Maladaptive Pain Research Articles

Psychosocial characteristics of chronic pain in cancer survivors referred to an Australian multidisciplinary pain clinic.

To describe the clinical and psychosocial characteristics of chronic pain in cancer survivors referred to one Australian hospital's ambulatory pain clinic over a 7-year period (2013-19), and to compare cancer treatment-related pain with comorbid non-malignant pain. Retrospective chart review including responses to standardized self-report questionnaires (Brief Pain Inventory, Depression Anxiety Stress Scale, Pain Self-Efficacy Questionnaire, Pain Catastrophizing Scale), routinely collected in all patients referred to pain clinics at Australian and New Zealand hospitals. Of 3510 new referrals during the study period, 267 (7.5%) had a history of cancer and 176 (5.0%) met the study's eligibility criteria. Their average age was 63±13years, with 55% female. Breast cancer survivors were commonest, followed by hematological, prostate, melanoma, and colorectal, a median of 3years post-diagnosis. Pain was attributed to cancer treatment in 87 (49%), surgery being the commonest modality. Multimodal treatment (n=89, 58%) was significantly commoner in the treatment-related pain group (p<0.001). Average pain severity was moderate, as was pain-related disability and distress. Pain cognitions were often maladaptive (low pain self-efficacy, high pain catastrophizing), predicted by pre-existing anxiety and depression. Associations between pain cognitions and outcomes were medium-to-large. Differences between treatment pain and comorbid pain were small-to-medium. Their scores were similar to Australian pain clinic norms. Cancer treatment causes tissue damage, but pain-related distress and disability in survivors is associated with maladaptive pain cognitions. Survivors with poor pain outcomes should be evaluated for unhelpful thoughts and beliefs especially when they have pre-existing depression or anxiety.

Quality of life in children and adolescents with eosinophilic esophagitis

ABSTRACT EoE symptoms and treatments place affected children at risk for reduced quality of life. Yet relatively little is known about the factors that affect health related quality of life (HRQoL) in youth with EoE. This study examined symptom burden and HRQoL in 267 children and adolescents with EoE. Pain catastrophizing was significantly related to both EoE symptom reports and HRQoL (p < .001). Further, children with significantly elevated psychological symptom reports experienced more symptom burden and worse HRQoL (p < .001). Effective health care for children with EoE includes addressing quality of life, psychological symptoms, and maladaptive pain cognitions when present, in addition to managing inflammation.

Catastrophizing and Pain: The Problem May be Everywhere, but an Answer's in Your Head

AIM: The aim of this investigation was to evaluate the evidence surrounding catastrophizing in the pain patient, its effects on patient experience and patient outcomes, and strategies to help minimize catastrophizing, reverse its maladaptive effects, and support more restorative patterns of thinking. METHODS: The current data on catastrophizing, maladaptive pain behaviors, the pain catastrophizing scale and treatment strategies was reviewed from a perspective of behavioral health and neuroscience both in adults and children RESULTS: Catastrophizing is a common behavior among pain patients.

“I don't want to be a burden” A qualitative study of the beliefs of women with chronic low back pain in relation to their painful experience

BackgroundWomen's pain is still poorly understood. Moreover, maladaptive pain beliefs contribute to the disability associated with low back pain and play a key role in the transition from acute to chronic symptoms. ObjectivesTo explore the beliefs of women with non-specific chronic low back pain in terms of nature of symptoms, fears associated with pain, expectations for recovery, family, social and work-related limitations, and perceived self-efficacy. Design and methodsA qualitative study with an interpretative approach was undertaken. Face-to-face, semi-structured individual interviews were performed. Study participants were 10 women with non-specific chronic low back pain living in the Metropolitan Region of Chile. Thematic analysis was used to analyze the data. A deductive process was used to code the text and categorize the data. ResultsParticipants described maladaptive beliefs about pain, leading to fearful attitudes and low expectations for recovery. These beliefs seemed to perpetuate pain and limit engagement in daily tasks and meaningful activities. Some of these beliefs were associated with information provided by healthcare professions. Despite having maladaptive beliefs, women perceived themselves as self-effective. ConclusionWomen with chronic low back pain described a range of different pain beliefs across a complex categorial structure. The contents of such structure may interfere with their decisions about therapeutic options. Their beliefs were often ungrounded in scientific principles, even if the information may have been provided by healthcare providers. Physical therapists would benefit from these findings to improve communication with their patients and assess the role of beliefs in decision-making.

Pain catastrophizing mediates rapid benefits of accessing in-person chiropractic care during the COVID-19 lockdown.

BackgroundIn March 2020, the COVID‐19 pandemic forced the Spanish government to declare a state of emergency. A stringent lockdown was enforced, restricting access to healthcare services, including chiropractic. Reduced access to care provision in combination with psychological stress, social isolation and physical inactivity during the lockdown were shown to negatively influence pain conditions. However, data on strategies to mitigate the impact of the pandemic on these conditions are lacking.MethodsUpon easing of restrictions in May 2020, 51 chiropractic clinics throughout Spain pseudo‐randomly invited patients, recruiting a total of 385 participants. During a 14‐day period, participants were exposed to in‐person chiropractic care in either one (n = 177) or multiple encounters (n = 109) or to no care (n = 99). The effects of access to chiropractic care on patients’ pain‐related and psychological outcomes were assessed online through validated self‐reported questionnaires before and after the period of care. Coprimary outcomes included pain intensity, pain interference and pain cognitions.ResultsWhen comparing to participants without access to care, pain intensity and interference were significantly decreased at follow‐up, irrespective of the number of encounters. Kinesiophobia was also significantly reduced at follow‐up, though only after multiple encounters. The relationship between fear of movement, changes in pain intensity and interference was mediated by catastrophizing.ConclusionAccess to in‐person chiropractic care may provide pain relief, associated with reductions in interference and pain cognitions. Prioritizing in‐person care for patients with maladaptive pain cognitions may help dampen the detrimental consequences of the pandemic on physical and psychological well‐being.

FeTMPyP a peroxynitrite decomposition catalyst ameliorated functional and behavioral deficits in chronic constriction injury induced neuropathic pain in rats

Neuropathic pain is a maladaptive pain phenotype that results from injury or damage to the somatosensory nervous system and is proposed to be linked to a cascade of events including excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation and apoptosis. Oxidative/nitrosative stress is a critical link between neuroinflammation and neurodegeneration through poly (ADP) ribose polymerase (PARP) overactivation. Hence, the present study investigated the antioxidant and anti-inflammatory effects of peroxynitrite decomposition catalyst; FeTMPyP in chronic constriction injury (CCI) of sciatic nerve-induced neuropathy in rats. CCI of the sciatic nerve manifested significant deficits in behavioral, biochemical, functional parameters and was markedly reversed by administration of FeTMPyP. After 14 days of CCI induction, oxidative/nitrosative stress and inflammatory markers such as iNOS, NF-kB, TNF-α and IL-6 were elevated in sciatic nerves of CCI rats along with depleted levels of ATP and elevated levels of poly (ADP) ribose (PAR) in both sciatic nerves in ipsilateral (L4-L5) dorsal root ganglions (DRG’s), suggesting over activation of PARP. Additionally, CCI resulted in aberrations in mitochondrial function as evident by decreased Mn-SOD levels and respiratory complex activities with increased mitochondrial fission protein DRP-1. These changes were reversed by treatment with FeTMPyP (1 & 3 mg/kg, p.o.). Findings of this study suggest that FeTMPyP, by virtue of its antioxidant properties, reduced both PARP over-activation and subsequent neuroinflammation resulted in protection against CCI-induced functional, behavioral and biochemical deficits.

NOCICEPTRA: Gene and microRNA Signatures and Their Trajectories Characterizing Human iPSC-Derived Nociceptor Maturation.

Nociceptors are primary afferent neurons serving the reception of acute pain but also the transit into maladaptive pain disorders. Since native human nociceptors are hardly available for mechanistic functional research, and rodent models do not necessarily mirror human pathologies in all aspects, human induced pluripotent stem cell‐derived nociceptors (iDN) offer superior advantages as a human model system. Unbiased mRNA::microRNA co‐sequencing, immunofluorescence staining, and qPCR validations, reveal expression trajectories as well as miRNA target spaces throughout the transition of pluripotent cells into iDNs. mRNA and miRNA candidates emerge as regulatory hubs for neurite outgrowth, synapse development, and ion channel expression. The exploratory data analysis tool NOCICEPTRA is provided as a containerized platform to retrieve experimentally determined expression trajectories, and to query custom gene sets for pathway and disease enrichments. Querying NOCICEPTRA for marker genes of cortical neurogenesis reveals distinct similarities and differences for cortical and peripheral neurons. The platform provides a public domain neuroresource to exploit the entire data sets and explore miRNA and mRNA as hubs regulating human nociceptor differentiation and function.

Does the Addition of Pain Neurophysiology Education to a Therapeutic Exercise Program Improve Physical Function in Women with Fibromyalgia Syndrome? Secondary Analysis of a Randomized Controlled Trial.

Therapeutic exercise (TE) is one of the most investigated approaches for the management of FMS. Pain neurophysiology education (PNE) helps toward understanding the pain condition, leading to maladaptive pain cognitions and coping strategies in patients with chronic pain. Our study aimed to assess the effects of therapeutic exercise and pain neurophysiology education versus TE in isolation on fatigue, sleep disturbances, and physical function in the short term and at three months of follow-up in women with fibromyalgia syndrome (FMS). A single-blind randomized controlled trial was carried out. A total of 32 women with FMS referred from medical doctors and fibromyalgia association were randomized in 2 groups: PNE + TE group or TE group. Fatigue and sleep disturbances (Visual Analog Score) and physical function (Senior Fitness Test) were assessed before, after intervention, and at three months of follow-up. Significant improvements were achieved in the Timed Up and Go test (p = 0.042) and Arm Curl test (p = 0.043) after intervention and on handgrip in the non-dominant side at three months of follow-up (p = 0.036) on the PNE + TE group. No between-groups differences were found for fatigue, sleep disturbances, and the rest of test included in the Senior Fitness Test. In conclusion, these results suggest that PNE + TE appears to be more effective than TE in isolation for the improvement of physical function (Timed Up and Go test and Arm Curl test) in women with FMS in the short term.

Chronic Pain in Dogs and Cats: Is There Place for Dietary Intervention with Micro-Palmitoylethanolamide?

Simple SummaryChronic pain is being increasingly recognized and addressed in small animal practice. The recent recognition that inability to communicate does not negate the possibility to experience pain requires veterinarians to actively recognize, assess and manage animal pain. In order to successfully treat pain while limiting side effects, a combination of different therapeutic weapons (e.g., analgesic drugs, acupuncture, physiotherapy and dietary interventions) is currently preferred. In this perspective, the endocannabinoid-like palmitoylethanolamide represents a promising option, since it is naturally occurring in food sources and animal tissues, addresses the mechanisms of chronic pain (i.e., immune cell hyperactivity) and is presently used in complementary feeds for dogs and cats in highly absorbable micronized formulations (i.e., micro-palmitoylethanolamide). In the present paper, the role of immune non-neuronal cells in chronic pain is reviewed. Moreover, the function of body-own palmitoylethanolamide in controlling pain through non-neuronal cell modulation is discussed. Finally, data on pain-relieving effects provided by dietary supplementation with micro-palmitoylethanolamide are presented. The critical mass of data here reviewed might help veterinary practitioners in the process of evidence-based decision-making regarding the management of chronic pain in cats and dogs.The management of chronic pain is an integral challenge of small animal veterinary practitioners. Multiple pharmacological agents are usually employed to treat maladaptive pain including opiates, non-steroidal anti-inflammatory drugs, anticonvulsants, antidepressants, and others. In order to limit adverse effects and tolerance development, they are often combined with non-pharmacologic measures such as acupuncture and dietary interventions. Accumulating evidence suggests that non-neuronal cells such as mast cells and microglia play active roles in the pathogenesis of maladaptive pain. Accordingly, these cells are currently viewed as potential new targets for managing chronic pain. Palmitoylethanolamide is an endocannabinoid-like compound found in several food sources and considered a body’s own analgesic. The receptor-dependent control of non-neuronal cells mediates the pain-relieving effect of palmitoylethanolamide. Accumulating evidence shows the anti-hyperalgesic effect of supplemented palmitoylethanolamide, especially in the micronized and co-micronized formulations (i.e., micro-palmitoylethanolamide), which allow for higher bioavailability. In the present paper, the role of non-neuronal cells in pain signaling is discussed and a large number of studies on the effect of palmitoylethanolamide in inflammatory and neuropathic chronic pain are reviewed. Overall, available evidence suggests that there is place for micro-palmitoylethanolamide in the dietary management of chronic pain in dogs and cats.

Clinical Presentation and Evaluation of Pelvic Venous Disorders in Women

The term pelvic venous disorders (PeVD) describes a group of related clinical entities with overlapping clinical presentations that were previously characterized by separate imprecise syndromic terminology. The clinical manifestations of PeVD may variously include chronic pelvic pain; pelvic origin extrapelvic lower extremity and genital varices; lower extremity pain and swelling; and left flank pain and hematuria. This manuscript focuses on the primary manifestations of PeVD in women - chronic pelvic pain and pelvic origin lower extremity and vulvar varices - and will review the underlying pathophysiology and related complicating factors (such as maladaptive pain responses) to explain the variety of clinical presentations.

Circuit-Specific Plasticity of Callosal Inputs Underlies Cortical Takeover.

Injury induces synaptic, circuit, and systems reorganization. After unilateral amputation or stroke, this functional loss disrupts the interhemispheric interaction between intact and deprived somatomotor cortices to recruit deprived cortex in response to intact limb stimulation. This recruitment has been implicated in enhanced intact sensory function. In other patients, maladaptive consequences such as phantom limb pain can occur. We used unilateral whisker denervation in male and female mice to detect circuitry alterations underlying interhemispheric cortical reorganization. Enhanced synaptic strength from the intact cortex via the corpus callosum (CC) onto deep neurons in deprived primary somatosensory barrel cortex (S1BC) has previously been detected. It was hypothesized that specificity in this plasticity may depend on to which area these neurons projected. Increased connectivity to somatomotor areas such as contralateral S1BC, primary motor cortex (M1) and secondary somatosensory cortex (S2) may underlie beneficial adaptations, while increased connectivity to pain areas like anterior cingulate cortex (ACC) might underlie maladaptive pain phenotypes. Neurons from the deprived S1BC that project to intact S1BC were hyperexcitable, had stronger responses and reduced inhibitory input to CC stimulation. M1-projecting neurons also showed increases in excitability and CC input strength that was offset with enhanced inhibition. S2 and ACC-projecting neurons showed no changes in excitability or CC input. These results demonstrate that subgroups of output neurons undergo dramatic and specific plasticity after peripheral injury. The changes in S1BC-projecting neurons likely underlie enhanced reciprocal connectivity of S1BC after unilateral deprivation consistent with the model that interhemispheric takeover supports intact whisker processing.SIGNIFICANCE STATEMENT Amputation, peripheral injury, and stroke patients experience widespread alterations in neural activity after sensory loss. A hallmark of this reorganization is the recruitment of deprived cortical space which likely aids processing and thus enhances performance on intact sensory systems. Conversely, this recruitment of deprived cortical space has been hypothesized to underlie phenotypes like phantom limb pain and hinder recovery. A mouse model of unilateral denervation detected remarkable specificity in alterations in the somatomotor circuit. These changes underlie increased reciprocal connectivity between intact and deprived cortical hemispheres. This increased connectivity may help explain the enhanced intact sensory processing detected in humans.

Neuropathic Pain: How to Assess and Treat a Maladaptive Pain Response

Neuropathic pain is associated with primary lesion or dysfunction of the peripheral and central nerve systems, affecting up to 10% of the general population. Although both nociceptive pain and neuropathic pain utilize the same nervous system pathways, physiologic differences exist in the pathologic mechanism, clinical presentation, and treatments. Ectopic activity in primary afferent fibers, excitatory and inhibitory somatosensory signaling, nociceptive neuron alterations, and central pain modulation have been implicated in neuropathic pain. These neuropathic mechanisms are associated with the complexity of symptoms, difficult treatment decisions, and challenging poor outcomes. Treatment options include pharmacologic (e.g., anticonvulsants, antidepressants, lidocaine, N-methyl-D-aspartate antagonist, opioids), physical, psychological (e.g., cognitive behavioral therapy), or interventional management (e.g., peripheral or neuro-axial nerve blockade, spinal cord stimulators, intrathecal medications). Medication selection should be individualized, considering patients’ symptoms and potential beneficial or deleterious effects (side effects) on comorbidities. The interventional management of chronic neuropathic pain should be considered for patients who have not responded to pharmacologic and non-interventional treatments, as an integral component of a more comprehensive approach. This article presents an overview of physiological mechanisms, clinical presentation, and assessment of neuropathic pain, and discusses treatment options for neuropathic pain.

Does Pain Neuroscience Education and Cognition-Targeted Motor Control Training Improve Cervical Motor Output? Secondary Analysis of a Randomized Clinical Trial.

In the context of interventions aimed at reducing pain, disability, and maladaptive pain cognitions in chronic neck pain, it is hypothesized that patients who have greater symptom reduction possibly also demonstrate greater improvement in cervical motor output. Therefore, the aim of this study was to examine the effect of pain neuroscience education plus cognition-targeted motor control training on cervical motor output. Impairments in cervical motor output were measured in 64 subjects with chronic neck pain using standardized tests. Cervical muscle strength, cervical mobility, balance, and cervical neuromuscular control were derived. To assess the differences between groups in response to treatment, a random-intercept linear mixed-models analysis, applying a diagonal covariance matrix, was used. A significant treatment × time interaction effect was found for neuromuscular control of the deep cervical flexors, favoring the experimental treatment at 3months' follow-up (mean group difference: 1.982; 95% confidence interval 0.779, 3.185; large effect size d=0.82). Significant main effects of time were found for the neuromuscular capacity of scapulothoracic muscles and for cervical mobility. No significant effects were found for balance, cervical muscle strength, or endurance of cervical flexors. Pain neuroscience education combined with cognition-targeted motor control training is not more effective than biomedically focused education and exercise therapy for improving cervical motor output in people with chronic neck pain. Our findings question the relative importance of factors such as pain, disability, and maladaptive pain cognitions on cervical motor output and the need to address it in treatment.

Treatment of chronic neuropathic pain: purine receptor modulation.

Extracellular nucleosides and nucleotides have widespread functions in responding to physiological stress. The "purinome" encompasses 4 G-protein-coupled receptors (GPCRs) for adenosine, 8 GPCRs activated by nucleotides, 7 adenosine 5'-triphosphate-gated P2X ion channels, as well as the associated enzymes and transporters that regulate native agonist levels. Purinergic signaling modulators, such as receptor agonists and antagonists, have potential for treating chronic pain. Adenosine and its analogues potently suppress nociception in preclinical models by activating A1 and/or A3 adenosine receptors (ARs), but safely harnessing this pathway to clinically treat pain has not been achieved. Both A2AAR agonists and antagonists are efficacious in pain models. Highly selective A3AR agonists offer a novel approach to treat chronic pain. We have explored the structure activity relationship of nucleoside derivatives at this subtype using a computational structure-based approach. Novel A3AR agonists for pain control containing a bicyclic ring system (bicyclo [3.1.0] hexane) in place of ribose were designed and screened using an in vivo phenotypic model, which reflected both pharmacokinetic and pharmacodynamic parameters. High specificity (>10,000-fold selective for A3AR) was achieved with the aid of receptor homology models based on related GPCR structures. These A3AR agonists are well tolerated in vivo and highly efficacious in models of chronic neuropathic pain. Furthermore, signaling molecules acting at P2X3, P2X4, P2X7, and P2Y12Rs play critical roles in maladaptive pain neuroplasticity, and their antagonists reduce chronic or inflammatory pain, and, therefore, purine receptor modulation is a promising approach for future pain therapeutics. Structurally novel antagonists for these nucleotide receptors were discovered recently.

Cytotoxic Immunity in Peripheral Nerve Injury and Pain.

Cytotoxicity and consequent cell death pathways are a critical component of the immune response to infection, disease or injury. While numerous examples of inflammation causing neuronal sensitization and pain have been described, there is a growing appreciation of the role of cytotoxic immunity in response to painful nerve injury. In this review we highlight the functions of cytotoxic immune effector cells, focusing in particular on natural killer (NK) cells, and describe the consequent action of these cells in the injured nerve as well as other chronic pain conditions and peripheral neuropathies. We describe how targeted delivery of cytotoxic factors via the immune synapse operates alongside Wallerian degeneration to allow local axon degeneration in the absence of cell death and is well-placed to support the restoration of homeostasis within the nerve. We also summarize the evidence for the expression of endogenous ligands and receptors on injured nerve targets and infiltrating immune cells that facilitate direct neuro-immune interactions, as well as modulation of the surrounding immune milieu. A number of chronic pain and peripheral neuropathies appear comorbid with a loss of function of cellular cytotoxicity suggesting such mechanisms may actually help to resolve neuropathic pain. Thus while the immune response to peripheral nerve injury is a major driver of maladaptive pain, it is simultaneously capable of directing resolution of injury in part through the pathways of cellular cytotoxicity. Our growing knowledge in tuning immune function away from inflammation toward recovery from nerve injury therefore holds promise for interventions aimed at preventing the transition from acute to chronic pain.

Pain Is Inevitable But Suffering Is Optional: Relationship of Pain Coping Strategies to Performance in Multistage Ultramarathon Runners

Ultramarathon runners commonly endure musculoskeletal pain during endurance events. However, the effect of pain coping skills on performance has not been examined. A prospective observational study during three 250 km (155 mi), 6 stage ultramarathons was conducted. Finish line surveys were completed after each of the four 40 km (25 mi) and one 80 km (50 mi) stages of racing. Variables gathered included pain intensity, pain coping strategy use, pain interference, finishing position (quintile), and successful race completion. A total of 204 participants (age 41.4±10.3 y; 73% male) reported average pain intensity of 3.9 (±2.0 SD) and worst pain intensity of 5.3 (±2.3) on a 0 to 10 scale. They used greater adaptive pain coping strategies (3.0±1.3) relative to maladaptive strategies (1.3±1.1). Worst pain and pain interference increased over each stage of the race for all runners (P<0.001), with worst pain being significantly different by finishing status (P=0.02). Although all runners endured increased pain and interference, the nonfinishers (28 [14%]) had significantly greater differences in changes in pain intensity (P<0.01) and pain interference (P<0.001). Maladaptive pain coping strategies were more common in nonfinishers; with each 1-point increase (0-6 scale), there was a 3 times increase in odds of not finishing the race. Although increased pain intensity and pain interference was found in all multistage ultramarathon runners, successful event completion was significantly associated with less maladaptive pain coping. Training in coping with pain may be a beneficial part of ultramarathon preparation.

Pack-years of tobacco cigarette smoking as a predictor of spontaneous pain reporting and experimental pain reactivity.

The pack-years formula is a widely used estimate of lifetime tobacco smoking exposure, and greater pack-years have been associated with greater risk of chronic pain development and poorer pain-related outcomes among smokers with chronic pain. The pathophysiology underlying these associations is poorly understood. Regular tobacco smoking exposure may dysregulate homeostatic pain processes, producing an allostatic state of pain facilitation. Maladaptive pain mechanisms, such as central and peripheral sensitization, are chronic pain risk factors. Yet no published research has examined the relation between lifetime-smoking exposure and dysregulated pain processing. The current study used hierarchical linear regression analyses to test pack-years of tobacco smoking as a predictor of (a) pain reporting (current pain severity, pain frequency in the last 180 days) among a sample of 228 daily smokers without chronic pain, and (b) experimental capsaicin-induced pain reactivity (pain intensity, area of flare, mechanical pain sensitivity, and area of mechanical hyperalgesia) among 101 daily smokers without chronic pain. As hypothesized, results indicated that pack-years smoking was positively and significantly associated with current pain severity, past 180-day pain frequency, experimental pain intensity, mechanical pain sensitivity ratings, and area of mechanical hyperalgesia. Pack-years smoking was not significantly associated with neurogenic flare. These findings implicate central sensitization as a factor that may underlie the association between chronic tobacco smoking and increased risk for persistent pain. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Nerve Injury-Induced Neuronal PAP-I Maintains Neuropathic Pain by Activating Spinal Microglia.

Pancreatitis-associated proteins (PAPs) display multiple functions in visceral diseases. Previous studies showed that the expression level of PAP-I was low in the DRG of naive rats but was de novo expressed after peripheral nerve injury. However, its role in neuropathic pain remains unknown. We found that PAP-I expression was continuously upregulated in the DRG neurons from rat spared nerve injury models, and transported toward the spinal dorsal horn to act as a proinflammatory factor. Intrathecal delivery of PAP-I enhanced sensory hyperalgesia, whereas PAP-I deficiency by either gene knockout or antibody application alleviated tactile allodynia at the maintenance phase after spared nerve injury. Furthermore, PAP-I functioned by activating the spinal microglia via C-C chemokine receptor Type 2 that participated in neuropathic pain. Inhibition of either microglial activation or C-C chemokine receptor Type 2 abolished the PAP-I-induced hyperalgesia. Thus, PAP-I mediates the neuron-microglial crosstalk after peripheral nerve injury and contributes to the maintenance of neuropathic pain.SIGNIFICANCE STATEMENT Neuropathic pain is maladaptive pain condition, and the maintaining mechanism is largely unclear. Here we reveal that, after peripheral nerve injury, PAP-I can be transported to the spinal dorsal horn and is crucial in the progression of neuropathic pain. Importantly, we prove that PAP-I mainly functions through activating the spinal microglia via the CCR2-p38 MAPK pathway. Furthermore, we confirm that the proinflammatory effect of PAP-I is more prominent after the establishment of neuropathic pain, thus indicating that microglia also participate in the maintenance phase of neuropathic pain.

Adaptive mechanisms driving maladaptive pain: how chronic ongoing activity in primary nociceptors can enhance evolutionary fitness after severe injury.

Chronic pain is considered maladaptive by clinicians because it provides no apparent protective or recuperative benefits. Similarly, evolutionary speculations have assumed that chronic pain represents maladaptive or evolutionarily neutral dysregulation of acute pain mechanisms. By contrast, the present hypothesis proposes that chronic pain can be driven by mechanisms that evolved to reduce increased vulnerability to attack from predators and aggressive conspecifics, which often target prey showing physical impairment after severe injury. Ongoing pain and anxiety persisting long after severe injury continue to enhance vigilance and behavioural caution, decreasing the heightened vulnerability to attack that results from motor impairment and disfigurement, thereby increasing survival and reproduction (fitness). This hypothesis is supported by evidence of animals surviving and reproducing after traumatic amputations, and by complex specializations that enable primary nociceptors to detect local and systemic signs of injury and inflammation, and to maintain low-frequency discharge that can promote ongoing pain indefinitely. Ongoing activity in nociceptors involves intricate electrophysiological and anatomical specializations, including inducible alterations in the expression of ion channels and receptors that produce persistent hyperexcitability and hypersensitivity to chemical signals of injury. Clinically maladaptive chronic pain may sometimes result from the recruitment of this powerful evolutionary adaptation to severe bodily injury. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.

55. Ending opioid addiction following spine surgery

BACKGROUND CONTEXT Opioid addiction is the number one health care issue in the United States with spinal ailments the leading medical condition associated with opioid addiction. Patients with chronic pain syndrome and opioid addiction going for spine surgery are at high risk for several poor outcomes, including life-long use of opioids. Current evidence-based methods to optimize patients prior to spine surgery have been: (1) transition from opioids to nonopioid medications, (2) cardiovascular exercise program, (3) smoking cessation, (4) alcohol cessation, and (5) psychotherapy to treat mood and maladaptive pain behavior. PURPOSE The authors hypothesized that an initiation of an interdisciplinary “prehab” protocol utilizing all five aforementioned modalities prior to spine surgery in patients with chronic pain syndrome and opioid addiction would optimize postoperative outcomes, including decreased pain and opioid consumption. STUDY DESIGN/SETTING Prospective and retrospective review of patients with and without an interdisciplinary “prehab” program prior to spine surgery. PATIENT SAMPLE Eighty-nine patients with and 85 patients without prior to spine surgery. OUTCOME MEASURES Opioid usage, visual analog scale (VAS) for axial pain and radiculopathy, EQ-5D, QALY, PHQ-9, pain castrophizing scale (PCS), and chronic pain acceptance questionnaire (CPAQ). METHODS A review from 2013 to 2017 at a single institution was performed on patients undergoing spine surgery. Inclusion criteria were patients undergoing spine surgery who had preoperative chronic pain syndrome and opioid addiction. Two cohorts were investigated which included patients going for spine surgery with and without a multidisciplinary prehab protocol. The protocol was the initiation of a multidisciplinary task team to preoperatively optimize patients with opioid addiction and chronic pain syndrome going for spine surgery. Collaboration was between the spine surgery division, pain management, pharmacy, psychiatry, psychology, primary care, physical therapy, and nutritionist. Patients in the prehab cohort underwent a preoperative optimization checklist: patients were transitioned off of opioids with utilization of nonopioid medications; patients who were smokers were enrolled in an smoking cessation program; patients who had alcohol dependence had a behavioral medicine consult with psychology; patients who were obese (BMI >35) were enrolled in a multidisciplinary weight loss program through monitored cardiovascular exercising and nutritionist consultation; and all patients had a consultation with behavioral medicine for their chronic pain syndrome to forge healthy relationships with their pain. RESULTS Demographics and case breakdown (surgery type performed) were similar between cohorts. A significantly greater amount of patients receiving were opioid-free following spine surgery compared to patients without (8% vs 72%, respectively, p CONCLUSIONS A multidisciplinary “prehab” program for patients with opioid addiction and chronic pain syndrome going for spine surgery is efficacious at reducing opioid addiction and pain, improving quality of life and depression, and forging a healthier relationship with pain. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.