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.

Nitric oxide and pro-inflammatory cytokines correlate with pain intensity in chronic pain patients.

OBJECTIVE: Inflammatory cytokines as well as nitric oxide (NO) play a key role in the pathogenesis of persistent and exaggerated pain states. To document this, we investigated whether a range of cytokines and NO were detectable in the plasma of chronic pain patients and whether cytokine and NO levels correlated with pain severity. METHODS: Plasma samples of 94 chronic pain patients and 6 healthy volunteers were obtained. Average pain intensity during the last 24 h was assessed on a 11-point numeric rating scale and patients were distributed to three groups: light, moderate and severe pain. The concentrations of TNF-alpha, GM-CSF, interleukin (IL)-1beta, IL-6, IL-8, interferon (IFN)-gamma, IL-2, IL-4, IL-5, IL-10 and nitrate/nitrite were determined. RESULTS: Patients with light pain demonstrated significantly increased levels of IL-6 compared to controls. In the severe pain group IL-6 and nitrate/nitrite were significantly increased. Serum concentrations of IL-1beta, TNF-alpha, IL-2 and IL-4 were increased but as we adjusted the level of significance at p = 0.0045, most cytokine plasma levels failed to reach statistical significance. CONCLUSIONS: Pro-inflammatory cytokines (IL-1beta, IL-2, IL-6, IFN-gamma, TNF-alpha) in the plasma correlate with increasing pain intensity. Chronic pain patients show a significant increase in plasma levels of NO in comparison to healthy controls.

The effect of mirtazapine in patients with chronic pain and concomitant depression.

OBJECTIVE: To evaluate the safety, tolerability and efficacy of mirtazapine in patients with the primary diagnosis of chronic pain and concomitant depression in an open post-marketing surveillance study. RESEARCH DESIGN AND METHODS: 594 patients with a primary diagnosis of at least one chronic pain syndrome (minimum duration of 3 months) and the diagnosis of concomitant depression, appropriately made by a neurologist or psychiatrist, were recruited at psychiatric and/or neurological outpatient facilities throughout Germany. The primary efficacy parameter was pain at baseline and endpoint using a patient self-assessment scale. Secondary analyses were performed at baseline, week 1 (day 7 +/- 2), week 4 (day 28 +/- 4) and at endpoint (day 42 +/- 4 or early termination) and included safety and tolerability assessments. Investigators rated the severity of different potential co-morbidities (including depression) with a four-step rating scale (not present, mild, moderate, severe). RESULTS: 594 patients were enrolled and treated with mirtazapine (mean daily dose of 34.5 +/- 10.4 mg at study endpoint). A statistically significant (p < 0.0001; one sample sign test) reduction of pain from baseline to endpoint was found for the overall population. The percentage of patients free of pain or with only moderate pain increased significantly, irrespective of patients' age or pain syndromes. Furthermore, we found a substantial improvement from baseline to endpoint regarding co-morbidities such as sleep disturbance, irritability and exhaustion. The number of adverse events was low (<7%; n = 37), with fatigue (n = 13) and weight gain (n = 11) occurring most frequently. No previously-unknown side effects occurred. One hundred and six patients (18%) discontinued mirtazapine during the study. The main reason was lack of efficacy (6%, n = 33), which may be a reflection of sub-optimal response to the anti-depressant or analgesic effect of the drug, but no appropriate rating scale was used to clarify this question. Only a small number of patients stopped the drug due to adverse events (3%; n = 15). At study endpoint, the majority of physicians and patients rated the overall efficacy and tolerability of mirtazapine as good or very good. Most patients (80%) continued the therapy after 6 weeks. CONCLUSIONS: Despite the limitations of an open observational study, our findings suggest that mirtazapine is a safe and well-tolerated drug for use in daily clinical practice. It still remains unclear whether the reduction of pain, the enhancement of the depressed mood or the combination of both effects led to these results. Nevertheless, our data point to a potential beneficial effect of mirtazapine in the treatment of patients with pain and concomitant depression. However, more systematic research, including placebo-controlled studies, and further empirical testing are necessary.

A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies.

BACKGROUND: Painful HIV-associated sensory neuropathies (HIV-SN) are a common complication of HIV infection. The pathogenesis is unknown and the treatment very limited. Gabapentin (GBP) is effective in painful diabetic neuropathy and postherpetic neuralgia and its effectiveness on painful HIV-SN has been reported anecdotally. DESIGN: Multicenter, prospective, randomised, double-blind, placebo-controlled study. METHODS: Patients were followed for a 1-week screening, a 4-week double-blind and a 2-week open treatment phase. GBP was initiated at 400 mg/d, titrated over 2 weeks to 1200 mg/d, and then either maintained at this level or-if not beneficial-titrated to 2400 mg/d. After 4 weeks the medication was unblinded and the patient had the choice to begin, to maintain or to increase GBP to 3600 mg/d. The primary outcome measure was an improvement in median pain on the Visual Analogue Scale (VAS) from the screening week compared to the 4(th) treatment week. A secondary efficacy measure was the median sleep score (VAS). RESULTS: 15 patients received GBP and 11 placebo. In each group one patient dropped out during the doubleblind phase. Median pain (GBP 5.1; placebo 4.7) and sleep score (GBP 4.5; placebo 5.6) did not differ between both groups at baseline. In the GBP-group there was a significant decrease of the pain to 2.85 (-44.1 %) as well as of the sleep VAS to 2.3 (-48.9 %). No significant decrease in the pain (median VAS=3.3, -29.8 %) as well as in the sleep score (median VAS=4.95, -11.6 %) was observed in the placebo-group. GBP was generally well tolerated. The most frequent side effect was somnolence reported in 80% of GBP-treated patients. CONCLUSIONS: GBP was more effective than placebo in reducing pain and sleep interference in patients with HIV-SN.

Potential c-fiber damage in Wilson's disease.

OBJECTIVES: To find out about potential involvement of the peripheral and autonomic nervous system in Wilson's disease (WD). MATERIAL AND METHODS: Seventeen patients with laboratory proven WD were examined with quantitative sensory testing (QST) (thermal, pain and vibratory sensation), pupillometric evaluation and electrophysiological testing of basal ganglia motor function [frequency of most rapid alternating movements (MRAM), reaction time (RT), contraction time (CT)]. Results were compared with those obtained in 20 healthy controls. RESULTS: After correction for multiple comparisons, patients with WD showed significantly higher thresholds for warm sensation [sural and peroneal nerve, thermal sensory limen (TSL), unpaired t-test]. Individual results were pathological in eight (peroneal) and nine (sural nerve) patients, respectively. Pupil function was not altered. Patients with WD showed significant slowing of MRAM and prolongation of RT and CT. There was no significant correlation between RT and QST results. CONCLUSIONS: These findings are compatible with a potential involvement of unmyelinated warm-specific C fibers in WD, independent from predominant basal ganglia motor dysfunction.

Delayed motor learning and psychomotor slowing in HIV-infected children.

OBJECTIVE: To find out whether HIV-associated subclinical psychomotor slowing is present in HIV-infected children despite effective highly active antiretroviral therapy (HAART). PATIENTS AND METHODS: An electrophysiological motor test battery shown to sensitively describe HIV-associated CNS disease in adults (tremor peak frequency []TPF], most rapid alternating movements [MRAM], reaction time [RT] and contraction time [CT]) was performed in 17 HIV seropositive (+) right-handed children. Results were compared to 16 HIV seronegative (-) children. RESULTS: HIV (-) children showed slower frequencies (TPF, MRAM) and longer RT and CT than (-) adults. They showed a significant correlation (p = 0.0263) between RT (right = dominant hand) and age. HIV (+) children showed significant prolongations of RT (right hand) and CT (both hands) compared to HIV (-) children. RT right hand did not accelerate with age in HIV (+) children. CT were significantly prolonged in 10 children with detectable HIV plasma viral burden and normal in 7 children with no detectable HIV plasma viral load. There was no correlation between CT and CD 4 cell counts. CONCLUSIONS: Despite effective HAART, electrophysiological motor testing in HIV (+) children reveals significant subclinical CNS dysfunction, especially in children with insufficient viral load suppression.

HIV-1-positive female migrants in Northrhine-Westphalia--relevant, but unfocussed problem?

Data of 204 HIV-1-positive female migrants from Sub-Saharan Africa, Asia and European countries other than Germany were analysed and compared to those of 282 German female virus carriers. Because not much is known about this subpopulation, the first step was to get an overview about the existing data and to describe them statistically in order to design prospective studies. A first result was that female migrants generally are tested for HIV-1 at a younger age than the control subjects. Predominant infection mode in the migrant population was heterosexual intercourse, whereas in the controls there were significantly more i.v. drug users. Distribution to the CDC-stages, CD4+-cell count and plasma viral load did not differ in both groups except for a higher percentage of AIDS-defined individuals among the controls. Surprisingly, significantly more migrants were treated with antiretroviral drugs than in the control group. However, both groups showed the same pattern of AIDS-defining diseases, only tuberculosis occurs more often in migrants. The data show that migrants are a vulnerable subpopulation which can be once being integrated in the health system of the host country effectively treated. - Results are discussed with respect to the international literature. The urgent need for adequate preventive strategies is underlined.

Antiretroviral therapy regimens for neuro-AIDS.

In the era of highly active antiretroviral therapy (HAART) the central nervous system (CNS) becomes increasingly important as a sanctuary site for the human immunodeficiency virus (HIV-1). HIV-1-associated brain disease is subdivided into the minor cognitive/motor disorder, the minor cognitive/motor complex and the AIDS dementia complex, all of which are predictive for patients' deaths. CNS effective therapy therefore influences the prognosis of each individual patient. Thus, there is urgent need both for prophylactic and therapeutic strategies preventing or treating HIV-1-associated CNS disease. HAART consisting of two nucleoside analogues (NAs), one or two protease inhibitors (PIs) and/or one non-nucleoside inhibitor of the reverse transcriptase (NNRTI) has a neuroprophylactic value with regard to the manifestation of HIV-I associated CNS disease. With regard to therapeutic effects, the NAs zidovudine and stavudine penetrate into the cerebrospinal fluid and positively influence HIV-1-associated brain disease. Adding a second NA has no additional therapeutic effect. NNRTIs (nevirapine and efavirenz) are also CNS effective. However, there is a subgroup of non-responders, who obviously need other forms of therapeutic interventions. The very few existing studies point out that patients with high plasma viral loads and neurological abnormalities should be treated with a combination of two NAs and one NNRTI. The value of PIs for CNS protection remains to be evaluated.

[Treatment of HIV infection from the neurologic viewpoint. Therapy must reach the brain]. / Behandlung der HIV-Infektion aus neurologischer Sicht. Die Therapie muss das Hirn erreichen.

An effective highly active antiretroviral therapy (HAART) can prevent the manifestation of HIV-1-associated encephalopathy. Also, HIV-1-associated minor cognitive/motor deficits--an early form of HIV-1-associated dementia--are improved. Clinically manifest HIV-1-associated encephalopathy is an indication for HAART treatment, irrespective of immune status. To date, minor cognitive and/or motor deficits in the presence of good immune status have not been identified as an indication for HAART treatment. Any CNS-effective treatment should be based on either zidovudine or stavudine, since these substances readily enter the CSF; however, NNRTI can also be applied. Side effects of HAART on the central and peripheral nervous system, as well as interactions with known neurological medicaments must be taken into account.

Soluble cerebrospinal fluid factors induce Ca2+ dysregulation in rat cultured cortical astrocytes in HIV-1-associated dementia complex.

OBJECTIVES: To investigate the effect of cerebrospinal fluid (CSF) of HIV-1-seropositive patients with and without HIV-1-associated dementia complex (HADC) on the intracellular Ca2+ regulation of cultured cortical astrocytes. DESIGN: In a blinded study the effects of CSF samples from HADC patients and from HIV-1-seropositive but not demented patients on intracellular Ca2+ regulation of cultured cortical astrocytes were investigated. Astrocytes were chosen because they contribute to both electrophysiological and immunological processes within the brain. METHODS: Astrocytes were incubated in CSF samples for 1 h, loaded with the Ca2+ indicator dye Fura-2 and intracellular Ca2+ responses upon glutamate application were measured. RESULTS: CSF samples from 10 out of 11 HADC patients induced a significant reduction of the intracellular Ca2+ increase upon glutamate application. On the contrary, seven out of 10 CSF samples from HIV-1-seropositive patients without HADC as well as 10 out of 10 CSF samples from HIV-1-seronegative controls did not affect the intracellular Ca2+ response. CONCLUSIONS: Our data strongly confirm the hypothesis that CSF samples of HADC patients contain soluble factors which interfere with the function of astrocytes. These factors may include HIV-1 proteins, locally released cytokines or neurotoxins.

Basal ganglia metabolite abnormalities in minor motor disorders associated with human immunodeficiency virus type 1.

BACKGROUND: Minor motor disorders (MMDs) associated with human immunodeficiency virus type 1 (HIV-1) predict HIV-1 dementia and death. Little is known about the time course and neuropathologic mechanisms of HIV-1 MMDs. OBJECTIVE: To investigate the relationship between HIV-1 MMDs, as assessed by psychomotor speed, and metabolic alterations in the basal ganglia, as detected by proton magnetic resonance spectroscopy. PATIENTS AND METHODS: A total of 32 HIV-1-seropositive patients (10 with no MMD, 8 with incipient MMD, and 14 with sustained MMD, assessed through electrophysiologic testing of psychomotor speed including contraction times; 29 treated with highly active antiretroviral therapy) and 14 HIV-1-seronegative control subjects were examined for cerebral metabolite abnormalities in the basal ganglia by means of magnetic resonance spectroscopy. RESULTS: The 3 patient groups showed significantly different ratios of myoinositol/creatine (P =.02) in the basal ganglia. Whereas patients with no MMD or incipient MMD showed normal ratios, patients with sustained MMD showed higher values for myoinositol/creatine as a sign of glial proliferation. No differences in N-acetyl compounds, indicative of neuronal loss, were found. CONCLUSION: Whereas metabolic alterations in the basal ganglia were not detected in patients with incipient HIV-1 MMD, patients with sustained HIV-1 MMD did have significantly altered metabolic spectra indicative of glial proliferation.

[HIV infection and pain. Recommendations for pain therapy are rarely revised]. / HIV-Infektion und Schmerz. Die Empfehlungen für die Schmerztherapie werden zu selten umgesetzt.

Although pain is a common symptom in HIV-positive and AIDS patients, in particular the chronic variety is frequently not adequately treated in this population. The present review article identifies possible reasons for this situation, summarizes the most common causes of chronic pain, and draws attention to the therapeutic problems specific to these particular groups.

Therapeutic effects of nucleoside analogues on psychomotor slowing in HIV infection.

OBJECTIVE: Since psychomotor slowing predicts the development of HIV-1-associated dementia, AIDS and death independently of the immune status, there is urgent need for a neurological therapeutic rationale. METHODS: The therapeutic efficacy of nucleoside analogues with different abilities to penetrate into the cerebrospinal fluid was assessed in 410 HIV-1-seropositive patients using the results of detailed fine motor tests, which detect minor motor deficits. Patients were selected who showed pathological psychomotor slowing as signs of central nervous system (CNS) dysfunction before therapy onset and who were then treated only with nucleoside analogues for at least 6 months. RESULTS: Both zidovudine and didanosine improve CNS function to an equal degree when given as monotherapy. Adding a second nucleoside analogue (didanosine, lamivudine, zalcitabine) to zidovudine does not further improve psychomotor performance. However, adding a second nucleoside after a period of zidovudine monotherapy does result in a second but less remarkable therapeutic effect. Combinations containing stavudine are as effective as those including zidovudine when given as first antiretroviral treatment. Furthermore, stavudine effectively improves motor performance even after pretreatment with zidovudine.

Depression does not influence basal ganglia-mediated psychomotor speed in HIV-1 infection.

The authors examined the effects of depressive mood (Hamilton Rating Scale for Depression [Ham-D]) on basal ganglia-mediated psychomotor speed (motor test battery) in 202 HIV-1 seropositive homosexual males with no prior history of antiretroviral treatment. HIV-1 seropositive patients showed a significant slowing of most rapid alternating movements (MRAM) and significantly prolonged contraction times (CT) compared with 66 HIV-1 seronegative male control subjects. Factor analysis of Ham-D scores isolated a factor containing the items depressed mood, suicide, and psychic and somatic anxiety. This factor did not correlate with MRAM or CT. Depression and psychomotor speed are independent in HIV-1infection.

HIV-1 protein Tat reduces the glutamate-induced intracellular Ca2+ increase in cultured cortical astrocytes.

The trans-activator protein Tat of the human immunodeficiency virus type 1 (HIV-1) is regarded as an injurious molecule in the pathogenesis of HIV-1 associated encephalopathy (HIVE). We investigated the effects of Tat on neuroligand-induced intracellular Ca2+ increase in cultured astroglial cells. Rat cortical astrocytes, human glioblastoma cells and glial restricted precursor cells, from a human embryonic teratocarcinoma cell line, were incubated with recombinant Tat (100 ng/mL for 60 min) which induced a significant reduction of glutamate or ATP-induced intracellular Ca2+ increase ("glutamate response", "ATP response"). The reduction of the glutamate response was also observed following cell incubation with cell extracts of HeLa-T4+ cells transiently transfected with an expression plasmid coding for Tat. However, inactivation of the transcriptional trans-activity of Tat, by using a mutant form of Tat, as well as inhibition of de novo protein synthesis by cycloheximide abolished the effect on the glutamate response. This suggests that Tat acts upon induction of a so far unknown cellular gene whose gene product causes the reduction of glutamate responses. As the effect of Tat resembles the effect of TNFalpha on glutamate responses [Köller et al. (2001) Brain Res., 893, 237-243] which is locally released within the brains of HIVE patients, we also tested for synergistic effects of Tat and TNFalpha on the glutamate response. Low concentrations of Tat in combination with subthreshold concentrations of TNFalpha also elicited a marked reduction of astroglial glutamate responses. Our data suggest that Tat and TNFalpha, both by itself and synergistically, induce astroglial dysfunction.

Potential time course of human immunodeficiency virus type 1-associated minor motor deficits: electrophysiologic and positron emission tomography findings.

BACKGROUND: We tested whether metabolic abnormalities in the prefrontal-striatal circuitry as demonstrated by positron emission tomography (PET) were present in patients seropositive for human immunodeficiency virus type 1 (HIV-1) with HIV-1-associated minor motor deficits as demonstrated by quantitative motor testing. PATIENTS: We examined 19 HIV-1-positive patients, covering the range from normal results of quantitative motor testing to clearly pathologic psychomotor slowing indicative of HIV-1-associated minor motor deficits. None fulfilled the clinical criteria for HIV-1-associated dementia. Results were compared with those of 15 healthy volunteers. METHODS: All subjects underwent clinical examination, routine magnetic resonance (MR) imaging, and electrophysiologic motor testing at the time of PET. RESULTS: Seven HIV-1-positive patients showed significant hypermetabolism in the basal ganglia. Nine patients showed a significant frontomesial hypometabolism. CONCLUSIONS: The data of our cross-sectional study strongly suggest a characteristic time course in the development of HIV-1-associated minor motor deficits. Hypermetabolism in the basal ganglia is associated initially with normal motor performance. Moderate motor slowing appears at a later stage when basal ganglia hypermetabolism drops toward hypometabolism. More severe functional deficits and highly pathologic motor slowing become manifest when hypometabolism is most widespread in the basal ganglia. This stage leads to dementia.

HAART is neuroprophylactic in HIV-1 infection.

BACKGROUND: To find out about the prophylactic value of antiretroviral therapy on HIV-1-associated subclinical and clinical psychomotor slowing as one marker of HIV-1-associated CNS disease. METHODS: Prospective study with regular clinical and neurophysiologic examination every three months of 1482 consecutive HIV-1-seropositive and AIDS patients seen at our department till June 30, 1999. RESULTS: Antiretroviral therapy has a significant prophylactic value over an individual observation period of ten years with regard to the first, potentially transient manifestation of HIV-1-associated subclinical psychomotor slowing and with regard to the clinical manifestation of motor signs. However, a subgroup of patients is characterized through a second, more sustained manifestation of subclinical psychomotor slowing which cannot be prevented by any type of currently available antiretroviral therapy. CONCLUSIONS: These findings suggest the existence of different pathomechanisms underlying HIV-1-associated brain disease which may in part be effectively prevented, but which in part also escape all antiretroviral treatment strategies in use today.

Electromyographically evident changes in skeletal muscles during tibial lengthening in dogs using the Ilizarov method.

Twenty-four beagle dogs underwent a lower leg lengthening on the right side of 2.5 cm at a distraction rate of 2 times 0.5 mm per day using a circular fixator system. After a latency phase of 5 days and a distraction phase of 25 days, 12 dogs (30-day dogs) underwent electromyography (EMG) of the gastrocnemius muscle on the lengthened and on the control side. The remaining half of the dogs underwent EMG after a consolidation phase of 25 days following the end of distraction (55-day dogs). During every EMG, at least 20 different muscle potentials were analyzed, and the duration, amplitude, and number of phases were determined of each individual potential. The 30-day dogs had significantly longer potential phases on the lengthened side and insignificantly smaller amplitudes compared with the control side. Furthermore, we observed a slightly larger number of polyphasic potentials on the distraction side. In the 55-day dogs, no significant differences were observed in the various parameters between the lengthened and the control side. Comparing 30- and 55-day dogs, the duration of the potentials on the distraction side was not significantly shorter in the 55-day dogs, and the amplitude significantly higher. These findings could indicate combined neurogenous and myopathic alterations of the muscles during the early distraction phase which will be compensated during the later distraction period and the consolidation phase by reparative and reinnervation processes, leaving no lasting functional damage.