From acute to chronic pain: tapentadol in the progressive stages of this disease entity.

OBJECTIVE: Chronic pain is now recognized as a neural disease, which results from a maladaptive functional and structural transformation process occurring over time. In its chronic phase, pain is not just a symptom but also a disease entity. Therefore, pain must be properly addressed, as many patients still report unsatisfactory pain control despite on-going treatment. The selection of the therapy - taking into account the pathophysiological mechanisms of pain - and the right timing can result in a successful analgesic outcome. This review will present the functional and structural modifications leading to chronification of pain, focusing on the role of tapentadol in this setting. MATERIALS AND METHODS: For inclusion in this review, research studies were retrieved via a keyword-based query of multiple databases (MEDLINE, Embase, Cochrane). The search was last updated in November 2016; no limitations were applied. RESULTS: Functional and structural abnormalities of the nervous system associated with pain chronification have been reported in several conditions, including osteoarthritis, chronic back pain, chronic pelvic pain and fibromyalgia. Correct identification and treatment of pain in recurrent/progressive stage is crucial to prevent chronification and related changes in neural structures. Among analgesic drugs, tapentadol, with its dual mechanism of action (opioid agonist and noradrenaline reuptake blocker), has recently resulted active in pain control at both central and spinal level. CONCLUSIONS: Tapentadol represents a suitable candidate for patients at early progressive stage of pain who have developed neuroplasticity with modification of pain pathways. The availability of different doses of tapentadol may help clinicians to tailor treatment based on the individual need of each patient, with the aim to enhance therapeutic appropriateness in the treatment of musculoskeletal and neuropathic pain.

What to Do, and What Not to Do, When Diagnosing and Treating Breakthrough Cancer Pain (BTcP): Expert Opinion.

Clinical management of breakthrough cancer pain (BTcP) is still not satisfactory despite the availability of effective pharmacological agents. This is in part linked to the lack of clarity regarding certain essential aspects of BTcP, including terminology, definition, epidemiology and assessment. Other barriers to effective management include a widespread prejudice among doctors and patients concerning the use of opioids, and inadequate assessment of pain severity, resulting in the prescription of ineffective drugs or doses. This review presents an overview of the appropriate and inappropriate actions to take in the diagnosis and treatment of BTcP, as determined by a panel of experts in the field. The ultimate aim is to provide a practical contribution to the unresolved issues in the management of BTcP. Five 'things to do' and five 'things not to do' in the diagnosis and treatment of BTcP are proposed, and evidence supporting said recommendations are described. It is the duty of all healthcare workers involved in managing cancer patients to be mindful of the possibility of BTcP occurrence and not to underestimate its severity. It is vital that all the necessary steps are carried out to establish an accurate and timely diagnosis, principally by establishing effective communication with the patient, the main information source. It is crucial that BTcP is treated with an effective pharmacological regimen and drug(s), dose and administration route prescribed are designed to suit the particular type of pain and importantly the individual needs of the patient.

The effects of nonsteroidal anti-inflammatory drugs on clinical outcomes, synovial fluid cytokine concentration and signal transduction pathways in knee osteoarthritis. A randomized open label trial.

OBJECTIVE: We investigated the effects of celecoxib, diclofenac, and ibuprofen on the disease-specific quality of life, synovial fluid cytokines and signal transduction pathways in symptomatic knee osteoarthritis (OA). DESIGN: Ninety patients scheduled for a total knee arthroplasty (TKA) were randomized to six groups that were treated with low and high dosages of celecoxib, diclofenac or ibuprofen. At the time of the first admission (T0) and at surgery (T1 = 14 days after beginning of the nonsteroidal anti-inflammatory drugs (NSAIDs)), samples of knee synovial fluid were obtained from each patient for analysis. During the surgery the synovial tissue was harvested from the knee of patients. The Western Ontario and McMaster universities (WOMAC) score was used to evaluate the patient disease-specific quality of life at T0 and T1. Microarray tests performed at T0 and T1 were used to evaluate the effects of NSAIDs on Tumor necrosis factor (TNF)-alpha, Interleukin-6 (IL-6), IL8 and Vascular endothelial growth factor (VEGF) concentration in the synovial fluid. Western blot assays evaluated the effects of NSAIDs on MAP kinase (MAPK) signal transduction pathway in the synovial membrane. RESULTS: NSAID treatment induced a statistically significant improvement in the WOMAC score and a statistically significant decrease in the IL-6, VEGF and TNF-alpha concentration in the synovial fluid. Higher dosages of NSAIDs provided a greater improvement in the disease-specific quality of life of patients and lower concentrations of pro-inflammatory cytokines in the synovial fluid. Inhibition of MAPKs was noted after NSAID treatment. CONCLUSION: Short-term NSAID treatment improves the patient disease-specific quality of life with a parallel decrease in pro-inflammatory synovial fluid cytokine levels in knee OA. Signal transduction pathways may be involved in regulating the anti-inflammatory effects of NSAIDs. ClinicalTrial.gov: NCT01860833.

Ethmoidal adenocarcinoma with lung metastases: diagnosis and multimodal treatment.

We report a case of 68-year-old patient underwent a magnetic resonance imaging (MRI) of the skull and a computed tomography (CT) of the thorax for rhinorrhea and dyspnea. The MRI showed an irregular ethmoidal lesion and the CT of the thorax underlined a solid nodular neoformation in the upper right pulmonary lobe. The patient underwent rhinoscopy with biopsies that showed an ethmoidal adenocarcinoma; excision of the tumour was carried out via trans-sphenoid. After one month the patient underwent wedge-resections in video-thoracoscopy (VATS). Perioperative histologic examination revealed a lung metastases due to an adenocarcinoma of the ethmoid. The patient was treated with chemotherapy and did not show relapses after 12 months from VATS.

Kindled seizure-induced c-fos and prodynorphin mRNA expressions are unrelated in the rat brain.

Levels of mRNA for c-fos and prodynorphin were studied by in situ hybridization in adjacent coronal sections taken from kindled rats 30-60 min after the last seizure. Within this time frame, expression of both genes was induced in multiple brain areas. Anatomical colocalization of the induced gene expressions was found in the hippocampus. Induction of c-fos in the dentate gyrus was bilateral and symmetrical in a subgroup of rats, ipsilateral in another subgroup and absent in a third subgroup. However, no relative increase was observed in the ipsilateral compared with the contralateral prodynorphin expression in the dentate gyrus when c-fos expression was induced ipsilaterally only. These observations suggest that, at variance with other experimental situations, Fos is not involved in the mechanisms of kindled seizure-induced activation of prodynorphin transcription in the rat forebrain.

Binding profile of benextramine at neuropeptide Y receptor subtypes in rat brain areas.

Binding studies in rat whole brain, frontoparietal cortex and brainstem membrane preparations revealed that benextramine displaced [3H]neuropeptide Y specific binding from a low and a high affinity site with IC50 values in the microM (36 +/- 2, 4.4 +/- 1.4 and 300 +/- 120 microM, respectively) and the pM (29.3 +/- 12.1, 0.35 +/- 0.11 and 0.42 +/- 0.03 pM, respectively) range, whereas in rat hippocampus benextramine displaced [3H]neuropeptide Y specific binding from one site only with an IC50 value of 22.8 +/- 5.7 microM. With the exception of frontoparietal cortex binding assay, benextramine was not able to completely inhibit [3H]neuropeptide Y specific binding revealing the presence of a benextramine nonsensitive third binding site. Benextramine pretreatment followed by membrane washing demonstrated that benextramine inhibited irreversibly both high and low affinity sites.

Alterations in vasoactive intestinal polypeptide-related peptides after pentylenetetrazole-induced seizures in rat brain.

The possible involvement of vasoactive intestinal polypeptide-related peptides in pentylenetetrazol (PTZ)-induced seizures in rats was investigated. The chemoconvulsant PTZ was administered (45 mg/kg i.p.) either acutely or chronically for three days. The detailed time course of changes in VIP-(1-28) and VIP-(22-28) was examined in several rat brain areas 5 and 20 min and 24 h after acute treatment and after three days chronic treatment. Ir-VIP levels dramatically decreased in all areas 5 min after PTZ injection, remained low after 20 min and progressively increased back to control values after 24 h and after three days of repeated treatment (except for the cortex). Chromatographic analysis of extracts prepared from PTZ-treated rats revealed a concomitant decrease in VIP-(1-28) and increase in VIP-(22-28). Thus VIP-(22-28) might be a product of the internal cleavage of the precursor VIP-(1-28) after its neuronal release; alternatively, VIP-(22-28) might be generated by post-transcriptional processing of VIP-(1-28), and thus be an 'independent' neuropeptide. The results suggest that VIP-(1-28)/VIP-(22-28)-containing neurons might be involved in PTZ-induced seizures in rat brain, and that VIP-(22-28) might play a role in these experimental seizures.

Substance P levels are decreased in lesional skin of atopic dermatitis.

There is increasing evidence that neuropeptides (NP) such as substance P (SP) and vasoactive intestinal polypeptide (VIP) are involved in the pathogenesis of atopic dermatitis (AD). Vasoactive intestinal polypeptide levels were found to be significantly elevated in lesional skin of AD as compared to controls. We evaluated by radioimmunoassay the SP content in whole skin homogenates from chronic lichenified lesions of patients with AD. The levels of SP were significantly decreased in lesional skin from AD patients as compared to control skin (0.25 +/- 0.03 vs. 0.97 +/- 0.24 pmol/g tissue, p < 0.01). The diminished SP levels as opposed to increased VIP concentrations could be consistent with different roles of these NP as modulatory agents in the mechanisms associated with AD.

[Functional recovery in subtotal laryngectomies]. / Il recupero funzionale nelle laringectomie subtotali.

Subtotal laryngectomy, a valid treatment for carefully selected patients, is a safe oncologic procedure which preserves the cricoid-arytenoid unit creating a successful "neo-larynx" with valid phonatory and deglutition functions. At the E.N.T. Clinic of "La Sapienza" University of Rome from Jan. 1984 to Feb. 1992, 85 subjects underwent subtotal laryngectomy, 50 of which then underwent phoniatric examination. The remaining patients were not suitable candidates because of the trachealis cannula (14), or because they were lost at follow up (16). A total of 50 male subjects were examined. Twenty-eight underwent crico-hyoid-pexia, while 22 patients underwent crico-hyoid-epiglotto-pexia. Attention is drawn to the results which appear to be extremely variable with regard to each study group. We obtained better results with crico-hyoid-epiglotto-pexia than with crico-hyoid-pexia and we guaranteed a good social re-insertion in all cases.

Substance P is diminished and vasoactive intestinal peptide is augmented in psoriatic lesions and these peptides exert disparate effects on the proliferation of cultured human keratinocytes.

An involvement of neurogenic components in the pathogenesis of psoriatic lesions has been suggested and neuropeptides are thought to play a modulatory role in cutaneous inflammation. In this study, we evaluated the immunoreactivity of the neuropeptides vasoactive intestinal polypeptide (VIP) and substance P (SP) in the skin of patients with chronic plaque psoriasis, by immunohistochemistry and radioimmunoassay. No differences were observed, by immunohistochemistry, in the expression and localization of VIP and SP between psoriatic and normal skin. Using the radioimmunologic technique on whole skin homogenates, VIP levels were significantly increased in psoriatic lesions as compared to normal skin. By contrast, SP levels were significantly lower in lesional and non-lesional psoriatic skin than in normal skin. In addition, we examined the effect of VIP and SP on the proliferation of cultured normal human keratinocytes. VIP (1-28) (1 nM-1 microM) as well as VIP fragments (10-28) (1 nM-1 microM) and (22-28) (1 nM-1 microM) stimulated the proliferation of keratinocytes in a dose-dependent manner, whereas the VIP fragment (1-12) (1 nM-1 microM) was ineffective. The VIP antagonist (N-Ac-Tyr1, D-Phe2)-GRF (1-29)-NH2 (0.1 microM) significantly inhibited the VIP effect on keratinocytes. On the other hand, SP (0.1 microM) not only failed to stimulate keratinocyte growth, but also blocked the VIP-induced stimulation of these cells. The imbalance of cutaneous VIP and SP and their disparate effects on the proliferation of normal human keratinocytes in culture would suggest that these peptides are involved in the pathogenesis of psoriasis and may exert different modulatory activities in the mechanisms underlying the psoriatic lesion.

[Rehabilitation of oro-pharyngeal dysphagia of neurogenic etiology using radiological examination: preliminary results]. / Riabilitazione della disfagia oro-faringeaad eziologia neurogena guidata dall'indagine radiologica: risultati preliminari.

Dysphagia is more frequently observed in patients with neurologic diseases (stroke, bulbar or pseudo-bulbar syndrome, amyotrophic lateral sclerosis, cranial trauma). Furthermore, the presence of this pathology is obviously more frequently noted in the light of the increase in the length of the human life span. It has become evident that alternative feeding procedures such as the nasogastric tube or gastrostomy may bring about complications and deprive patients of the oral phase of deglutition which plays a leading role in stimulating digestive functions. The Authors report a systematic research on the rehabilitation aspects of neurogenous dysphagia. All the patients studied underwent a neurological examination and oropharyngeal functional evaluation using echo-videorecording of the oral phase of deglutition and fluoro-videorecording of the pharyngeal phase. The data obtained allowed for the selection of five patients considered suitable for the rehabilitation program. One of them had a multi-infarct encephalopathy, two a spastic hemiplegia f.b.c., a fourth a cerebellar syndrome and the last a sequela of meningioma removal of the ponto-cerebellar angle with peripheral paralysis of the right VII, IX, X, XI cranial nerves. This last patient also underwent a crico-pharyngeal myotomy. Therapy consisted in making the patient sensitive to swallowing movements and in training them to assume a compensatory posture as well as functional rehabilitation of the organs involved in deglutition. The first datum emerging from the study is the lack of etiological homogeneity found in the cases treated with evident variability in different deglutition organ impairment, even though there was the common denominator of the dysphagia symptom. With regard to the results obtained, there was a complete resolution in one patient, while in the other four there was such an improvement as to allow the patients a safe autonomous oral assumption of food. The positive results obtained are not only linked to the recovery of damaged organs, but also to the development of compensatory strategies such as the choice of appropriate food consistency and the assumption of postures which protect the respiratory tract from aspiration and favor crico-pharyngeal relaxation.

Skin levels of vasoactive intestinal polypeptide in atopic dermatitis.

Atopic dermatitis (AD) can be exacerbated by various factors, including emotional stress, scratching and sweating. The aim of the present study was to evaluate the hypothesis that the inflammatory reaction in AD is also neurogenic. For this purpose, the levels of vasoactive intestinal polypeptide were measured radioimmunologically in whole-tissue homogenates of lesional skin of 13 patients with atopic dermatitis. Radioimmunoassay was performed using an antiserum, AH78, recognizing the carboxy-terminal fragment vasoactive intestinal polypeptide (22-28). Vasoactive intestinal polypeptide immunoreactivity was detected in relatively low amounts in control skin (0.428 +/- 0.08 pmol/g tissue), whereas a marked increase in the peptide was observed in lesional skin of patients with atopic dermatitis (5.62 +/- 1.25 pmol/g tissue). These results seem to suggest that vasoactive intestinal polypeptide could have a pathogenetic relevance in skin lesions of atopic dermatitis.

Distribution and characterization of VIP-related peptides in the rat spinal cord.

The possible existence in the rat spinal cord of a peptide related to VIP, VIP(22-28), has been evaluated. VIP contains paired basic aminoacid residues at which posttranslational cleavage of these peptides might occur. The lumbo-sacral region of rat spinal cord had the most VIP(22-28)-like immunoreactivity (ir-VIP(22-28]. Chromatographic analysis of spinal extracts showed that ir-VIP(22-28) consisted of two major peaks, one eluting as authentic VIP(1-28) and the other as VIP(22-28). HPLC confirmed these results, revealing the presence of intact VIP(1-28) and two or more less hydrophobic peptides, one of which corresponded to authentic VIP(22-28). The other two components found have not yet been identified. Further studies are necessary to provide information on the biological significance of VIP(22-28).

Vasoactive intestinal polypeptide carboxy-terminal fragment, VIP(22-28), and other fragments of VIP, in the central nervous system of the rat.

The possible existence in rat brain tissues of shorter peptides related to VIP has been examined. VIP and PHI both contain paired basic amino acid residues at which posttranslational cleavage of these peptides might occur. Antiserum to VIP(22-28) was raised in rabbits. The antiserum was carboxy-terminus directed, showing cross-reactivity with all tested peptides containing the VIP carboxy-terminus sequences. Chromatographic analysis of rat brain extracts demonstrated that recovered VIP(22-28) immunoreactivity [VIP(22-28)-ir] was heterogeneous, consisting of a major fraction [60-70% of total VIP(22-28)-ir] which eluted as authentic VIP(1-28) on gel filtration and on reversed phase high performance liquid chromatography (HPLC) columns. A second fraction (30-35% of total VIP(22-28)-ir] eluted from gel filtration columns in the position of VIP(22-28). HPLC analysis of this fraction from extracts of rat cortex, hippocampus, and midbrain indicated that it was heterogeneous. One component corresponded to authentic VIP(22-28). The other two components have not been identified; one appears to be a VIP fragment intermediate in size between VIP(1-28) and VIP(22-28).

Differential effects of selective brain lesions on hypothalamic and pituitary ir-dynorphin.

Selective radiofrequency and neurotoxic lesions of the serotonergic pathways caused in the rat a significant reduction of ir-dynorphin A and B in the hypothalamus but not at pituitary level. These data confirm that dynorphin-related peptides are regulated independently in these areas.

Effects of hypothalamic lesions on the content of dynorphin immunoreactivity in pituitary.

Radiofrequency lesion of medial basal hypothalamus (MBH) caused a approximately 50% depletion of immunoreactive dynorphin (ir-dyn) both in the anterior and neurointermediate lobe of the pituitary, whereas radiofrequency lesions of both supraoptic and paraventricular nuclei (SON, PVN) resulted in an approximately 30% reduction in neurointermediate lobe only. MBH cells and/or fibers contribute, therefore, to adenohypophysis pool of ir-dyn. Moreover, since the loss of ir-dyn in neurohypophysis ascertained after MBH lesion is significantly higher than that obtained with SON and PVN destruction, it may be assumed that MBH also participate to ir-dyn pool in neurohypophysis.