Behavioural alteration in chronic pain: are brain glia involved?

Behavioural symptoms such as abnormal emotionality (including anxious and depressive episodes) and cognition (for instance weakened decision-making) are highly frequent in both chronic pain patients and their animal models. The theory developed in the present article posits that alterations in glial cells (astrocytes and microglia) in cortical and limbic brain regions might be the origin of such emotional and cognitive chronic pain-associated impairments. Indeed, in mood disorders (unipolar depression, anxiety disorders, autism or schizophrenia) glial changes in brain regions involved in mood control (prefrontal and cingulate cortices, amygdala and the hippocampus) have been recurrently described. Besides, glial cells have been undoubtedly identified as key actors in the sensory component of chronic pain, owing to the profound phenotypical changes they undergo throughout the sensory pathway. Hence, the possibility arises that brain astrocytes and microglia react in upper brain structures as well, mediating the related mood and cognitive dysfunctions in chronic pain. So far, only very few studies have provided results in this prospect, mainly indirectly in pain-independent researches. Nevertheless, the first scant available data seem to merge in a unified description of a brain glial reaction occurring after chronic peripheral lesion. The present article uses this scarce literature to formulate the provocative theory of a glia-driven mood and cognitive dysfunction in chronic pain, expounding upon its validity and putative therapeutical impact as well as its current limitations and expected future developments.

La fonction de Moi auxiliaire dans la prise en charge des douloureux chroniques [The role of the auxiliary ego in the care of the chronic pain patient]

La prise en charge des patients souffrant de douleurs chroniques, à l'interface entre corps et psyché, nécessite une approche globale et souvent un réseau de soins coordonnés, contenant et stable. La psychiatrie de liaison a naturellement trouvé sa place dans ce réseau de soins spécifiques auprès des différents soignants impliqués. Les réflexions issues de cette expérience ont pour objectif de mieux comprendre le rôle thérapeutique des soignants et font émerger la notion de Moi auxiliaire comme élément clé dans le traitement de ces patients. Dans cet article, nous reprendrons les fondements historiques et conceptuels de la fonction de Moi auxiliaire pour nous intéresser à ses différentes applications dans ces prises en charge : consultation médicale, psychothérapie individuelle ou de groupe, colloque interdisciplinaire. The management of the patient suffering from chronic pain, situated on the interface between body and psyche, necessitates a global approach and often a coordinated, stable and containing network of care. Liaison psychiatry has become part of this network, together with various health care professionals from somatic disciplines. Based on these experiences, this article aims to better understand the therapeutic role of those who take care of the chronic pain patient by identifying the auxiliary ego as a key element of care. The historical development and conceptual framework of the auxiliary ego are utilized to highlight its roles in the different aspects of care of these patients:in the medical consultation, individual psychotherapy, group psychotherapy and in the interdisciplinary meetings.

The appropriate use of neurostimulation: avoidance and treatment of complications of neurostimulation therapies for the treatment of chronic pain.

INTRODUCTION: The International Neuromodulation Society (INS) has determined that there is a need for guidance regarding safety and risk reduction for implantable neurostimulation devices. The INS convened an international committee of experts in the field to explore the evidence and clinical experience regarding safety, risks, and steps to risk reduction to improve outcomes. METHODS: The Neuromodulation Appropriateness Consensus Committee (NACC) reviewed the world literature in English by searching MEDLINE, PubMed, and Google Scholar to evaluate the evidence for ways to reduce risks of neurostimulation therapies. This evidence, obtained from the relevant literature, and clinical experience obtained from the convened consensus panel were used to make final recommendations on improving safety and reducing risks. RESULTS: The NACC determined that the ability to reduce risk associated with the use of neurostimulation devices is a valuable goal and possible with best practice. The NACC has recommended several practice modifications that will lead to improved care. The NACC also sets out the minimum training standards necessary to become an implanting physician. CONCLUSIONS: The NACC has identified the possibility of improving patient care and safety through practice modification. We recommend that all implanting physicians review this guidance and consider adapting their practice accordingly.

Polyanalgesic Consensus Conference-2012: Recommendations to Reduce Morbidity and Mortality in Intrathecal Drug Delivery in the Treatment of Chronic Pain.

Introduction:  Targeted intrathecal drug infusion to treat moderate to severe chronic pain has become a standard part of treatment algorithms when more conservative options fail. This therapy is well established in the literature, has shown efficacy, and is an important tool for the treatment of both cancer and noncancer pain; however, it has become clear in recent years that intrathecal drug delivery is associated with risks for serious morbidity and mortality. Methods:  The Polyanalgesic Consensus Conference is a meeting of experienced implanting physicians who strive to improve care in those receiving implantable devices. Employing data generated through an extensive literature search combined with clinical experience, this work group formulated recommendations regarding awareness, education, and mitigation of the morbidity and mortality associated with intrathecal therapy to establish best practices for targeted intrathecal drug delivery systems. Results:  Best practices for improved patient care and outcomes with targeted intrathecal infusion are recommended to minimize the risk of morbidity and mortality. Areas of focus include respiratory depression, infection, granuloma, device-related complications, endocrinopathies, and human error. Specific guidance is given with each of these issues and the general use of the therapy. Conclusions:  Targeted intrathecal drug delivery systems are associated with risks for morbidity and mortality that can be devastating. The panel has given guidance to treating physicians and healthcare providers to reduce the incidence of these problems and to improve outcomes when problems occur.

Chronic pain and antidepressants: A systematic review of efficacy

Background and aims: chronic pain is a major public health care problem with a prevalence in Europe as high as 19% in the general population (Breivik et al. 2006). Beside classical analgesics, Antidepressants (AD) remain an essential part of the therapeutic armamentarium. The present study was aimed at reviewing current evidence for efficacy of AD in main chronic pain conditions. Methods: We performed a systematic literature search through Ovid Medline, Psychinfo and Cochrane database to retrieve controlled studies and reviews on the use of AD in specific chronic pain conditions: neuropathic pain, migraine and tension-type headache, muskuloskeletal pain, and fibromyalgia. Results: There is sufficient data to support the use of tricyclic antidepressants (TCAs) in neuropathic pain, migraine and tension-type headache. There is also good evidence for a beneficial effect of TCAs in chronic low back pain and fibromyalgia. The SNRI venlafaxine and duloxetine are drugs with less established efficacy in neuropathic pain, tension type headache and fibromyalgia, but may be recommended as second line treatment. Available data do not support the use of SSRIs in any of these conditions. Given the limitations of available studies, there is still room to better characterize putative benefits of SNRIs and SSRIs in some of these conditions. Conclusions: Efficacy of AD in chronic pain appear to vary greatly between type of AD. Beneficial effects when present seem independent of the effect on mood. There is a lack of long term controlled trials in most type of chronic pain conditions.

Selective inhibition of JNK with a peptide inhibitor attenuates pain hypersensitivity and tumor growth in a mouse skin cancer pain model.

Cancer pain significantly affects the quality of cancer patients, and current treatments for this pain are limited. C-Jun N-terminal kinase (JNK) has been implicated in tumor growth and neuropathic pain sensitization. We investigated the role of JNK in cancer pain and tumor growth in a skin cancer pain model. Injection of luciferase-transfected B16-Fluc melanoma cells into a hindpaw of mouse induced robust tumor growth, as indicated by increase in paw volume and fluorescence intensity. Pain hypersensitivity in this model developed rapidly (<5 days) and reached a peak in 2 weeks, and was characterized by mechanical allodynia and heat hyperalgesia. Tumor growth was associated with JNK activation in tumor mass, dorsal root ganglion (DRG), and spinal cord and a peripheral neuropathy, such as loss of nerve fibers in the hindpaw skin and induction of ATF-3 expression in DRG neurons. Repeated systemic injections of D-JNKI-1 (6 mg/kg, i.p.), a selective and cell-permeable peptide inhibitor of JNK, produced an accumulative inhibition of mechanical allodynia and heat hyperalgesia. A bolus spinal injection of D-JNKI-1 also inhibited mechanical allodynia. Further, JNK inhibition suppressed tumor growth in vivo and melanoma cell proliferation in vitro. In contrast, repeated injections of morphine (5 mg/kg), a commonly used analgesic for terminal cancer, produced analgesic tolerance after 1 day and did not inhibit tumor growth. Our data reveal a marked peripheral neuropathy in this skin cancer model and important roles of the JNK pathway in cancer pain development and tumor growth. JNK inhibitors such as D-JNKI-1 may be used to treat cancer pain.

Cellules gliales et douleur chronique: du laboratoire a l'espoir clinique [Glial cells and chronic pain: from the laboratory to clinical hope].

Despite their high prevalence, associated disability and seemingly rich pharmacopeia, the various forms of chronic pain remain frequently intractable. The past decade witnessed the rise of a concept stating that non-neuronal cells of the central nervous system, astrocytes and microglia, are crucial elements in pathological pain. This review gathers and summarizes the experimental data underpinning this theory in animal models and addresses their pertinence in humans. The potential opportunities and constraints of glial inhibition are exposed and compared to more moderate strategies of selective modulation. This therapeutic hope is particularly highlighted in our discussion of the first completed clinical trials employing glial inhibitors in the treatment of chronic pain.

Traitement de la douleur chronique: rôle de la stimulation transcrânienne du cortex moteur [Treatment of chronic pain: transcranial stimulation of the motor cortex?].

Chronic pain refractory to medical therapy poses a therapeutic challenge. The repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS) modulate brain activity offering a new approach. Current evidence suggests a potential therapeutic efficacy of motor cortex stimulation for the treatment of pain, but does not (yet) support their recommendation for clinical practice. These methods allow to deepen our knowledge in the pathophysiology of chronic pain while providing new therapeutic approaches.

A meta-analysis of acupuncture for chronic pain.

Results of 14 randomized controlled trials of acupuncture for chronic pain were pooled in a meta-analysis and analysed in three subgroups according to site of pain; and in two subgroups each according to type to trial, type of treatment, type of control, 'blindness' of participating agents, trial size, and type of journal in which results were published. While few individual trials had statistically significant results, pooled results of many subgroups attained statistical significance in favour of acupuncture. Various potential sources of bias, including problems with blindness, precluded a conclusive finding although most results apparently favoured acupuncture.

Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes.

In the peripheral sensory nervous system the neuronal expression of voltage-gated sodium channels (Navs) is very important for the transmission of nociceptive information since they give rise to the upstroke of the action potential (AP). Navs are composed of nine different isoforms with distinct biophysical properties. Studying the mutations associated with the increase or absence of pain sensitivity in humans, as well as other expression studies, have highlighted Nav1.7, Nav1.8, and Nav1.9 as being the most important contributors to the control of nociceptive neuronal electrogenesis. Modulating their expression and/or function can impact the shape of the AP and consequently modify nociceptive transmission, a process that is observed in persistent pain conditions. Post-translational modification (PTM) of Navs is a well-known process that modifies their expression and function. In chronic pain syndromes, the release of inflammatory molecules into the direct environment of dorsal root ganglia (DRG) sensory neurons leads to an abnormal activation of enzymes that induce Navs PTM. The addition of small molecules, i.e., peptides, phosphoryl groups, ubiquitin moieties and/or carbohydrates, can modify the function of Navs in two different ways: via direct physical interference with Nav gating, or via the control of Nav trafficking. Both mechanisms have a profound impact on neuronal excitability. In this review we will discuss the role of Protein Kinase A, B, and C, Mitogen Activated Protein Kinases and Ca++/Calmodulin-dependent Kinase II in peripheral chronic pain syndromes. We will also discuss more recent findings that the ubiquitination of Nav1.7 by Nedd4-2 and the effect of methylglyoxal on Nav1.8 are also implicated in the development of experimental neuropathic pain. We will address the potential roles of other PTMs in chronic pain and highlight the need for further investigation of PTMs of Navs in order to develop new pharmacological tools to alleviate pain.

High-frequency electroacupuncture versus carprofen in an incisional pain model in rats

The objective of the present study was to compare the effect of electroacupuncture (EA) and carprofen (CP) on postoperative incisional pain using the plantar incision (PI) model in rats. A 1-cm longitudinal incision was made through skin, fascia and muscles of a hind paw of male Wistar rats and the development of mechanical and thermal hypersensitivity was determined over 4 days using the von Frey and Hargreaves methods, respectively. Based on the experimental treatments received on the third postoperative day, the animals were divided into the following groups: PI+CP (CP, 2 mg/kg, po); PI+EAST36 (100-Hz EA applied bilaterally at the Zusanli point (ST36)); PI+EANP (EA applied to a non-acupoint region); PI+IMMO (immobilization only); PI (vehicle). In the von Frey test, the PI+EAST36 group had higher withdrawal force thresholds in response to mechanical stimuli than the PI, PI+IMMO and PI+EANP groups at several times studied. Furthermore, the PI+EAST36 group showed paw withdrawal thresholds in response to mechanical stimuli that were similar to those of the PI+CP group. In the Hargreaves test, all groups had latencies higher than those observed with PI. The PI+EAST36 group was similar to the PI+IMMO, PI+EANP and PI+CP groups. We conclude that 100-Hz EA at the ST36 point, but not at non-acupoints, can reduce mechanical nociception in the rat model of incisional pain, and its effectiveness is comparable to that of carprofen.

An improved experimental model for peripheral neuropathy in rats

A modification of the Bennett and Xie chronic constriction injury model of peripheral painful neuropathy was developed in rats. Under tribromoethanol anesthesia, a single ligature with 100% cotton glace thread was placed around the right sciatic nerve proximal to its trifurcation. The change in the hind paw reflex threshold after mechanical stimulation observed with this modified model was compared to the change in threshold observed in rats subjected to the Bennett and Xie or the Kim and Chung spinal ligation models. The mechanical threshold was measured with an automated electronic von Frey apparatus 0, 2, 7, and 14 days after surgery, and this threshold was compared to that measured in sham rats. All injury models produced significant hyperalgesia in the operated hind limb. The modified model produced mean ± SD thresholds in g (19.98 ± 3.08, 14.98 ± 1.86, and 13.80 ± 1.00 at 2, 7, and 14 days after surgery, respectively) similar to those obtained with the spinal ligation model (20.03 ± 1.99, 13.46 ± 2.55, and 12.46 ± 2.38 at 2, 7, and 14 days after surgery, respectively), but less variable when compared to the Bennett and Xie model (21.20 ± 8.06, 18.61 ± 7.69, and 18.76 ± 6.46 at 2, 7, and 14 days after surgery, respectively). The modified method required less surgical skill than the spinal nerve ligation model.