Unresolved early post-operative pain trajectory predicts moderate-to-severe persistent pain after breast cancer surgery-An observational cohort study.

BACKGROUND: Modelling acute post-operative pain trajectories may improve the prediction of persistent pain after breast cancer surgery (PPBCS). This study aimed to investigate the predictive accuracy of early post-operative pain (EPOP) trajectories in the development of PPBCS. MATERIALS & METHODS: This observational study was conducted in a French Comprehensive Cancer Centre and included patients who underwent breast cancer surgery from December 2017 to November 2018. Perioperative and follow-up data were obtained from medical records, and anaesthesia and perioperative charts. EPOP was defined as pain intensity during the first 24 h after surgery, and modelled by a pain trajectory. K-means clustering method was used to identify patient subgroups with similar EPOP trajectories. The prevalence of moderate-to-severe PPBCS (numeric rating scale ≥4) was evaluated until 24 months after surgery. RESULTS: A total of 608 patients were included in the study, of which 18% (n = 108) and 9% (n = 52) reported mild and moderate-to-severe PPBCS, respectively. Based on EPOP trajectories, we were able to identify a low (64%, n = 388), resolved (30%, n = 182), and unresolved (6%, n = 38) pain group. Multivariate analysis identified younger age, axillary lymph node dissection, and unresolved EPOP trajectory as independent risk factors for moderate-to-severe PPBCS development. When compared to patients reporting mild PPBCS, moderate-to-severe PPBCS patients experienced significantly more neuropathic pain features, pain-related interference, and delayed opioid cessation. CONCLUSION: EPOP trajectories can distinguish between resolved and unresolved acute pain after breast cancer surgery, allowing early identification of patients at risk to develop significant PPBCS.

First Evaluation Switching From Ropivacaine to Highly Concentrated Bupivacaine in Intrathecal Mixtures for Cancer Pain.

BACKGROUND: Intrathecal drug delivery is widely used for intractable cancer pain treatment. A combination of drugs with morphine and bupivacaine is recommended in first line therapy. In France, we use ropivacaine 10 mg/mL instead of bupivacaine 5 mg/mL, the only concentration available. Bupivacaine 40 mg/mL has been available in France only since July 2020 under temporary authorization of use. OBJECTIVES: The main objective of the study was to evaluate the safety, efficacy by pain assessment, to analyze drug dosage changes, to report adverse events (AEs) and conversion ratios switching from ropivacaine to bupivacaine. Secondary objective was to evaluate costs differences. MATERIALS AND METHODS: We conducted this retrospective follow-up monocentric study within the Institut de Cancérologie de l'Ouest (ICO) Pain Department in Angers, France. We included 14 patients aged 18 years and above, implanted with an Intrathecal Drug Delivery Systems (IDDS) for cancer pain treatment and followed up at ICO from July 2020 to February 2021 after switching from ropivacaine to bupivacaine. We used a continuous infusion mode and Bolus could be added through Personal Therapy Manager (PTM). RESULTS: The median conversion ratio between ropivacaine and bupivacaine was 0.68 (0.65; 0.69) and resulted in no significant change in numeric rating scale evaluation (p = 0.10). We observed moderate and rapidly reversible AEs such as clinical hypotension (29%) and motor block after bolus (21%). The estimated median hospital cost per day was significantly lower (p = 0.05) for the bupivacaine refills than for the last ropivacaine pump refill, decreasing from US$ 61.7 (49.6; 70.5) to US$ 50.4 (45.9; 60.4). The median reimbursement per day from the National Health Insurance (NHI) was three times lower for bupivacaine pump refill when compared to the last ropivacaine pump refill (p < 0.01), decreasing from US$ 179.10 (156.79; 182.91) to US$ 64.59 (59.85; 71.89). CONCLUSION: Switching from ropivacaine to bupivacaine in IDDS appears more efficacious while remaining just as secure, and at lower cost.

Preventing Post Dural Puncture Headache after Intrathecal Drug Delivery System Implantation Through Preventive Fibrin Glue Application: A Retrospective Study.

BACKGROUND: Cerebrospinal fluid (CSF) leakage resulting in post dural puncture headache (PDPH) is a frequent adverse effect observed after intrathecal drug delivery system (IDDS) implantation. CSF leakage symptoms negatively affect patient quality of life and can result in additional complications. Fibrin glue was used to treat CSF leakage syndrome. We developed a procedure to reduce the incidence of PDPH by preventing CSF leakage with the use of fibrin glue during surgery. OBJECTIVES: The main outcome criterion for this study was the incidence of PDPH syndrome after IDDS implantation with or without preventive fibrin glue application during the procedure. STUDY DESIGN: We designed a monocentric retrospective cohort study to compare the incidence of PDPH due to CSF leakage syndrome after lumbar puncture in patients with an implanted intrathecal pump, with or without preventive fibrin glue application during the procedure. SETTING: The study was held in the Anesthesiology and Pain department of the  Integrative Cancer Institute (ICO), Angers - France. METHODS: The study compared 2 patient cohorts over 2 successive periods. Fibrin glue was injected into the introducer needle puncture pathway after placement of the catheter immediately following needle removal. RESULTS: The no-glue group included 107 patients, whereas the glue group included 92 patients.Two application failures were observed (2.04%). Fibrin glue application results in a significant decrease in PDPH incidence, from 32.7% in the no-glue group to 10.92 % (P < 0.001) in the glue group. In regard to severity, in the no-glue group, 37.1% of PDPH syndromes were mild, 34.3% were moderate, and 28.6% were severe. In the fibrin glue group, 80% of PDPH syndromes were mild, and 20% were moderate. No severe PDPHs were reported after fibrin glue application. Duration of symptoms was also statistically shorter in the fibrin glue group (maximum of 3 days vs. 15 days in the no-glue group). In a univariate analysis, preventive fibrin glue application and age are significant to prevent PDPH. In multivariate analysis, only fibrin glue application was statistically significant (odds ratio, 0.26; P = 0.0008). No adverse effects linked to fibrin glue were observed. LIMITATIONS: The main limitation of this study is its retrospective nature. In addition, this study is from a single center with a potential selection bias and a center effect. CONCLUSIONS: The novel use of fibrin glue is promising in terms of its effect on PDPH and its safety profile. Its moderate cost and reproducibility make it an affordable and efficient technique.

Optimizing Initial Intrathecal Drug Ratio for Refractory Cancer-Related Pain for Early Pain Relief. A Retrospective Monocentric Study.

OBJECTIVE: Intrathecal (IT) drug delivery has shown its efficiency in treating refractory cancer pain, but switching opioids from the systemic to the intrathecal route is a challenging phase. Moreover, associations are widely used and recommended. Few data deal with the initial dosage of each drug. Analyzing conversion factors and initial dosages used in intrathecal therapy seems essential to decreasing the length of titration and to delivering quick pain relief to patients. METHODS: We retrospectively analyzed data from consecutive adult patients implanted with an intrathecal device for cancer pain and treated at the Institut de Cancérologie de l'Ouest, in Angers, France, for four years. The main goal was to identify factors associated with early pain relief after intrathecal drug delivery system (IDDS) implantation. RESULTS: Of the 220 IDDS-treated patients, 70 (32%) experienced early pain relief (EaPR) and 150 (68%) delayed pain relief (DePR). Performance Status stage and initial IT ropivacaine:IT morphine ratio were the variables independently associated with EaPR. The best IT ropivacaine:IT morphine ratio to predict EaPR was 5:1, with a 73% (95% confidence interval [CI] = 64.8% to 79.6%) sensitivity and a 67.1% (95% CI = 54.9% to 77.9%) specificity. EaPR subjects experienced better pain relief (-84% vs -60% from baseline pain score, P < 0.0001), shorter length of hospitalization (7 vs 10 days, P < 0.0001), and longer survival (155 vs 82 days, P = 0.004). CONCLUSIONS: Local anesthetic:morphine ratio should be considered when starting IDDS treatment. EaPR during the IT analgesia titration phase was associated with better pain relief and outcomes in patients with refractory cancer-related pain.

Intrathecal Drug Delivery Systems for Refractory Pancreatic Cancer Pain: Observational Follow-up Study Over an 11-Year Period in a Comprehensive Cancer Center.

BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer-related death in Europe and the United States. Studies have demonstrated that patients with pancreatic cancer have a high prevalence of pain, with rates varying from 47% to 82%. Analgesia using intrathecal drug delivery systems (IDDS) has been poorly studied specifically in this population. METHODS: The IDDS for pancreatic cancer pain was a follow-up observational study designed to evaluate 11-year results of IDDS for refractory pancreatic cancer pain at the Institut de Cancérologie de L'Ouest, Paul Papin in France. Patients were followed from March 2006 to April 2017. Patients were selected for IDDS based on multidisciplinary meeting discussion. All IDDS-treated patients were prescribed a combined intrathecal analgesics regimen through a catheter placed according to painful metameric level. Postimplant assessment of pain was determined using a numerical rating scale (NRS). Patients were followed via day-hospital visits and telephone calls at least monthly until death. Pain scores were compared using the Wilcoxon signed rank test. Overall survival (OS) was estimated using the Kaplan-Meier method and compared between groups by log rank tests. RESULTS: Ninety-three patients received IDDS, and total therapy duration accounts for 10,300 IDDS days. Implanted patients suffered from severe pain before implantation (median presurgical NRS, 8 [interquartile range, 7-9]) despite a median 360 mg (260-600) oral morphine equivalent daily dose. Median OS in the whole cohort after intrathecal treatment start was 82 days (95% confidence interval, 59-95). Median OS after surgery for implantable pump was 91 days (83-111) and for external pump 27 days (20-49; P < .0001). IDDS was associated with pain relief with a significant statistical difference between preimplantation NRS pain score and 1 week (median, -6 [-7 to -4]; P < .001), 1 month (median, -5 [-6 to -3]; P < .001), and 3 months (median, -6 [-7 to -4]; P < .001). Severe pain (NRS score, ≥7) decreased from 89.2% before surgery to 4.5% after 1 week, 6.7% after 1 month, and 10.3% after 3 months of IDDS implant (P < .01). Global complications rate was low, consistent with published literature. CONCLUSIONS: Despite our study's limitations, results suggest that long-term IDDS for refractory malignant pain due to pancreatic cancer was both efficacious and safe in pancreatic cancer pain. We have demonstrated, in the largest series of IDDS for pancreatic cancer pain reported yet, a clinically and statistically significant pain reduction in patients receiving IDDS.

Rationale for Prospective Assays of Intrathecal Mixtures Including Morphine, Ropivacaine and Ziconotide: Prevention of Adverse Events and Feasibility in Clinical Practice.

BACKGROUND: Use of intrathecal admixtures is widespread, but compounding these is sometimes challenging and may result in errors and complications causing super-potency or sub potency adverse events in patients or malfunctions in the pump itself. OBJECTIVE: The purpose of this study is to evaluate the accuracy of compounding of intrathecal admixtures through a prospective, systematic quantitative analysis of each component of the mixture before delivery to patients. STUDY DESIGN: Observational follow up prospective study of intrathecal mixtures components concentrations before refills. SETTINGS: Assays were performed on all intrathecal admixtures produced by the ICO-Paul Papin compounding pharmacy between January 2013 and October 2014 using Ultra High Performance Liquid Chromatography (U.H.P.L.C.). In addition, pH levels of admixtures have been measured since June 2014. When measured concentrations were 15% above or below the required concentrations, the mixture was excluded and compounded again. RESULTS: 1729 mixtures were analyzed. Mean deviation from theoretical values was -1.17% ± 0.28% for morphine, -0.95% ± 1.07% for ropivacaine, and 4.82% ± 0.6% for ziconotide. Exclusion rates were 8.33% overall, but fell from 11.67% in 2013 to 4.97% in 2014. Most exclusions were caused by inaccuracy in the dose of ziconotide. Average mixture pH of the 603 tested admixtures was 4.83 ± 0.6%. LIMITATIONS: This study is monocentric and limitations include also its non-randomized nature with no clinical comparison of the rate of adverse events with a refill process without control of each component concentrations. CONCLUSION: Prospective assays provide benefits in ensuring accuracy of intrathecal mixture compounding and in preventing overdosing or sub dosing, most notably concerning Ziconotide.

Ziconotide adverse events in patients with cancer pain: a multicenter observational study of a slow titration, multidrug protocol.

BACKGROUND: Ziconotide is a new analgesic agent administered intrathecally. It is challenging to use and can induce several and sometimes serious adverse events. A low initial dosage followed by slow titration may reduce serious adverse events. OBJECTIVE: To determine whether a low starting dosage of ziconotide, followed by slow titration, decreases the incidence of major adverse events associated with ziconotide when used for intractable cancer pain. STUDY DESIGN: Observational cohort study. SETTING: Three French cancer centers. METHODS: Patients with incurable cancer causing chronic pain rated above 6/10 on a numerical scale while receiving high-dose opioid therapy (more than 200 mg/d of oral morphine equivalent) and/or exhibiting severe opioid-related adverse events received intrathecal infusions of ziconotide combined with morphine, ropivacaine, and clonidine. RESULTS: Seventy-seven patients were included. Adverse events were recorded in 57% of them; moderate adverse events occurred in 51%. Adverse events required treatment discontinuation in 7 (9%) including 5 (6%) for whom a causal role for ziconotide was highly likely; among them 4 (5%) were serious. All patients experienced a significant and lasting decrease in pain intensity (by 48%) in response to intrathecal analgesic therapy that included ziconotide. LIMITATIONS: Limitations include the nonrandomized, observational nature of the study. Determining the relative contributions of each drug to adverse events was difficult, and some of the adverse events manifested as clinical symptoms of a subjective nature. CONCLUSIONS: The rates of minor and moderate adverse events were consistent with previous reports. However, the rate of serious adverse events was substantially lower. Our study confirms the efficacy of intrathecal analgesia with ziconotide for relieving refractory cancer pain. These results indicate that multimodal intrathecal analgesia in patients with cancer pain should include ziconotide from the outset in order to provide time for subsequent slow titration.