Consensus on the detection and management of patients with depression and pain as an associated somatic symptom.

INTRODUCTION: Globally, depression is the most common psychiatric disorder and is frequently associated with somatic symptom disorders, including pain as a physical symptom. There is a current need to improve the detection and management of the individuals in which depression and pain coexist. Hence, the aim of this document is to provide recommendations in the diagnosis and management of patients with major depressive disorder (MDD) who have pain as a physical symptom (PPS), in order to reduce the variability of clinical practice. MATERIAL AND METHODS: The methodology used is based on the internationally recognized RAND/UCLA consensus method. The scientific committee, consisted of a group of eight multidisciplinary experts, defined 12 clinically relevant questions. After the systematic review of the literature, the scientific committee assessed the evidence and developed recommendations. The panel group with 15 participants validated these recommendations using a single Delphi round. To conclude, there was a final consensus meeting held to redefine with minor modifications the final recommendations. RESULTS: The scientific committee developed a total of 19 recommendations on the diagnosis and detection, impact of PPS in MDD, treatment of MDD with associated PPS, use of healthcare resources, additional recommendations, and care coordination of these patients. Globally, a substantial level of agreement (≥80%) was reached on all items during the Delphi round. All the 19 achieved consensus, seven of them (37%) were agreed with unanimity during the Delphi round. The recommendations with higher consensus were in relation to diagnosis, impact of PPS in MDD, treatment and use of healthcare resources. CONCLUSIONS: Currently, the evidence base for patients with MDD and PPS is still being developed and this consensus statement aims to bridge that gap by providing practical recommendations.

Pain and depression comorbidity causes asymmetric plasticity in the locus coeruleus neurons.

There is strong comorbidity between chronic pain and depression, although the neural circuits and mechanisms underlying this association remain unclear. By combining immunohistochemistry, tracing studies and western blotting, with the use of different DREADDS (designer receptor exclusively activated by designer drugs) and behavioural approaches in a rat model of neuropathic pain (chronic constriction injury), we explore how this comorbidity arises. To this end, we evaluated the time-dependent plasticity of noradrenergic locus coeruleus neurons relative to the site of injury: ipsilateral (LCipsi) or contralateral (LCcontra) locus coeruleus at three different time points: short (2 days), mid (7 days) and long term (30-35 days from nerve injury). Nerve injury led to sensorial hypersensitivity from the onset of injury, whereas depressive-like behaviour was only evident following long-term pain. Global chemogenetic blockade of the LCipsi system alone increased short-term pain sensitivity while the blockade of the LCipsi or LCcontra relieved pain-induced depression. The asymmetric contribution of locus coeruleus modules was also evident as neuropathy develops. Hence, chemogenetic blockade of the LCipsi→spinal cord projection, increased pain-related behaviours in the short term. However, this lateralized circuit is not universal as the bilateral chemogenetic inactivation of the locus coeruleus-rostral anterior cingulate cortex pathway or the intra-rostral anterior cingulate cortex antagonism of alpha1- and alpha2-adrenoreceptors reversed long-term pain-induced depression. Furthermore, chemogenetic locus coeruleus to spinal cord activation, mainly through LCipsi, reduced sensorial hypersensitivity irrespective of the time post-injury. Our results indicate that asymmetric activation of specific locus coeruleus modules promotes early restorative analgesia, as well as late depressive-like behaviour in chronic pain and depression comorbidity.

The prevention of relapses in first episodes of schizophrenia: The 2EPs Project, background, rationale and study design.

Up to 80% of first-episode psychosis patients suffer a relapse within five years of the remission. Relapse should be an important focus of prevention given the potential harm to the patient and family. It threatens to disrupt their psychosocial recovery, increases the risk of resistance to treatment and has been associated with greater direct and indirect costs for society. Based on a previous project entitled "Genotype-phenotype and environment. Application to a predictive model in first psychotic episodes" (PEPs Project), the project "Clinical and neurobiological determinants of second episodes of schizophrenia. Longitudinal study of first episode of psychosis" was designed, also known as the 2EPs Project. It aimed to identify and characterize those factors that predict a relapse within the years immediately following a first episode. This project has focused on following the clinical course, with neuropsychological assessments, biological and neuroanatomical measures, genetic adherence and physical health monitoring in order to compare a subgroup of patients with a second episode to another group of patients which remains in remission. The main objective of the present article is to describe the rationale of the 2EPs Project, explaining the measurement approach adopted and providing an overview of the selected clinical and functional measures. 2EPs Project is a multicenter, coordinated, naturalistic, longitudinal follow-up study over three years in a Spanish sample of patients in remission after a first-psychotic episode of schizophrenia. It is closely monitoring the clinical course of the cases recruited to compare the subgroup of patients with a second episode to that which remains in remission. The sample is composed of 223 subjects recruited from 15 clinical centres in Spain with experience of the preceding PEPs Study project, albeit 2EPs being an expanded version with new basic groups in biological research. From the total sample recruited, 63 patients presented a relapse (44%). 2EPs arose to characterize first episodes in an exhaustive, novel and multimodal way, thus contributing towards the development of a predictive model of relapse. Identifying the characteristics of patients who relapse could improve early detection and intervention.

Neuropathic pain increases spontaneous and noxious-evoked activity of locus coeruleus neurons.

The noradrenergic locus coeruleus nucleus is an important station in both the ascending and descending pain regulatory pathways. These neurons discharge in tonic and phasic modes in response to sensory stimuli. However, few studies have set out to characterize the electrophysiological response of the locus coeruleus to noxious stimuli in conditions of neuropathic pain. Thus, the effects of mechanical nociceptive stimulation of the sciatic nerve area on spontaneous (tonic) and sensory-evoked (phasic) locus coeruleus discharge were studied by extracellular recording in anesthetized rats seven, fourteen and twenty-eight days after chronic constriction injury. Minor significant electrophysiological changes were found seven and fourteen days after nerve injury. However, alterations to the spontaneous activity in both the ipsilateral and contralateral locus coeruleus were found twenty-eight days after nerve constriction, as witnessed by an increase of burst firing incidence and irregular firing patterns. Furthermore, noxious-evoked responses were exacerbated in the contralateral and ipsilateral nucleus at twenty-eight days after injury, as were the responses evoked when stimulating the uninjured paw. In addition, mechanical stimulation of the hindpaw produced a significant sensitization of neuronal tonic activity after 28 days of neuropathy. In summary, long-term nerve injury led to higher spontaneous activity and exacerbated noxious-evoked responses in the locus coeruleus to stimulation of nerve-injured and even uninjured hindpaws, coinciding temporally with the development of depressive and anxiogenic-like behavior.

The management of pediatric chronic pain in Spain: a web-based survey study.

OBJECTIVE: To improve understanding of current practices in the treatment of children and adolescents with chronic pain in Spain. METHODS: A web-based survey was conducted with a representative sample of healthcare professionals (i.e. general practitioners [GP] and pediatricians [P]) in Spain. The survey included 23 questions on the pain education and training they had been given, and on organizational issues and current practices in the assessment and management of children and adolescents with chronic pain in their current work. RESULTS: The survey was completed by 191 professionals (75 GP and 116 P) with wide experience (mean number of years = 21; SD = 8) in the management of children and adolescents with chronic pain. Half of the participants reported that they had not been given any specific education or training on pediatric chronic pain management during their studies, and 80% acknowledged important gaps in their training. Although the majority assessed pain when attending children with chronic pain (80%), and almost all (96%) believed that protocols to guide the management of chronic pain in young people were necessary, only a third reported that they usually use a specific protocol. Less than 25% were part of a multidisciplinary team addressing the needs of children and adolescents with chronic pain. CONCLUSIONS: This survey has identified considerable limitations in the management of children and adolescents with chronic pain in Spain. This information can now be used by policy makers to improve the care given to children and adolescents suffering from chronic pain and their families.

Modelos experimentales de evaluación del dolor en artrosis / Experimental models for pain evaluation in osteoarthritis

La osteoartritis (OA) es una de las principales patologías asociadas al dolor crónico y, a pesar de décadas de estudio, todavía se desconocen muchos aspectos clave de su fisiopatología, lo que impulsa a seguir investigando opciones terapéuticas capaces de controlar el dolor de manera eficaz y segura. El uso de modelos experimentales de OA sigue siendo una de las alternativas más útiles para la comprensión tanto de la etiopatogenia de la OA como para el desarrollo de posibles biomarcadores y tratamientos. A pesar de la utilidad de los modelos experimentales en el avance del conocimiento de la OA, no existe un modelo o procedimiento técnico único que nos permita estudiar en él la gran variedad de cambios estructurales y sintomáticos que suceden en el paciente a lo largo de su enfermedad. No obstante, hoy en día disponemos de modelos y técnicas para la evaluación del dolor que nos permiten comprender los mecanismos que subyacen en la OA, así como comprender y explorar nuevas oportunidades terapéuticas para su control más eficaz y seguro.(AU)

Osteoarthritis (OA) is one of the main pathologies associated with chronic pain, and despite decades of study many key aspects of its pathophysiology are still unknown, which contributes to continuing to investigate therapeutic options capable of effectively and safely controlling pain. The use of experimental models of OA continues to be one of the most useful alternatives for understanding both the etiopathogenesis of OA and for the development of possible biomarkers and treatments. Despite the usefulness of experimental models in the advancement of knowledge of OA, there is no single model or technical procedure that allows us to study in it the great variety of structural and symptomatic changes that occur in the patient throughout his illness. However, today we have models and techniques for pain assessment that allow us to understand the mechanisms underlying OA as well as to understand and explore new therapeutic opportunities for its more effective and safe control.(AU)

Chemogenetic Silencing of the Locus Coeruleus-Basolateral Amygdala Pathway Abolishes Pain-Induced Anxiety and Enhanced Aversive Learning in Rats.

BACKGROUND: Pain affects both sensory and emotional aversive responses, often provoking anxiety-related diseases when chronic. However, the neural mechanisms underlying the interactions between anxiety and chronic pain remain unclear. METHODS: We characterized the sensory, emotional, and cognitive consequences of neuropathic pain (chronic constriction injury) in a rat model. Moreover, we determined the role of the locus coeruleus (LC) neurons that project to the basolateral amygdala (BLA) using a DREADD (designer receptor exclusively activated by designer drugs). RESULTS: Chronic constriction injury led to sensorial hypersensitivity in both the short term and long term. Otherwise, long-term pain led to an anxiety-like profile (in the elevated zero maze and open field tests), as well as increased responses to learn aversive situations (in the passive avoidance and fear conditioning tests) and an impairment of nonemotional cognitive tasks (in the novel object recognition and object pattern of separation tests). Chemogenetic blockade of the LC-BLA pathway and intra-BLA or systemic antagonism of beta-adrenergic receptors abolished both long-term pain-induced anxiety and enhanced fear learning. By contrast, chemogenetic activation of this pathway induced anxiety-like behaviors and enhanced the aversive learning and memory index in sham animals, although it had little effect on short- and long-term chronic constriction injury animals. Interestingly, modulation of LC-BLA activity did not modify sensorial perception or episodic memory. CONCLUSIONS: Our results indicate that dimensions associated with pain are processed by independent pathways and that there is an overactivation of the LC-BLA pathway when anxiety and chronic pain are comorbid, which involves the activity of beta-adrenergic receptors.

Diez años de investigación traslacional colaborativa en enfermedades mentales: el CIBERSAM / CIBERSAM: Ten years of collaborative translational research in mental disorders

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Monoamines as Drug Targets in Chronic Pain: Focusing on Neuropathic Pain.

Monoamines are involved in regulating the endogenous pain system and indeed, peripheral and central monoaminergic dysfunction has been demonstrated in certain types of pain, particularly in neuropathic pain. Accordingly, drugs that modulate the monaminergic system and that were originally designed to treat depression are now considered to be first line treatments for certain types of neuropathic pain (e.g., serotonin and noradrenaline (and also dopamine) reuptake inhibitors). The analgesia induced by these drugs seems to be mediated by inhibiting the reuptake of these monoamines, thereby reinforcing the descending inhibitory pain pathways. Hence, it is of particular interest to study the monoaminergic mechanisms involved in the development and maintenance of chronic pain. Other analgesic drugs may also be used in combination with monoamines to facilitate descending pain inhibition (e.g., gabapentinoids and opioids) and such combinations are often also used to alleviate certain types of chronic pain. By contrast, while NSAIDs are thought to influence the monoaminergic system, they just produce consistent analgesia in inflammatory pain. Thus, in this review we will provide preclinical and clinical evidence of the role of monoamines in the modulation of chronic pain, reviewing how this system is implicated in the analgesic mechanism of action of antidepressants, gabapentinoids, atypical opioids, NSAIDs and histaminergic drugs.

The onset of treatment with the antidepressant desipramine is critical for the emotional consequences of neuropathic pain.

Neuropathic pain is a chronic condition that is challenging to treat. It often produces considerable physical disability and emotional distress. Patients with neuropathic pain often experience depression and anxiety both of which are known to be temporally correlated with noradrenergic dysfunction in the locus coeruleus (LC) as pain becomes chronic. Antidepressants are the first-line drug therapy for neuropathic pain, and the LC represents a potential target for such therapy. In this study, we evaluated the efficacy of the tricyclic antidepressant desipramine (DMI, a noradrenaline reuptake inhibitor) in preventing or relieving the noradrenergic impairment induced by neuropathic pain. The treatment started before or after the onset of the anxiodepressive phenotype ("early or late treatment") in adult rats subjected to chronic sciatic constriction. Electrophysiological and western blotting assays showed LC dysfunction (increased bursting activity, alpha2-adrenoceptor sensitivity, tyrosine hydroxylase, and noradrenaline transporter expression) in chronic constriction injury at long term. These noradrenergic changes were concomitant to the progression of anxiety and despair-like features. Desipramine induced efficient analgesia, and it counteracted the despair-like behavior in chronic constriction injury-DMI animals, reducing the burst rate and tyrosine hydroxylase expression. Surprisingly, "early" DMI treatment did not modify pain-induced anxiety, and it dampened pain aversion, although these phenomena were abolished when the treatment commenced after noradrenaline impairment had been established. Hence, DMI seems to produce different outcomes depending when the treatment commences, indicating that the balance between the benefits and adverse effects of DMI therapy may shift as neuropathy progresses.

The complex association between the antioxidant defense system and clinical status in early psychosis.

Oxidative stress is a pathophysiological mechanism potentially involved in psychiatric disorders. The objective of this study was to assess the relationship between total antioxidant status (TAS) and the functional status of patients with a first episode of psychosis at the onset of the disease. For this purpose, a sample of 70 patients aged between 9 and 17 years with a first episode of psychosis were followed up for a period of two years. Blood samples were drawn to measure TAS levels at three time points: at baseline, at one year, and at two years. Clinical symptoms and functioning were also assessed at the same time points using various scales. Linear regression analysis was performed to investigate the relationship between TAS and clinical status at each assessment, adjusting for potential confounding factors. The distribution of clinical variables was grouped in different percentiles to assess the dose-response in the relation between clinical variables and TAS. At baseline, patient's score on Children's Global Assessment Scale (CGAS) was directly and significantly associated with TAS with a monotonic increase in percentiles, and surprising this association was reversed after one and two years of follow-up with a monotonic decrease. In summary at the onset of the illness, TAS is positively related to clinical status, whereas as the illness progresses this correlation is reversed and becomes negative. This may be the result of an adaptive response.

Factors Influencing Cognitive Impairment in Neuropathic and Musculoskeletal Pain and Fibromyalgia.

Objective: To assess cognitive performance of chronic pain (CP) patients diagnosed with three types of pain-neuropathic pain (NP), musculoskeletal (MSK), and fibromyalgia (FM)-and to analyze the factors influencing cognitive difficulties in each group. Methods: Two hundred fifty-four CP patients-104 NP, 99 MSK, 51 FM-and 72 pain-free subjects were included in the study. The "Test Your Memory" (TYM) scale was used to assess cognitive performance. Pain intensity was measured by means of the visual analog scale (VAS); the Hospital Anxiety and Depression scale was used to assess mental status, and the Medical Outcome Study (MOS) sleep scale to assess sleep quality. The relationships between cognitive performance and these factors were analyzed using linear regression models. Results: The mean score in the TYM was significantly lower (worse cognitive function) in CP patients than controls (40.5 vs 43.9, P < 0.001). In the separate analysis of each group, depression was observed to have a negative impact on MSK pain patients (ß = -0.37, 95% confidence interval [CI] = -0.53 to -0.2, P < 0.001) and on FM subjects (ß =-1.01, 95% CI = -1.05 to -2.38, P = 0.022). A significant interaction between pain intensity and depression was observed in the FM patients. In addition, a U-shaped association was found between the duration of pain and cognitive performance in the NP patients. Neither anxiety nor sleep impairment affected cognitive performance in any of the CP patients. Conclusions: These results highlight the importance of taking into account the type of pain when assessing cognitive performance in CP patients and demonstrate the influence of the emotional state of the patient, especially if depression is present.

Discovery and development of tramadol for the treatment of pain.

INTRODUCTION: Tramadol is an opioid drug that, unlike classic opioids, also modulates the monoaminergic system by inhibiting noradrenergic and serotoninergic reuptake. For this reason, tramadol is considered an atypical opioid. These special pharmacological characteristics have made tramadol one of the most commonly prescribed analgesic drugs to treat moderate to severe pain. Areas covered: The aim of this review is to provide a historical description of the biochemistry, pharmacokinetics and particularly, the mechanisms of action of tramadol. In addition, a summary is offered of the analgesic effects of tramadol in a variety of animal models of acute and chronic pain. Finally, clinical studies that demonstrate the efficacy and safety of tramadol in the treatment of pain are also assessed. Expert opinion: The discovery that tramadol combines opioid and monoaminergic effects represented a milestone in the evolution of pain treatment. Given its 'mild effect' on opioid receptors, tramadol induces fewer side effects than classic opioids. Tramadol produces satisfactory analgesia against various types of pain and it is currently approved for the treatment of moderate to severe pain. Thus, the combination of monoamine and opioid mechanisms opens new avenues for the design of innovative analgesics.

Single oral dose of cannabinoid derivate loaded PLGA nanocarriers relieves neuropathic pain for eleven days.

Neuropathic pain, resistant to opiates and other drugs, is a chronic/persistent state with a complex treatment and often poor efficacy. In this scenario, cannabinoids are increasingly regarded as a genuine alternative. In this paper, and in an experimental animal model of neuropathic pain, we studied the efficacy of three kinds of PLGA nanoparticles containing synthetic cannabinoid CB13: (i) plain nanoparticles (PLGA); (ii) particles coated with PEG chains (PLGA+PEG) and (iii) particles possessing hydrophilic surfaces obtained by covalently binding PEG chains (PLGA-PEG). The optimized formulation, CB13-PLGA-PEG, showed high drug loading (13%) and small size (<300nm) with a narrow distribution and controlled surface properties (near-neutral zeta potential and stable PEG corona). Animal nociceptive behavioral studies were conducted by paw pressure and acetone tests. Versus the free CB13, CB13-PLGA-PEG nanoparticles showed a very noticeable analgesic efficacy with the longest sustained pain-relieving effect, lasting up to eleven days after one oral dose.

Activation of Extracellular Signal-Regulated Kinases (ERK 1/2) in the Locus Coeruleus Contributes to Pain-Related Anxiety in Arthritic Male Rats.

Background: There is increasing evidence suggesting that the Locus Coeruleus plays a role in pain-related anxiety. Indeed, we previously found that prolonged arthritis produces anxiety-like behavior in rats, along with enhanced expression of phosphorylated extracellular signal-regulated kinase 1/2 (a marker of plasticity) in the Locus Coeruleus. However, it is unknown how this effect correlates with the electrophysiological activity of Locus Coeruleus neurons or pain-related anxiety. Methods: Using the complete Freund's adjuvant model of monoarthritis in male Sprague-Dawley rats, we studied the behavioral attributes of pain and anxiety as well as Locus Coeruleus electrophysiology in vivo 1 (MA1W) and 4 weeks (MA4W) after disease induction. Results: The manifestation of anxiety in MA4W was accompanied by dampened tonic Locus Coeruleus activity, which was coupled to an exacerbated evoked Locus Coeruleus response to noxious stimulation of the inflamed and healthy paw. When a mitogen-activating extracellular kinase inhibitor was administered to the contralateral Locus Coeruleus of MA4W, the phosphorylated extracellular signal-regulated kinase 1/2 levels in the Locus Coeruleus were restored and the exaggerated evoked response was blocked, reversing the anxiogenic-like behavior while pain hypersensitivity remained unaltered. Conclusion: As phosphorylated extracellular signal-regulated kinase 1/2 blockade in the Locus Coeruleus relieved anxiety and counteracted altered LC function, we propose that phosphorylated extracellular signal-regulated kinase 1/2 activation in the Locus Coeruleus plays a crucial role in pain-related anxiety.