Application of Theory in Chronic Pain Rehabilitation Research and Clinical Practice

Application of Theory in Chronic Pain Rehabilitation Research and Clinical Practice

The Open Sports Sciences Journal 16 Dec 2021 REVIEW ARTICLE DOI: 10.2174/1875399X02114010106



Chronic pain has multiple aetiological factors and complexity. Pain theory helps us to guide and organize our thinking to deal with this complexity. The objective of this paper is to critically review the most influential theory in pain science history (the gate control theory of pain) and focus on its implications in chronic pain rehabilitation to minimize disability.


In this narrative review, all the published studies that focused upon pain theory were retrieved from Ovoid Medline (from 1946 till present), EMBAS, AMED and PsycINFO data bases.


Chronic pain is considered a disease or dysfunction of the nervous system. In chronic pain conditions, hypersensitivity is thought to develop from changes to the physiological top-down control (inhibitory) mechanism of pain modulation according to the pain theory. Pain hypersensitivity manifestation is considered as abnormal central inhibitory control at the gate controlling mechanism. On the other hand, pain hypersensitivity is a prognostic factor in pain rehabilitation. It is clinically important to detect and manage hypersensitivity responses and their mechanisms.


Since somatosensory perception and integration are recognized as a contributor to the pain perception under the theory, then we can use the model to direct interventions aimed at pain relief. The pain theory should be leveraged to develop and refine measurement tools with clinical utility for detecting and monitoring hypersensitivity linked to chronic pain mechanisms.

Keywords : Chronic pain , Hypersensitivity , Theory , Rehabilitation , Disability , T-cell.


“From the brain alone arise our pleasures, laughter, and jests, as well as our sorrows, pain, and griefs.” Hippocrates. Pain is an ancient topic and our thinking on the nature of pain has been shifted over the centuries from the Cartesian dualistic concept to the Gate Control Theory (GCT) of Pain, a better global model of pain. It is difficult to define chronic pain due to its complex nature. The need for a better definition was emphasized by John Bonica [1], who referred to the diverse taxonomies in use as “the tower of Babel”. The International Association for the Study of Pain (IASP) has led efforts to establish a common taxonomy: it defines chronic pain as a pain syndrome lasting for more than 3 months [2]. Chronic pain has multiple aetiologies, including chronic diseases like arthritis; acute injuries with lingering symptoms after fracture [3]; or can persist following major surgery. The incidence of chronic pain in the general population is estimated at 20% to 50% [4]. According to the National Institute of Health, pain affects more people than diabetes, heart disease, and cancer combined [5, 6]. The economic costs of pain have been estimated as being more than $100 billion yearly in United States [5, 6]. In 2010, the IASP recognized chronic pain as a serious global chronic health problem with a huge economic impact [7]. The IASP identified chronic pain as a highly stigmatized condition regardless of associated diagnoses, and highlighted the need for appropriate assessment to reduce burden [7]. As a signal of its importance, pain is now considered as the 5th vital sign [7, 8], despite complexity in the nature of pain.

Pain is a protective mechanism that ideally warns of imminent tissue damage. However, in some cases, the organism can be too sensitive (hypersensitive) and perceive pain where no tissue damage is imminent, or where the stimulus intensity is below the normal threshold necessary to elicit a pain response [9]. Pain hypersensitivity, used here as an umbrella term incorporating both allodynia and hyperalgesia (Table 1), manifests as a spread of increased somatosensory responsiveness into adjacent normal tissues, even after the end of a noxious (painful) stimulus (e.g. in nociplastic pain) [10]. Evidence synthesis indicates strong evidence of hypersensitivity (abnormal pain response) as a prognostic factor for poor outcomes in chronic musculoskeletal pain [11]. There is increasing awareness that chronic pain is, at least in part, a disease of the nervous system [9, 12]. Thus, it is important to have a conceptual framework to interrogate and interpret how the nervous system contributes to pain.

Table 1.
Two common hypersensitivity phenomena: allodynia and hyperalgesia [2, 10].
Topic Allodynia Hyperalgesia
IASP Definition Pain due to a stimulus that does not normally provoke pain. Increased pain from a stimulus that normally provokes pain.
Pain mechanism Lowered threshold Increased response
Stimulus and response mode Differ same
Abbreviation: IASP = International Association for the Study of Pain.
Note: The table is reused with permission from Uddin Z and MacDermid JC. Pain Studies and Treatment. 2014;2(2):31-35.

Theory helps us to guide and organize our thinking to deal with the complexity of pain by explicating our assumptions and systematically testing relationships. Existing pain theories are capable of explaining some aspects of pain, but there is no comprehensive theory or model that we can use to interpret or explain all aspects of pain [13, 14]. Theory can help us frame our understanding of complex phenomena like pain, and to interpret what we observe in clinical practice [15]. In pain science, theories help determine how we study neurophysiology, how we interpret the observations from pain bench or lab studies; and how we treat patients with pain [16, 17]. Pain mechanisms are not yet completely understood. Nonetheless, the widely accepted GCT holds some testable propositions to explain the pain. The purpose of this paper is to highlight the importance of theory (as an example of the most influential GCT in the pain science history) and explain its implications in chronic pain rehabilitation, focusing on both research and clinical practice.


Melzack and Wall (in 1965), proposed a “gate” system within the dorsal horn of the human spinal cord, which regulates pain perception by a dynamic inhibitory-facilitatory mechanism [18]. GCT consists of four basic structural components (Fig. 1): small fibers (A-delta and C fiber), large fiber (A-beta nerve fiber), substantia gelatinosa (SG, lamina-II of dorsal horn), and the hypothetical first central transmission cell. The theory explains the relationship between these four components. The small and large nerve fibers project toward the SG of lamina-II and first central transmission cell. The modulatory (inhibitory) effect on pain processing is increased in SG by activation of large fibers and decreased by small fibers activity. A diagrammatic representation of the GCT (Fig. 1) shows the gate control system in the dorsal horn receiving feedback from the central control, and reflecting the central inhibitory influence of pain [18]. The central inhibitory influence plays a major role in both hypersensitivity and chronic pain mechanisms [19-23].

GCT explains the role of the central nervous system (both spinal cord and brain) in the perception of acute and chronic pain conditions [24]. The gate models how a peripheral stimuli interact to modulate pain sensation and perception. The theory explains the role of A-beta fibers, pain fibers (i.e. A-delta and C fiber), and the dorsal horn of the spinal cord for central transmission of pain perception [25]. It reflects physiologic mechanisms (e.g. central summation of pain stimulus, and other somatosensory inputs) into the control of pain. The theory helped us thinking about how pain generates away from peripheral nervous system into the central nervous system with central summation and somatosensory input and contributions to our pain perception. Fundamentally, two opposing gate controlling mechanisms (inhibition and facilitation) in GCT are key factors of pain modulation. In chronic pain scenario, hypersensitivity phenomena is thought to develop from physiological changes to the inhibitory component in the GCT [19-23]. From a GCT perspective, the clinical manifestation of hypersensitivity is considered to represent central abnormal inhibitory control within the gate control mechanism (Fig. 1).

The theory explains pain regulation in a way that can account for both abnormal (hypersensitive or hyperpathic) and normal (physiological) pain responses. The theory hypothesized pain sensation (nociception) is regulated dynamically in the dorsal horn, which can lead to a decrease or increase pain sensitivity [11]. A noise in the inhibitory controlling mechanism is thought of as one of the key causes of developing hypersensitivity [19-23]. Hypersensitivity is a reflection of imbalance within the two opposing neurophysiological pain modulatory activities, such as, gate control or top-down control (Fig. 2).


In 1965, the original paper proposed the theory in light of spinal neurophysiologic observations. Subsequently, the authors extended the scope of the GCT views to include other components in the central nervous system [24, 26]. Even the revised format retains simplicity in how it portrays the neurophysiologic basis of pain [26]. The characteristics of a good theory (e.g. accuracy, consistency, scope, simplicity, and fruitfulness) are reflected in studies that support the GCT [26]; and how this theory helps to address problems [18, 26, 27].

Fig. (1). Gate control theory (18): Components and basic links of gate mechanism with normal and abnormal (hypersensitive) pain response. SG = Substantia Gelatinosa; T-cell= 1st central Transmission cell. The figure is reused with permission from Uddin Z and MacDermid JC. Pain Studies and Treatment. 2014;2(2):31-35
Fig. (2). Stages of neural process in somatosensory system to produce pain hypersensitivity and chronic pain (adapted from Woolf & Salter) (98). The bidirectional relationships (bottom-up and top-down control mechanism) of pain processing in the brain and spinal cord are also an important part of the gate control theory. The figure is reused with permission from Uddin Z and MacDermid JC. Pain Med. 2016;17(9):1694-1703.

Since the inhibitory pathway play an important role in pain hypersensitivity, research support for that aspect of the model is focused. The GCT suggested a role of inhibition by endogenous mechanisms of pain control [28]. An experimental study showed that repeated electrical stimulation in peripheral nerve fibers can produce electro-analgesia [29], which was consistent with expectations based on the GCT. Further evidence of the accuracy of the model came from the discovery of endogenous inhibitory circuits [30]. These findings were consistent as they were replicated by several independent studies showing that pain hypersensitivities are produced by interrupted pain inhibitory mechanisms in the spinal cord; [31-38] also studies showing that improving inhibition can reduce hypersensitivity [39-42].

Britton and colleagues [43] took a unique approach to evaluate the accuracy of the GCT by creating a mathematical model from the concept of the theory and then testing whether the resultant mathematical computations fit the observations in existing research. The mathematical model of GCT [43] supported that the large fibers connected to the higher brain (cognitive control mechanism) via dorsal column can modulate pain by inhibition or facilitation. The mathematical model also supported the theory in that it was a robust model that explained a number of different pain phenomena. However, this modelling also demonstrated short falls where it did not adequately explain all observations (i.e. stimulation of large fiber doesn’t reduce pain always).

Patrick Wall [26] noted that although the mechanism by which the gate control achieved is not fully understood, the model does support continued investigation of the functional role and mechanisms, demonstrating that it is considered “fruitful” in supporting pain research. Finally, support for the GTC is demonstrated by its longevity [17]. Since proposed in 1965, there have been minor changes; but basically, no major opposition has been raised by a competing theory.


There are some limitations anomalies in the GCT. Some studies with humans did not identify evidence of the gating mechanism in the spinal cord by measuring cutaneous sensory stimulations and its impact on electrical recordings from non-myelinated fibers [44-49]. According to the GCT of pain, the large fiber stimulation should inhibit pain. However, Nathan and Rudge [50] stimulated large fiber in humans; and did not find reductions in pain. They suggested that some essential parts of GCT might be wrong. The critical review of GCT by Nathan [51] described the limitations of the antagonist relationship between the large and small fibers; and how the theory would collapse if the antagonist relationship fails.

There are gaps where the GTC is not able to explain phenomena [50]. One such identified gap is the GCT does not address stimulus specificity (e.g. thermal, mechanical, electrical and chemical) in the peripheral nervous system. Another gap is the theory is overly simplistic and does not clarify whether the facilitation and inhibition are pre or post-synaptic, or both [51]. Pre-synaptic facilitation and inhibition in GCT remain a debated issue, although it has remained difficult to isolate the role of pre-synaptic and postsynaptic fibers.

The GCT does not explain the T-cell (first central transmission cell) as a specific central connecting neuron or tract, but assumes the presence of a wide dynamic range neuron that connects to multiple areas within the brain. However, functional and anatomical findings suggested the existence of a specific labeled line of central pain pathways [52]. The GCT does not specify the location of T-cell, but it assumes as the high-frequency signal toward the midbrain [43]. The theory cannot explain all types of pain (e.g. phantom limb pain, central post-stroke pain), but as our understanding of different pain phenomena continues to evolve [53], our understanding of the explanatory power of gate control will also evolve. The pain processing mechanism and response within the brain are not explained in detail by the GCT. Moreover, motor adaptation (sensory-motor control) and pain are not explained in theory.

After acknowledging these limitations, it is perhaps necessary to briefly look at the scope of the pain theory literature to situate GCT. Other pain theorists have focused on pain processing in the brain, postulating a ‘pain matrix’ to describe the interrelationships of neural centres activated by nocioceptive inputs from the periphery, which mark the emergence of the pain entity [54]. However, there is an acknowledgement that other brain centres not included in the ‘matrix’ ultimately modulate those signals, and influence the efferent responses. Hodges’ theory of motor adaptation in pain [55] further posits both biological and behavioural responses in the central nervous system and periphery as inherent to the pain experience. Considered in isolation, each of these theories fails to explain the entire spectrum of the pain phenomenon, but considered together, they expand our ability to understand the complexity and inform individualized treatment planning. Our intent herein was not to ignore the breadth of these contrasting and complimentary perspectives, but to explore the singular depth of GCT.


The GCT played a major role in the pain research direction and many influential scientific findings. It has been reported in a meta-trend analysis, which accounted pain research from 1975 to 2007 [56], and demonstrated the original GCT article [18] as the top most cited paper. The study was based on 4525 research papers published in the official journal of IASP (Pain) and illustrated the predominance of GCT in the field of pain research. The meta-trend analysis also identified chronic pain as the most common clinical condition, which should be studied keeping in view the hypersensitivity phenomena.

Within clinical pain interventional type of research, rehabilitation interventions have interpreted electrotherapies using the GCT lens (e.g. transcutaneous electrical stimulation). A recent bibliometric analysis from research studies [57], on rehabilitation interventions highlights the importance of this evidence. The analysis has demonstrated physical modalities as the most investigated topic [57]. It was based on an analysis of 2519 treatment-focused publications between 1980 -2009 in the “Physical Therapy” journal. This piece of evidence reflects the predominance GCT conceptual premise intervention (i.e. gate closure via A-beta fiber and pain inhibition) type of research in physical rehabilitation.

Over the last four decades, most of the novel discoveries in pain areas relied on the concept of GCT [58] and it remains a framework for promising new research areas. Current research trend areas where GCT is fundamental to the line of investigation include: diffuse noxious inhibitory control of pain (i.e. an endogenous pain modulatory pathway), hypersensitivity, and endogenous opioid receptors. Hypersensitivity is a specific area of the recent focus in rehabilitation research, in that pain typology is now being used to define treatment needs and to predict future outcomes. For example, there is a substantial body of work now showing whiplash patients who demonstrate early abnormalities in cold sensitivity have a poor prognosis and require different rehabilitation approaches [59]. Mechanical allodynia has been related to lowered adherence and poor prognosis in complex regional pain syndrome [60, 61], and emerging work is focusing on developing evidence for accurate assessment and treatment strategies [62-64].


The tenets of GCT have also informed and shaped pain rehabilitation practice over four decades. A proposition of GCT explains neurophysiological consequences of large fiber stimulation and its output in pain modulation [18]. Rehabilitation therapy uses that principle to gain pain control by manipulating the fast conducting large fibers [18]. Physical agents/modalities, such as whirlpool, fluidotherapy, and massage among many other therapies are applied, which are based on principles of gaining pain relief by stimulating large fibers. For example, large fibers are stimulated by touch or gentle rubbing on skin [65, 66] and can be used strategically to reduce painful sensitivity [62, 67]. Further, in our understanding, the theory has an influential role on therapeutics electro-analgesic mechanism. Since the ancient time of Aristotle, electro-analgesic has been used to treat pain [68] and it was thought as a quackery practice. The GCT is a scientific foundation of electro stimulation based therapies and it was accepted by the medical community for pain relief soon after the publication of Wall and Sweet [27]. Later, endogenous opioids supported the chemical basis of using electrical stimulations and the explanatory model derived from GCT [69].

The theory has coincided with the recognition of therapy professions and their modalities. GCT has been integrated in pain science curriculum for therapists, which is helpful for better understanding rehabilitation interventions in pain. Many pain related clinical conditions mechanisms are poorly understood, but the therapist can use a theoretical rationale to explain pain from an unknown mechanism (i.e. phenomena like pain hypersensitivity, referred pain, etc.). It now underpins much of pain neuroscience education, which in itself has demonstrated the effect for pain management as part of a comprehensive approach to rehabilitation [70, 71].

Since the theory suggests that pain response and perception are triggered by sensory feedback and central integration via the dorsal horn, this can give us leverage to alter the pain perception by sensory input intervention. For example, desensitization uses graded exposure based therapy to different sensory inputs for modifying pain input [72], which would lead to reducing pain sensitivity via inhibitory mechanism. Interventions used in physical rehabilitation, including hands-on therapy, graded exercise result in sensory inputs via the “gate” in a way, which facilitates better pain control [54]. The theory can help rehabilitation professionals for extending their interventions into an innovative way to alter pain perception.


The GCT can explain pain hypersensitivity, which assist us in understanding some of the mechanisms at play in chronic musculoskeletal pain. Both researcher and clinician might be beneficial from theory-informed research and practice. Pain hypersensitivity responses after tissue injury are linked with the somatosensory signalling within the central nervous system [73]. Clinically, hypersensitivity manifests as two common but distinct abnormal pain responses (Table 1) either by lowering the pain threshold (allodynia) or increasing the pain response (hyperalgesia). These pain hypersensitivity phenomena have been found in different musculoskeletal pain conditions [9, 59, 74-83]. There is emerging evidence that early hypersensitivity is predictive of outcomes after injury, e.g. whiplash [59], and in chronically painful musculoskeletal conditions [11, 83]. However, we do not know if this extends to a number of upper extremity disorders, such as distal radius fracture, tenosynovitis, epicondylitis, and persistent post-operative pain after carpal tunnel release. Furthermore, much of this research has been conducted in controlled laboratory conditions and with devices not used in clinical practice making it difficult to move the findings into clinical practice. This underscores the need to continue to support the implementation of those devices and techniques validated with clinical populations and accessible for clinical use [84-98]. The GCT is a framework for understanding hypersensitivity in chronic pain. One of the critical next steps needed is reliable and valid psychophysical techniques for measuring hypersensitivity (pain sensitivity) and sensitivity to physical activity that can be operationalized in clinical settings using readily available testing equipment [99, 100].


Pain in humans is a multi-dimensional, complex sensation-perception that ultimately generates a huge burden to the society. It is affected by multidimensional factors (e.g. cognitive, emotional, and social). Many theories of pain have been proposed by scientists over the centuries, however, very few were accepted. The GCT has become the predominant theory with a resultant far-reaching impact on the understanding of pain mechanisms, providing a useful way for us to deal with the complexity of pain. The GCT stimulated an intense research interest and discovery in all branches of pain science for the last 50 years, due to the physiology-based, testable propositions of the theory.

Since somatosensory perception and integration are recognized as a contributor to the pain perception under GCT, then we can use the model to direct interventions aimed at pain relief. The theoretical concepts of pain from the gate control theory underpinning neurophysiology-based models of central integration continues to inform research and mechanism-specific management. Moving forward, the pain theory should be leveraged to develop and refine measurement tools with clinical utility for detecting and monitoring hypersensitivity, which can continue to elucidate the complexity behind pain responses and mechanisms. Application of GCT based model can assist the better clinical practice in chronic pain rehabilitation as well as improve research outcomes with the chronic pain population.


IASP = International Association for the Study of Pain
GCT = Gate Control Theory
SG = Substantia Gelatinosa
T-Cellfirst = Central Transmission Cell


All authors contributed in the Conceptualization of the study, Writing - original draft.


Not applicable.


This study was funded by the McMaster University School of Rehabilitation Science Graduate Scholarship, Canadian National Graduate Scholarship in Rehabilitation Science, CIHR Chair award (Gender in Measurement and Rehabilitation of Musculoskeletal Work Disability) and the Michael G. DeGroote Institute for Pain Research and Care.


The authors declare no conflict of interest, financial or otherwise.


Declared none.


Bonica JJ. The need of a taxonomy. Pain 1979; 6(3): 247-52.
Merskey H, Bogduk N, Eds. Classifications of chronic pain: description of pain syndromes and definition of pain terms 2nd ed. 1994.
MacDermid JC, Donner A, Richards RS, Roth JH. Patient versus injury factors as predictors of pain and disability six months after a distal radius fracture. J Clin Epidemiol 2002; 55(9): 849-54.
Macrae WA. Chronic post-surgical pain: 10 years on. Br J Anaesth 2008; 101(1): 77-86.
National Institutes of Health. New Directions in Pain Research 1998.
U. National Centres for Health Statistics. Chart book on Trends in the Health of Americans 2006.
Declaration of Montréal - IASP. n.d.
Morone NE, Weiner DK. Pain as the fifth vital sign: exposing the vital need for pain education. Clin Ther 2013; 35(11): 1728-32.
Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011; 152(3)(Suppl.): S2-S15.
IASP Taxonomy - IASP. n.d.
Mallen CD, Peat G, Thomas E, Dunn KM, Croft PR. Prognostic factors for musculoskeletal pain in primary care: a systematic review. Br J Gen Pract 2007; 57(541): 655-61.
Henry JL. The need for knowledge translation in chronic pain. Pain Res Manag 2008; 13(6): 465-76.
Mendell LM. Constructing and deconstructing the gate theory of pain. Pain 2014; 155(2): 210-6.
Borsook D, Edwards R, Elman I, Becerra L, Levine J. Pain and analgesia: the value of salience circuits. Prog Neurobiol 2013; 104: 93-105.
Hebb DO. The organization of behavior: A neuropsychological theory. Psychology Press 2005.
Nijs J, Meeus M, Cagnie B, et al. A modern neuroscience approach to chronic spinal pain: combining pain neuroscience education with cognition-targeted motor control training. Phys Ther 2014; 94(5): 730-8.
Katz J, Rosenbloom BN. The golden anniversary of Melzack and Wall’s gate control theory of pain: Celebrating 50 years of pain research and management. Pain Res Manag 2015; 20(6): 285-6.
Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965; 150(3699): 971-9.
Sandkühler J. The role of inhibition in the generation and amplification of pain. Current Topics in Pain: 12th World Congress on Pain 2009; 53-71.
Sandkühler J. Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 2009; 89(2): 707-58.
Kuner R. Central mechanisms of pathological pain. Nat Med 2010; 16(11): 1258-66.
Woolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004; 140(6): 441-51.
Curatolo M, Arendt-Nielsen L, Petersen-Felix S. Central hypersensitivity in chronic pain: mechanisms and clinical implications. Phys Med Rehabil Clin N Am 2006; 17(2): 287-302.
Melzack R, Wall PD. The challenge of pain 1988.
Moayedi M, Davis KD. Theories of pain: from specificity to gate control. J Neurophysiol 2013; 109(1): 5-12.
Wall PD. The gate control theory of pain mechanisms. A re-examination and re-statement. Brain 1978; 101(1): 1-18.
Wall PD, Sweet WH. Temporary abolition of pain in man. Science 1967; 155(3758): 108-9.
Price TJ, Cervero F, Gold MS, Hammond DL, Prescott SA. Chloride regulation in the pain pathway. Brain Res Brain Res Rev 2009; 60(1): 149-70.
Ignelzi RJ, Nyquist JK. Excitability changes in peripheral nerve fibers after repetitive electrical stimulation. Implications in pain modulation. J Neurosurg 1979; 51(6): 824-33.
Basbaum AI, Fields HL. Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu Rev Neurosci 1984; 7: 309-38.
Loomis CW, Khandwala H, Osmond G, Hefferan MP. Coadministration of intrathecal strychnine and bicuculline effects synergistic allodynia in the rat: an isobolographic analysis. J Pharmacol Exp Ther 2001; 296(3): 756-61.
Malan TP, Mata HP, Porreca F. Spinal GABA(A) and GABA(B) receptor pharmacology in a rat model of neuropathic pain. Anesthesiology 2002; 96(5): 1161-7.
Schoffnegger D, Ruscheweyh R, Sandkühler J. Spread of excitation across modality borders in spinal dorsal horn of neuropathic rats. Pain 2008; 135(3): 300-10.
Sherman SE, Loomis CW. Strychnine-sensitive modulation is selective for non-noxious somatosensory input in the spinal cord of the rat. Pain 1996; 66(2-3): 321-30.
Sivilotti L, Woolf CJ. The contribution of GABAA and glycine receptors to central sensitization: disinhibition and touch-evoked allodynia in the spinal cord. J Neurophysiol 1994; 72(1): 169-79.
Sorkin LS, Puig S, Jones DL. Spinal bicuculline produces hypersensitivity of dorsal horn neurons: effects of excitatory amino acid antagonists. Pain 1998; 77(2): 181-90.
Yaksh TL. Behavioral and autonomic correlates of the tactile evoked allodynia produced by spinal glycine inhibition: effects of modulatory receptor systems and excitatory amino acid antagonists. Pain 1989; 37(1): 111-23.
Ugarte SD, Homanics GE, Firestone LL, Hammond DL. Sensory thresholds and the antinociceptive effects of GABA receptor agonists in mice lacking the beta3 subunit of the GABA(A) receptor. Neuroscience 2000; 95(3): 795-806. [pii].
Eaton MJ, Plunkett JA, Martinez MA, et al. Transplants of neuronal cells bioengineered to synthesize GABA alleviate chronic neuropathic pain. Cell Transplant 1999; 8(1): 87-101.
Hwang JH, Yaksh TL. The effect of spinal GABA receptor agonists on tactile allodynia in a surgically-induced neuropathic pain model in the rat. Pain 1997; 70(1): 15-22. [pii].
Rode F, Jensen DG, Blackburn-Munro G, Bjerrum OJ. Centrally-mediated antinociceptive actions of GABA(A) receptor agonists in the rat spared nerve injury model of neuropathic pain. Eur J Pharmacol 2005; 516(2): 131-8.
Stubley LA, Martinez MA, Karmally S, Lopez T, Cejas P, Eaton MJ. Only early intervention with gamma-aminobutyric acid cell therapy is able to reverse neuropathic pain after partial nerve injury. J Neurotrauma 2001; 18(4): 471-7.
Britton NF, Skevington SM. A mathematical model of the gate control theory of pain. J Theor Biol 1989; 137(1): 91-105.
Torebjörk HE, Afferent G. Afferent C units responding to mechanical, thermal and chemical stimuli in human non-glabrous skin. Acta Physiol Scand 1974; 92(3): 374-90.
Torebjörk HE, Hallin RG. C-fibre units recorded from human sensory nerve fascicles in situ. A preliminary report. Acta Soc Med Ups 1970; 75(1-2): 81-4.
Torebjörk HE, Hallin RG. Perceptual changes accompanying controlled preferential blocking of A and C fibre responses in intact human skin nerves. Exp Brain Res 1973; 16(3): 321-32.
Torebjörk HE, Hallin RG. Identification of afferent C units in intact human skin nerves. Brain Res 1974; 67(3): 387-403.
Hallin RG, Torebjörk HE. Electrically induced A and C fibre responses in intact human skin nerves. Exp Brain Res 1973; 16(3): 309-20.
Van Hees J, Gybels JM. Pain related to single afferent C fibers from human skin. Brain Res 1972; 48: 397-400.
Nathan PW, Rudge P. Testing the gate-control theory of pain in man. J Neurol Neurosurg Psychiatry 1974; 37(12): 1366-72.
Nathan PW. The gate-control theory of pain. A critical review. Brain 1976; 99(1): 123-58.
Craig AD. Pain mechanisms: labeled lines versus convergence in central processing. Annu Rev Neurosci 2003; 26: 1-30.
Vaso A, Adahan H-M, Gjika A, et al. Peripheral nervous system origin of phantom limb pain. Pain 2014; 155(7): 1384-91.
Moseley GL. A pain neuromatrix approach to patients with chronic pain. Man Ther 2003; 8(3): 130-40.
Hodges PW. Pain and motor control: From the laboratory to rehabilitation. J Electromyogr Kinesiol 2011; 21(2): 220-8.
Mogil JS, Simmonds K, Simmonds MJ. Pain research from 1975 to 2007: a categorical and bibliometric meta-trend analysis of every Research Paper published in the journal, Pain. Pain 2009; 142(1-2): 48-58.
Coronado RA, Riddle DL, Wurtzel WA, George SZ. Bibliometric analysis of articles published from 1980 to 2009 in physical therapy, journal of the american physical therapy association. Phys Ther 2011; 91(5): 642-55.
Melzack R, Katz J. The gate control theory: Reaching for the brain. Pain: Psychological Perspectives 2004; 13-34.
Sterling M, Jull G, Vicenzino B, Kenardy J. Sensory hypersensitivity occurs soon after whiplash injury and is associated with poor recovery. Pain 2003; 104(3): 509-17.
Wertli M, Bachmann LM, Weiner SS, Brunner F. Prognostic factors in complex regional pain syndrome 1: a systematic review. J Rehabil Med 2013; 45(3): 225-31.
van Eijs F, Smits H, Geurts JW, et al. Brush-evoked allodynia predicts outcome of spinal cord stimulation in complex regional pain syndrome type 1. Eur J Pain 2010; 14(2): 164-9.
Packham TL, Spicher CJ, MacDermid JC, Michlovitz S, Buckley DN. Somatosensory rehabilitation for allodynia in complex regional pain syndrome of the upper limb: A retrospective cohort study. J Hand Ther 2017; 1-9.
Packham TL, MacDermid JC, Michlovitz S, Cup E, Van de Ven-Stevens L. Cross cultural adaptation and refinement of an English version of a Dutch patient-reported questionnaire for hand sensitivity: The Radboud Evaluation of Sensitivity. J Hand Ther 2018; 31(3): 371-80.
Packham TL, Spicher CJ, MacDermid JC. Evaluating a sensitive issue: Reliability and validity of allodynia measures used in the somatosensory rehabilitation method. Can J Pain 2017; 1: A158.
Mancini F, Beaumont A-L, Hu L, Haggard P, Iannetti GDD. Touch inhibits subcortical and cortical nociceptive responses. Pain 2015; 156(10): 1936-44.
Wall PD. Comments after 30 years of the gate control theory. Pain Forum 1996; 5-22.12-22.
Moseley LG, Zalucki NM, Wiech K. Tactile discrimination, but not tactile stimulation alone, reduces chronic limb pain. Pain 2008; 137(3): 600-8.
Kane K, Taub A. A history of local electrical analgesia. Pain 1975; 1(2): 125-38.
Sluka KA, Walsh D. Transcutaneous electrical nerve stimulation: basic science mechanisms and clinical effectiveness. J Pain 2003; 4(3): 109-21.
Louw A, Zimney K. E. “Louie” J. Puentedura, Retention of pain neuroscience knowledge: a multicentre trial. New Zeal J Physiother 2016; 44: 91-6.
Louw A, Zimney K, Puentedura EJ, Diener I. The efficacy of pain neuroscience education on musculoskeletal pain: A systematic review of the literature. Physiother Theory Pract 2016; 32(5): 332-55.
Goransson I, Cederlund R. A study of the effect of desensitization on hyperaesthesia in the hand and upper extremity after injury or surgery. Hand Ther 2010; 16: 12-8.
Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature 1983; 306(5944): 686-8.
Strauch B, Lang A, Ferder M, Keyes-Ford M, Freeman K, Newstein D. The ten test. Plast Reconstr Surg 1997; 99(4): 1074-8.
Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011; 152(3)(Suppl.): S2-S15.
Arendt-Nielsen L, Yarnitsky D. Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and viscera. J Pain 2009; 10(6): 556-72.
Graven-Nielsen T, Arendt-Nielsen L. Peripheral and central sensitization in musculoskeletal pain disorders: an experimental approach. Curr Rheumatol Rep 2002; 4(4): 313-21.
P. F., G. Pavlaković, F. Petzke, The role of quantitative sensory testing in the evaluation of musculoskeletal pain conditions. Curr Rheumatol Rep 2010; 0: 455-61.
Rivat C, Becker C, Blugeot A, et al. Chronic stress induces transient spinal neuroinflammation, triggering sensory hypersensitivity and long-lasting anxiety-induced hyperalgesia. Pain 2010; 150(2): 358-68.
Fernández-Carnero J, Fernández-de-las-Peñas C, Sterling M, Souvlis T, Arendt-Nielsen L, Vicenzino B. Exploration of the extent of somato-sensory impairment in patients with unilateral lateral epicondylalgia. J Pain 2009; 10(11): 1179-85.
Gwilym SE, Keltner JR, Warnaby CE, et al. Psychophysical and functional imaging evidence supporting the presence of central sensitization in a cohort of osteoarthritis patients. Arthritis Rheum 2009; 61(9): 1226-34.
Lewis C, Souvlis T, Sterling M. Sensory characteristics of tender points in the lower back. Man Ther 2010; 15(5): 451-6.
Lim ECW, Sterling M, Stone A, Vicenzino B. Central hyperexcitability as measured with nociceptive flexor reflex threshold in chronic musculoskeletal pain: a systematic review. Pain 2011; 152(8): 1811-20.
Strauch B, Lang A, Ferder M, Keyes-Ford M, Freeman K, Newstein D. The ten test. Plast Reconstr Surg 1997; 99(4): 1074-8.
Uddin Z, MacDermid J, Packham T. The ten test for sensation. J Physiother 2013; 59(2): 132.
Uddin Z, Macdermid JC. Novel physiotherapies a knowledge translation perspective on the two quantitative sensory tests and their usability with clinicians 2015; 5
Traynor R, MacDermid JC. Immersion in Cold-Water Evaluation (ICE) and self-reported cold intolerance are reliable but unrelated measures. Hand (N Y) 2008; 3(3): 212-9.
Uddin Z, Macdermid J, Packham T. Ice-water (cold stress) immersion testing. J Physiother 2013; 59(4): 277.
Uddin Z, MacDermid JC, Galea V, Gross AR, Pierrynowski MR. The current perception threshold test differentiates categories of mechanical neck disorder. J Orthop Sports Phys Ther 2014; 44(7): 532-540, C1.
Uddin Z, MacDermid JC, Moro J, Galea V, Gross AR, Goetze C. Psychophysical and patient factors as determinants of pain, function and health status in shoulder disorders. Open Orthop J 2016; 10: 466-80.
Uddin Z, MacDermid JC. Quantitative sensory testing in chronic musculoskeletal pain. Pain Med 2016; 17(9): 1694-703.
Uddin Z, Macdermid JC, Woodhouse LJ, Triano JJ, Galea V, Gross AR. The effect of pressure pain sensitivity and patient factors on self- reported pain-disability in patients with chronic neck pain 2014; 323-30.
Uddin Z, MacDermid JC, Ham HH. Test-retest reliability and validity of normative cut-offs of the two devices measuring touch threshold: Weinstein enhanced sensory test and pressure-specified sensory device. Hand Ther 2014; 19: 3-10.
Uddin Z, Macdermid JC, Galea V, Gross AR, Pierrynowski MR. Reliability indices, limits of agreement, and construct validity of the current perception threshold test in mechanical neck disorder. Crit Rev Phys Rehabil Med 2013; 25: 3-4.
Uddin Z, Macdermid J, Packham T. Clinical implementation of two quantitative sensory tests: Cold stress test and the ten test. Physiother Pract Res 2014; 35: 33-40.
Uddin Z, Woznowski-Vu A, Flegg D, Aternali A, Wickens R, Wideman TH. Evaluating the novel added value of neurophysiological pain sensitivity within the fear-avoidance model of pain. Eur J Pain 2019; 23(5): 957-72.
Woznowski-Vu A, Uddin Z, Flegg D, et al. Comparing novel and existing measures of sensitivity to physical activity among people with chronic musculoskeletal pain: the importance of tailoring activity to pain. Clin J Pain 2019; 35(8): 656-67.
Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; (5472): 1765-8.
Uddin Z, Woznowski-Vu A, Flegg D, Aternali A, Wideman TH. A cumulative impact of psychological and sensitization risk factors on pain‐related outcomes. Pain Pract 2021; 21(5): 523-35.
Uddin Z. Movement-evoked Pain (MEP). Clin J Pain 2021; 37(4): 310-1.