Mild Traumatic Brain Injury-Induced Augmented Postsurgical Pain Is Driven by Central Serotonergic Pain-Facilitatory Signaling.

BACKGROUND: Individuals recovering from mild traumatic brain injury (mTBI) have increased rates of acute and chronic pain. However, the mechanism through which mTBI triggers heightened pain responses and the link between mTBI and postsurgical pain remain elusive. Recent data suggest that dysregulated serotonergic pain-modulating circuits could be involved. We hypothesized that mTBI triggers dysfunction in descending serotonergic pain modulation, which exacerbates acute pain and delays pain-related recovery after surgery. METHODS: Using mouse models of mTBI and hindpaw incision for postsurgical pain in C57BL/6J mice, mechanical withdrawal thresholds were assessed throughout the postsurgical period. To determine whether mTBI leads to persistent alteration of endogenous opioid tone, mu-opioid receptors (MORs) were blocked with naloxone. Finally, the role of descending serotonergic signaling on postsurgical allodynia in animals with mTBI was examined using ondansetron (5-HT 3 receptor antagonist) or a serotonin-specific neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), to ablate descending serotonergic fibers. The treatment effects on withdrawal thresholds were normalized to baseline (percentage of maximum possible effect, MPE%), and analyzed using paired t -test or 2-way repeated-measures ANOVA with post hoc multiple comparisons. RESULTS: Post-mTBI mice demonstrated transient allodynia in hindpaws contralateral to mTBI, while no nociceptive changes were observed in sham-mTBI animals (mean difference, MD, MPE%, post-mTBI day 3: -60.9; 95% CI, -88.7 to -35.0; P < .001). After hindpaw incision, animals without mTBI exhibited transient allodynia, while mice with prior mTBI demonstrated prolonged postsurgical allodynia (MD-MPE% postsurgical day 14: -65.0; 95% CI, -125.4 to -4.5; P = .04). Blockade of MORs using naloxone transiently reinstated allodynia in mTBI animals but not in sham-mTBI mice (MD-MPE% post-naloxone: -69.9; 95% CI, -94.8 to -45.1; P < .001). Intrathecal administration of ondansetron reversed the allodynia observed post-mTBI and postincision in mTBI mice (compared to vehicle-treated mTBI mice, MD-MPE% post-mTBI day 3: 82.7; 95% CI, 58.5-106.9; P < .001; postsurgical day 17: 62.5; 95% CI, 38.3-86.7; P < .001). Both the acute allodynia after TBI and the period of prolonged allodynia after incision in mTBI mice were blocked by pretreatment with 5,7-DHT (compared to sham-mTBI mice, MD-MPE% post-mTBI day 3: 0.5; 95% CI, -18.5 to 19.5; P = .99; postsurgical day 14: -14.6; 95% CI, -16.7 to 45.9; P = .48). Similar behavioral patterns were observed in hindpaw ipsilateral to mTBI. CONCLUSIONS: Collectively, our results show that descending serotoninergic pain-facilitating signaling is responsible for nociceptive sensitization after mTBI and that central endogenous opioid tone opposes serotonin's effects. Understanding brain injury-related changes in endogenous pain modulation may lead to improved pain control for those with TBI undergoing surgery.

Temporal Contribution of Myeloid-Lineage TLR4 to the Transition to Chronic Pain: A Focus on Sex Differences.

Complex regional pain syndrome (CRPS) is a chronic pain disorder with a clear acute-to-chronic transition. Preclinical studies demonstrate that toll-like receptor 4 (TLR4), expressed by myeloid-lineage cells, astrocytes, and neurons, mediates a sex-dependent transition to chronic pain; however, evidence is lacking on which exact TLR4-expressing cells are responsible. We used complementary pharmacologic and transgenic approaches in mice to more specifically manipulate myeloid-lineage TLR4 and outline its contribution to the transition from acute-to-chronic CRPS based on three key variables: location (peripheral vs central), timing (prevention vs treatment), and sex (male vs female). We demonstrate that systemic TLR4 antagonism is more effective at improving chronic allodynia trajectory when administered at the time of injury (early) in the tibial fracture model of CRPS in both sexes. In order to clarify the contribution of myeloid-lineage cells peripherally (macrophages) or centrally (microglia), we rigorously characterize a novel spatiotemporal transgenic mouse line, Cx3CR1-CreERT2-eYFP;TLR4fl/fl (TLR4 cKO) to specifically knock out TLR4 only in microglia and no other myeloid-lineage cells. Using this transgenic mouse, we find that early TLR4 cKO results in profound improvement in chronic, but not acute, allodynia in males, with a significant but less robust effect in females. In contrast, late TLR4 cKO results in partial improvement in allodynia in both sexes, suggesting that downstream cellular or molecular TLR4-independent events may have already been triggered. Overall, we find that the contribution of TLR4 is time- and microglia-dependent in both sexes; however, females also rely on peripheral myeloid-lineage (or other TLR4 expressing) cells to trigger chronic pain.SIGNIFICANCE STATEMENT The contribution of myeloid cell TLR4 to sex-specific pain progression remains controversial. We used complementary pharmacologic and transgenic approaches to specifically manipulate TLR4 based on three key variables: location (peripheral vs central), timing (prevention vs treatment), and sex (male vs female). We discovered that microglial TLR4 contributes to early pain progression in males, and to a lesser extent in females. We further found that maintenance of chronic pain likely occurs through myeloid TLR4-independent mechanisms in both sexes. Together, we define a more nuanced contribution of this receptor to the acute-to-chronic pain transition in a mouse model of complex regional pain syndrome.

Opioids and Public Health: The Prescription Opioid Ecosystem and Need for Improved Management.

While U.S. opioid prescribing has decreased 38% in the past decade, opioid deaths have increased 300%. This opioid paradox is poorly recognized. Current approaches to opioid management are not working, and new approaches are needed. This article reviews the outcomes and shortcomings of recent U.S. opioid policies and strategies that focus primarily or exclusively on reducing or eliminating opioid prescribing. It introduces concepts of a prescription opioid ecosystem and opioid pool, and it discusses how the pool can be influenced by supply-side, demand-side, and opioid returns factors. It illuminates pressing policy needs for an opioid ecosystem that enables proper opioid stewardship, identifies associated responsibilities, and emphasizes the necessity of making opioid returns as easy and common as opioid prescribing, in order to minimize the size of the opioid pool available for potential diversion, misuse, overdose, and death. Approaches are applicable to opioid prescribing in general, and to opioid prescribing after surgery.

IL-6 signaling mediates the germinal center response, IgM production and nociceptive sensitization in male mice after tibia fracture.

BACKGROUND: Up-regulated interleukin 6 (IL-6) signaling, immune system activation, and pronociceptive autoantibodies are characteristic of complex regional pain syndrome (CRPS). IL-6 is known to promote B cell differentiation, thus we hypothesized that IL-6 signaling plays a crucial role in the development of adaptive immune responses and nociceptive sensitization in a murine tibia fracture model of CRPS. METHODS: Mice deficient in IL-6 expression (IL-6-/-) or B cell deficient (muMT) underwent tibia fracture and 3 weeks of cast immobilization or sham injury. The deposition of IgM in fractured limbs was followed using Western blotting, and passive serum transfer to muMT fracture mice was used to detect nociception-supporting autoantibodies. Lymph nodes were assessed for hypertrophy, IL-6 expression was measured using qPCR and ELISA, and germinal center formation was evaluated using FACS and immunohistochemistry. The therapeutic effects of exogenous neutralizing anti-IL-6 antibodies were also evaluated in the CRPS fracture model. RESULTS: Functional IL-6 signaling was required for the post fracture development of nociceptive sensitization, vascular changes, and IgM immune complex deposition in the skin of injured limbs. Passive transfer of sera from wild-type, but not IL-6-/- fracture mice into muMT fracture mice caused enhanced allodynia and postural unweighting. IL-6-/- fracture mice displayed reduced popliteal lymphadenopathy after fracture. Germinal center responses were detected in the popliteal lymph nodes of wild-type, but not in IL-6-/- fracture mice. We observed that IL-6 expression was dramatically enhanced in popliteal lymph node tissue after fracture. Conversely, administration of anti-IL-6 antibodies reduced nociceptive and vascular changes after fracture and inhibited lymphadenopathy. CONCLUSIONS: Collectively, these data support the hypothesis that IL-6 signaling in the fracture limb of mice is required for germinal center formation, IgM autoantibody production and nociceptive sensitization. Anti-IL-6 therapies might, therefore, reduce pain after limb fracture or in the setting of CRPS.

Dimethyl Fumarate Reduces Oxidative Stress and Pronociceptive Immune Responses in a Murine Model of Complex Regional Pain Syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) is a highly disabling cause of pain often precipitated by surgery or trauma to a limb. Both innate and adaptive immunological changes contribute to this syndrome. Dimethyl fumarate (DMF) works through the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor and other targets to activate antioxidant systems and to suppress immune system activation. We hypothesized that DMF would reduce nociceptive, functional, and immunological changes measured in a model of CRPS. METHODS: Male C57BL/6 mice were used in the well-characterized tibial fracture model of CRPS. Some groups of mice received DMF 25 mg/kg/d orally, per os for 3 weeks after fracture versus vehicle alone. Homozygous Nrf2 null mutant mice were used as test subjects to address the need for this transcription factor for DMF activity. Allodynia was assessed using von Frey filaments and hindlimb weight-bearing data were collected. The markers of oxidative stress malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) were quantified in the skin of the fractured mice using immunoassays along with the innate immune system cytokines IL-1ß and IL-6. The accumulation of IgM in the fractured limbs and lymph node hypertrophy were used as indexes of adaptive immune system activation, and the passive transfer of serum from wildtype fractured mice to B cell-deficient fractured muMT mice (mice lacking B cells and immunoglobulin) helped to assess the pronociceptive activity of humoral factors. RESULTS: We observed that oral DMF administration strongly prevented nociceptive sensitization and reduced uneven hindlimb weight bearing after fracture. DMF was also very effective in reducing the accumulation of markers of oxidative stress, activation of innate immune mediator production, lymph node hypertrophy, and the accumulation of IgM in fractured limbs. The sera of fractured vehicle-treated but not DMF-treated mice conferred pronociceptive activity to recipient mice. Unexpectedly, the effects of DMF were largely unchanged in the Nrf2 null mutant mice. CONCLUSIONS: Oxidative stress and immune system activation are robust after hindlimb fracture in mice. DMF strongly reduces activation of those systems, and the Nrf2 transcription factor is not required. DMF or drugs working through similar mechanisms might provide effective therapy for CRPS or other conditions where oxidative stress causes immune system activation.

Angiotensin receptor blockade mimics the effect of exercise on recovery after orthopaedic trauma by decreasing pain and improving muscle regeneration.

KEY POINTS: Our tibial fracture orthopaedic injury model in mice recapitulates the major manifestations of complex trauma, including nociceptive sensitization, bone fracture, muscle fibrosis and muscle fibre loss. Delayed exercise after complex orthopaedic trauma results in decreased muscle fibrosis and improved pain Losartan, an angiotensin-receptor blocker with anti-fibrotic abilities, recapitulates the effect of exercise on post-injury recovery and may provide an enhanced recovery option for those who are unable to exercise after injury ABSTRACT: Chronic pain and disability after limb injury are major public health problems. Early mobilization after injury improves functional outcomes for patients, although when and how to implement rehabilitation strategies remains a clinical challenge. Additionally, whether the beneficial effects of exercise can be reproduced using pharmacological tools remains unknown and may benefit patients who are unable to exercise as a result of immobilization. We developed a murine model of orthopaedic trauma combining tibia fracture and pin fixation with muscle damage. Behavioural measures included mechanical nociceptive thresholds and distances run on exercise wheels. Bone healing was quantified using microcomputed tomagraphic scanning, and muscle fibre size distribution and fibrosis were followed using immunohistochemistry. We found that the model provided robust mechanical allodynia, fibrosis and a shift to smaller average muscle fibre size lasting up to 5 weeks from injury. We also observed that allowing 'late' (weeks 1-2) rather than 'early' (weeks 0-1) exercise after injury resulted in greater overall running activity and greater reversal of allodynia. In parallel, the late running paradigm was associated with reduced muscle fibrosis, earlier increase in muscle fibre diameter and a short-term benefit in reducing callus volume. Providing the anti-fibrotic angiotensin receptor blocker losartan to mice in drinking water reduced both allodynia and muscle fibrosis. Combining losartan and late exercise provided no additional benefit. We conclude that early healing after orthopaedic trauma must be allowed prior to the initiation of exercise to achieve optimal pain, functional and physiological outcomes and that losartan is a viable candidate for translational studies.

Germinal center formation, immunoglobulin production and hindlimb nociceptive sensitization after tibia fracture.

Emerging evidence suggests that Complex Regional Pain Syndrome (CRPS) is in part a post-traumatic autoimmune disease mediated by an adaptive immune response after limb injuries. We previously observed in a murine tibial fracture model of CRPS that pain-related behaviors were dependent upon adaptive immune mechanisms including the neuropeptide-dependent production of IgM for 5 months after injury. However, the time course of induction of this immune response and the demonstration of germinal center formation in lymphoid organs has not been evaluated. Using the murine fracture model, we employed behavioral tests of nociceptive sensitization and limb dysfunction, serum passive transfer techniques, western blot analysis of IgM accumulation, fluorescence-activated cell sorting (FACS) of lymphoid tissues and immunohistochemistry to follow the temporal activation of the adaptive immune response over the first 3 weeks after fracture. We observed that: 1) IgM protein levels in the skin of the fractured mice were elevated at 3 weeks post fracture, but not at earlier time points, 2) serum from fracture mice at 3 weeks, but not 1 and 2 weeks post fracture, had pro-nociceptive effects when passively transferred to fractured muMT mice lacking B cells, 3) fracture induced popliteal lymphadenopathy occurred ipsilateral to fracture beginning at 1 week and peaking at 3 weeks post fracture, 4) a germinal center reaction was detected by FACS analysis in the popliteal lymph nodes from injured limbs by 3 weeks post fracture but not in other lymphoid tissues, 5) germinal center formation was characterized by the induction of T follicular helper cells (Tfh) and germinal center B cells in the popliteal lymph nodes of the injured but not contralateral limbs, and 6) fracture mice treated with the Tfh signaling inhibitor FK506 had impaired germinal center reactions, reduced IgM levels, reduced nociceptive sensitization, and no pronociceptive serum effects after administration to fractured muMT mice. Collectively these data demonstrate that tibia fracture induces an adaptive autoimmune response characterized by popliteal lymph node germinal center formation and Tfh cell dependent B cell activation, resulting in nociceptive sensitization within 3 weeks.

Incisional Injury Modulates Morphine Reward and Morphine-Primed Reinstatement: A Role of Kappa Opioid Receptor Activation.

BACKGROUND: Persistent use of prescription opioids beyond the period of surgical recovery is a large part of a public health problem linked to the current opioid crisis in the United States. However, few studies have been conducted to examine whether morphine reward is influenced by acute pain and injury. METHODS: In a mouse model of incisional injury and minor trauma, animals underwent conditioning, extinction, and drug-primed reinstatement with morphine to examine the rewarding properties of morphine in the presence of acute incisional injury and drug-induced relapse, respectively. In addition, we sought to determine whether these behaviors were influenced by kappa opioid receptor signaling and measured expression of prodynorphin messenger RNA in the nucleus accumbens and medial prefrontal cortex after conditioning and before reinstatement with morphine and incisional injury. RESULTS: In the presence of incisional injury, we observed enhancement of morphine reward with morphine-conditioned place preference but attenuated morphine-primed reinstatement to reward. This adaptation was not present in animals conditioned 12 days after incisional injury when nociceptive sensitization had resolved; however, they showed enhancement of morphine-primed reinstatement. Prodynorphin expression was greatly enhanced in the nucleus accumbens and medial prefrontal cortex of mice with incisional injury and morphine conditioning and remained elevated up to drug-primed reinstatement. These changes were not observed in mice conditioned 12 days after incisional injury. Further, kappa opioid receptor blockade with norbinaltorphimine before reinstatement reversed the attenuation induced by injury. CONCLUSIONS: These findings suggest enhancement of morphine reward as a result of incisional injury but paradoxically a protective adaptation with incisional injury from drug-induced relapse resulting from kappa opioid receptor activation in the reward circuitry. Remote injury conferred no such protection and appeared to enhance reinstatement.

Perioperative Opioid Prescribing Patterns and Readmissions After Total Knee Arthroplasty in a National Cohort of Veterans Health Administration Patients.

OBJECTIVE: Among Veterans Health Administration (VHA) patients who undergo total knee arthroplasty (TKA) nationally, what are the underlying readmission rates and associations with perioperative opioid use, and are there associations with other factors such as preoperative health care utilization? METHODS: We retrospectively examined the records of 5,514 TKA patients (primary N = 4,955, 89.9%; revision N = 559, 10.1%) over one fiscal year (October 1, 2010-September 30, 2011) across VHA hospitals nationwide. Opioid use was classified into no opioids, tramadol only, short-acting only, or any long-acting. We measured readmission within 30 days and the number of days to readmission within 30 days. Extended Cox regression models were developed. RESULTS: The overall 30-day hospital readmission rate was 9.6% (N = 531; primary 9.5%, revision 11.1%). Both readmitted patients and the overall sample were similar on types of preoperative opioid use. Relative to patients without opioids, patients in the short-acting opioids only tier had the highest risk for 30-day hospital readmission (hazard ratio = 1.38, 95% confidence interval = 1.14-1.67). Preoperative opioid status was not associated with 30-day readmission. Other risk factors for 30-day readmission included older age (≥66 years), higher comorbidity and diagnosis-related group weights, greater preoperative health care utilization, an urban location, and use of preoperative anticonvulsants. CONCLUSIONS: Given the current opioid epidemic, the routine prescribing of short-acting opioids after surgery should be carefully considered to avoid increasing risks of 30-day hospital readmissions and other negative outcomes, particularly in the context of other predisposing factors.

The hippocampal extracellular matrix regulates pain and memory after injury.

Chronic pain poses a heavy burden for the individual and society, comprising personal suffering, comorbid psychiatric symptoms, cognitive decline, and disability. Treatment options are poor due in large part to pain centralization, where an initial injury can result in lasting CNS maladaptations. Hippocampal cellular plasticity in chronic pain has become a focus of study due to its roles in cognition, memory, and the experience of pain itself. However, the extracellular alterations that parallel and facilitate changes in hippocampal function have not been addressed to date. Here we show structural and biochemical plasticity in the hippocampal extracellular matrix (ECM) that is linked to behavioral, cellular, and synaptic changes in a mouse model of chronic pain. Specifically, we report deficits in working location memory that are associated with decreased hippocampal dendritic complexity, altered ECM microarchitecture, decreased ECM rigidity, and changes in the levels of key ECM components and enzymes, including increased levels of MMP8. We also report aberrations in long-term potentiation (LTP) and a loss of inhibitory interneuron perineuronal ECM nets, potentially accounting for the aberrations in LTP. Finally, we demonstrate that MMP8 is upregulated after injury and that its genetic downregulation normalizes the behavioral, electrophysiological, and extracellular alterations. By linking specific extracellular changes to the chronic pain phenotype, we provide a novel mechanistic understanding of pain centralization that provides new targets for the treatment of chronic pain.

Morphine Exacerbates Postfracture Nociceptive Sensitization, Functional Impairment, and Microglial Activation in Mice.

BACKGROUND: Emerging evidence suggests that opioid use immediately after surgery and trauma may worsen outcomes. In these studies, the authors aimed to determine whether morphine administered for a clinically relevant time period (7 days) in a tibia fracture orthopedic surgery model had adverse effects on postoperative recovery. METHODS: Mice were given morphine twice daily for 7 days after unilateral tibial fracture and intramedullary pin fixation to model orthopedic surgery and limb trauma. Mechanical allodynia, limb-specific weight bearing, gait changes, memory, and anxiety were measured after injury. In addition, spinal cord gene expression changes as well as glial activation were measured. Finally, the authors assessed the effects of a selective Toll-like receptor 4 antagonist, TAK-242, on nociceptive and functional changes after injury. RESULTS: Tibial fracture caused several weeks of mechanical nociceptive sensitization (F(1, 216) = 573.38, P < 0.001, fracture + vehicle vs. sham + vehicle, n = 10 per group), and this change was exacerbated by the perioperative administration of morphine (F(1, 216) = 71.61, P < 0.001, fracture + morphine vs. fracture + vehicle, n = 10 per group). In additional testing, injured limb weight bearing, gait, and object location memory were worse in morphine-treated fracture mice than in untreated fracture mice. Postfracture expression levels of several genes previously associated with opioid-induced hyperalgesia, including brain-derived neurotrophic factor and prodynorphin, were unchanged, but neuroinflammation involving Toll-like receptor 4 receptor-expressing microglia was observed (6.8 ± 1.5 [mean ± SD] cells per high-power field for fracture + vehicle vs. 12 ± 2.8 fracture + morphine, P < 0.001, n = 8 per /group). Treatment with a Toll-like receptor 4 antagonist TAK242 improved nociceptive sensitization for about 2 weeks in morphine-treated fracture mice (F(1, 198) = 73.36, P < 0.001, fracture + morphine + TAK242 vs. fracture + morphine, n = 10 per group). CONCLUSIONS: Morphine treatment beginning at the time of injury impairs nociceptive recovery and other outcomes. Measures preventing glial activation through Toll-like receptor 4 signaling may reduce the adverse consequences of postoperative opioid administration.

Pain Management and Opioid Regulation: Continuing Public Health Challenges.

The still-growing US opioid epidemic lies at the intersection of two major public health challenges: reducing suffering from pain and containing the rising toll of harms associated with the use of opioids medications. Responding successfully to these challenges requires a substantial investment in surveillance and research on many fronts and a coordinated policy response by federal and state agencies and stakeholder organizations.A 2017 report of the National Academies of Sciences, Engineering and Medicine (NASEM) called for improved methods of measuring pain and the effects of alternative modalities of treatment as well as intensive surveillance of opioid-related harms; urged a long-term cultural transformation of how pain is perceived, assessed and treated; and outlined a comprehensive and balanced public health framework to guide Food and Drug Administration approval, monitoring, and review of opioids.We, authors of the NASEM report, use the articles published in this special section of AJPH as a platform for commenting on the public health burden of pain, the role of opioids in managing pain, global disparities in access to opioids for pain management, divergent approaches to opioid regulation, and the challenge of striking a reasonable balance between the needs of patients in pain and the prevention of opioid-related harms.

Pharmacological Characters of Oliceridine, a µ-Opioid Receptor G-Protein-Biased Ligand in Mice.

BACKGROUND: A major advancement in the field of analgesic pharmacology has been the development of G-protein-biased opioid agonists that display less respiratory depression than conventional drugs. It is uncertain, however, whether these new drugs cause less tolerance, hyperalgesia, and other maladaptations when administered repeatedly. METHODS: The archetypical µ-opioid receptor agonist morphine and, separately, the G-protein-biased µ-opioid receptor agonist oliceridine were administered to mice. These drugs were used in models of acute analgesia, analgesic tolerance, opioid-induced hyperalgesia, reward, and physical dependence. In addition, morphine and oliceridine were administered for 7 days after tibia fracture and pinning; mechanical allodynia and gait were followed for 3 weeks. Finally, the expression of toll-like receptor-4 and nacht domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NALP3) and interleukin-1ß mRNA were quantified in spinal tissue to measure surgical and drug effects on glia-related gene expression. RESULTS: We observed using the tail flick assay that oliceridine was a 4-fold more potent analgesic than morphine, but that oliceridine treatment caused less tolerance and opioid-induced hyperalgesia than morphine after 4 days of ascending-dose administration. Using similar analgesic doses, morphine caused reward behavior in the conditioned place preference assay while oliceridine did not. Physical dependence was, however, similar for the 2 drugs. Likewise, morphine appeared to more significantly impair the recovery of nociceptive sensitization and gait after tibial fracture and pinning than oliceridine. Furthermore, spinal cord toll-like receptor-4 levels 3 weeks after fracture were higher in fracture mice given morphine than those given oliceridine. CONCLUSIONS: Aside from reduced respiratory depression, G-protein-biased agonists such as oliceridine may reduce opioid maladaptations and enhance the quality of surgical recovery.

Overdose Risk Associated with Opioid Use upon Hospital Discharge in Veterans Health Administration Surgical Patients.

OBJECTIVE: To determine an association between opioid use upon hospital discharge (ongoing and newly started) in surgical patients and risks of opioid overdose and delirium for the first year. DESIGN: Retrospective, cohort study. SETTING: Population-level study of Veterans Health Administration patients. SUBJECTS: All Veterans Health Administration patients (N = 64,391) who underwent surgery in 2011, discharged after one or more days, and without a diagnosis of opioid overdose or delirium from 90 days before admission through 30 days postdischarge (to account for additional opioid dosing in the context of chronic use). METHODS: Patients' opioid use was categorized as 1) no opioids, 2) tramadol only, 3) short-acting only, 4) long-acting only, 5) short- and long-acting. We calculated unadjusted incidence rates and the incidence rate ratio (IRR) for opioid overdose and drug delirium for two time intervals: postdischarge days 0-30 and days 31-365. We then modeled outcomes of opioid overdose and delirium for postdischarge days 31-365 using a multivariable extended Cox regression model. Sensitivity analysis examined risk factors for overdose for postdischarge days 0-30. RESULTS: Incidence of overdose was 11-fold greater from postdischarge days 0-30 than days 31-365: 26.3 events/person-year (N = 68) vs 2.4 events/person-year (N = 476; IRR = 10.80, 95% confidence interval [CI] = 8.37-13.92). Higher-intensity opioid use was associated with increasing risk of overdose for the year after surgery, with the highest risk for the short- and long-acting group (hazard ratio = 4.84, 95% CI = 3.28-7.14). Delirium (IRR = 10.66, 95% CI = 7.96-14.29) was also associated with higher opioid intensity. CONCLUSIONS: Surgical patients should be treated with the lowest effective intensity of opioids and be monitored to prevent opioid-related adverse events.

Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome.

BACKGROUND: Both dysfunctional neuropeptide signaling and immune system activation are characteristic of complex regional pain syndrome (CRPS). Unknown is whether substance P (SP) or calcitonin gene-related peptide (CGRP) support autoantibody production and, consequently, nociceptive sensitization. METHODS: These experiments involved the use of a well-characterized tibia fracture model of CRPS. Mice deficient in SP expression (Tac1-/-) and CGRP signaling (RAMP1-/-) were used to probe the neuropeptide dependence of post-fracture sensitization and antibody production. The deposition of IgM in the spinal cord, sciatic nerves, and skin was followed using Western blotting, as was expression of the CRPS-related autoantigen cytokeratin 16 (Krt16). Passive serum transfer to B-cell-deficient muMT mice was used to assess the production of functional autoantibodies in CRPS model mice. The use of immunohistochemistry allowed us to assess neuropeptide-containing fiber distribution and Langerhans cell abundance in mouse and human CRPS patient skin, while Langerhans cell-deficient mice were used to assess the functional contributions of these cells. RESULTS: Functional SP and CGRP signaling were required both for the full development of nociceptive sensitization after fracture and the deposition of IgM in skin and neural tissues. Furthermore, the passive transfer of serum from wildtype but not neuropeptide-deficient mice to fractured muMT mice caused enhanced allodynia and postural unweighting. Langerhans cells were increased in number in the skin of fracture mice and CRPS patients, and those increases in mice were reduced in neuropeptide signaling-deficient animals. Unexpectedly, Langerhans cell-deficient mice showed normal nociceptive sensitization after fracture. However, the increased expression of Krt16 after tibia fracture was not seen in neuropeptide-deficient mice. CONCLUSIONS: Collectively, these data support the hypothesis that neuropeptide signaling in the fracture limb of mice is required for autoantigenic IgM production and nociceptive sensitization. The mechanism may be related to neuropeptide-supported autoantigen expression.

Exercise Reverses Nociceptive Sensitization, Upregulated Neuropeptide Signaling, Inflammatory Changes, Anxiety, and Memory Impairment in a Mouse Tibia Fracture Model.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: This study tested the hypothesis that ad lib running wheel exercise in a tibia fracture model of complex regional pain syndrome can reverse hindlimb nociceptive sensitization and inflammation in mice. METHODS: Three weeks after tibia fracture, the cast was removed and hindlimb von Frey thresholds and unweighting were tested; the mice were then randomized to either ad lib access to a running wheel for 4 weeks or no wheel access. After 4 weeks the behavioral testing was repeated and then skin, sciatic nerve, and spinal cord tissues collected for polymerase chain reaction and enzyme immunoassay measurements of neuropeptide and inflammatory mediator levels. A similar protocol was used in fracture mice treated with exercise for 4 weeks, and then the running wheel was removed for 2 weeks. Memory and anxiety were measured in both groups with use of open-field, zero-maze, and novel-objects recognition assays. RESULTS: At 7 weeks postfracture the mice with no wheel access exhibited hindlimb allodynia and unweighting, anxiety, memory loss, upregulated spinal neuropeptide signaling, and increased hind paw and spinal inflammatory mediator expression, but the postfracture mice allowed to exercise for 4 weeks exhibited none of these changes (n = 12/cohort). When exercise was stopped for 2 weeks after 4 weeks of running, hindlimb allodynia and unweighting were rekindled, and this nociceptive sensitization was associated with increased sciatic nerve neuropeptide levels and hind paw skin interleukin 6 and nerve growth factor expression (n = 12/cohort). CONCLUSIONS: Daily exercise reversed nociceptive sensitization, inflammation, anxiety, and memory loss after tibia fracture.

Chronic Pain After Traumatic Brain Injury: Pathophysiology and Pain Mechanisms.

Background: Traumatic brain injury refers to a broad range of neurological, cognitive, and emotional factors that result from the application of an external force to the head. Individuals recovering from traumatic brain injury will frequently experience acute and chronic pain. Objective: The objective of this paper is to discuss the pathophysiological changes resulting from traumatic brain injury and how these may be involved in the development and persistence of pain after injury. Methods: We based our review on articles retrieved from the MEDLINE database of references and abstracts on life sciences and biomedical topics (1966 to present) using the search engine PubMed (United States National Library of Medicine). The published literature focused on traumatic brain injury and pain. Conclusions: This review presents evidence that pain is common after traumatic brain injury. However, while there are many potential mechanisms explaining this problem such as neuroinflammation, excitotoxicity, and axonal degeneration, we have no clear understanding of which of them contribute in individual patients. The authors highlight the priorities for research that will expand our knowledge and that may lead to the rational design of therapies that both reduce pain and provide optimal overall outcomes after traumatic brain injury.

The Complement System Component C5a Produces Thermal Hyperalgesia via Macrophage-to-Nociceptor Signaling That Requires NGF and TRPV1.

UNLABELLED: The complement cascade is a principal component of innate immunity. Recent studies have underscored the importance of C5a and other components of the complement system in inflammatory and neuropathic pain, although the underlying mechanisms are largely unknown. In particular, it is unclear how the complement system communicates with nociceptors and which ion channels and receptors are involved. Here we demonstrate that inflammatory thermal and mechanical hyperalgesia induced by complete Freund's adjuvant was accompanied by C5a upregulation and was markedly reduced by C5a receptor (C5aR1) knock-out or treatment with the C5aR1 antagonist PMX53. Direct administration of C5a into the mouse hindpaw produced strong thermal hyperalgesia, an effect that was absent in TRPV1 knock-out mice, and was blocked by the TRPV1 antagonist AMG9810. Immunohistochemistry of mouse plantar skin showed prominent expression of C5aR1 in macrophages. Additionally, C5a evoked strong Ca(2+) mobilization in macrophages. Macrophage depletion in transgenic macrophage Fas-induced apoptosis mice abolished C5a-dependent thermal hyperalgesia. Examination of inflammatory mediators following C5a injection revealed a rapid upregulation of NGF, a mediator known to sensitize TRPV1. Preinjection of an NGF-neutralizing antibody or Trk inhibitor GNF-5837 prevented C5a-induced thermal hyperalgesia. Notably, NGF-induced thermal hyperalgesia was unaffected by macrophage depletion. Collectively, these results suggest that complement fragment C5a induces thermal hyperalgesia by triggering macrophage-dependent signaling that involves mobilization of NGF and NGF-dependent sensitization of TRPV1. Our findings highlight the importance of macrophage-to-neuron signaling in pain processing and identify C5a, NGF, and TRPV1 as key players in this cross-cellular communication. SIGNIFICANCE STATEMENT: This study provides mechanistic insight into how the complement system, a key component of innate immunity, regulates the development of pain hypersensitivity. We demonstrate a crucial role of the C5a receptor, C5aR1, in the development of inflammatory thermal and mechanical sensitization. By focusing on the mechanisms of C5a-induced thermal hyperalgesia, we show that this process requires recruitment of macrophages and initiation of macrophage-to-nociceptor signaling. At the molecular level, we demonstrate that this signaling depends on NGF and is mediated by the heat-sensitive nociceptive channel TRPV1. This deeper understanding of how immune cells and neurons interact to regulate pain processing is expected to facilitate mechanism-based approaches in the development of new analgesics.