Stability of sufentanil and baclofen mixtures for intrathecal analgesia at different concentrations in polypropylene syringes.

BACKGROUND: Intrathecal analgesia is a method using various molecules alone or in combination. Among these, the association sufentanil/ baclofen is widely used. Instead of moving patients to the few expert centers taking charge of these specific preparations, it could be better to transport syringes to peripheral centers managing pump refilling. That is why, it is interesting to demonstrate the stability of the mixture, and so to be able to ensure the best transport conditions of syringes. METHODS: A stability indicating UPLC-DAD method was developed and validated according to the ICH guidelines. Four mixtures of sufentanil baclofen stored in 5±3°C and 25±2°C were evaluated for seven days and compared to the initial observed concentrations. RESULTS: The stability is demonstrated only for preparations stored at 5±3°C for seven days thanks to relative concentrations (95% confidence intervals of the mean of 3 samples) systematically positioned between 90% and 110%. On the other hand, after few days, degradation products of sufentanil appeared for all mixtures stored at 25°C±2°C. CONCLUSION: This study shows the stability of a weakly and a highly concentrated mixture of sufentanil and baclofen solutions in polypropylene syringes stored at 5±3°C for seven days. This result will allow the transport of the preparation under optimal conditions. Advance preparations for intrathecal pump refills could also be feasible.

Validated chromatographic method for the simultaneous determination of eight drugs (morphine, ropivacaine, bupivacaine, baclofen, clonidine, sufentanil, fentanyl and ziconotide) for intrathecal analgesia.

Intrathecal analgesia has increased over the past two decades in various indications: chronic refractory pain from cancerous or non-cancerous origins, spasticity. These different indications involve the use of different molecules alone or in combination such as morphine, ropivacaine, bupivacaine, fentanyl, sufentanil, clonidine, baclofen and ziconotide. Pump refills are prepared at the pharmacy under a laminar flow hood. An analytical control should be carried out before release of the preparation. A new method of analytical control by chromatography has been developed and validated according to the International Conference on Harmonization guideline in order to secure the production process.

A phase III randomized controlled study on the efficacy and improved bowel function of prolonged-release (PR) oxycodone-naloxone (up to 160/80 mg daily) vs oxycodone PR.

BACKGROUND: Oxycodone/naloxone (OXN PR) is a prolonged-release formulation containing oxycodone and naloxone in a 2:1 ratio. This study aimed to evaluate the tolerability and efficacy of doses up to OXN160/80 mg PR compared with oxycodone prolonged-release formulation (OxyPR) in a randomised controlled trial. METHODS: Two hundred and forty-three patients were randomised to treatment with OXN PR (n = 123) or OxyPR (n = 120) during the 5-week double-blind study. Measured were: opioid-induced constipation [bowel function index score (BFI)]; analgesic efficacy (NRS 0-10); daily laxative rescue medication use; rescue medication use, and the number of complete spontaneous bowel movements (CSBMs) per week. A subanalysis was conducted in cancer patients. RESULTS: Greater reductions in mean BFI scores were reported for the OXN PR group compared with OxyPR from Week 1 onwards; at Week 5 the mean change from baseline was -32.5 versus -14.2. Average 24-h pain scores were low and remained stable in the range 3-4 in both treatment groups. Analgesic rescue medication use was similar between the groups. Patients receiving OXN PR used significantly lower mean daily doses of laxative rescue medication than those receiving OxyPR (P = 0.006). The number of CSBM in the OXN PR group approximately doubled compared with a 25% decrease in the OxyPR group. Comparable results to the total study population were reported in the cancer patient subgroup. CONCLUSIONS: OXN PR in daily doses of up to 160/80 mg significantly improves bowel function compared with equivalent doses of OxyPR while still providing comparable analgesic efficacy. SIGNIFICANCE: Effective analgesia can be achieved using oxycodone/naloxone PR up to 160/80 mg daily without compromising bowel function. A similar outcome was reported in cancer and non-cancer patients.

Long-term efficacy and safety of oxycodone-naloxone prolonged-release formulation (up to 180/90 mg daily) - results of the open-label extension phase of a phase III multicenter, multiple-dose, randomized, controlled study.

BACKGROUND: The inclusion of naloxone with oxycodone in a fixed combination prolonged-release formulation (OXN PR) improves bowel function compared with oxycodone (Oxy) alone without compromising analgesic efficacy. In a recent 5-week, randomized, double-blind comparative trial of OXN PR and OxyPR, it could be shown that the beneficial properties of OXN PR extend to doses up to 160/80 mg. METHODS: Bowel function, pain, quality of life (QoL) and safety of OXN PR up to 180/90 mg daily were evaluated in a 24-week open-label extension phase of the 5-week randomized comparative study in patients with non-malignant or malignant pain requiring opioids and suffering from opioid-induced constipation. RESULTS: During treatment with a mean (SD) daily dose OXN PR of 130.7 (26.56) mg (median, maximum: 120 and 180 mg), the Bowel Function Index (BFI) decreased from 45.3 (26.37) to 26.7 (21.37) with the largest decrease seen in the first week. The average pain over the last 24 h remained stable (median Pain Intensity Scale score 4.0) and QoL was maintained throughout the study. Adverse events were consistent with the known effects of OXN PR and no new safety concerns emerged. Equivalent efficacy and safety benefits were observed in cancer patients. CONCLUSIONS: The OXN PR in doses up to 180/90 mg provides effective analgesia with maintenance of bowel function during long-term treatment. The beneficial effects of such dose levels of OXN PR contribute to stable patient-reported QoL and health status despite serious underlying pain conditions, such as cancer. SIGNIFICANCE: In patients with pain requiring continuous opioid therapy at doses above 80 mg of oxycodone, stable and effective long-term analgesia can be achieved using OXN PR up to 180/90 mg daily without compromising bowel function and may be preferential to supplemental oxycodone.

Curative cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis and synchronous resectable liver metastases arising from colorectal cancer.

OBJECTIVES: This study describes the outcomes of patients with colorectal peritoneal carcinomatosis (PC) with or without liver metastases (LMs) after curative surgery combined with hyperthermic intraperitoneal chemotherapy, in order to assess prognostic factors. BACKGROUND: Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) increases overall survival (OS) in patients with PC. The optimal treatment both for PC and for LMs within one surgical operation remains controversial. METHODS: Patients with PC who underwent CRS followed by HIPEC were evaluated from a prospective database. Overall survival and disease free survival (DFS) rates in patients with PC and with or without LMs were compared. Univariate and multivariate analyses were performed to evaluate predictive variables for survival. RESULTS: From 1999 to 2011, 22 patients with PC and synchronous LMs (PCLM group), were compared to 36 patients with PC alone (PC group). No significant difference was found between the two groups. The median OS were 36 months [range, 20-113] for the PCLM group and 25 months [14-82] for the PC group (p > 0.05) with 5-year OS rates of 38% and 40% respectively (p > 0.05). The median DFS were 9 months [9-20] and 11.8 months [6.5-23] respectively (p = 0.04). The grade III-IV morbidity and cytoreduction score (CCS) >0 (p < 0.05) were identified as independent factors for poor OS. Resections of LMs and CCS >0 impair significantly DFS. CONCLUSIONS: Synchronous complete CRS of PC and LMs from a colorectal origin plus HIPEC is a feasible therapeutic option. The improvement in OS is similar to that provided for patients with PC alone.

Hypersensitivity reactions to Patent Blue V in breast cancer surgery: a prospective multicentre study.

BACKGROUND: An increasing number of immediate hypersensitivity reactions (HSR) have been reported after the use of Patent Blue V (PBV) for breast cancer surgery. This is the first study to publish prospective data with systematic allergological assessment. METHODS: We conducted a multicentre study in 10 French cancer centres for over 6 months. All patients scheduled for breast surgery with injection of PBV were included in the study. Patients were screened for past medical history, atopy, and known food and drug allergies. When suspected HSR or unexplained reactions occurred after injection of PBV, blood samples were taken, and plasma histamine and serum tryptase concentrations were measured. HSR to PBV was suggested if skin tests performed 6 weeks later were positive. RESULTS: Nine suspected HSR to PBV were observed in 1742 patients. Skin tests were positive in six patients, giving an incidence of 0.34%. Four grade I and two grade III HSR were observed, both requiring intensive care unit treatment. Mean onset time of the reaction was 55 ± 37 min. Plasma histamine was elevated in four patients, while serum tryptase was normal. We found no risk factors associated with HSR to PBV. CONCLUSION: An incidence rate of one in 300 HSR to PBV was observed for patients exposed to PBV during sentinel lymph node detection. This rate is higher than rates reported after the use of neuromuscular blocking agents, latex or antibiotics.