Association between pain, central sensitization and anxiety in postherpetic neuralgia.

BACKGROUND: In postherpetic neuralgia (PHN), dorsal root ganglia neurons are damaged. According to the proposed models, PHN pain might be associated with nociceptive deafferentation, and peripheral (heat hyperalgesia) or central sensitization (allodynia). METHODS: In 36 PHN patients, afferent nerve fibre function was characterized using quantitative sensory testing and histamine-induced flare analysis. Psychological factors were evaluated with the Hospital Anxiety and Depression Scale (HADS), disease-related quality of life (QoL) with SF-36 and pain with the McGill questionnaire [pain rating index (PRI)]. The patients were also divided into subgroups according to the presence or absence of brush-evoked allodynia as a sign of central sensitization. RESULTS: For all patients, warm, cold and mechanical detection was impaired (p < 0.001 each) and the size of the histamine flare was diminished on the affected side (p < 0.05); pain thresholds with the exception of brush-evoked allodynia (p < 0.05) were unaltered. Correlation analysis revealed allodynia, anxiety, depression, QoL and age as relevant factors associated with pain severity (PRI). Allodynia was present in 23 patients (64%). In these patients, heat pain perception was preserved; the histamine flare was larger; the pinprick pain was increased as were McGill PRI sensory subscore, actual pain rating and almost significantly pain (McGill PRI) over the last 4 weeks. CONCLUSIONS: PHN is associated with damage of afferent fibres. Central sensitization (i.e., allodynia) might contribute to PHN pain. There was a striking association between anxiety, depression and age, and the magnitude of PHN pain.

Cell type-dependent pathogenic functions of overexpressed human cathepsin B in murine breast cancer progression.

The cysteine protease cathepsin B (CTSB) is frequently overexpressed in human breast cancer and correlated with a poor prognosis. Genetic deficiency or pharmacological inhibition of CTSB attenuates tumor growth, invasion and metastasis in mouse models of human cancers. CTSB is expressed in both cancer cells and cells of the tumor stroma, in particular in tumor-associated macrophages (TAM). In order to evaluate the impact of tumor- or stromal cell-derived CTSB on Polyoma Middle T (PyMT)-induced breast cancer progression, we used in vivo and in vitro approaches to induce human CTSB overexpression in PyMT cancer cells or stromal cells alone or in combination. Orthotopic transplantation experiments revealed that CTSB overexpression in cancer cells rather than in the stroma affects PyMT tumor progression. In 3D cultures, primary PyMT tumor cells showed higher extracellular matrix proteolysis and enhanced collective cell invasion when CTSB was overexpressed and proteolytically active. Coculture of PyMT cells with bone marrow-derived macrophages induced a TAM-like macrophage phenotype in vitro, and the presence of such M2-polarized macrophages in 3D cultures enhanced sprouting of tumor spheroids. We employed a doxycycline (DOX)-inducible CTSB expression system to selectively overexpress human CTSB either in cancer cells or in macrophages in 3D cocultures. Tumor spheroid invasiveness was only enhanced when CTSB was overexpressed in cancer cells, whereas CTSB expression in macrophages alone did not further promote invasiveness of tumor spheroids. We conclude that CTSB overexpression in the PyMT mouse model promotes tumor progression not by a stromal effect, but by a direct, cancer cell-inherent mode of action: CTSB overexpression renders the PyMT cancers more invasive by increasing proteolytic extracellular matrix protein degradation fostering collective cell invasion into adjacent tissue.

[Prevalence and risk factors of phantom limb pain and phantom limb sensations in Germany. A nationwide field survey]. / Prävalenz und Risikofaktoren von Phantomschmerzen und Phantomwahrnehmungen in Deutschland. Eine bundesweite Befragung.

BACKGROUND: Data on the incidence and intensity of phantom limb pain (PLP) and phantom limb sensations (PLS) were collected in a nationwide survey. MATERIALS AND METHODS: Supported by a manufacturer of artificial limbs and press notices a total of 537 amputees were contacted and interviewed by questionnaire. RESULTS: The questionnaire containing 62 questions was filled in by 537 out of 1,088 amputees. Of the amputees 14.8% were pain free, 74.5% had PLP, 45.2% stump pain (SP) and 35.5% a combination of both. In addition 62.4% of the amputees reported disturbed sleep, of those with PLP it was even higher at 77.3% and 66.8% of patients with PLP woke up several times during the night. The prevailing features of PLP included burning sensation (13.6%), cramp (15.3%), prickling (23.4%), electrification (21%) and tingling (20.4%). Phantom sensations were felt by 73.4% and were described as being mobile (66.8%), of normal temperature (64%), warm (19.5%), cold (16.5%), bare (35.9%), clothed (13.6%), not unpleasant (31.7%), pressed (29.6%), contorted (7.5%) and blown up (5.8%). Of the patients with PLP, 35.7% described the location as mostly ventral, 26.7% as mostly dorsal. Significantly more PLP was found in the presence of PLS than in its absence (p <0.0001), but unrelated to the type of PLS, to demographic factors, or to the level or side of amputation. Perception of the artificial limb being "a foreign body" was highly significantly more often associated with PLP than with a sensation of "fusing with the body" (p <0.0001). CONCLUSION: To our knowledge the present study constitutes the largest field survey on phantom limb pain carried out in Europe and corroborates the high prevalence and intensity of PLP, unusual PLS and amputation-related sleep disturbances. The significance and manageability of phantom feelings and its risk factors need further research.

[Long-term treatment of phantom- and stump pain with Botulinum toxin type A over 12 months. A first clinical observation]. / Langszeitbehandlung von Phantom- und Stumpfschmerzen mit Botulinumtoxin Typ A über 12 Monate. Eine erste klinische Beobachtung.

Recently we were able to describe the successful treatment of phantom pain and stump pain with botulinum toxin A in a first pilot study. This case report over a 1-year period now demonstrates that long-term treatment for this indication is possible. We injected 4 x 25 IU of botulinum toxin A (Botox) into trigger points of the stump muscles of a lower limb amputee who suffered from severe phantom and stump pain. With four injections performed every 3 months, the patient became almost completely pain-free, and his intrathecal morphine therapy could be reduced to 40% of the initial dose. Intrathecal clonidine was eliminated completely, as were the oral analgesics. A surgical treatment suggested for the stump pain was no longer necessary, and we suppose that botulinum toxin can also improve the tolerance of artificial limbs in cases of stump pain.

[Treatment of phantom pain with botulinum-toxin A. A pilot study]. / Botulinum-Toxin-A in der Behandlung von Phantomschmerzen. Eine Pilotstudie.

BACKGROUND: Therapy of phantom pain following amputation is still difficult, since pathophysiological mechanisms are not clarified. Botulinum-toxin A never has been used for this issue. We report four successfully treated cases with chronic phantom pain longer than 3 years. METHODS: We injected 100 IU botulinum-toxin A (4x25 IU in 0,5 ml preservative-free saline 0.9%) in four muscle-triggerpoints of the amputation stump of each patient. All triggerpoints were painful to compression before injection, all patients reported referred sensations in the phantom-foot from at least one of them. Controls were performed by questioning and pain-diaries after 1,2 and 5 weeks. RESULTS: In all cases phantom pain was reduced about 60-80%. The three patients, who had pain attacks, reported a dramatically reduction of the number of attacks (about 90%). In two of them duration of attacks shortened from 120 to 5-10 min and a reduction of pain intensity from VAS 9 to VAS 1 and VAS 9 to VAS 2 was reported. Disorder of sleep disappeared in both affected patients within 2-3 weeks. Three patients,who could move the phantom foot (mental), had a subjective weakness a few days after botulinum-toxin A injection; in one case although injection was performed in the muscles of the femur! CONCLUSIONS: This is the first report of the use of botulinum-toxin A in the treatment of phantom pain. The contribution of the muscles in the cause of phantom pain is unclear and may be local, as a trigger of spinal reflexes or by modulation of "cortical reorganisation" after amputation. Botulinum-toxin A could work analgesic by the relaxation of the stump muscles or by modulation of neuronal transmitters, for example substance P, with an indirect influence of the CNS.

Erosion investigation and sediment quality measurements for a comprehensive risk assessment of contaminated aquatic sediments.

In this paper, an assessment strategy is introduced which allows one to evaluate the ecological hazard of contaminated sediments in connection with the risk of in-stream erosion. Special techniques for sediment sampling, non-intrusive density profiling, and depth related measurement of erosion are presented, which, in combination with ecological aspects, lead to a comprehensive risk assessment of fluvial sediments. The strategy was applied to a lock-regulated reach of the River Neckar in Germany. The spatial pattern of contamination in the river reservoir was found to be remarkably heterogeneous. At some sites, very high heavy metal concentrations were detected at the sediment surface. A sudden increase in contamination with depth at other sites could be attributed to an erosional unconformity. The critical shear stress of erosion for old contaminated sediments is higher than for recently deposited material. Nevertheless, during major flood events, bottom shear stress in the river exceeds the critical shear stresses of erosion of all sediments. Accordingly, there is a substantial risk that old contaminated sediment can be mobilised from the reservoir and transported downstream.

Chronic central nervous system involvement in Lyme borreliosis.

We describe four patients with marked chronic meningoencephalomyelitis caused by tick-transmitted Borrelia burgdorferi infection. Imaging techniques showed either MS-like lesions or evidence of vascular involvement, as in other spirochetal infections, especially in meningovascular syphilis.

On the adverse reactions and efficacy of long-term treatment with flupirtine: preliminary results of an ongoing twelve-month study with 200 patients suffering from chronic pain states in arthrosis or arthritis.

In order to investigate the efficacy and safety of long-term treatment with flupirtine in patients with chronic pain, in particular arthrosis and arthritis, a study was planned which, when completed, will encompass the treatment of 200 patients over a 12-month period. The present paper is a preliminary report of this ongoing study. The report deals with 104 patients: 55 of whom completed the 12-month treatment period and a 2-week follow-up phase, during which flupirtine was replaced by placebo in order to be able to detect drug-withdrawal effects. Forty nine patients withdrew from the study. Most of the patients were suffering from degenerative rheumatic arthrosis or inflammatory rheumatic arthritis. The average daily dosage was 300 mg. The incidence of drop-outs was highest in the first months with hardly any patients withdrawing in the last six months. Fifteen patients dropped out because of side effects (dizziness, nausea, sleep disturbances, and headache). Ten patients dropped out because of ineffectiveness, seven because of side effects plus ineffectiveness, and three because of side effects and other reasons. The remaining 14 patients dropped out because of other or non-medical reasons. For the 55 patients who completed the study, the analgesic took effect within 45 minutes to 2 hours, the duration of effect was 4-6 hours. Three-quarters of the patients responded to the drug, one-quarter did not. The analgesic effect remained constant during the 12-month treatment, as did the average number of capsules taken per month. There was no evidence that tolerance developed. The most frequent side effects were drowsiness (9% of patients), dizziness (11%), dry mouth (5%) and pruritus (9%). The withdrawal symptom scale completed every month during treatment (to determine baseline values) and every day throughout the 2-week placebo post-treatment phase showed no changes in the median. The mean value increased during the withdrawal phase, however, indicating that the symptomatology was more pronounced in some subjects. After withdrawal, the non-specific symptoms increased to a greater extent than symptoms from the opiate scale. The symptoms were present throughout the withdrawal phase. If the withdrawal phenomena had corresponded to the flupirtine's terminal half-life, then the symptoms ought to have been present mainly in the first few days. There was a slight trend for lowering systolic blood pressure but no changes in diastolic blood pressure or heart rate, nor changes in the ECG or laboratory analysis that could be related to flupirtine. These preliminary data suggest that flupirtine is safe when given for a period of one year.

[Treatment of disorders of cerebral performance in the aged in ambulatory care using bencyclane. Results of a controlled double-blind phase III study versus placebo]. / Die Behandlung von Hirnleistungsstörungen im Alter in der ambulanten Praxis mit Bencyclan. Ergebnisse einer kontrollierten Doppelblindstudie Phase III versus Placebo.

A placebo-controlled, randomized double-blind study conducted at a general practitioner's surgery was designed to investigate the efficacy of bencyclane in 120 outpatients with cerebral dysfunctions based on organic brain syndrome. The study started with a 4-week placebo washout phase and then continued with a 12-week treatment phase. 200 mg Bencyclane-hydrogenfumarate was administered b.i.d. Efficacy was assessed by a doctor's symptom rating (SCAG) and a study nurse's rating (BGP) as well as by two performance tests (CFF and ZVT-G). Data from 106 patients (52 under bencyclane and 54 under placebo) were statistically analysed. More side effects were seen under bencyclane than under placebo, in particular insomnia, headache, akathisia, nausea and vomiting. As an a priori hypothesis, it was stated that after alpha-adjustment there should be a statistically significant difference in symptomatology (SCAG, BGP) and performance (CFF, ZVT-G). With regard to performance, the zero hypothesis could be rejected on the 5% level, and on the 1% level with respect to symptomatology. The experimental error on both the performance and the symptom level was below 6%. The drug effects were significant on a confirmatory level and are considered to be also of clinical relevance.

On the effects of pyritinol on functional deficits of patients with organic mental disorders.

In 120 geriatric patients suffering from cerebral functional disorders with a moderate to rather severe degree of chronic brain syndrome, the effects of pyritinol were investigated in a placebo-controlled, randomized double-blind study. Furthermore, we attempted to find some evidence for the validity of a neurophysiological vigilance model which had already been used earlier. In the previous study it had been possible to show a rise in the vigilance level in patients under pyritinol treatment. The investigation began with a two-week single-blind placebo wash-out phase and continued over a 12-week treatment period, with six weeks' treatment in a hospital ward and six weeks' outpatient treatment (or in a geriatric home within a hospital setting). Pyritinol was administered three times daily in coated tablets each containing 200 mg. The course of the trial was controlled using two rating scales (SCAG, BGP), a physician's Global Impression (GI) and two performance tests (SKT, ZVT-G). There were 13 drop-outs, four because of intercurrent diseases, nine because they did not fulfill the inclusion criteria. The data of 107 patients were included in the statistical analysis, 54 on pyritinol and 53 on placebo. No notable adverse drug reactions were observed that were not similarly reported in the placebo group (Table 1). Statistically significant results were found in favor of pyritinol compared with placebo in both the level of clinical symptomatology (Fig. 1) and the performance level (Fig. 4). Particularly impressive was the superiority of pyritinol in the factor "social behavior" of the SCAG. Considering the clinical relevance of the changes it can be concluded that in both groups improvements occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Contribution to the search for vigilance-indicative EEG variables. Results of a controlled, double-blind study with pyritinol in elderly patients with symptoms of mental dysfunction.

We used a clinical pharmacological model to test pyritinol versus placebo in patients with mental deficiency and a clinical diagnosis of beginning chronic brain syndrome. Following a two weeks' washout phase, 50 patients were randomly allocated to two treatment groups of 25 patients each, receiving either 200 mg pyritinol three times daily, or placebo under double-blind conditions. The treatment period lasted 8 weeks. To be included in the study, patients had to have at least 50% subvigil phases in the 15-min EEG resting recording. We define such behaviour as a neurophysiological disturbance of vigilance. Scores in the Benton test were to be 2 points below the expected value, and/or the NAF score was to be above a standard value attained in an old peoples' home (greater than or equal to 14). We used this clinical pharmacological model for an internal validation of our Vigilance Index (VI). According to our definition, the Vigilance Index should express vigilance in the sense of an optimalization of the neuronal system to enable this system to perform better. The delta F power and the alpha slow-wave index have been considered as vigilance-indicative variables in the EEG. We believe that vigilance can be better expressed by a multidimensional approach, which takes into account all EEG elements that express vigilance, such as the replacement of the occipital basic rhythm (e.g. alpha or beta rhythm) into slow waves, the lowering of the dominant occipital frequency (be it an alpha or beta frequency), the anteriorization of the basic rhythm in the occipital field to the frontal region.(ABSTRACT TRUNCATED AT 250 WORDS)

[Demonstration of bencyclane effects in a clinico-pharmacologic vigilance model]. / Darstellungen von Bencyclanwirkungen in einem klinisch-pharmakologischen Vigilanzmodell.

The effects of 8 weeks' treatment with 2x 200 mg Bencyclan daily were investigated versus placebo in 50 patients. A clinical diagnosis had revealed the onset of organic mental disorders in all patients who, after fulfilling neurophysiologically and neuropsychologically defined screening criteria, were admitted to the trial. The patients were randomly allocated to two parallel groups of 25 for this controlled, double-blind study. Patients had to show 50% subvigil phases in a 15 min resting-EEG recording. We define such behaviour as a neurophysiological disturbance of vigilance. Scores in the Benton test were to be 2 points below the expected value or the NAF-score was to be above a standard value attained in an old people's home (greater than 14). On a neurophysiological level, inference statistical tests indicated effects in line with the hypothesis: A statistically significant difference in favour of Bencyclan was apparent after 8 weeks' treatment when compared with placebo. The Vigilance Index (VI) was higher under Bencyclan than after placebo. We regard the VI as a plausible indicator of vigilance-dependent disturbances in the elderly. On a behavioral level, Bencyclan was tendentially superior with respect to age-dependent complaints and performance-related activatedness, whereby one could not exclude the possibility that there were chance findings. The clear proof of efficacy on the neurophysiological level and the unclear effectiveness on the behavioral level can be attributed to the fact that time- and placebo effects were less marked on the former level. The intensive supervision of the patients led to considerable placebo effects on the behavioral level. Two groups of 25 patients are therefore not sufficient to be able to detect drug effects within a treatment period of only 8 weeks.

Effect and efficacy - on the function of models for the assessment of therapeutic efficacy.

Whilst the "effect" of a drug can be observed or deduced from observational data, the concept of "therapeutic efficacy" represents mainly a theoretical construction of a high degree of abstraction which is inconceivable without reciprocal combination with other theoretical constructs. The "therapeutic efficacy" of drugs can be investigated only via clinical-pharmacological or clinical models. Several examples are given. The strength of evidence of models is discussed as well as the necessity to continually test them empirically.