Application of Theory in Chronic Pain Rehabilitation Research and Clinical Practice

Introduction: 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. Methods: 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. Results: 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. Conclusion: 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.

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Mechanism of Peripheral Nerve Stimulation in Chronic Pain

Pain Medicine ◽

10.1093/pm/pnaa164 ◽

2020 ◽

Vol 21 (Supplement_1) ◽

pp. S6-S12 ◽

Cited By ~ 1

Author(s):

Tiffany Lin ◽

Akshat Gargya ◽

Harmandeep Singh ◽

Eellan Sivanesan ◽

Amitabh Gulati

Keyword(s):

Chronic Pain ◽

Literature Review ◽

Peripheral Nerve ◽

Nerve Stimulation ◽

Peripheral Nerve Stimulation ◽

Cochrane Library ◽

Gate Control Theory ◽

Comprehensive Literature Review ◽

Gate Control ◽

Chronic Pain Conditions

Abstract Introduction With the advancement of technology, peripheral nerve stimulation (PNS) has been increasingly used to treat various chronic pain conditions. Its origin is based on the gate control theory postulated by Wall and Melzack in 1965. However, the exact mechanism behind PNS’ analgesic effect is largely unknown. In this article, we performed a comprehensive literature review to overview the PNS mechanism of action. Design A comprehensive literature review on the mechanism of PNS in chronic pain. Methods Comprehensive review of the available literature on the mechanism of PNS in chronic pain. Data were derived from database searches of PubMed, Scopus, and the Cochrane Library and manual searches of bibliographies and known primary or review articles. Results Animal, human, and imaging studies have demonstrated the peripheral and central analgesic mechanisms of PNS by modulating the inflammatory pathways, the autonomic nervous system, the endogenous pain inhibition pathways, and involvement of the cortical and subcortical areas. Conclusions Peripheral nerve stimulation exhibits its neuromodulatory effect both peripherally and centrally. Further understanding of the mechanism of PNS can help guide stimulation approaches and parameters to optimize the use of PNS.

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REPRINTED WITH PERMISSION OF IASP – PAIN 160 (2019) 2679–2690: Conditioned pain modulation as a biomarker of chronic pain: a systematic review of its concurrent validity

Ból ◽

10.5604/01.3001.0014.6061 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1-15

Author(s):

Carina Fernandes ◽

Marina Pidal-Miranda ◽

Noelia Samartin-Veiga ◽

María T. Carrillo-de-la-Peña

Keyword(s):

Systematic Review ◽

Chronic Pain ◽

Concurrent Validity ◽

Clinical Symptoms ◽

Clinical Manifestations ◽

Experimental Pain ◽

Pain Modulation ◽

Conditioned Pain Modulation ◽

Pain Mechanisms ◽

Chronic Pain Conditions

Conditioned pain modulation (CPM) is a promising psychophysical biomarker of central pain mechanisms because it significantly discriminates patients with chronic pain from healthy controls. Nevertheless, it is unclear in what extent CPM assessed experimentally is correlated with clinical manifestations of pain. To assess the concurrent validity of CPM, we performed a systematic review of the literature reporting correlations between CPM responses and pain intensity, disability, duration, and area in patients with different chronic pain conditions. We included 32 studies that altogether encompassed data from 1958 patients and provided 62 correlations. The majority of the results (69%) reported nonsignificant correlations between CPM efficiency and clinical manifestations of pain, whereas the remaining results showed a correlation between CPM reduction and worse clinical symptoms of pain. The modality of stimulation, the type of pain, and the stimulation site appear to be critical variables that influenced the pattern of results. Given that most of the studies were conducted with highly heterogeneous methodologies and unclear risk of bias, the findings highlight the need for future studies using standardized measures of clinical and experimental pain before considering CPM as a valid biomarker of pain. We discuss some guidelines to overcome the constraints in this promising line of research.

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Role of endogenous pain modulation in chronic pain mechanisms and treatment

Pain ◽

10.1097/01.j.pain.0000460343.46847.58 ◽

2015 ◽

Vol 156 ◽

pp. S24-S31 ◽

Cited By ~ 141

Author(s):

David Yarnitsky

Keyword(s):

Chronic Pain ◽

Pain Modulation ◽

Pain Mechanisms ◽

Endogenous Pain Modulation

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Characterization of New TRPM8 Modulators in Pain Perception

International Journal of Molecular Sciences ◽

10.3390/ijms20225544 ◽

2019 ◽

Vol 20 (22) ◽

pp. 5544 ◽

Cited By ~ 8

Author(s):

Carmen De Caro ◽

Claudia Cristiano ◽

Carmen Avagliano ◽

Alessia Bertamino ◽

Carmine Ostacolo ◽

...

Keyword(s):

Chronic Pain ◽

Pain Perception ◽

Transient Receptor Potential ◽

Pain Modulation ◽

The Body ◽

Sprague Dawley ◽

Transient Receptor Potential Melastatin ◽

Pain Models ◽

Excessive Activation

Background: Transient Receptor Potential Melastatin-8 (TRPM8) is a non-selective cation channel activated by cold temperature and by cooling agents. Several studies have proved that this channel is involved in pain perception. Although some studies indicate that TRPM8 inhibition is necessary to reduce acute and chronic pain, it is also reported that TRPM8 activation produces analgesia. These conflicting results could be explained by extracellular Ca2+-dependent desensitization that is induced by an excessive activation. Likely, this effect is due to phosphatidylinositol 4,5-bisphosphate (PIP2) depletion that leads to modification of TRPM8 channel activity, shifting voltage dependence towards more positive potentials. This phenomenon needs further evaluation and confirmation that would allow us to understand better the role of this channel and to develop new therapeutic strategies for controlling pain. Experimental approach: To understand the role of TRPM8 in pain perception, we tested two specific TRPM8-modulating compounds, an antagonist (IGM-18) and an agonist (IGM-5), in either acute or chronic animal pain models using male Sprague-Dawley rats or CD1 mice, after systemic or topical routes of administration. Results: IGM-18 and IGM-5 were fully characterized in vivo. The wet-dog shake test and the body temperature measurements highlighted the antagonist activity of IGM-18 on TRPM8 channels. Moreover, IGM-18 exerted an analgesic effect on formalin-induced orofacial pain and chronic constriction injury-induced neuropathic pain, demonstrating the involvement of TRPM8 channels in these two pain models. Finally, the results were consistent with TRPM8 downregulation by agonist IGM-5, due to its excessive activation. Conclusions: TRPM8 channels are strongly involved in pain modulation, and their selective antagonist is able to reduce both acute and chronic pain.

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Manganese-enhanced MRI depicts a reduction in brain responses to nociception upon mTOR inhibition in chronic pain rats

Molecular Brain ◽

10.1186/s13041-020-00687-1 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Myeounghoon Cha ◽

Songyeon Choi ◽

Kyeongmin Kim ◽

Bae Hwan Lee

Keyword(s):

Chronic Pain ◽

Nerve Injury ◽

Pain Perception ◽

Imaging Techniques ◽

Insular Cortex ◽

Pain Modulation ◽

Anterior Cingulate ◽

Related Area ◽

Mtor Inhibition ◽

The Brain

AbstractNeuropathic pain induced by a nerve injury can lead to chronic pain. Recent studies have reported hyperactive neural activities in the nociceptive-related area of the brain as a result of chronic pain. Although cerebral activities associated with hyperalgesia and allodynia in chronic pain models are difficult to represent with functional imaging techniques, advances in manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) could facilitate the visualization of the activation of pain-specific neural responses in the cerebral cortex. In order to investigate the alleviation of pain nociception by mammalian target of rapamycin (mTOR) modulation, we observed cerebrocortical excitability changes and compared regional Mn2+ enhancement after mTOR inhibition. At day 7 after nerve injury, drugs were applied into the intracortical area, and drug (Vehicle, Torin1, and XL388) effects were compared within groups using MEMRI. Therein, signal intensities of the insular cortex (IC), primary somatosensory cortex of the hind limb region, motor cortex 1/2, and anterior cingulate cortex regions were significantly reduced after application of mTOR inhibitors (Torin1 and XL388). Furthermore, rostral-caudal analysis of the IC indicated that the rostral region of the IC was more strongly associated with pain perception than the caudal region. Our data suggest that MEMRI can depict pain-related signal changes in the brain and that mTOR inhibition is closely correlated with pain modulation in chronic pain rats.

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The Effectiveness of a Non-Invasive Shot Blocking Device for Reducing Pain of In-office Injections in Hand Surgery

Hand ◽

10.1177/1558944719884655 ◽

2019 ◽

pp. 155894471988465

Author(s):

Brian D. Rinker ◽

David A. Atashroo ◽

Megan A. Stout ◽

F. Ryan Wermeling

Keyword(s):

Pain Score ◽

Pain Perception ◽

Hand Surgery ◽

Pain Tolerance ◽

Rank Test ◽

Control Group ◽

Pain Scores ◽

Gate Control Theory ◽

Gate Control ◽

Blocking Device

Background: The gate control theory asserts that non-painful stimuli can block pain perception. The ShotBlocker™ device is a plastic disk with blunt projections that rests on the skin, and we hypothesize that it will reduce pain during hand injections. Methods: This is a prospective randomized trial of 117 patients undergoing injections for common hand conditions. Patients were randomized into 3 groups: device, placebo (device with projections removed), and control. Patients recorded on an analog pain scale the pain severity of the injection, as well as their most recent tetanus shot. A normalized pain score was obtained from the difference between the injection and tetanus shot pain scores. The mean non-normalized and normalized scores for each treatment group were compared to the control group using the Wilcoxon signed rank test. Results: There were 91 women and 26 men. Common diagnoses included trigger finger (n = 53), DeQuervain’s tendonitis (n = 33), and basal joint arthritis (n = 22). The groups did not differ significantly in age, gender, or diagnosis. Mean pain score in the device group was 5.2 out of 10, and it was 5.7 for the control group. The normalized pain score in the device group was significantly lower than the control group. Normalized and non-normalized pain scores for the placebo group were not significantly lower than the control group. Conclusions: The shot blocking device effectively reduced pain of injection versus controls when pain scores were normalized for pain tolerance. The modified device did not reduce the pain of injection, suggesting that gate control is the mechanism of action.

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Neuropathic pain in patients with haemophilia, that is the question

Hämostaseologie ◽

10.1055/s-0037-1619823 ◽

2015 ◽

Vol 35 (S 01) ◽

pp. S5-S9 ◽

Cited By ~ 6

Author(s):

S. Krüger ◽

T. Hilberg

Keyword(s):

Rheumatoid Arthritis ◽

Chronic Pain ◽

Neuropathic Pain ◽

Differential Diagnosis ◽

Pain Management ◽

Pain Mechanisms ◽

Number Of Patients ◽

Paindetect Questionnaire ◽

Chronic Disorders ◽

Chronic Pain Conditions

SummaryChronic pain caused by recurrent joint bleedings affects a large number of patients with haemophilia (PwH). The basis of this pain, nociceptive or neuropathic, has not been investigated so far. In other pain-related chronic disorders such as osteoarthritis or rheumatoid arthritis, initial studies showed nociceptive but also neuropathic pain features. 137 PwH and 33 controls (C) completed the painDETECT-questionnaire (pDq), which identifies neuropathic components in a person´s pain profile. Based on the pDq results, a neuropathic pain component is classified as positive, negative or unclear. A positive neuropathic pain component was found in nine PwH, but not in C. In 20 PwH an unclear pDq result was observed. In comparison to C the allocation of pDq results is statistically significant (p≤0.001). Despite various pDq results in PwH and C a similar appraisal pain quality, but on a different level, was determined. Summarising the results, there is a potential risk to misunderstand underlying pain mechanisms in PwH. In chronic pain conditions based on haemophilic arthopathy, a differential diagnosis seems to be unalterable for comprehensive and individualised pain management in PwH.

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Neuronal Plasticity Associated with Burn Injury and Its Relevance for Perception and Management of Pain in Burn Patients

Pain Research and Management ◽

10.1155/2000/541502 ◽

2000 ◽

Vol 5 (3) ◽

pp. 205-213

Author(s):

Terence J Coderre ◽

Manon Choinière

Keyword(s):

Neuronal Plasticity ◽

Pain Perception ◽

Burn Injury ◽

Clinical Care ◽

Strong Support ◽

Burn Injuries ◽

Burn Patients ◽

Pain Mechanisms ◽

Gate Control Theory

Through the introduction of the gate control theory and various subsequent works, Ronald Melzack has inspired many investigators worldwide to realize two important facts about pain. First, incoming pain messages are subject to both negative and positive modulation, which significantly affect its perception. Second, the progression of knowledge about the basic mechanisms underlying persistent and chronic pain is critically dependent on the increased understanding of the complexity of the symptoms experienced by pain patients. The present paper examines these two very important issues in an effort to understand better the mechanisms that underlie the pain suffered by burn patients. The physiological responses to burn injury involve many different mediators and mechanisms, all of which contribute to pain perception and development of neuronal plasticity underlying short and long term changes in pain sensitivity. While experimental burn injuries in humans and animals are typically well controlled and mild, in burn victims, the severity is much more variable, and clinical care involves repeated traumas and manipulations of the injured sites. Recurrent inputs from damaged and redamaged tissue impinge on a nervous system that becomes an active participant in the initiation of changes in sensory perception and maintenance of long term sensory disturbances. Recently acquired experimental evidence on postburn hyperalgesia, central hyperexcitability and changes in opioid sensitivity provides strong support that burn patients need an analgesic approach aimed at preventing or reducing the 'neural' memory of pain, including the use of more than one treatment modality. Burn injuries offer a unique opportunity to combine experimental and clinical research to understand pain mechanisms better. Over the years, Ronald Melzack has insisted that one of the most laudable enterprises in research is to span the gap between these two often separate worlds.

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Spinal NGF Restores Opioid Sensitivity in Neuropathic Rats: Possible Role of NGF as a Regulator of CCK-Induced Anti-Opioid Effects

Pain Research and Management ◽

10.1155/2000/347212 ◽

2000 ◽

Vol 5 (1) ◽

pp. 49-57 ◽

Cited By ~ 1

Author(s):

Catherine M Cahill ◽

Terence J Coderre

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Nerve Injury ◽

Postnatal Period ◽

Spontaneous Pain ◽

Pain Mechanisms ◽

Nociceptive Neurons ◽

Nociceptive Transmission ◽

Chronic Pain Conditions ◽

Injury Models

The breadth of peripheral effects produced by nerve growth factor (NGF) in nociceptive processing has been well documented. However, less is known about the functional significance of central NGF in nociceptive transmission. The effect of NGF on the nervous system is dependent on the developmental stage. During the prenatal developmental period, NGF is critical for survival of nociceptors; in the postnatal period it regulates the expression of nociceptor phenotype, and in the adult it contributes to pain following an inflammatory insult. The implications for central NGF in the expression and regulation of spinal neuropeptides that are involved in pain mechanisms are reviewed. Knowledge has been gained by studies using peripheral nerve injury models that cause a deprivation of central NGF. These models also give rise to the development of pain syndromes, which encompass spontaneous pain, hyperalgesia and allodynia, routinely referred to as neuropathic pain. These models provide an approach for examining the contribution of central NGF to nociceptive transmission. Chronic pain emanating from a nerve injury is typically refractory to traditional analgesics such as opioids. Recent evidence suggests that supplementation of spinal NGF restores morphine-induced antinociception in an animal model of neuropathic pain. This effect appears to be mediated by alterations in spinal levels of cholecystokinin. The authors hypothesize that NGF is critical in maintaining neurochemical homeostasis in the spinal cord of nociceptive neurons, and that supplementation may be beneficial in restoring and/or maintaining opioid analgesia in chronic pain conditions resulting from traumatic nerve injury.

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The association between pain-induced autonomic reactivity and descending pain control is mediated by the periaqueductal grey

10.1101/2020.10.26.355529 ◽

2020 ◽

Author(s):

Elena Makovac ◽

Alessandra Venezia ◽

David Hohenschurz-Schmidt ◽

Ottavia Dipasquale ◽

Jade B Jackson ◽

...

Keyword(s):

Chronic Pain ◽

Functional Connectivity ◽

Pain Control ◽

Brain Regions ◽

Pain Modulation ◽

Autonomic Reactivity ◽

Pain Mechanisms ◽

Cold Pain ◽

Periaqueductal Grey ◽

Descending Pain Modulation

AbstractThere is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored.Here, we sought to determine brain regions mediating ANS and descending pain control associations. 30 participants underwent Conditioned Pain Modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between ‘pressure-only’ and ‘pressure+cold’ stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain-free and one during cold-pain, were acquired. Heart Rate Variability (HRV) was simultaneously recorded.Low frequency HRV (LF-HRV) and the CPM score were negatively correlated; individuals with higher LF-HRV during pain reported reductions in pain during CPM. PAG-frontal medial cortex (FMC) and PAG-rostral ventro-medial medulla (RVM) functional connectivity correlated negatively with the CPM. Importantly, PAG-FMC functional connectivity mediated the strength of HRV-CPM association. CPM response magnitude was also negatively associated with PAG and positively associated with FMC grey matter volumes.Our multi-modal approach, using behavioral, physiological and MRI measures, provides important new evidence of interactions between ANS and descending pain mechanisms. ANS dysregulation and dysfunctional descending pain modulation are characteristics of chronic pain. We suggest that further investigation of body-brain interactions in chronic pain patients may catalyse the development of new treatments.

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