[Rapid release fentanyl administration forms. Comments of the Working Group on Tumor Pain of the German Pain Society]. / Schnell freisetzende Fentanylapplikationsformen. Stellungnahme des Arbeitskreises Tumorschmerz der Deutschen Schmerzgesellschaft.

The spectrum of indications for rapid release fentanyl preparations is controversial. For this reason the Working Group on Tumor Pain will formulate comments on how to deal with these substances. Breakthrough pain should receive individualized therapy; therefore, the use of opioids of various galenic formulations seems to be advisable. New rapid release fentanyl preparations are suitable for alleviating spontaneous breakthrough pain in tumor patients due to a rapid but short-acting effect. However, a prior optimization of the analgesic basis medication is absolutely necessary. Uncontrolled prescription for non-cancer pain must be criticized due to the problem of addiction. The medical profession should be informed about the benefits of rapid release fentanyl preparations but must also be made aware of the risk of a rapid development of addiction and tolerance. A self-commitment of the pharmaceutical industry to waive advertising for the dangerous off-label use would be desirable. In the opinion of the Working Group on Tumor Pain the use of fentanyl should be openly discussed and further scientific investigations are imperative with the aim of formulating clear recommendations.

Laxative management in ambulatory cancer patients on opioid therapy: a prospective, open-label investigation of polyethylene glycol, sodium picosulphate and lactulose.

Constipation and the laxatives polyethylene glycol (PEG), sodium picosulphate (SPS) and lactulose (L) were investigated in outpatients with cancer and on opioid therapy. Randomly selected patients were enrolled in a prospective, controlled, open-label trial. Endpoints were number of patients taking laxatives >28 days, number of patients with a stool-free interval >72 h (sfi72), dosage, numerical rating scale (NRS) for constipation, and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) questionnaire scores. The 348 patients had comparable demographic and medical data. In this ambulatory population, mobility scores remained unaffected. Constipation incidence was 5.7%, with sfi72 42, mean NRS 2.3557 and mean QoL 2.1. A total of 53.2% discontinued their laxative medication. Laxative use correlated with higher opioid usage (morphine-equivalent mg/day: no laxative 98.2, SPS 128.2, PEG 139.9, L 154.5). PEG was the most frequently prescribed laxative (PEG 27.3%, SPS 10.3%, L 9.2%). PEG (sfi72 12.6%, NRS 2.2, QoL 2.1) and SPS (sfi72 11.1%, NRS 2.7, QoL 2.2) proved more effective than L (sfi72 15.5%, NRS 3.8, QoL 2.5). In spite of opioid therapy, the incidence of constipation was low in these ambulatory cancer pain patients at an early disease stage. For prevention of constipation, PEG or SPS is recommended instead of L.

[Teaching pain management. An innovative curriculum model at the University of Witten/Herdecke (UWH)]. / Schmerztherapie in der Lehre. Ein innovatives Curriculumsmodell an der Universität Witten/Herdecke (UWH).

BACKGROUND: The subject of pain and pain therapy is not mandatory in medical curricula in Germany. Therefore, the German Society for the Study of Pain (DGSS) has developed a core-curriculum for pain and suggested its implementation for all medical faculties. METHOD: At the University of Witten/Herdecke this DGSS core curriculum was extended in terms of a "pain week", which comprised 22 h of seminars and clinical teaching and started in 2009. The knowledge gained by the students regarding the intended learning issues was measured by a pre-post self-assessment questionnaire. RESULTS: In almost every category the students reported significant knowledge gain. The learning issues were rated as relevant for the professional career. CONCLUSION: The "pain week" is intended to be a constant part of the medical curriculum at the University of Witten/Herdecke in the future. It will be integrated into the new cross-sectional subject of palliative care and be assessed by examinations.

[Modafinil for the treatment of cancer-related fatigue : an intervention study]. / Modafinil zur behandlung der tumorfatigue : eine interventionsstudie.

AIM: the authors conducted an open-label investigation examining the effects of modafinil in reducing fatigue in patients with cancer, undergoing cancer treatment, and receiving opioid therapy. METHODS: after approval by the local Ethics Committee and informed consent cancer patients who reported fatigue - defined as persistent tiredness interfering with usual functioning - were enrolled in the study. Once daily, patients received 100 mg open-label modafinil. The Fatigue Severity Scale (FSS), Epworth Sleepiness Scale (ESS), and a visual analogue scale (VAS, 0-10) were performed at baseline (t1), day 7 (t2), and day 28 (t3). Further assessment comprised the d2 Test of Attention (d2), the Hamilton Depression Scale (HAMD), the Eastern Cooperative Oncology Group-Score (ECOG), side effects, and patients' satisfaction with modafinil treatment. RESULTS: of the 37 patients who were enrolled, 29 completed all assessments in the study. Modafinil had a significant effect on the FSS (t1 44.6+/-12.2, t2 39+/-12.4, t3 35.3+/-13.8 (p=0.015), on the VAS (t1 6+/-3.1), t2 4.5+/-2.8, t3 3.7+/-2.8 (p=0.005), and an insignificant effect on d2 parameters of neurophysiological functioning and ESS. No differences were seen for ECOG and patients' satisfaction. No severe adverse effects were detected. CONCLUSION: modafinil improved alertness and cognitive skills in patients receiving cancer pain treatment by enhancing vigilance and cognitive performance. Although confirmation of this preliminary result is needed, these findings suggest that modafinil may improve quality of life in this patient population. However, in Germany the use of modafinil for fatigue is off-label and careful assessment of fatigue is needed prior to treatment. Randomized controlled trials are needed to confirm this evidence.

[Implementation of a standardized perioperative pain management concept in three hospitals of a consortium]. / Implementierung eines standardisierten perioperativen Schmerzmanagementkonzepts in drei Krankenhäusern eines Klinikverbundes.

BACKGROUND: Provision of sufficient perioperative pain therapy is an obligation in the clinical management of patients suffering from pain. The implementation of a standardized pain management concept was planned to be introduced in the clinical routine. The results of three hospitals are shown. MATERIAL AND METHODS: The concept included tools which gave information about legal aspects and basic fundamentals of pain relief, management modules regarding agreements on the implementation of perioperative pain therapy, instruments to measure pain intensity, assigning accountability and documentation modules. Questionnaires were carried out according to Picker. RESULTS: The project revealed that, according to the Picker questionnaire, about 50% of the patients treated in the hospitals had pain, 30-40% still had intensive pain during the stay in hospital and 90% of the patients received pain relief medication within 10 min of the request. More than 78% of the patients thought the hospital staff did their best to relieve the pain and over 92% found the pain treatment adequate. CONCLUSION: It was possible to implement a standardized perioperative pain therapy concept in three hospitals of a consortium. Whether an adequate pain relief can be improved with the help of standard measurements and documentation, could not be evaluated in this study.

Efficacy and safety of pregabalin in treatment refractory patients with various neuropathic pain entities in clinical routine.

AIMS: Conventional approaches to the management of neuropathic pain (NeP) often yield unsatisfactory results. We aimed to investigate pregabalin, a gamma-aminobutyric acid (GABA)-analogue, in a wide range of pregabalin naive patients with treatment refractory NeP. METHODS: Investigator-initiated, 4-week, open, prospective multicentre study in tertiary care. Pregabalin was prescribed at physicians' discretion based on patients' individual responses and tolerability, with or without concomitant analgesics. Consecutive patients were requested to fill in questionnaires at baseline and after 14 and 28 days with numerical pain rating scales (0, none; 10, worst possible), sleep rating scales, parts of the Brief Pain Inventory, Pain Experience Scale, Short Questionnaire on Current Burden and the SF-12 health-related quality of life scale. RESULTS: In 55 patients, the mean pregabalin dose was 142 +/- 26 mg at day 1 and 348 +/- 161 mg at day 28. The mean pain score decreased from 6.5 +/- 1.7 to 5.5 +/- 1.9 at day 14 and to 4.9 +/- 1.8 at day 28 (-24.6%, p < 0.0001). Significant and rapid improvements were noted in the sleep interference score (p < 0.00001), Short Questionnaire on Current Burden (p < 0.01) and SF-12 (somatic score p < 0.001; psychological score p < 0.01). Pregabalin was well tolerated, and only three patients (5%) discontinued treatment prematurely. CONCLUSIONS: Our findings suggest that pregabalin is an effective and well-tolerated drug in difficult-to-treat NeP patients under daily clinical practice conditions. A flexible dosing approach appears appropriate to ensure patient compliance and treatment success.

Design and evaluation of immunotoxicity studies.

The evaluation of potential adverse effects of pharmaceuticals on the immune system is part of the standard drug development procedures and needs to be available prior to the start of phase III clinical trials. Although the histopathological assessment of lymphoid organs/tissues is considered fundamental for the identification and characterization of immunotoxic reactions, additional investigations are now recommended by the European guidelines for repeated-dose toxicity testing of medicinal products in order to achieve an accurate assessment of immune system functionality with regard to immunomodulation. In the present paper, we describe and discuss a study design which permits the investigation of the immune function in a 4-week study in rats following immunization by subcutaneous administration of the T-dependent antigen Keyhole Limpet Hemocynin (KLH). This includes assessment of hematology parameters, titration of KLH-specific antibodies in serum, lymphocyte immunophenotyping in blood, thymus, spleen and lymph nodes, macroscopic pathology and histopathological evaluation of the lymphatic organs/tissues and of the injection sites.

[Controlled-release hydromorphone in elderly patients with severe pain of different etiologies. Results of an observational study]. / Retardiertes Hydromorphon bei älteren Patienten mit starken Schmerzen unterschiedlicher Atiologie. Ergebnisse einer Beobachtungsstudie.

BACKGROUND: Elderly patients (older than 65) do not always receive adequate analgesic treatment, or else they suffer from side effects of the administered opioid. An alternative is oral controlled-release hydromorphone, the efficacy and tolerability of which in patientswith cancer-related pain and pain of other genesis has been confirmed in clinical studies. AIMS AND METHODS: A total of 2650 patients (effective group 2412 patients) average age 64.3 +/- 13.4 most of whom suffering from tumor-related (56.2%) or musculoskeletal (49.4%) pain were recruited to a multicenter observational study to investigate controlled-release hydromorphone administered mainly on an ambulatory basis. Pain intensity and quality of life were self-assessed by the patients and recorded in a questionnaire. RESULTS: Pain intensity decreased by 64.3% from 7.0 initially to 2.5 at the final examination (0 = no pain, 10 = most severe pain). Quality of life improved by 51.9%. This corresponded to a self-assessed decrease of impairment of quality of life from 45.9 initially to 22.1 at the final examination (0 = no impairment, 70 = most severe impairment). Opioid-type side effects, documented before initiating treatment, decreased appreciably under treatment with hydromorphone. The efficacy and tolerability of the medication, as well as patient compliance, were assessed by the participating physicians as "very good" or "good". CONCLUSIONS: Controlled-release, orally administered hydromorphone is well suited for the treatment of elderly patients with severe pain of different etiologies, in particular those with cancer pain. It is both effective and well tolerated, and has an appreciable positive impact on the patient's quality of life.

[Neuropathic pain]. / Chamäleon neuropathischer Schmerz: Kennen Sie alle Facetten der quálenden Schmerzen?

Neuropathic pain poses a challenge, since there is no consensus on what constitutes optimal management, and current strategies for diagnosing and treating this heterogeneous condition are largely empirical. In the daily routine a neurological examination that includes a sensory examination with some simple bedside-tests often suffices to establish a tentative diagnosis. The author proposes a basic algorithm that may help clinicians to optimize available therapeutic options and improve pain relief and quality of life in patients with this type of pain. Such first-line drugs as antidepressants, anticonvulsants and sustained-release opioids form the basis for a treatment strategy that is appropriate for the individual patient.

Meizothrombin, an intermediate of prothrombin cleavage potently activates renal carcinoma cells by interaction with PAR-type thrombin receptors.

Recently, meizothrombin (MT), an intermediate enzyme in the prothrombin cleavage cascade has been shown to activate cells of a brain tumor cell line by interaction with PAR-1-type thrombin receptors with a potency comparable to that of thrombin. In this study, we investigated the effect of recombinant human MT (rMT) on calcium mobilization in primary cultures established from surgically resected human renal cell carcinomas. Meizothrombin induced very rapidly transient calcium mobilization in RCC cells comparable to that observed with thrombin. RCC cells stimulated with thrombin after rMT challenge were unable to elicit a new calcium response and vice versa. Therefore, rMT and thrombin seem to activate calcium signaling in primary RCC cultures by similar mechanisms including PAR-1- and PAR-3-type thrombin receptors as shown by using PAR-type specific antibodies. Our results demonstrate rMT as a potent activator of human RCC cells suggesting a function of not only thrombin but also of this catalytically active thrombin precursor enzyme in human renal cell carcinoma.

The serine proteinase thrombin promotes migration of human renal carcinoma cells by a PKA-dependent mechanism.

In this study, we demonstrated that thrombin activates protein kinase C (PKC), mitogen activated protein kinases (MAP kinases), transcription factor nuclear factor-kappa B (NF-kappa B), and cAMP-dependent protein kinase (PKA) in the human renal carcinoma cell line A-498. In addition, it enhanced the migratory capacity, but had no effect on the proliferation of A-498 cells. The effect of thrombin on migration could be blocked by the PKA inhibitor H-89 but was not influenced by inhibition of PKC, MAP kinases or NF-kappa B. We concluded, that thrombin acts as a regulator on human A-498 renal carcinoma cell migration including PKA.

PAR-1- and PAR-3-type thrombin receptor expression in primary cultures of human renal cell carcinoma cells.

In this study, we report coexpression of proteinase-activated receptor (PAR)-1- and PAR-3-type thrombin receptors in primary cultures obtained from surgically resected specimens of renal cell carcinomas (RCCs). Receptor expression on RNA level was evaluated by using the RT-PCR technique. Results demonstrated the presence of mRNA encoding PAR-1 and PAR-3, but mRNA encoding PAR-4 could not be found in human RCC cells. The expression of PAR-1 and PAR-3 on protein level was investigated with confocal laser fluorescence and freeze-fracture electron microscopy. Both thrombin receptor types were localized on the cell membrane but were also found on intracellular compartments of RCC cells. On the outer cell membrane, clustering of PAR-1 and PAR-3 molecules was partly observed. This is the first study demonstrating presence of both PAR-1 and PAR-3 in human carcinoma cells.

Differential expression of cytokines and cytokine receptors in renal cell carcinoma.

Modulation of immunomechanisms by tumor cells can be caused by secretion of cytokines. In vitro data are usually gained in culture systems. It is debatable whether these systems are representative of the conditions inside the respective tumor tissues. Immunohistochemical studies of tumor tissue cryostats were compared with those in matched primary renal cell carcinoma tumor cell cultures. Results were correlated with histopathological characteristics and the in vitro cytotoxic effect of autologous tumor infiltrating lymphocytes (TILs). Expression of all studied cytokines and cytokine receptors could be shown in cryostats and cell cultures, but the detection pattern varied individually. The immunohistochemical results in cryostats were in good accordance with those in cell cultures. Expression of TGFbeta1 both in cryostats and cell cultures significantly correlated with the lack of cytotoxic activity of autologous TILs. Representative data can be obtained in tumor culture systems of primary renal cell carcinoma. TGFbeta1 secretion could play an important role in the interactions between tumor and cytotoxic cells.

Interferon-alpha suppresses the antiapoptotic effect of NF-kB and sensitizes renal cell carcinoma cells in vitro to chemotherapeutic drugs.

BACKGROUND: Immunochemotherapy (ICT) with interleukin-2 (IL-2) and interferon-alpha (IFNalpha) with a secondary effector (5-fluorouracil, 5 FU) is the only promising treatment for advanced renal cell carcinoma (RCC). With IFNalpha, besides the activation mechanisms of the immunosystem, a direct antitumor effect on tumor cells is expected. MATERIALS AND METHODS: NF-kB activity in three permanent cell lines (Hep2, HepG2, HT29) and in primary RCC cell lines was measured after incubation with tumor necrosis factor-alpha (TNFalpha), IFNalpha, IFN-gamma, TNFalpha+IFNalpha, and IFNgamma+TNFalpha, respectively. NF-kB activity and induction of apoptosis by chemotherapeutic drugs (5FU and doxorubicin) were determined in cells transfected with a constitutively active NF-kB p65 or a dominant negative IkB. RESULTS: NF-kB signaling induced by TNFalpha is suppressed by IFNalpha and IFNgamma in the permanent cell lines and in the primary RCC tumor cell cultures. In an in vitro ICT model we show that pretreatment of RCC with IL-2 and IFNalpha leads to a diminished NF-kB response to TNFalpha. In certain tumors, this correlates with increased susceptibility to investigated chemotherapeutic drugs as shown by annexin stain and cell elimination. Modulation of the cellular NF-kB state by a constitutively active p65 or a dominant negative IkB mimics this effect. The IkB construct leads to the same effects as IL-2/IFNalpha pretreatment as shown by predominant elimination of the transfected cells from the overall population, while introduction of p65 leads to a partial rescue from the effect of IL-2 and IFNalpha. The described effect, however, applies only to a selection of primary cell cultures. CONCLUSIONS: Besides the immunomodulation effects, treatment of RCC with IL-2/IFNalpha leads to a proapoptotic state in certain tumors. The relevant mediator seems to be IFNalpha by suppression of the antiapoptotic effect of NF-kB. These data can provide an experimental base for correlation with real patient outcome after ICT.

Mesenchymal stem cells as vehicles for gene delivery.

Mesenchymal stem cells contribute to the regeneration of mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, adipose, and marrow stroma. Transduction of mesenchymal stem cells from species other than humans is required for the development of disease models in which mesenchymal stem cells-based gene delivery is evaluated. Attempts to transduce mesenchymal stem cells from some species with amphotropic retroviral vectors were unsuccessful, leading to comparative mesenchymal stem cells transductions with xenotropic and gibbon-ape leukemia virus envelope-pseudotyped retroviral vectors. Human, baboon, canine, and rat mesenchymal stem cells were transduced optimally with amphotropic vector supernatants. In contrast, sheep, goat, and pig mesenchymal stem cells showed highest transduction levels with xenotropic retroviral vector supernatant, and rabbit mesenchymal stem cells were transduced optimally with gibbon-ape-enveloped vectors. Using a myeloablative canine transplantation model and gene-marked canine mesenchymal stem cells, the biodistribution of infused and ex vivo expanded mesenchymal stem cells were examined. The majority of transduced canine mesenchymal stem cells were found in the bone marrow samples. The current study shows the use of mesenchymal stem cells as a delivery vehicle for gene transfer studies, and validates the feasibility of delivering mesenchymal stem cells to the marrow compartment for stromal regeneration after cancer-associated cytotoxic therapies.