Spinal cord stimulation does not change peripheral skin blood flow in patients with neuropathic pain.

BACKGROUND AND OBJECTIVE: Spinal cord stimulation has been used successfully for many years in the management of neuropathic pain. Nociceptive pathways are closely integrated into many autonomic reflexes. The aim was to test the hypothesis that pain relief caused by spinal cord stimulation is related to changes in peripheral skin blood flow. METHODS: Twelve patients with spinal cord stimulators implanted as a treatment for neuropathic pain were entered into the study. Laser Doppler perfusion scanning was used as a direct method for selective measurement of changes in skin (peripheral) blood flow. Measurements were taken before and after the onset of spinal cord stimulation over the site of its sensory projection. The degree of pain relief due to spinal cord stimulation and the skin temperature of each patient were also recorded. RESULTS: Apart from one patient, spinal cord stimulation did not change skin blood flow in a statistically significant manner. CONCLUSIONS: Pain relief due to spinal cord stimulation is not related to changes of skin blood flow.

Efficacy of intravenous magnesium in neuropathic pain.

BACKGROUND: Postherpetic neuralgia is a complication of acute herpes zoster characterized by severe pain and paraesthesia in the skin area affected by the initial infection. There is evidence that the N-methyl-D-aspartate receptor is involved in the development of hypersensitivity states and it is known that magnesium blocks the N-methyl-D-aspartate receptor. METHOD: A double-blind, placebo-controlled, cross-over study was conducted in which magnesium sulphate was administered as an i.v. infusion. Spontaneous pain was recorded and qualitative sensory testing with cotton wool was performed in seven patients with postherpetic neuralgia before and after the i.v. administration of either magnesium sulphate 30 mg kg(-1) or saline. RESULTS: During the administration, pain scores were significantly lower for magnesium compared with placebo at 20 and 30 min (P=0.016) but not at 10 min. I.V. magnesium sulphate was safe, well-tolerated and effective in patients with postherpetic neuralgia. CONCLUSION: The present study supports the concept that the N-methyl-D-aspartate receptor is involved in the control of postherpetic neuralgia.

Generation and subcellular distribution of histamine in human blood monocytes and monocyte subsets.

OBJECTIVE AND DESIGN: This study was designed to establish the sites of formation and storage of histamine and histidine decarboxylase (HDC) in human monocytes and two of their subsets. MATERIALS AND METHODS: The experiments were carried out using monocytes from buffy coats of healthy blood donors. Histamine was quantitated by RIA, HDC activity by the formation of histamine. RESULTS: The monocyte subtype RM3/1 contained significantly more histamine than the subset 27E10 (0.041+/-0.025 vs. 0.005+/-0.004 pg/cell, p < 0.05) and also more HDC activity and HDC mRNA. After fractionation of monocyte homogenates in a discontinuous Percoll gradient or by differential centrifugation more than 80% of both, HDC activity and histamine, were recovered from the cytosolic fractions. About 50% of this histamine was found to be bound to proteins. CONCLUSIONS: In monocytes histamine and HDC are colocalized in the cytoplasm indicating a subcellular distribution different from mast cells or basophils. The data also show that histamine is synthesized by the monocytes themselves.

Cytochrome P450 1B1: a major P450 isoenzyme in human blood monocytes and macrophage subsets.

In this study, cytochrome P450 (CYP; EC 1.14.14.1)-dependent activities and P450 isoenzyme patterns were determined in human monocytes and macrophages, which play a major role in antigen processing including small molecular weight compounds which cause contact dermatitis or drug-allergic reactions. Using reverse transcriptase-polymerase chain reaction (RT-PCR) we determined the mRNA expression of eight CYPs (1A1, 1A2, 1B1, 2B6/7, 2E1, 3A3/4, 3A7 and 4B1) in human blood monocytes and macrophage subsets 27E10 and RM3/1. To study the influence of known P450 inducers, monocytes were incubated in vitro with ethanol, dexamethasone, cyclosporin A (CSA), benzanthracene (BA), phenobarbital (PB), lipopolysaccharide (LPS) and 12-O-tetradecanoyl-phorbol-13-acetat (TPA) for 24 hr. Percoll density gradient isolated monocytes as well as the pro-inflammatory macrophage subtype 27E10 expressed 1B1, 2E1 and 2B6/7. On the other hand, in the anti-inflammatory macrophage subtype RM3/1, predominantly 1B1 and to some extent 2B6/7 were found. Treatment with cyclosporin A, phenobarbital, benzanthracene or ethanol resulted in induction of the expression of 3A3/4. CYP1B1 was the predominant isoenzyme in all monocytes and macrophages. In monocytes purified by adherence or induced by benzanthracene, lipopolysaccharide or 12-O-tetradecanoyl-phorbol-13-acetat, 1A1 was also expressed. Northern blot analysis confirmed the presence of CYP1B1 in monocytes and macrophages, a presence which was also demonstrated on the protein level by immunoblot and by immunohistochemical staining of the cells. The expression of several CYPs in monocytes/macrophages suggests that these cells may be important in the metabolism of small molecular weight compounds, which play a role in allergic contact dermatitis and drug reactions. Of particular interest is the remarkably strong expression of the recently identified dioxin inducible CYP1B1, known to be present in a wide range of malignant tumors.

The use of lamotrigine in neuropathic pain.

Sodium channel antagonists have been used in the management of neuropathic pain for several years. Recent evidence suggests that lamotrigine, which is active at glutaminergic excitatory synapses, is very effective in producing pain relief. We have successfully used lamotrigine in two patients suffering from neuropathic pain. Our results suggest that this novel channel antagonist can be used to treat neuropathic pain. Double blind placebo control studies are therefore needed to substantiate these findings.

Phantom pain and sensation among British veteran amputees.

Using a mail-delivered questionnaire, we surveyed 590 veteran amputees concerning phantom pain, phantom sensation and stump pain. They were selected randomly from a population of 2974 veterans with long-standing limb amputation(s) using a computer random number generator. Eighty-nine percent responded and of these, 55% reported phantom limb pain and 56% stump pain. There was a strong correlation between phantom pain and phantom sensation. The intensity of phantom sensation was a significant predictor for the time course of phantom pain. In only 3% of phantom limb pain sufferers did the condition become worse. One hundred and forty-nine amputees reporting phantom pain discussed their pain with their family doctors; 49 were told that there was no treatment available. Transcutaneous electric nerve stimulation, analgesics and non-steroidal anti-inflammatory drugs were satisfactory methods for controlling phantom limb pain.

The value of SPECT scans in identifying back pain likely to benefit from facet joint injection.

Lumbar facet disease is sometimes implicated in low back pain. Identification is difficult and this may account for a variable response. Single photon emission computerized tomography (SPECT) is a scanning technique which enables localization of facet joint pathology. We determined whether recognition of facet disease by this method improved the response to corticosteroid injection treatment. Fifty-eight patients with low back pain and displaying accepted clinical criteria for facet joint disease were evaluated by SPECT. Twenty-two had facetal uptake of isotope. These and the tender facet joints of 36 scan-negative patients were injected with 40 mg methylprednisolone and 1 ml 1% lignocaine under X-ray control. Pain was assessed by a blind observer using the McGill questionnaire (MGQ), Present Pain Intensity score (PPI) and a Visual Analogue Scale (VAS). VAS, PPI and MGQ were reduced in the scan-positive patients at 1 month (P = 0.05, P = 0.0005, P = 0.005) and MGQ at 3 months (P = 0.01), whilst scan-negative patients were unchanged. The percentage of scan-positive patients who reported improvement was 95% at 1 month and 79% at 3 months, significantly greater than the control group (P = 0.0005, P = 0.01). Within 6 months, pain improvement in the SPECT-positive group was no longer statistically significant. Tenderness did not correlate with increased uptake on SPECT scan. Osteoarthritis of the facets was more common in the SPECT-positive patients (P < 0.001), but did not correspond with sites of increased uptake on SPECT scan. These results suggest that SPECT can enhance the identification of back pain sufferers likely to obtain short-term benefit from facet joint injection.

Characterization of a novel anti-inflammatory factor produced by RM3/1 macrophages derived from glucocorticoid treated human monocytes.

Glucocorticoids exert their anti-inflammatory activity by modulating the functions of various cell types including macrophages. They also induce the generation of a distinct macrophage subtype defined by the surface antigen RM3/1 which appears to be associated with the down-regulation of inflammation. Supernatants from these cells were found to exert a dose-dependent anti-inflammatory effect, particularly in the early phase as shown in the 5-hydroxytryptamine (5-HT) induced footpad edema of mice. By using conventional purification methods the anti-inflammatory factor was found to have a molecular mass of about 78 kD and an isoelectric point of about 7.9. Heat lability and sensitivity to trypsin and proteinase K indicate the protein nature of the anti-inflammatory factor. The inhibition of the early phase of inflammation and the molecular weight suggest that the anti-inflammatory agent released from RM3/1 macrophages is a novel protein different from other anti-inflammatory proteins described so far.

Secretion of leukaemia inhibitory factor after allogeneic bone marrow transplantation: a study of CD4+ and CD8+ TCR alpha beta+ T-cell clones derived from four leukaemia patients.

CD4+ and CD8+ TCR alpha beta+ T-cell clones were derived from 4 leukaemia patients early (4-6 weeks) after allogeneic bone marrow transplantation. Leukemia inhibitory factor (LIF) secretion in response to the activation signal accessory cells (AC) + phytohaemagglutinin (PHA) was investigated for each individual clone. Only a minority of CD4+ TCR alpha beta+ T-cell clones secreted LIF in response to AC + PHA, whereas most T-cell clones were capable of LIF secretion when exogenous interleukin 2 was added together with AC + PHA. LIF secretion could also be demonstrated for CD8+ TCR alpha beta+ posttransplant T-cell clones. Thus, posttransplant CD4+ and CD8+ TCR alpha beta+ clonogenic T-cells are capable of LIF secretion, and LIF secretion may be a T-cell effector mechanism in graft versus host disease, graft versus leukaemia effects or posttransplant haematopoietic reconstitution.

IFN-gamma and TNF-alpha secretion by CD4+ and CD8+ TCR alpha beta + T-cell clones derived early after allogeneic bone marrow transplantation.

Secretion of the potentially antileukaemic cytokines IFN-gamma and TNF-alpha was investigated for CD4+ and CD8+ TCR alpha beta + T-cell clones derived from 4 leukaemia patients 3-6 weeks after allogeneic BMT. We investigated cytokine secretion in response to the activation signal accessory cells+phytohaemagglutinin+Interleukin 2. All clones derived after BMT were capable of IFN-gamma and TNF-alpha secretion, and both for CD4+ (n = 96) and CD8+ (n = 8) T cells quantities of IFN-gamma and TNF-alpha were significantly correlated with one another. When comparing the overall results for posttransplant and normal T-cell clones derived from 2 bone marrow donors (n = 65), both CD4+ and CD8+ TCR alpha beta + T-cell clones showed increased IFN-gamma production, and CD4+ but not CD8+ clones showed a decreased TNF-alpha secretion. The results suggest that noncytotoxic T cells derived after allogeneic BMT can produce IFN-gamma and TNF-alpha and may thus be capable of mediating antileukaemic effects.

Secretion of IL-2, IL-3, IL-4, IL-6 and GM-CSF by CD4+ and CD8+ TCR alpha beta+ T-cell clones derived early after allogeneic bone marrow transplantation.

Secretion of different cytokines may be an important T-cell effector mechanism for bone marrow engraftment, graft versus host disease and graft versus leukaemia effects after allogeneic bone marrow transplantation (BMT). Cytokine secretion and autocrine proliferative capacity of T-cell clones derived from leukaemia patients 3-6 weeks after allogeneic bone marrow transplantation were investigated. Only a minority of post-transplant T-cell clones (23/120; 19%) was capable of undergoing autocrine proliferation. By contrast, 21/65 (32%) normal control clones from the marrow donors derived under the same conditions were autocrine proliferative. All clones were interleukin-2 (IL-2) responsive. A majority (12/17; 71%) of autocrine proliferating post-transplant clones secreted detectable IL-2. Compared with control clones, CD4+ T-cell clones derived early after BMT produced decreased levels of interleukin-4 (IL-4) and interleukin-6 (IL-6), whereas secretion of interleukin-3 (IL-3) and granulocyte/macrophage colony-stimulating factor (GM-CSF) showed no significant difference. The small number (n = 8) of posttransplant CD8+ clones showed decreased production of IL-3, IL-4 and IL-6 compared with control clones, but normal secretion of GM-CSF. Neither CD4+ nor CD8+ T-cell clones secreted interleukin-7 (IL-7).

CD4+ TCR alpha beta+ T-cell clones derived shortly after allogeneic bone marrow transplantation: theophyllamine and verapamil inhibit proliferation of functionally heterogeneous T-cells.

CD4+ TCR alpha beta+ T-cell clones were prepared from three CML-patients 4-6 weeks after allogeneic bone marrow transplantation and the effects of theophyllamine and verapamil on clonal growth then assessed. Both drugs inhibited PHA-stimulated autocrine proliferation of clones as well as proliferation of clones dependent on exogenous growth factors. Inhibition was seen when using different accessory cells (PBM or BCL) during T-cell activation, and both for IL2- and IL4-dependent proliferation of previously activated T-cells. The isomer R-verapamil inhibited PHA-stimulated proliferation as well as IL2- and IL4-dependent T-cell proliferation. The drugs also inhibited proliferation of CD8+ T-cells. Although the T-cell clones were functionally heterogeneous and were derived from different patients and priming cultures, both drugs inhibited all clones investigated. However, the degree of inhibition varied between different clones.

IL2- and IL4-dependent proliferation of T-cell clones derived early after allogeneic bone marrow transplantation: studies of patients with chronic myelogenous leukaemia.

In an attempt to explore T-cell functions shortly after allogeneic bone marrow transplantation more fully, IL2- and IL4-dependent proliferation was assessed on CD4+ TCR alpha beta+ T-cell clones derived 4-6 weeks after transplantation. Both allogeneic pooled peripheral blood mononuclear cells and Epstein-Barr virus-transformed B-cell lines (BCL) could function as accessory cells (AC) for PHA activation of T-cell clones. Although minimal clonal proliferation was seen when the T-cell activation signal was BCL+PHA+IL4, a majority of the clones could undergo IL4-dependent proliferation after previous activation with AC+PHA+IL2. For certain clones, IL4 also showed an additive effect with IL2. Thus, IL4 was a growth factor for a majority of the investigated posttransplant T-cell clones, and in vivo modulation of IL4-dependent T-cell functions may thus become a future therapeutic possibility to enhance graft-versus-leukaemia effects in bone marrow transplant recipients.

Continuous lumbar sympathetic block.

A 74-year-old woman with peripheral vascular disease suffered from rest pain in the right big toe and intermittent claudication. Because of concomitant venous congestion, a chemical lumbar sympathectomy was considered to carry an increased risk of leg edema. A continuous lumbar sympathetic block with local anesthetic abolished the pain in the toe without side effects. After this reversible block, a chemical lumbar sympathectomy was performed producing pain relief for 4 weeks when the patient was last seen.