Clinical Integration of Digital Patient-Reported Outcome Measures in Primary Health Care for Chronic Disease Management: Protocol for a Systematic Review.

BACKGROUND: Health measurement guides policies and health care decisions are necessary to describe and attain the quintuple aim of improving patient experience, population health, care team well-being, health care costs, and equity. In the primary care setting, patient-reported outcome measurement allows outcome comparisons within and across settings and helps improve the clinical management of patients. However, these digital patient-reported outcome measures (PROMs) are still not adapted to the clinical context of primary health care, which is an indication of the complexity of integrating these tools in this context. We must then gather evidence of their impact on chronic disease management in primary health care and understand the characteristics of effective implementation. OBJECTIVE: We will conduct a systematic review to identify and assess the impact of electronic PROMs (ePROMs) implementation in primary health care for chronic disease management. Our specific objectives are to (1) determine the impact of ePROMs in primary health care for chronic disease management and (2) compare and contrast characteristics of effective ePROMs' implementation strategies. METHODS: We will conduct a systematic review of the literature in accordance with the guidelines of the Cochrane Methods Group and in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for its reporting. A specific search strategy was developed for relevant databases to identify studies. Two reviewers will independently apply the inclusion criteria using full texts and will extract the data. We will use a 2-phase sequential mixed methods synthesis design by conducting a qualitative synthesis first, and use its results to perform a quantitative synthesis. RESULTS: This study was initiated in June 2022 by assembling the research team and the knowledge transfer committee. The preliminary search strategy will be developed and completed in September 2022. The main search strategy, data collection, study selection, and application of inclusion criteria were completed between October and December 2022. CONCLUSIONS: Results from this review will help support implementation efforts to accelerate innovations and digital adoption for primary health care and will be relevant for improving clinical management of chronic diseases and health care services and policies. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42022333513; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=333513. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48155.

The impact of technology systems and level of support in digital mental health interventions: a secondary meta-analysis.

BACKGROUND: The majority of people with a chronic disease (e.g., diabetes, hypertension, COPD) have more than one concurrent condition and are also at higher risk for developing comorbidities in mental health, including anxiety and depression. There is an urgent need for more relevant and accurate data on digital interventions in this area to prepare for an increase demand for mental health services. The aim of this study was to conduct a meta-analysis of the digital mental health interventions for people with comorbid physical and mental chronic diseases to compare the effect of technology systems and level of support. METHODS: This secondary meta-analysis follows a rapid review of systematic reviews, a virtual workshop with knowledge users to identify research questions and a modified Delphi study to guide research methods: What types of digital health interventions (according to a recognized categorization) are the most effective for the management of concomitant mental health and chronic disease conditions in adults? We conducted a secondary analysis of the primary studies identified in the rapid review. Two reviewers independently screened the titles and abstracts and applied inclusion criteria: RCT design using a digital mental health intervention in a population of adults with another chronic condition, published after 2010 in French or English, and including an outcome measurement of anxiety or depression. RESULTS: Seven hundred eight primary studies were extracted from the systematic reviews and 84 primary studies met the inclusion criteria Digital mental health interventions were significantly more effective than in-person care for both anxiety and depression outcomes. Online messaging was the most effective technology to improve anxiety and depression scores; however, all technology types were effective. Interventions partially supported by healthcare professionals were more effective than self-administered. CONCLUSIONS: While our meta-analysis identifies digital intervention's characteristics are associated with better effectiveness, all technologies and levels of support could be used considering implementation context and population. TRIAL REGISTRATION: The protocol for this review is registered in the National Collaborating Centre for Methods and Tools (NCCMT) COVID-19 Rapid Evidence Service (ID 75).

Digital health interventions for the management of mental health in people with chronic diseases: a rapid review.

OBJECTIVE: Determine the effectiveness of digital mental health interventions for individuals with a concomitant chronic disease. DESIGN: We conducted a rapid review of systematic reviews. Two reviewers independently conducted study selection and risk of bias evaluation. A standardised extraction form was used. Data are reported narratively. INTERVENTIONS: We included systematic reviews of digital health interventions aiming to prevent, detect or manage mental health problems in individuals with a pre-existing chronic disease, including chronic mental health illnesses, published in 2010 or after. MAIN OUTCOME MEASURE: Reports on mental health outcomes (eg, anxiety symptoms and depression symptoms). RESULTS: We included 35 reviews, totalling 702 primary studies with a total sample of 50 692 participants. We structured the results in four population clusters: (1) chronic diseases, (2) cancer, (3) mental health and (4) children and youth. For populations presenting a chronic disease or cancer, health provider directed digital interventions (eg, web-based consultation, internet cognitive-behavioural therapy) are effective and safe. Further analyses are required in order to provide stronger recommendations regarding relevance for specific population (such as children and youth). Web-based interventions and email were the modes of administration that had the most reports of improvement. Virtual reality, smartphone applications and patient portal had limited reports of improvement. CONCLUSIONS: Digital technologies could be used to prevent and manage mental health problems in people living with chronic conditions, with consideration for the age group and type of technology used.

Mechanistic insights into the role of the chemokine CCL2/CCR2 axis in dorsal root ganglia to peripheral inflammation and pain hypersensitivity.

BACKGROUND: Pain is reported as the leading cause of disability in the common forms of inflammatory arthritis conditions. Acting as a key player in nociceptive processing, neuroinflammation, and neuron-glia communication, the chemokine CCL2/CCR2 axis holds great promise for controlling chronic painful arthritis. Here, we investigated how the CCL2/CCR2 system in the dorsal root ganglion (DRG) contributes to the peripheral inflammatory pain sensitization. METHODS: Repeated intrathecal (i.t.) administration of the CCR2 antagonist, INCB3344 was tested for its ability to reverse the nociceptive-related behaviors in the tonic formalin and complete Freund's adjuvant (CFA) inflammatory models. We further determined by qPCR the expression of CCL2/CCR2, SP and CGRP in DRG neurons from CFA-treated rats. Using DRG explants, acutely dissociated primary sensory neurons and calcium mobilization assay, we also assessed the release of CCL2 and sensitization of nociceptors. Finally, we examined by immunohistochemistry following nerve ligation the axonal transport of CCL2, SP, and CGRP from the sciatic nerve of CFA-treated rats. RESULTS: We first found that CFA-induced paw edema provoked an increase in CCL2/CCR2 and SP expression in ipsilateral DRGs, which was decreased after INCB3344 treatment. This upregulation in pronociceptive neuromodulators was accompanied by an enhanced nociceptive neuron excitability on days 3 and 10 post-CFA, as revealed by the CCR2-dependent increase in intracellular calcium mobilization following CCL2 stimulation. In DRG explants, we further demonstrated that the release of CCL2 was increased following peripheral inflammation. Finally, the excitation of nociceptors following peripheral inflammation stimulated the anterograde transport of SP at their peripheral nerve terminals. Importantly, blockade of CCR2 reduced sensory neuron excitability by limiting the calcium mobilization and subsequently decreased peripheral transport of SP towards the periphery. Finally, pharmacological inhibition of CCR2 reversed the pronociceptive action of CCL2 in rats receiving formalin injection and significantly reduced the neurogenic inflammation as well as the stimuli-evoked and movement-evoked nociceptive behaviors in CFA-treated rats. CONCLUSIONS: Our results provide significant mechanistic insights into the role of CCL2/CCR2 within the DRG in the development of peripheral inflammation, nociceptor sensitization, and pain hypersensitivity. We further unveil the therapeutic potential of targeting CCR2 for the treatment of painful inflammatory disorders.

Data set describing the in vitro biological activity of JMV2009, a novel silylated neurotensin(8-13) analog.

Neurotensin (NT) is a tridecapeptide displaying interesting antinociceptive properties through its action on its receptors, NTS1 and NTS2. Neurotensin-like compounds have been shown to exert better antinociceptive properties than morphine at equimolar doses. In this article, we characterized the molecular effects of a novel neurotensin (8-13) (NT(8-13)) analog containing an unnatural amino acid. This compound, named JMV2009, displays a Silaproline in position 10 in replacement of a proline in the native NT(8-13). We first examined the binding affinities of this novel NT(8-13) derivative at both NTS1 and NTS2 receptor sites by performing competitive displacement of iodinated NT on purified cell membranes. Then, we evaluated the ability of JMV2009 to activate NTS1-related G proteins as well as to promote the recruitment of ß-arrestins 1 and 2 by using BRET-based cellular assays in live cells. We next assessed its ability to induce p42/p44 MAPK phosphorylation and NT receptors internalization using western blot and cell-surface ELISA, respectively. Finally, we determined the in vitro plasma stability of this NT derivative. This article is associated with the original article "Pain relief devoid of opioid side effects following central action of a silylated neurotensin analog" published in European Journal of Pharmacology[1]. The reader is directed to the associated article for results interpretation, comments, and discussion.

Pain relief devoid of opioid side effects following central action of a silylated neurotensin analog.

Neurotensin (NT) exerts naloxone-insensitive antinociceptive action through its binding to both NTS1 and NTS2 receptors and NT analogs provide stronger pain relief than morphine on a molecular basis. Here, we examined the analgesic/adverse effect profile of a new NT(8-13) derivative denoted JMV2009, in which the Pro10 residue was substituted by a silicon-containing unnatural amino acid silaproline. We first report the synthesis and in vitro characterization (receptor-binding affinity, functional activity and stability) of JMV2009. We next examined its analgesic activity in a battery of acute, tonic and chronic pain models. We finally evaluated its ability to induce adverse effects associated with chronic opioid use, such as constipation and analgesic tolerance or related to NTS1 activation, like hypothermia. In in vitro assays, JMV2009 exhibited high binding affinity for both NTS1 and NTS2, improved proteolytic resistance as well as agonistic activities similar to NT, inducing sustained activation of p42/p44 MAPK and receptor internalization. Intrathecal injection of JMV2009 produced dose-dependent antinociceptive responses in the tail-flick test and almost completely abolished the nociceptive-related behaviors induced by chemical somatic and visceral noxious stimuli. Likewise, increasing doses of JMV2009 significantly reduced tactile allodynia and weight bearing deficits in nerve-injured rats. Importantly, repeated agonist treatment did not result in the development of analgesic tolerance. Furthermore, JMV2009 did not cause constipation and was ineffective in inducing hypothermia. These findings suggest that NT drugs can act as an effective opioid-free medication for the management of pain or can serve as adjuvant analgesics to reduce the opioid adverse effects.

Publisher Correction: Dichotomic effects of clinically used drugs on tumor growth, bone remodeling and pain management.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The Quebec Low Back Pain Study: a protocol for an innovative 2-tier provincial cohort.

INTRODUCTION: The neurobiological mechanisms underlying recovery from or persistence of low back pain (LBP) remain misunderstood, limiting progress toward effective management. We have developed an innovative two-tier design to study the transition from acute to chronic LBP. The objective of the first tier is to create a provincial web-based infrastructure to recruit and monitor the trajectory of individuals with acute LBP. The objective of the second tier is to fuel hypothesis-driven satellite data collection centers with specialized expertise to study the role of biomechanical, epigenetic, genetic, neuroanatomical, ontological, physiological, psychological, and socioeconomic factors in LBP chronicity. METHODS: This article describes the first tier of the protocol: establishment of the Core Dataset and Cohort. Adults with acute LBP will be recruited through networks, media, and health care settings. A web-based interface will be used to collect self-reported variables at baseline and at 3, 6, 12, and 24 months. Acute LBP will be defined according to the Dionne 2008 consensus. Measurements will include the Canadian minimum data set for chronic LBP research, DN4 for neuropathic pain, comorbidities, EQ-5D-5L for quality of life, and linkage with provincial medico-administrative databases. The primary outcome will be the transition to chronic LBP, as defined by Deyo 2014. Secondary outcomes include health care resource utilization, disability, sick leave, mood, and quality of life. PERSPECTIVE: This study brings together diverse research expertise to investigate the transition from acute to chronic LBP, characterize the progression to recovery or chronicity, and identify patterns associated with that progression.

Dichotomic effects of clinically used drugs on tumor growth, bone remodeling and pain management.

Improvements in the survival of breast cancer patients have led to the emergence of bone health and pain management as key aspects of patient's quality of life. Here, we used a female rat MRMT-1 model of breast cancer-induced bone pain to compare the effects of three drugs used clinically morphine, nabilone and zoledronate on tumor progression, bone remodeling and pain relief. We found that chronic morphine reduced the mechanical hypersensitivity induced by the proliferation of the luminal B aggressive breast cancer cells in the tumor-bearing femur and prevented spinal neuronal and astrocyte activation. Using MTT cell viability assay and MRI coupled to 18FDG PET imaging followed by ex vivo 3D µCT, we further demonstrated that morphine did not directly exert tumor growth promoting or inhibiting effects on MRMT-1 cancer cells but induced detrimental effects on bone healing by disturbing the balance between bone formation and breakdown. In sharp contrast, both the FDA-approved bisphosphonate zoledronate and the synthetic cannabinoid nabilone prescribed as antiemetics to patients receiving chemotherapy were effective in limiting the osteolytic bone destruction, thus preserving the bone architecture. The protective effect of nabilone on bone metabolism was further accompanied by a direct inhibition of tumor growth. As opposed to zoledronate, nabilone was however not able to manage bone tumor-induced pain and reactive gliosis. Altogether, our results revealed that morphine, nabilone and zoledronate exert disparate effects on tumor growth, bone metabolism and pain control. These findings also support the use of nabilone as an adjuvant therapy for bone metastases.

Combination of high-fat/high-fructose diet and low-dose streptozotocin to model long-term type-2 diabetes complications.

The epidemic of type 2 diabetes mellitus (T2DM) is fueled by added fructose consumption. Here, we thus combined high-fat/high-fructose diet, with multiple low-dose injections of streptozotocin (HF/HF/Stz) to emulate the long-term complications of T2DM. HF/HF/Stz rats, monitored over 56 weeks, exhibited metabolic dysfunctions associated with the different stages of the T2DM disease progression in humans: an early prediabetic phase characterized by an hyperinsulinemic period with modest dysglycemia, followed by a late stage of T2DM with frank hyperglycemia, normalization of insulinemia, marked dyslipidemia, hepatic fibrosis and pancreatic ß-cell failure. Histopathological analyses combined to [18F]-FDG PET imaging further demonstrated the presence of several end-organ long-term complications, including reduction in myocardial glucose utilization, renal dysfunction as well as microvascular neuropathy and retinopathy. We also provide for the first time a comprehensive µ-PET whole brain imaging of the changes in glucose metabolic activity within discrete cerebral regions in HF/HF/Stz diabetic rats. Altogether, we developed and characterized a unique non-genetic preclinical model of T2DM adapted to the current diet and lifestyle that recapitulates the major metabolic features of the disease progression, from insulin resistance to pancreatic ß-cell dysfunction, and closely mimicking the target-organ damage occurring in type 2 diabetic patients at advanced stages.

The Canadian minimum dataset for chronic low back pain research: a cross-cultural adaptation of the National Institutes of Health Task Force Research Standards.

BACKGROUND: To better standardize clinical and epidemiological studies about the prevalence, risk factors, prognosis, impact and treatment of chronic low back pain, a minimum data set was developed by the National Institutes of Health (NIH) Task Force on Research Standards for Chronic Low Back Pain. The aim of the present study was to develop a culturally adapted questionnaire that could be used for chronic low back pain research among French-speaking populations in Canada. METHODS: The adaptation of the French Canadian version of the minimum data set was achieved according to guidelines for the cross-cultural adaptation of self-reported measures (double forward-backward translation, expert committee, pretest among 35 patients with pain in the low back region). Minor cultural adaptations were also incorporated into the English version by the expert committee (e.g., items about race/ethnicity, education level). RESULTS: This cross-cultural adaptation provides an equivalent French-Canadian version of the minimal data set questionnaire and a culturally adapted English-Canadian version. Modifications made to the original NIH minimum data set were minimized to facilitate comparison between the Canadian and American versions. INTERPRETATION: The present study is a first step toward the use of a culturally adapted instrument for phenotyping French- and English-speaking low back pain patients in Canada. Clinicians and researchers will recognize the importance of this standardized tool and are encouraged to incorporate it into future research studies on chronic low back pain.

Functional inhibition of chemokine receptor CCR2 by dicer-substrate-siRNA prevents pain development.

BACKGROUND: Accumulating evidence suggests that the C-C chemokine ligand 2 (CCL2, or monocyte chemoattractant protein 1) acts as a neuromodulator in the central nervous system through its binding to the C-C chemokine receptor 2 (CCR2). Notably, it is well established that the CCL2/CCR2 axis plays a key role in neuron-glia communication as well as in spinal nociceptive transmission. Gene silencing through RNA interference has recently emerged as a promising avenue in research and drug development, including therapeutic management of chronic pain. In the present study, we used 27-mer Dicer-substrate small interfering RNA (DsiRNA) targeting CCR2 and assessed their ability to reverse the nociceptive behaviors induced by spinal CCL2 injection or following intraplantar injection of complete Freund's adjuvant. RESULTS: To this end, we first developed high-potency DsiRNAs designed to target different sequences distributed across the rat CCR2 (rCCR2) messenger RNA. For optimization, methyl groups were added to the two most potent DsiRNA candidates (Evader and M7 2'-O-methyl modified duplexes) in order to improve in vivo duplex stability and to reduce potential immunostimulatory activity. Our results demonstrated that all modified candidates formulated with the cell-penetrating peptide reagent Transductin showed strong RNAi activity following intrathecal delivery, exhibiting >50% rCCR2 knockdown in lumbar dorsal root ganglia. Accordingly, we found that these DsiRNA duplexes were able to reduce spinal microglia activation and were effective at blocking CCL2-induced mechanical hypersensitivity. Along with similar reductions of rCCR2 messenger RNA, both sequences and methylation patterns were similarly effective in inhibiting the CCL2 nociceptive action for the whole seven days testing period, compared to mismatch DsiRNA. DsiRNAs against CCR2 also reversed the hypernociceptive responses observed in the complete Freund's adjuvant-induced inflammatory chronic pain model. CONCLUSION: Altogether, these results validate CCR2 as a an appropriate molecular target for pain control and demonstrate that RNAi-based gene therapy represent an highly specific alternative to classical pharmacological approaches to treat central pathologies such as chronic pain.

A two-hit model of suicide-trait-related behaviors in the context of a schizophrenia-like phenotype: Distinct effects of lithium chloride and clozapine.

Schizophrenia patients show a high rate of premature mortality due to suicide. The pathophysiological mechanisms of these suicidal behaviors in schizophrenia do not appear to involve serotonergic neurotransmission as found in the general population. Our aim was to develop an in vivo model of schizophrenia presenting suicide-trait-related behaviors such as aggressiveness, impulsivity, anxiety and helplessness. We opted for a two-hit model: C57BL/6 dams were injected with polyI:C on gestational day 12. The pups were submitted to social isolation for 4weeks after weaning. During the last week of social isolation and 30min before behavioral testing, the mice received vehicle, lithium chloride or clozapine. Lithium chloride is well known for its suicide preventive effects in the non-schizophrenic population, while clozapine is the antipsychotic with the best-established suicide preventive effect. The two-hit model induced several schizophrenia-related and suicide-trait-related behaviors in male, but not female, mice. Additionally, lithium chloride improved prepulse inhibition, aggressiveness, impulsivity and anxiety-like behavior in socially isolated mice only, whereas clozapine prevented behavioral abnormalities mainly in mice prenatally exposed to polyI:C and submitted to isolated rearing. The distinct effects of lithium chloride and clozapine suggested that mice prenatally exposed to polyI:C and submitted to social isolation presented a distinct phenotype from that of mice submitted to social isolation only. Because diagnosing suicidal risk in patients is a challenge for psychiatrists given the lack of specific clinical predictors, our in vivo model could help in gaining a better understanding of the mechanisms underlying suicidal behavior in the context of schizophrenia.

Relationship between blood- and cerebrospinal fluid-bound neurotransmitter concentrations and conditioned pain modulation in pain-free and chronic pain subjects.

UNLABELLED: Descending pain inhibition is an endogenous pain control system thought to depend partially on the activation of bulbospinal monoaminergic pathways. Deficits in descending pain inhibition have been reported in numerous human chronic pain conditions, but there is currently no consensus regarding the neurochemical correlates responsible for this deficit. The aims of this study were to 1) assess the efficacy of descending pain inhibition in pain-free and chronic pain subjects, 2) screen for changes in centrally (ie, cerebrospinal fluid) and peripherally (ie, plasma) acting monoamine concentrations, and 3) explore the relationship between descending pain inhibition and monoamine neurotransmitter concentrations. Our results clearly show a deficit in pain inhibition, along with lower plasma norepinephrine and metanephrine concentrations in chronic pain subjects, compared to pain-free subjects. No differences were found in cerebrospinal fluid neurotransmitter concentrations. Finally, our results revealed a positive relationship between blood-bound norepinephrine and metanephrine concentrations and the efficacy of descending pain inhibition. Thus, basal monoamine levels in blood were related to descending pain inhibition. This finding supports the emerging idea that individual differences in descending pain inhibition may be linked to individual differences in peripheral processes, such as monoamines release in blood, which are possibly related to cardiovascular control. PERSPECTIVES: This article presents psychophysical and neurochemical findings that indicate that the latent potential of descending pain inhibitory responses is associated with differential activity in peripheral processes governed by monoamine neurotransmitter release, bringing insights into the relationship between descending pain inhibition and cardiovascular control in humans.

Functional up-regulation of Nav1.8 sodium channel in Aß afferent fibers subjected to chronic peripheral inflammation.

BACKGROUND: Functional alterations in the properties of Aß afferent fibers may account for the increased pain sensitivity observed under peripheral chronic inflammation. Among the voltage-gated sodium channels involved in the pathophysiology of pain, Na(v)1.8 has been shown to participate in the peripheral sensitization of nociceptors. However, to date, there is no evidence for a role of Na(v)1.8 in controlling Aß-fiber excitability following persistent inflammation. METHODS: Distribution and expression of Na(v)1.8 in dorsal root ganglia and sciatic nerves were qualitatively or quantitatively assessed by immunohistochemical staining and by real time-polymerase chain reaction at different time points following complete Freund's adjuvant (CFA) administration. Using a whole-cell patch-clamp configuration, we further determined both total INa and TTX-R Na(v)1.8 currents in large-soma dorsal root ganglia (DRG) neurons isolated from sham or CFA-treated rats. Finally, we analyzed the effects of ambroxol, a Na(v)1.8-preferring blocker on the electrophysiological properties of Nav1.8 currents and on the mechanical sensitivity and inflammation of the hind paw in CFA-treated rats. RESULTS: Our findings revealed that Na(v)1.8 is up-regulated in NF200-positive large sensory neurons and is subsequently anterogradely transported from the DRG cell bodies along the axons toward the periphery after CFA-induced inflammation. We also demonstrated that both total INa and Na(v)1.8 peak current densities are enhanced in inflamed large myelinated Aß-fiber neurons. Persistent inflammation leading to nociception also induced time-dependent changes in Aß-fiber neuron excitability by shifting the voltage-dependent activation of Na(v)1.8 in the hyperpolarizing direction, thus decreasing the current threshold for triggering action potentials. Finally, we found that ambroxol significantly reduces the potentiation of Na(v)1.8 currents in Aß-fiber neurons observed following intraplantar CFA injection and concomitantly blocks CFA-induced mechanical allodynia, suggesting that Na(v)1.8 regulation in Aß-fibers contributes to inflammatory pain. CONCLUSIONS: Collectively, these findings support a key role for Na(v)1.8 in controlling the excitability of Aß-fibers and its potential contribution to the development of mechanical allodynia under persistent inflammation.

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties.

Neurotensin (NT) has emerged as an important modulator of nociceptive transmission and exerts its biological effects through interactions with 2 distinct GPCRs, NTS1 and NTS2. NT provides strong analgesia when administered directly into the brain; however, the blood-brain barrier (BBB) is a major obstacle for effective delivery of potential analgesics to the brain. To overcome this challenge, we synthesized chemical conjugates that are transported across the BBB via receptor-mediated transcytosis using the brain-penetrant peptide Angiopep-2 (An2), which targets LDL receptor-related protein-1 (LRP1). Using in situ brain perfusion in mice, we found that the compound ANG2002, a conjugate of An2 and NT, was transported at least 10 times more efficiently across the BBB than native NT. In vitro, ANG2002 bound NTS1 and NTS2 receptors and maintained NT-associated biological activity. In rats, i.v. ANG2002 induced a dose-dependent analgesia in the formalin model of persistent pain. At a dose of 0.05 mg/kg, ANG2002 effectively reversed pain behaviors induced by the development of neuropathic and bone cancer pain in animal models. The analgesic properties of ANG2002 demonstrated in this study suggest that this compound is effective for clinical management of persistent and chronic pain and establish the benefits of this technology for the development of neurotherapeutics.

Spinal NTS2 receptor activation reverses signs of neuropathic pain.

Management of painful peripheral neuropathies remains challenging, since patients with chronic pain respond poorly to the available pharmacopeia. In recent years, the G-protein-coupled receptor neurotensin (NT) type 2 (NTS2) emerged as an attractive target for treating transitory pain states. To date, however, there is no evidence for its role in the regulation of chronic peripheral neuropathies. Here, we found that NTS2 receptors were largely localized to primary afferent fibers and superficial dorsal horns. Changes in the time course of the gene expression profile of NT, NTS1, and NTS2 were observed over a 28-d period following the sciatic nerve constriction [chronic constriction injury (CCI) model]. We next determined the effects of central delivery of selective-NTS2 agonists to CCI-treated rats on both mechanical allodynia (evoked withdrawal responses) and weight-bearing deficits (discomfort and quality-of-life proxies). The NTS2 analogs JMV431, levocabastine, and ß-lactotensin were all effective in reducing ongoing tactile allodynia in CCI-treated rats. Likewise, amitriptyline, pregabalin, and morphine significantly attenuated CCI-induced mechanical hypersensitivity. NTS2 agonists were also efficient in reversing weight-bearing and postural deficits caused by nerve damage, unlike reference analgesics currently used in the clinic. Thus, NTS2 agonists may offer new treatment avenues for limiting pain associated with peripheral neuropathies and improve functional rehabilitation and well-being.

Prevalence of claims-based recurrent low back pain in a Canadian population: a secondary analysis of an administrative database.

BACKGROUND: There is a vast literature reporting that the point prevalence of low back pain (LBP) is high and increasing. It is also known that a large proportion of acute LBP episodes are recurrent within 12 months. However, few studies report the annual trends in the prevalence of recurrent LBP or describe these trends according to age and sex categories. METHODS: We conducted a retrospective cohort study involving 401 264 adults selected from the administrative database of physician claims for the province of Quebec, Canada. These adults, aged 18 years and over, met the criteria of having consulted a physician three times within a 365-day period between 2000 and 2007 for a LBP condition corresponding to ICD-9 codes 721, 722, 724 or 739. All data were analyzed by sex and clustered according to specific age categories. RESULTS: We observed a decrease from 1.64% to 1.33% in the annual prevalence between 2000 and 2007 for men. This decrease in prevalence was mostly observed between 35 and 59 years of age. Older (≥ 65 years) women were 1.35 times more at risk to consult a physician for LBP in a recurrent manner than older men. The most frequently reported diagnosis was non-specific LBP between 2000 to 2007. During the same period, sequelae of previous back surgery and spinal stenosis were the categories with the largest increases. CONCLUSION: The annual prevalence of claims-based recurrent LBP progressively decreased between 2000 and 2007 for younger adults (<65 years) while older adults (≥ 65 years) showed an increase. Given the aging Canadian population, recurrent low back pain could have an increasing impact on the quality of life of the elderly as well as on the healthcare system.

Mammary cancer bone metastasis follow-up using multimodal small-animal MR and PET imaging.

UNLABELLED: Despite tremendous progress in the management of breast cancer, the survival rate of this disease is still correlated with the development of metastases-most notably, those of the bone. Diagnosis of bone metastasis requires a combination of multiple imaging modalities. MR imaging remains the best modality for soft-tissue visualization, allowing for the distinction between benign and malignant lesions in many cases. On the other hand, PET imaging is frequently more specific at detecting bone metastasis by measuring the accumulation of radiotracers, such as (18)F-sodium fluoride ((18)F-NaF) and (18)F-FDG. Thus, the main purpose of this study was to longitudinally monitor bone tumor progression using PET/MR image coregistration to improve noninvasive imaging-assisted diagnoses. METHODS: After surgical implantation of mammary MRMT-1 cells in a rat femur, we performed minimally invasive imaging procedures at different time points throughout tumor development. The procedure consisted of sequential coregistered MR and PET image acquisition, using gadolinium-diethylenetriaminepentaacetic acid (DTPA) as a contrast agent for MR imaging and (18)F-FDG, (11)C-methionine, and (18)F-NaF as molecular tracers for PET imaging. The animals were then euthanized, and complementary radiologic (micro-CT scans) and histologic analyses were performed. RESULTS: In this preclinical study, we demonstrated that coregistered MR and PET images provide helpful information in a rat mammary-derived bone cancer model. First, MR imaging provided a high-definition anatomic resolution that made the localization of bone resorption and tumor extension detectable between days 9 and 18 after the injection of cancer cells in the medullary channel of the femur. Indeed, the calculation of mean standardized uptake value (SUVmean) and maximal SUV (SUVmax) in bone and soft-tissue regions, as defined from the gadolinium-DTPA contrast-enhanced MR images, showed (18)F-NaF uptake modifications and increased (18)F-FDG or (11)C-methionine uptake in the bone and surrounding soft tissues. (18)F-FDG and (11)C-methionine were compared in terms of the magnitude of change in their uptake and variability. We observed that (11)C-methionine SUVmean variations in the tumor were more important than those of (18)F-FDG. We also found fewer interindividual variations using SUVmean as a quantitative parameter than SUVmax. CONCLUSION: This preclinical evaluation demonstrated that a PET/MR image coregistration protocol provided a powerful tool to evaluate bone tumor progression in a rat model of bone metastasis and that this protocol could be translated to improve the clinical outcome for metastatic breast cancer management.

The effects of lidocaine spray and intracuff alkalinized lidocaine on the occurrence of cough at extubation: a double-blind randomized controlled trial.

PURPOSE: Our study aimed to evaluate the effects of lidocaine sprayed onto the larynx and/or injected into the tracheal tube cuff to decrease the incidence of cough at extubation and postoperative sore throat. METHODS: One hundred twenty women scheduled for gynecological surgery < 120 min in duration were enrolled in this randomized double-blind prospective study. Prior to tracheal intubation, 4% lidocaine or 0.9% saline was sprayed onto the patients' supra- and subglottic areas. After tracheal intubation, the tracheal tube cuff was filled with either an alkalinized 2% lidocaine solution or 0.9% saline. This resulted in four groups: spray-cuff, spray-saline, saline-cuff, and saline-saline. A logistic regression comprising the two factors was used for analysis. The primary outcome was the incidence of cough at extubation. The secondary outcome was the incidence and severity of sore throat reported by patients at 15 min, 60 min, and 24 hr after tracheal extubation. RESULTS: Cough occurred in 42%, 24%, 63%, and 69% of patients in the spray-cuff, spray-saline, saline-cuff, and saline-saline groups, respectively. The use of lidocaine spray decreased the incidence of cough at extubation (odds ratio = 0.256; 95% confidence interval 0.118 to 0.554; P < 0.001); however, the use of intracuff alkalinized lidocaine had no impact on the occurrence of cough (P = 0.471). Severity of sore throat was clinically low (visual analog scale [VAS] ≤ 3) in all groups. No significant difference was observed in hoarseness, dysphagia, nausea, or vomiting. CONCLUSION: Sprayed lidocaine decreases the incidence of cough at tracheal extubation in surgeries of less than two hours. The use of alkalinized lidocaine into high-volume/low-pressure endotracheal cuffs had no impact on decreasing the incidence of cough or pain.