Impacto del Programa de Rehabilitación Interdisciplinario de Dolor Crónico en pacientes sin y con trastornos del sueño / Impact of the Interdisciplinary Chronic Pain Rehabilitation Programme in patients with and without sleep disorders

Introducción: Los trastornos del sueño y el dolor crónico están relacionados bidireccionalmente. Ambos están relacionados con trastornos afectivos, fatiga, depresión, ansiedad y abuso de fármacos, y afectan significativamente a la calidad de vida. El objetivo del Programa Interdisciplinario de Dolor (PRID) es aliviar el dolor del paciente y mejorar su funcionalidad a través de la incorporación de hábitos posturales, del sueño y nutricionales saludables, técnicas de relajación, ejercicio físico y mecanismos cognitivoconductuales. Pacientes y métodos: Se realizó un estudio retrospectivo, observacional y transversal. Se examinó a 323 pacientes con dolor crónico que completaron el PRID. Se les evaluó al principio y al final del programa con escalas de dolor, depresión, calidad de vida e insomnio, y se les comparó entre grupos con y sin insomnio –índice de gravedad del insomnio (ISI) menor de 15 frente a mayor o igual a 15–. Se estudió a 58 pacientes con polisomnografía. Resultados: Se observó una mejoría significativa (p < 0,0001) del dolor, la depresión y la calidad de vida evaluados mediante la escala analógica visual (EVA), el inventario de Beck y el cuestionario Short Form-36 (SF-36), tanto en pacientes con dolor crónico con ISI menor de 15 como ISI mayor o igual a 15. Los resultados fueron superiores en el grupo de pacientes con insomnio. La presencia de un índice de apneas e hipopneas elevado y movimientos periódicos de los miembros inferiores en los pacientes no se relacionó con la mejoría de las escalas de Beck, SF-36, ISI y EVA. Conclusiones: En conclusión, el PRID beneficia a los pacientes con dolor crónico no oncológico en varias esferas afectadas, además del dolor, mediante un tratamiento integral. La polisomnografía puede ayudar a diagnosticar patologías específicas e individualizar el tratamiento farmacológico.(AU)

Introduction: Sleep disorders and chronic pain are linked to each other bidirectionally. Both are related to affective disorders, fatigue, depression, anxiety and drug abuse, and have a significant effect on quality of life. The Interdisciplinary Pain Programme (IDP) aims to relieve the patients’ pain and improve their functionality by incorporating healthy postural, sleep and nutritional habits, relaxation techniques, physical exercise and cognitive-behavioural mechanisms. Patients and methods: A retrospective, observational, cross-sectional study was conducted. A total of 323 patients with chronic pain who completed the IDP were examined. They were assessed at the beginning and at the end of the programme with pain, depression, quality of life and insomnia scales, and were then compared between groups with and without insomnia, that is, with an insomnia severity index (ISI) less than 15 versus greater than or equal to 15. Fifty-eight patients were studied by means of polysomnography. Results: A significant improvement (p < 0.0001) in pain, depression and quality of life, as assessed by the visual analogue scale (VAS), the Beck inventory and the Short Form-36 (SF-36) questionnaire was observed in chronic pain patients with an ISI below 15 and in those with an ISI greater than or equal to 15. The results were superior in the group of patients with insomnia. The presence of a high apnoea and hypopnoea index and periodic lower limb movements in patients was not related to improvements on the Beck, SF-36, ISI and VAS scales. Conclusions: In conclusion, IDP benefits patients with chronic non-cancer-induced pain in several affected areas, in addition to pain, due to a comprehensive treatment. Polysomnography can help diagnose specific pathologies and individualise pharmacological treatment.(AU)

[Impact of the Interdisciplinary Chronic Pain Rehabilitation Programme in patients with and without sleep disorders]. / Impacto del Programa de Rehabilitación Interdisciplinario de Dolor Crónico en pacientes sin y con trastornos del sueño.

INTRODUCTION: Sleep disorders and chronic pain are linked to each other bidirectionally. Both are related to affective disorders, fatigue, depression, anxiety and drug abuse, and have a significant effect on quality of life. The Interdisciplinary Pain Programme (IDP) aims to relieve the patients' pain and improve their functionality by incorporating healthy postural, sleep and nutritional habits, relaxation techniques, physical exercise and cognitive-behavioural mechanisms. PATIENTS AND METHODS: A retrospective, observational, cross-sectional study was conducted. A total of 323 patients with chronic pain who completed the IDP were examined. They were assessed at the beginning and at the end of the programme with pain, depression, quality of life and insomnia scales, and were then compared between groups with and without insomnia, that is, with an insomnia severity index (ISI) less than 15 versus greater than or equal to 15. Fifty-eight patients were studied by means of polysomnography. RESULTS: A significant improvement (p < 0.0001) in pain, depression and quality of life, as assessed by the visual analogue scale (VAS), the Beck inventory and the Short Form-36 (SF-36) questionnaire was observed in chronic pain patients with an ISI below 15 and in those with an ISI greater than or equal to 15. The results were superior in the group of patients with insomnia. The presence of a high apnoea and hypopnoea index and periodic lower limb movements in patients was not related to improvements on the Beck, SF-36, ISI and VAS scales. CONCLUSIONS: In conclusion, IDP benefits patients with chronic non-cancer-induced pain in several affected areas, in addition to pain, due to a comprehensive treatment. Polysomnography can help diagnose specific pathologies and individualise pharmacological treatment.

TITLE: Impacto del Programa de Rehabilitación Interdisciplinario de Dolor Crónico en pacientes sin y con trastornos del sueño.Introducción. Los trastornos del sueño y el dolor crónico están relacionados bidireccionalmente. Ambos están relacionados con trastornos afectivos, fatiga, depresión, ansiedad y abuso de fármacos, y afectan significativamente a la calidad de vida. El objetivo del Programa Interdisciplinario de Dolor (PRID) es aliviar el dolor del paciente y mejorar su funcionalidad a través de la incorporación de hábitos posturales, del sueño y nutricionales saludables, técnicas de relajación, ejercicio físico y mecanismos cognitivoconductuales. Pacientes y métodos. Se realizó un estudio retrospectivo, observacional y transversal. Se examinó a 323 pacientes con dolor crónico que completaron el PRID. Se les evaluó al principio y al final del programa con escalas de dolor, depresión, calidad de vida e insomnio, y se les comparó entre grupos con y sin insomnio ­índice de gravedad del insomnio (ISI) menor de 15 frente a mayor o igual a 15­. Se estudió a 58 pacientes con polisomnografía. Resultados. Se observó una mejoría significativa (p < 0,0001) del dolor, la depresión y la calidad de vida evaluados mediante la escala analógica visual (EVA), el inventario de Beck y el cuestionario Short Form-36 (SF-36), tanto en pacientes con dolor crónico con ISI menor de 15 como ISI mayor o igual a 15. Los resultados fueron superiores en el grupo de pacientes con insomnio. La presencia de un índice de apneas e hipopneas elevado y movimientos periódicos de los miembros inferiores en los pacientes no se relacionó con la mejoría de las escalas de Beck, SF-36, ISI y EVA. Conclusiones. En conclusión, el PRID beneficia a los pacientes con dolor crónico no oncológico en varias esferas afectadas, además del dolor, mediante un tratamiento integral. La polisomnografía puede ayudar a diagnosticar patologías específicas e individualizar el tratamiento farmacológico.

Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway.

The renin-angiotensin system (RAS) is a key regulator of vascular tone and blood pressure. In addition, angiotensin II also has a number of cellular effects that may contribute to disease pathogenesis. Using Agtr1a(-/-) mice, which lack AT(1A) receptors for angiotensin II, we have identified a novel function of the RAS to modulate the immune system. We find that angiotensin II, acting through type 1 (AT(1)) receptors on immune cells, triggers the proliferation of splenic lymphocytes. These actions contribute to the vigor of cellular alloimmune responses. Within lymphoid organs, sufficient components of the RAS are present to activate AT(1) receptors during an immune response, promoting cell growth. These actions require activation of calcineurin phosphatase. In an in vivo model of cardiac transplantation, the absence of AT(1) signaling accentuates the immunosuppressive effects of the calcineurin inhibitor cyclosporine. We conclude that inhibition of AT(1) receptor signaling should be useful as an anti-inflammatory and immunosuppressive therapy. Furthermore, the actions of the RAS to promote lymphocyte activation may contribute to inflammation that characterizes a number of diseases of the heart and the vascular system.

Colchicine interferes with L-selectin and leukocyte function-associated antigen-1 expression on human T lymphocytes and inhibits T cell activation.

Colchicine, which inhibits cell microtubule assembly by preventing polymerization of tubulin monomers, inhibits cell-mediated immune responses and promotes long-term survival of major histocompatibility complex-incompatible renal allografts in rats. Here we evaluated the effect of blocking cell microtubule assembly by colchicine on T cell and endothelial cell adhesion receptors involved in transducing signals for T cell activation. By using immunofluorescence flow cytometry analysis, evidence is presented that colchicine, in a dose-dependent fashion, downregulated L-selectin and leukocyte function-associated antigen-1, but not CD2 and CD44 on the surface of naive human peripheral blood lymphocytes. This effect was confirmed in two subsets of T lymphocytes, namely, CD45RA- and CD45RO-positive cells. However, colchicine did not influence the rapid shedding of L-selectin from T lymphocytes exposed to activating stimuli. Colchicine inhibited expression of interleukin-2 receptor on activated T lymphocytes. This effect was observed when T lymphocytes were stimulated with both anti-CD3 and anti L-selectin monoclonal antibodies. Colchicine also inhibited lymphocyte function in vitro as documented by inhibition of the human mixed lymphocyte response in a dose-dependent fashion. Moreover, colchicine downregulated surface expression of intercellular adhesion molecule-1 and E-selectin on activated human umbilical vein endothelial cells. These results indicate that blocking cell microfubule assembly inhibits surface expression of adhesion molecules on T cells and endothelial cells, and provides insights into the complex mechanisms of the action of colchicine in vivo.

Plasma clearance of nonradioactive iohexol as a measure of glomerular filtration rate.

Renal clearance of inulin is the best available indicator of GFR but cannot be used routinely for clinical purposes and is also difficult to perform for clinical investigation when repeated measurements are required. The aim of this study was to find a reliable alternative to inulin clearance that would allow one to avoid the use of radioactivity and problems related to the continuous infusion of the marker. The plasma clearance of unlabeled iohexol, a nonionic contrast agent, was used. Forty-one patients (creatinine clearance 6 to 160 mL/min per 1.73 m2) underwent simultaneous measurements of renal clearance of inulin and plasma clearance of iohexol. Iohexol was given as a single iv dose, and blood samples were drawn up to 600 min after the administration. Iohexol concentrations (by HPLC) were analyzed by a two-compartment, open-model system. A highly significant correlation between the plasma clearance of iohexol and the renal clearance of inulin over a wide range of GFR values was found. By analyzing the data with a simplified method that uses a one-compartment model corrected with the Bröchner-Mortensen formula, an excellent correlation with the inulin clearance was also observed. When only patients with moderate to severe renal failure were considered, a significant correlation between the two methods was found. A further comparison between GFR determined with iohexol and iopromide, a new low-osmolarity, low-viscosity contrast medium, was also performed in a subgroup of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcitonin gene-related peptide reduces renal vascular resistance and modulates ET-1-induced vasoconstriction.

Calcitonin gene-related peptide (CGRP) is a novel polypeptide that exerts important effect on the cardiovascular system through its vasorelaxant properties. We studied in vivo in normal rats the effect of acute administration of CGRP on whole kidney function and showed that the intravenous infusion of the peptide resulted in a fall of blood pressure associated with a marked increase in renal plasma flow (RPF) as well as glomerular filtration rate (GFR). These changes were reversible with discontinuation of CGRP infusion. To evaluate whether the renal hemodynamic responses to the peptide were mediated by endogenous vasodilatory prostaglandins of endothelial origin, animals were preexposed to indomethacin, a cyclooxygenase enzyme inhibitor. Inhibition of prostaglandins synthesis with indomethacin failed, however, to prevent the increase in RPF and GFR observed during CGRP infusion. By contrast, NG-nitro-L-arginine methyl ester (L-NAME), which inhibits the synthesis of nitric oxide, a newly discovered endothelium-derived relaxing factor, completely abolished the renal hemodynamic changes induced by CGRP. Moreover, L-arginine infusion in L-NAME-treated rats restored the renal response to CGRP. We have also shown that systemic infusion of CGRP progressively normalized RPF and GFR that were reduced in response to a bolus intravenous injection of the vasoconstrictor endothelin-1. This indicates that CGRP regulates renal hemodynamics and modulates the deleterious effects of vasoconstrictive substances on the kidney.

Following an initial decline, glomerular filtration rate stabilizes in heart transplant patients on chronic cyclosporine.

We previously reported that heart transplant patients given cyclosporine for more than 2 years (short-term evaluation) had severe renal lesions and markedly reduced glomerular filtration rate and renal plasma flow (Kidney Int 40:243-250, 1991). We report the analysis of renal function in the same patients after 3 additional years of follow-up (long-term evaluation) while they continued to take cyclosporine. Since the previous evaluation, the dose of cyclosporine was adjusted to maintain stable trough levels and antihypertensive therapy was unchanged. The mean time-averaged dose of cyclosporine during the follow-up was 4.5 +/- 2.1 mg/kg/d. The systolic blood pressure at long-term evaluation (146 +/- 16 mm Hg) was increased (P < 0.05) compared with that at short-term evaluation (140 +/- 13 mm Hg), whereas diastolic blood pressure (long-term 91 +/- 9 mm Hg v short-term 88 +/- 9 mm Hg) and mean blood pressure (long-term 110 +/- 12 mm Hg v short-term 108 +/- 11 mm Hg) did not change significantly. Serum creatinine concentrations at long-term (1.7 +/- 0.3 mg/dL) and at short-term (1.7 +/- 0.4 mg/dL) evaluations were similar. At long-term evaluation the renal plasma flow (300 +/- 64 mL/min/1.73 m2) was not decreased compared with that at short-term evaluation (325 +/- 94 mL/min/1.73 m2), while the glomerular filtration rate increased significantly (43 +/- 15 mL/min/1.73 m2 v 36 +/- 8 mL/min/1.73 m2, respectively; P < 0.05). None of the patients became proteinuric after short-term evaluation; in those patients who were already proteinuric, urinary protein excretion did not increase over time.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-converting enzyme inhibition and calcium channel blockade both normalize early hyperfiltration in experimental diabetes, but only the former prevents late renal structural damage.

We studied the potential renoprotective properties of a calcium channel blocker in moderately hyperglycemic diabetic rats both in the early phase of the disease and in the very long term, and compared such an effect with that of an angiotensin-I-converting enzyme (ACE) inhibitor. Three groups of diabetic rats, one receiving no therapy except insulin and the remaining two receiving insulin and the ACE inhibitor enalapril or the calcium blocker lacidipine and one group of nondiabetic control rats were followed for 4-6 weeks. Both antihypertensive drugs lowered systolic blood pressure comparably. At the end of the observation period, untreated diabetic rats exhibited elevation of glomerular filtration rate and renal plasma flow. Both enalapril and lacidipine treatment completely prevented whole-kidney hyperfiltration and hyperperfusion. Four additional groups of rats, similarly treated, were followed for 1 year. A comparable control of systolic blood pressure and blood glucose level was achieved with the two antihypertensive regimens throughout the whole study period. At 12 months, the average kidney weight was elevated to similar values in all diabetic groups relative to control rats. Untreated diabetic rats had progressive proteinuria and developed glomerulosclerosis. Enalapril markedly limited the development of proteinuria. By contrast, urinary protein excretion in diabetic rats given lacidipine markedly increased with time, and values were as high as those in untreated diabetic animals. Similarly, only enalapril was effective in limiting glomerular injury. These results indicate that ACE inhibition but not calcium channel blockade has a favorable effect in preventing renal disease progression in diabetic rats and suggest that the various antihypertensive regimens are not equally beneficial in protecting against diabetic glomerulopathy.

Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes.

The short- and long-term effects of specific angiotensin II (AII) receptor blockade on the evaluation of glomerular injury in moderately hyperglycemic diabetic rats were studied. Three groups of animals were used, a control group, a group of diabetic rats treated with insulin, and a group of insulin-treated diabetic rats receiving the AII receptor antagonist losartan in drinking water. After 4 to 6 wk of observation, diabetic rats showed higher systolic blood pressure and GFR than normal controls. Losartan treatment prevented both systolic blood pressure and GFR rise. Three other groups of rats, similarly treated for a 1-yr period, were used for renal functional and morphologic evaluation. Diabetic animals had higher urinary protein excretion and glomerulosclerosis incidence than did normal controls. Losartan significantly prevented proteinuria and glomerulosclerosis. Evaluation of the sieving properties of the glomerular membrane by Ficoll fractional clearance showed an important increase in the filtration of this marker in diabetic animals, as compared with that in controls, and almost complete prevention of this change in losartan-treated animals. Theoretical analysis of fractional clearance data with a heteroporous model of glomerular size-selectivity showed that in diabetic animals the size of membrane pores was increased uniformly, as compared with that in controls. These changes were completely prevented by the AII receptor antagonist. The results presented here strongly indicate that reduction of AII activity plays a crucial role in the preservation of glomerular structure and function and suggest that the favorable effects previously observed with angiotensin-converting enzyme inhibition in this model depend directly on the reduction of AII activity.

Calcium channel blockers protect transplant patients from cyclosporine-induced daily renal hypoperfusion.

Renal toxicity, possibly due to vasoconstriction and vascular injury, is the most relevant side-effect of chronic cyclosporine (CsA) therapy given to prevent graft rejection. In kidney transplant recipients each oral dose of CsA is invariably followed by a transient reduction in renal plasma flow (RPF) and glomerular filtration rate (GFR) that results from a form of acute reversible hypoperfusion. We sought to determine whether the Ca2+ channel blocker, lacidipine, prevented CsA-associated renal hypoperfusion in these patients. Parallel studies on CsA pharmacokinetics, renal function parameters (GFR and RPF), as inulin and p-aminohippurate (PAH) clearances, respectively, and urinary excretion of the vasoconstrictor endothelin in 10 consecutive renal transplant patients given CsA as a part of their immunosuppressive therapy were performed. Patients were studied at different time intervals after CsA alone, CsA and lacidipine (4 mg/day), and again seven days after lacidipine withdrawal. In all patients basal RPF and GFR declined on average 51% (139.3 +/- 20.7 ml/min/1.73 m2) and 50% (32.5 +/- 5.8 ml/min/1.73 m2), respectively, two to four hours after maximum blood CsA concentration was reached. As blood levels of CsA returned to trough, both parameters progressively increased to baseline. Lacidipine administration completely prevented the fall in RPF (pre-CsA: 277.1 +/- 23.6; 6 hr post-CsA: 304.5 +/- 31.1 ml/min/1.73 m2) and GFR (pre-CsA: 66.6 +/- 8.1; 6 hr post-CsA: 70.1 +/- 9.8 ml/min/1.73 m2). When lacidipine treatment was discontinued the abnormal RPF and GFR response to CsA administration was again observed.(ABSTRACT TRUNCATED AT 250 WORDS)

The acute effect of FK506 and cyclosporine on endothelial cell function and renal vascular resistance.

We have previously documented that cyclosporine exerts a direct cytotoxic effect on endothelial cells and causes an increase in renal vascular resistance (RVR) in the rat. In the present study we investigated whether FK506, a novel immunosuppressive agent thought to be less nephrotoxic than CsA, impairs endothelial cell function in vitro and affects RVR in vivo. In vitro eicosanoid release and endothelin release were measured in bovine aortic endothelial cells in culture exposed for 1, 6, and 24 hr to increasing concentrations of FK506 (1 nM to 10 microM) or CsA (0.5, 10 microM). No significant changes in TxB2 and 6-keto-PGF1 alpha (the stable breakdown products of TxA2 and PGI2, respectively) and endothelin release were found after 1 and 6 hr of incubation with all the concentrations of FK506 and CsA considered. FK506 did not affect endothelin release even after 24 hr of incubation. In contrast, cell exposure to CsA was associated with a dose-dependent increase in TxB2, 6-keto-PGF1 alpha, and endothelin release that reached statistical significance after incubation with 10 microM CsA. FK506 did not induce cell detachment or lysis at any concentration and time considered, while 10 microM CsA induced a significant reduction in cell count accompanied by cell lysis. In vivo studies showed that a single i.v. injection of FK506 to rats within a broad range of doses (28 ng/kg to 2.8 micrograms/kg) did not modify RVR. This was true even for a dose as high as 20 mg/kg, while 20 mg/kg CsA caused a dramatic increase in RVR. We conclude that FK506, unlike CsA, does not induce endothelial cell injury in vitro. Whether this explains the differences in renovascular resistance observed in vivo after acute injection of FK506 and CsA is an attractive possibility that needs to be further explored.

Daily renal hypoperfusion induced by cyclosporine in patients with renal transplantation.

A variety of side effects are associated with the use of cyclosporine, the most relevant of which remains the renal toxicity. We did parallel studies on cyclosporine pharmacokinetics and renal function in patients who had a recent kidney transplant and were given cyclosporine as a part of their immunosuppressive therapy. Seven consecutive renal transplant patients were studied at the end of a month of treatment while on different oral cyclosporine doses (5, 3.5, 2.5, or 1.5 mg/kg, twice a day, respectively). Cyclosporine pharmacokinetics profiles and renal function parameters (GFR and renal plasma flow [RPF], as inulin and p-amino hippurate clearances, respectively) were determined before and over a 12-hr period after each single dose of cyclosporine. Plasma levels and urinary excretion rate of endothelin were also studied before and after the highest cyclosporine dose (5 mg/kg). Mean trough levels, area under the curve values, and maximum concentration of blood cyclosporine were comparable after 5 and 3.5 mg/kg cyclosporine and decreased in a dose-dependent manner after the lower doses (2.5 and 1.5 mg/kg). In the same patients GFR declined on average 63%, 53%, 35%, and 18%, 2-4 hr after maximum cyclosporine concentration was reached. As blood levels of cyclosporine returned to trough, GFR progressively increased to baseline. Similar results were found for RPF; 5 mg/kg cyclosporine did not modify endothelin plasma levels. By contrast, urinary excretion of the peptide increased significantly (P less than 0.01) in the 6 hr that followed cyclosporine administration and returned within the normal range in the subsequent 6 hr. Following each oral administration of cyclosporine, 2-4 hr after peak blood concentration was reached, patients showed renal hypoperfusion, transient and rapidly reversible. This was associated with an increased urinary endothelin excretion rate that was also transient. It is speculated that an excessive renal synthesis of endothelin is the cause of the daily renal hypoperfusion observed in patients with renal transplants given cyclosporine.