and/or wind-up, which leads to dysfunctional endogenous analgesic control.”	Nijs, 2015 [81] Mayer, 2012 [25] Yunus, 2007 [95] Nijs, 2010 [76] Nijs, 2011 [96] Woolf, 2011 [18] Staud, 2007 [97] Meeus, 2008 [98] Meeus, 2007 [99]	NR	32.92 ± 12.76 (range: 16–66)	12 out of 38 (31.6%)
Ide, 2020 [56] #	“The International Association for the Study of Pain defines central sensitisation (CS) as “increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input”.”	Loeser, 2008 [7]	NR	CLBP only: 7.76 ± 6.43 CLBP+: 17.77 ± 9.93	CLBP only: 0 out of 46 (0%) CLBP+: 4 out of 206 (1.94%)
Knezevic, 2018 [57] #	“Central sensitisation (CS) represents “increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input.” Peripheral stimuli that are otherwise innocuous can produce augmented, prolonged, and widely spread pain.”	International Association for the Study of Pain, 2012 [100] Woolf, 2011 [18]	NR	CLBP only: 36.94 ± 16.15 CLBP+: 44.66 ± 14.98	CLBP only: 68 out of 157 (43.3%)
Knezevic, 2020 [58] #	“Central sensitisation refers to hypersensitivity of the central nervous system, resulting in enhancement of pain sensations.”	Woolf, 2011 [18] Mayer, 2012 [25] Neblett, 2017 [67]	NR	CLBP only: 36.42 ± 15.51 CLBP+: 44.64 ± 13.94	CLBP only: 65 out of 155 (41.9%) CLBP+: 51 out of 88 (58.0%)
Kregel, 2016 [59] #	“Central sensitisation (CS) is a neurophysiological state resulting in hyperexcitability in the central nervous system. According to Woolf, CS is “operationally defined as an amplification of neural signalling within the central nervous system that elicits pain hypersensitivity.” In clinical practice, CS manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, longer aftersensations, and enhanced temporal summation.”	Woolf, 2011 [18] Nijs, 2010 [76]	NR	CLBP only: 23.67 ± 10.50 CLBP+: 38.90 ± 14.77	CLBP only: 1 out of 4 (25.0%) CLBP+: 7 out of 11 (63.6%)
Kregel, 2018 [60]	“Dysregulations of ascending and descending pathways have been observed in chronic pain patients, resulting in clinical signs such as allodynia, hyperalgesia, hypersensitivity, increased or prolonged aftersensations, and temporal summation to noxious and non-noxious stimuli. Extended high-frequency stimulation of neurons has been found to cause long-lasting cellular changes because of elevated cell responsiveness, a diminished working of the inhibitory cells and network sprouting. This increase in excitability and synaptic working in the central nociceptive pathways is called central sensitisation.”	Woolf, 2011 [18] Schliessbach, 2013 [101] Baranauskas, 1998 [102] Nijs, 2015 [81] Lluch, 2014 [90] Maixner, 1998 [103] Wilgen, van, 2013 [104]	NR	CLBP: 39.06 ± 11.61	NR
Leemans, 2020 [61]	NR	NA	NR	CLBP: Experimental group: 35.9 ± 10.5 CLBP: Control group: 31 ± 10.8	NR
Mayer, 2012 [25]	In the abstract: “Central sensitisation has been proposed as a common pathophysiological mechanism to explain related syndromes for which no specific organic cause can be found.” In the introduction: “Central sensitisation, which involves an abnormal and intense enhancement of pain by mechanisms in the central nervous system, maybe the common link between these disorders.”	Yunus, 2007 [95]	NR	CLBP only: 41.6 ± 14.8	NR
McKernan, 2019 [62] #	“Central sensitisation—the amplification of neural signalling in the central nervous system contributing to hyperalgesia.”	Woolf, 2011 [18]	NR	CLBP only: 50.83 ± 16.67	NR
Mehta, 2017 [63]	“Central sensitisation; this may manifest as pain hypersensitivity, in particular dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, and enhanced temporal summation. Central sensitisation is a hyperexcitability state in nociceptive pathways and has been suggested to be the main cause of chronic pain conditions.”	NR	NR	NA	NA
Mibu, 2019 [64]	“The International Association for the Study of Pain defines central sensitisation as an increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input.”	Loeser, 2008 [7]	n = 104: 19 (18.3%) Based on PPT and TS	CLBP: 25.5 ± 12.2	NR
Miki, 2020 [65]	“Central sensitisation is defined by the International Academy of Pain as a functional dysregulation of the central nervous system to normal or subthreshold afferent input. The nociceptive hyperexcitability and perception threshold of sensory information are reduced, and pain and other clinical symptoms are amplified.”	Loeser, 2008 [7] Woolf, 1983 [16]	NR	CLBP: 24.44 ± 12.78	31 out of 238 (13.0%)
Müller, 2019 [66]	“Central hypersensitivity: Prolonged or intense nociceptive input induces neuroplastic changes that lead to central nervous system hypersensitivity.“	Woolf, 2011 [18]	NR	NA	NA
Neblett, 2017 [67] #	“Central sensitisation is a relatively new concept, which is gaining wide acceptance as a functional dysregulation in the central nervous system, resulting in nociceptive hyperexcitability and a lowered threshold for perception of sensory information, which amplifies pain and other clinical symptoms.”	Adams, 2015 [105]	NR	CLBP only: 44.21 ± 15.24 CLBP+: 49.24 ± 15.01	CLBP only: 200 out of 322 (62.1%) CLBP+: 237 out of 323 (73.4%)
Noord van der, 2018 [68] #	“Central sensitisation is a common neurophysiological phenomenon in patients with chronic pain. Central sensitisation involves a hyperexcitability to a stimulus, resulting in an abnormal response to both noxious and non-noxious stimuli.”	Schliessbach, 2013 [101] Woolf, 2011 [18]	NR	CLBP only: 29.41 ± 14.03 CLBP+: 40.55 ± 14.28	CLBP only: 4 out of 17 (23.5%) CLBP+: 32 out of 67 (47.8%)
Serrano-Ibáñez, 2020 [69] #	“The International Association of the Study of Pain has defined central sensitisation as the increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input.”	Loeser, 2008 [7]	NR	CLBP: 63.68 ± 13.57	CLBP: 16 out of 24 (66.7%)
Sharma, 2020 [70] #	“Central sensitisation involves the amplification of pain, and hypersensitivity to other environmental stimuli, within the central nervous system.”	Woolf, 2011 [18]	NR	CLBP only: 24.27 ± 13.12 CLBP+: 24.00 ± 12.53	CLBP only: 3 out of 22 (14.8%) CLBP+: 4 out of 27 (13.6%)
Smart, 2012 [71] #	“Central sensitisation pain (CSP) refers to pain that arises or persists as a result of aberrant processing and/or hypersensitivity within the diffuse neural networks of the central nervous system (CNS) engaged in nociception, in the absence of or disproportionate to somatic tissue or peripheral nerve pathology.”	Costigan, 2009 [106]	NR	NR	NR
Tesarz, 2015 [72]	NR	NA	NR	NA	NA
Tesarz, 2016 [73]	NR	NA	NR	NA	NA
		Total	50.65%	All	1013 out of 2347 (43.2%)
				CLBP only	289 out of 701 (41.2%)
				CLBP+	343 out of 819 (41.9%)

Legend: CBP: chronic back pain, CLBP: Chronic low back pain, CLBP+: patients with chronic low back pain in combination with other pain condition(s), CNS: central nervous system, CS: central sensitisation, CSI: central sensitisation inventory, CSP: central sensitisation pain. HACS: human assumed central sensitisation, IASP: International Association for the Study of Pain, NA: not applicable, NR: not reported, PPT: pressure pain threshold, TS: temporal summation, # Data provided by the authors.