Controlled-release oxycodone and naloxone in the treatment of chronic low back pain: a placebo-controlled, randomized study.

BACKGROUND: For Canadian regulatory purposes, an analgesic study was required to complement previously completed, pivotal studies on bowel effects and analgesia associated with controlled-release (CR) oxycodone/CR naloxone. OBJECTIVES: To compare the analgesic efficacy and safety of CR oxycodone/CR naloxone versus placebo in patients with chronic low back pain. METHODS: Patients requiring opioid therapy underwent a two- to seven-day opioid washout before being randomly assigned to receive either 10 mg/5 mg CR oxycodone/CR naloxone or placebo every 12 h, titrated weekly according to efficacy and tolerability to 20 mg/10 mg, 30 mg/15 mg or 40 mg/20 mg every 12 h. After four weeks, patients crossed over to the alternative treatment for an additional four weeks. Acetaminophen/codeine (300 mg/30 mg every 4 h to 6 h as needed) was provided as rescue medication. RESULTS: Of the 83 randomized patients, 54 (65%) comprised the per-protocol population. According to per-protocol analysis, CR oxycodone/CR naloxone resulted in significantly lower mean (± SD)pain scores measured on a visual analogue scale (48.6 ± 23.1 mm versus 55.9 ± 25.4 mm; P=0.0296) and five-point ordinal pain intensity scores (2.1 ± 0.8 versus 2.4 ± 0.9; P=0.0415) compared with placebo. After the double-blinded phase, patients and investigators both preferred CR oxycodone/CR naloxone over placebo. These outcomes continued in the 79% of patients who chose to continue receiving CR oxycodone/CR naloxone in a six-month, open-label evaluation. CONCLUSIONS: In patients complying with treatment as per protocol, CR oxycodone/CR naloxone was effective for the management of chronic low back pain of moderate or severe intensity.

A randomized, double-blind, crossover comparison of the efficacy and safety of oral controlled-release tramadol and placebo in patients with painful osteoarthritis.

OBJECTIVE: To compare the efficacy and safety of controlled-release (CR) tramadol (Zytram XL, Purdue Pharma, Canada) and placebo in patients with painful osteoarthritis. METHODS: Patients underwent analgesic washout for two to seven days before random assignment to 150 mg daily of CR tramadol or placebo, and were titrated weekly to 200 mg, 300 mg or a maximum of 400 mg once daily. After four weeks, patients crossed over to the alternate treatment for another four weeks. Plain acetaminophen was provided as a rescue analgesic. All patients who completed the crossover study were eligible to receive open label CR tramadol for six months. RESULTS: Seventy-seven of 100 randomly assigned patients were evaluable for efficacy. CR tramadol resulted in significantly lower visual analogue scale pain intensity scores (37.4+/-23.9 versus 45.1+/-24.3, P=0.0009). Western Ontario and McMaster Universities osteoarthritis index subscale scores for pain (189.0+/-105.0 versus 230.0+/-115.4; P=0.0001) and physical function (632.4+/-361.3 versus 727.4+/-383.4; P=0.0205) were significantly better with CR tramadol. Total pain and disability (22.8+/-14.5 versus 27.2+/-14.8; P=0.0004), and overall pain and sleep (104.7+/-98.0 versus 141.0+/-108.2; P=0.0005) scores in the Pain and Sleep Questionnaire were significantly lower for CR tramadol. Short-form 36 Health Survey scores were significantly better during CR tramadol treatment for the pain index (38.8+/-10.8 versus 35.6+/-9.0; P=0.0100), general health perception (46.5+/-11.2 versus 44.4+/-11.6; P=0.0262), vitality (43.1+/-13.2 versus 40.2+/-13.7; P=0.0255) and overall physical components (40.8+/-8.9 versus 37.8+/-7.7; P=0.0002). CR tramadol treatment was preferred by 55.8% of patients (P=0.0005) versus 20.8% and 23.4% of patients who chose placebo or had no preference, respectively. These improvements were sustained for up to six months, and 86.5% of patients reported at least moderate benefit from CR tramadol during long-term treatment. CONCLUSION: CR tramadol is effective for the management of painful osteoarthritis.

Once-daily, controlled-release tramadol and sustained-release diclofenac relieve chronic pain due to osteoarthritis: a randomized controlled trial.

OBJECTIVE: The present study was a randomized, parallel, double-blind comparison between controlled-release (CR) tramadol and sustained-release (SR) diclofenac in patients with chronic pain due to osteoarthritis of the hips and/or knees. METHODS: Patients with at least moderate pain intensity, and having received analgesics over the past three months, underwent a two- to seven-day washout of current analgesics before initiation of 200 mg CR tramadol or 75 mg SR diclofenac. During the eight-week study, patients returned to the clinic biweekly. CR tramadol doses were titrated to a maximum of 200 mg, 300 mg or 400 mg per day. SR diclofenac doses were titrated to 75 mg or 100 mg once daily, or 75 mg twice a day based on pain relief and the presence of side effects. For rescue analgesic, patients took acetaminophen as needed, up to 650 mg three times a day. RESULTS: Forty-five patients on CR tramadol and 52 patients on SR diclofenac were evaluable. Significant improvements from prestudy treatment were shown for visual analogue scale pain (P=0.0001), stiffness (P<0.0005) and physical function (P=0.0001) scores for both treatments. There were no significant differences between the two treatments in the Western Ontario and McMaster Universities subscales, overall pain, pain and sleep, or the clinical effectiveness evaluation. Overall incidence of adverse events was similar in both groups, with more opioid-related adverse events with CR tramadol, and two serious adverse events occurring with the use of SR diclofenac. CONCLUSIONS: CR tramadol is as effective as SR diclofenac in the treatment of pain due to knee or hip osteoarthritis, with the potential for fewer of the serious side effects that characterize nonsteroidal anti-inflammatory drug administration.

Evidence that the L-arginine pathway plays a role in the regulation of pumping activity in bovine mesenteric lymphatic vessels.

The objective of this study was to investigate the role of the L-arginine pathway in the regulation of lymphatic pumping. Bovine mesenteric lymphatic vessels (8 to 12 cm in length containing four to six lymphangions) were immersed in an organ bath with input provided by a reservoir filled with Krebs solution. The vessels were stimulated to pump by applying a 6 cm H2O transmural pressure. The addition of 10(-7)-10(-4) M oxyhemoglobin, NG-monomethyl-L-arginine (L-NMMA), or methylene blue to the reservoir resulted in a reduction in lymphatic pumping. L-Arginine (10(-7)-10(-4) M) had no effect on spontaneous pumping activity. However, L-arginine reversed the inhibition caused by oxyhemoglobin and L-NMMA. When tested between 10(-7) and 10(-6) M, sodium nitroprusside (sNP) had variable effects on lymphatics. sNP depressed pumping in approximately 2/3 of the vessels and increased pumping in the remaining 1/3 of ducts. When the results were meaned, sNP caused a significant depression in activity. However, the lower concentration of sNP (10(-7) M) was able to reverse the inhibitory effects of oxyhemoglobin, L-NMMA, and methylene blue whereas the higher concentration (10(-6) M) caused further reductions in pumping activity. These results suggest that bovine lymphatic vessels produce nitric oxide or a related compound. L-Arginine metabolites appear to facilitate the pumping response by an as yet undefined mechanism.

Importance of valves and lymphangion contractions in determining pressure gradients in isolated lymphatics exposed to elevations in outflow pressure.

Lymphatic pressures were measured at several locations along an isolated lymphatic system exposed to elevations in outflow pressure. The objective of this study was to determine the contributions of lymphangion contractions and valve function to the observed pressure gradients. In each experiment, five bovine mesenteric lymphatic vessels (each with four to nine lymphangions) were joined in series by t-pieces connected to pressure transducers. The vessels were placed in an organ bath with input provided by a reservoir filled with Krebs solution. With a constant inflow pressure of 4 cm H2O, outflow pressures were elevated in 2- or 5-cm H2O increments. Except for inflow and outflow pressures which were fixed, the pressures measured at four other locations along the system were pulsatile due to lymphatic contractions. The mean pressures increased as outflow pressures were raised. While mean pressures were highest at the outflow end, estimates of the net pressure generated by each segment suggested that all segments, including those at the most upstream locations, increased their contractile activity. In addition, diastolic pressure gradients formed across the system. These did not appear to be due to valve failure (endurance limit of valves was 168 +/- 32 cm H2O) but rather, appeared to relate to the progressive inability of lymphangions to empty which, for a given lymphangion, began to occur at a mean outflow pressure of 9.8 +/- 1.1 cm H2O.

Pressure-flow relationships in isolated sheep prenodal lymphatic vessels.

The objective of this study was to determine how isolated sheep prenodal popliteal lymphatic vessels responded to transmural and outflow pressure changes. Afferent lymphatics (0.5-1.0 mm diameter) were suspended in an organ bath with both inflow and outflow ends cannulated. Input to the duct was provided from a reservoir filled with Krebs solution. Two types of experiments were performed. In one group, a transmural pressure was applied to the ducts. In a second group of studies, the inflow pressure was fixed (at 2, 4, or 6 cmH2O) and the outflow pressure was increased in 4-cmH2O increments. The transmural pressure-flow relationship was expressed as a bell-shaped curve with pumping increasing up to 18-26 cmH2O and declining at higher pressures. Maximum flow rates averaged 1.4 +/- 0.6 ml/10 min. Greater than 50% of maximum pumping activity was available between approximately 12 and 43 cmH2O. In response to outflow pressures, variable responses were observed. In some vessels, elevations of outflow pressure had little impact on flow rates, until high outflow pressures were attained. In other ducts, pumping declined in response to outflow pressure challenge. With lower inflow pressures (2 or 4 cmH2O), flow rates occasionally increased with elevations of the outflow catheter. In ducts preset with inflow pressures of 6 cmH2O, the mean stop-flow pressure was 60 +/- 4.6 cmH2O. In comparison with previously published data on the pressure-flow relationships in postnodal lymphatics, prenodal vessels pumped over a larger range of transmural or outflow pressures.

Effect of outflow pressure on lymphatic pumping in vitro.

The objective of this study was to determine how lymphatic vessels responded to outflow pressure changes in vitro. Bovine mesenteric lymphatics were suspended in an organ bath preparation with both inflow and outflow ends cannulated. Input to the duct was provided from a reservoir filled with Krebs solution. To initiate pumping, a transmural pressure was applied to the ducts by elevating the fluid reservoir and outflow catheters and making their heights equal to one another. The outflow catheter was then elevated above the liquid in the reservoir in 2-cmH2O increments, and pumping activity was monitored for 10 min at each outflow pressure. Outflow pressures were calculated as the product of the flow rate and outflow cannula resistance plus the height of the tip of the outflow catheter above the liquid in the organ bath. At low transmural pressures (2-4 cmH2O), elevations in outflow pressure often had little effect on flow rates until high outflow pressures had been attained. In contrast, elevations in outflow pressures resulted in an increasingly rapid decline in flow rates as transmural pressures were incrementally increased. The mean power (in mu W) required to produce the observed flow rate was estimated at each outflow pressure as the product of the flow rate and the pressure across the lymphatic vessel. The ability of the lymphatics to generate sustained or enhanced power output in response to an increasing outflow pressure challenge was most pronounced at lower transmural pressures. As transmural pressures were increased, the range of outflow pressures that stimulated increased power production was diminished. We conclude that elevations in outflow pressure in an in vitro preparation result in a nonlinear decline in flow rates. This nonlinearity is due to an active lymphatic pump mechanism.

Role of endothelial cells in regulating hemoglobin-induced changes in lymphatic pumping.

Studies with a sheep isolated duct preparation in vivo demonstrated that the route of administration of hemoglobin was important in demonstrating its inhibitory effect on lymphatic pumping. With autologous oxyhemoglobin administered intravenously (final plasma concentration 5 x 10(-5) M), pumping was not inhibited. However, the addition of oxyhemoglobin (5 x 10(-5) M) into the reservoir (lumen of the duct) resulted in > 95% inhibition of pumping. The extraluminal administration of oxyhemoglobin (10(-5) M) to bovine mesenteric lymphatics in vitro resulted in a 40% inhibition of pumping, whereas the introduction of oxyhemoglobin (10(-5) M) into the lumen of the vessels suppressed pumping 95%. In vessels mechanically denuded of endothelium, intraluminal oxyhemoglobin inhibited pumping 50%. These results suggested that oxyhemoglobin depressed pumping through an effect on both smooth muscle and endothelium. Once pumping was inhibited with oxyhemoglobin administration, stimulation of the duct with elevations in transmural pressure restored pumping activity when endothelial cells were present. However, in the absence of endothelium, pumping decreased with increases in distending pressures. We conclude that oxyhemoglobin has a direct inhibitory effect on lymphatic smooth muscle. The ability of oxyhemoglobin to alter the pressure range over which the lymph pump operates appears to be dependent on an intact endothelium.

[Why is the Doppler pressure gradient higher than the one measured by catheter?]. / Miért nagyobb a Doppler-módszerrel meghatározott nyomásgradiens a katéterrel mérhetö értéknél?

Hemodynamic assessment of aorto-iliac occlusive disease is necessary for successful arterial reconstruction of the legs. Various methods have been proposed and the "pull-through" intra-arterial pressure measurement method is accepted as the best standard. The pressure readings, however, seemed to depend on the intraluminal position of the catheter. To explain these observations and make a comparison between the Doppler method and the "pull-through" method, we have studied center-line velocity changes at the stenosis throat by Doppler ultrasound, and axial and lateral pressure gradients using pressure transducers, mounted 10 mm and 40 mm downstream of short (4 mm) and long (40 mm) axisymmetric sharp-edged model stenoses having cross sectional reduced areas of 64%, 84%, 91%, and 96%. Axial manometric pressures measured 10 mm after the throat of 84% stenosis were more than twice as high as the lateral pressures. There was no significant difference between axial and lateral pressures measured 40 mm downstream from throat. This pressure distribution has important clinical relevance. Mean and peak pressure gradients for both the Doppler method and manometric measurements were compared. Measurements with Doppler method and manometric measurements, indicated that mean pressure gradients (r = 0.98; SEE = +/- -2.4 mmHg) correlate better than peak pressure gradients (r = 0.90; SEE = +/- 16.5 mmHg). Doppler gradients were higher than manometer gradients. Overestimation was 13% for mean pressure gradients, and ranging from 10% to 150% for peak pressure gradients. Explanation for the difference between mean Doppler and catheter gradient may be the pressure recovery occurring in the relaminarized poststenotic regions.

Validation of Doppler measurement of pressure gradients across peripheral model arterial stenosis.

Hemodynamic assessment of aortoiliac occlusive disease is necessary for successful arterial reconstruction of the legs. Various methods have been proposed, and the "pull through" intraarterial pressure measurement method is accepted as the best standard. The pressure readings, however, seemed to depend on the intraluminal position of the catheter. To explain these observations and make a comparison between the Doppler method and the pull through method, we have studied centerline velocity changes at the stenosis throat by Doppler ultrasonography, and axial and lateral pressure gradients by use of pressure transducers mounted 10 mm and 40 mm downstream of short (4 mm) axisymmetric sharp-edged model stenoses having cross-sectional reduced areas of 64%, 84%, 91%, and 96%. Axial manometric pressures measured 10 mm beyond the throat of 84% stenosis were more than twice as high as the lateral pressures. No significant difference was observed between axial and lateral pressures measured 40 mm downstream from the throat. This pressure distribution has important clinical relevance. Mean and peak pressure gradients for both the Doppler method and manometric measurements were compared. Measurements with Doppler method and manometric measurements indicated that mean pressure gradients (r = 0.98; SEE = +/- 2.4 mm Hg) correlate better than peak pressure gradients (r = 0.90; SEE = +/- 16.5 mm Hg). Doppler gradients were higher than manometer gradients. Overestimation was 13% for mean pressure gradients and ranged from 10% to 150% for peak pressure gradients. Explanation for the difference between mean Doppler and catheter gradient may be the pressure recovery occurring in the relaminarized poststenotic regions.

Lymphatic pumping in response to changes in transmural pressure is modulated by erythrolysate/hemoglobin.

Red blood cells and lysate products (erythrolysate) are observed consistently in lymph draining acute and chronic inflammatory reactions and from tissues subjected to trauma or surgical procedures. Using hemoglobin as a marker for erythrolysate, we have measured hemoglobin in lymph up to the 10(-6) M range in a number of pathophysiological states. Data demonstrate that erythrolysate alters the pumping characteristics of lymphatic vessels. To test the effects of erythrolysate on lymphatic pumping, bovine lymphatics were suspended in an organ bath preparation with the vessels cannulated at both inflow and outflow ends. By raising the heights of the Krebs reservoir and the outflow catheters appropriately, a transmural pressure that stimulated pumping activity could be applied to the vessels. With a fixed transmural pressure of 6 cm H2O applied to the ducts, sheep erythrolysate depressed pumping activity between 40% and 100%, with dilutions containing between 10(-8) and 10(-5) M hemoglobin. Although the active principle in the red blood cells has not been characterized, evidence from precipitation purification experiments suggests that hemoglobin is an important component. Once suppressed, pumping could be restored in many but not all vessels (often to control levels) by elevating the distending pressure above 6 cm H2O. The relation between transmural pressure and fluid pumping is expressed as a bell-shaped curve, with pumping increasing up to a peak pressure (usually 8 cm H2O) and declining at pressures above this level. By comparing pressure/flow curves, we were able to ascertain that hemoglobin shifted the lymphatic function curve to the right and, on average, reduced the maximum pumping capability of the vessels. We speculate that the presence of erythrolysate/hemoglobin in lymph may modulate the ability of lymphatic vessels to drain liquid and protein from the tissue spaces.