Examination of psychological risk factors for chronic pain following cardiac surgery: protocol for a prospective observational study.

INTRODUCTION: Approximately 400 000 Americans and 36 000 Canadians undergo cardiac surgery annually, and up to 56% will develop chronic postsurgical pain (CPSP). The primary aim of this study is to explore the association of pain-related beliefs and gender-based pain expectations on the development of CPSP. Secondary goals are to: (A) explore risk factors for poor functional status and patient-level cost of illness from a societal perspective up to 12 months following cardiac surgery; and (B) determine the impact of CPSP on quality-adjusted life years (QALYs) borne by cardiac surgery, in addition to the incremental cost for one additional QALY gained, among those who develop CPSP compared with those who do not. METHODS AND ANALYSES: In this prospective cohort study, 1250 adults undergoing cardiac surgery, including coronary artery bypass grafting and open-heart procedures, will be recruited over a 3-year period. Putative risk factors for CPSP will be captured prior to surgery, at postoperative day 3 (in hospital) and day 30 (at home). Outcome data will be collected via telephone interview at 6-month and 12-month follow-up. We will employ generalised estimating equations to model the primary (CPSP) and secondary outcomes (function and cost) while adjusting for prespecified model covariates. QALYs will be estimated by converting data from the Short Form-12 (version 2) to a utility score. ETHICS AND DISSEMINATION: This protocol has been approved by the responsible bodies at each of the hospital sites, and study enrolment began May 2015. We will disseminate our results through CardiacPain.Net, a web-based knowledge dissemination platform, presentation at international conferences and publications in scientific journals. TRIAL REGISTRATION NUMBER: NCT01842568.

Combination of pregabalin with duloxetine for fibromyalgia: a randomized controlled trial.

Fibromyalgia is a syndrome characterized by chronic widespread pain and associated with sleep disturbance, depression, fatigue, and cognitive dysfunction. Polypharmacy is commonly used, but supportive evidence is limited. Most fibromyalgia trials focus primarily on pain reduction with monotherapy. This trial compares a pregabalin-duloxetine combination to each monotherapy. Using a randomized, double-blind, 4-period crossover design, participants received maximally tolerated doses of placebo, pregabalin, duloxetine, and pregabalin-duloxetine combination-for 6 weeks. Primary outcome was daily pain (0-10); secondary outcomes included global pain relief, Fibromyalgia Impact Questionnaire, SF-36 survey, Medical Outcomes Study Sleep Scale, Beck Depression Inventory (BDI-II), adverse events, and other measures. Of 41 participants randomized, 39 completed ≥2 treatments. Daily pain during placebo, pregabalin, duloxetine, and combination was 5.1, 5.0, 4.1, and 3.7, respectively (P < 0.05 only for combination vs placebo, and pregabalin). Participants (%) reporting ≥moderate global pain relief were 18%, 39%, 42%, and 68%, respectively (P < 0.05 for combination vs placebo, pregabalin, and duloxetine). Fibromyalgia Impact Questionnaire scores were 42.9, 37.4, 36.0, and 29.8, respectively (P < 0.05 for combination vs placebo, pregabalin, and duloxetine). SF-36 scores were 50.2, 55.7, 56.0, and 61.2, respectively (P < 0.05 for combination vs placebo, pregabalin, and duloxetine). Medical Outcomes Study Sleep Scale scores were 48.9, 35.2, 46.1, and 32.1, respectively (P < 0.05 only for combination vs placebo, and duloxetine). BDI-II scores were 11.9, 9.9, 10.7, and 8.9, respectively (P < 0.05 only for combination vs placebo). Moderate-severe drowsiness was more frequent during combination vs placebo. Combining pregabalin and duloxetine for fibromyalgia improves multiple clinical outcomes vs monotherapy. Continued research should compare this and other combinations to monotherapy for fibromyalgia.

Combination of morphine with nortriptyline for neuropathic pain.

First-line neuropathic pain drugs, including tricyclic antidepressants, are not always effective, and opioids have been recommended as second line. This trial evaluates a nortriptyline-morphine combination, compared with each monotherapy. In this randomized, double-blind crossover trial, patients with neuropathic pain were enrolled at 1 site between January 25, 2010, and May 22, 2014, and randomized in a 1:1:1 ratio using a balanced Latin square design to receive oral nortriptyline, morphine, and their combination. During each of three 6-week periods, doses were titrated toward maximal tolerated dose (MTD). The primary outcome was average daily pain at MTD, and secondary outcomes included other pain, mood and quality of life measures, and adverse effects. Sixty-two patients were screened, 52 enrolled, and 39 completed at least 2 treatment periods. Average daily pain (0-10) at baseline was 5.3 and at MTD was 2.6 for combination vs 3.1 for nortriptyline (P = 0.046) and 3.4 for morphine (P = 0.002). Brief Pain Inventory scores for average and present pain were also significantly lower for combination vs each monotherapy. Combination treatment resulted in moderate-severe constipation in 43% vs 46% with morphine (P = 0.82) and 5% with nortriptyline (P < 0.0001). Combination treatment resulted in moderate-severe dry mouth in 58% vs 49% with nortriptyline (P = 0.84) and 13% with morphine (P < 0.0001). This trial suggests superior efficacy of a nortriptyline-morphine combination over either monotherapy with constipation, dry mouth, and somnolence as the most frequent adverse effects.

The effect of triple vs. double nonopioid therapy on postoperative pain and functional outcome after abdominal hysterectomy: a randomised double-blind control trial.

BACKGROUND: Movement-evoked pain is more severe than pain at rest and is likely to interfere more with functional recovery after surgery. OBJECTIVE: To compare triple vs. double nonopioid perioperative analgesic regimens in women undergoing abdominal hysterectomy. DESIGN: A randomised, parallel design, double-blind controlled trial. SETTING: A single-centre trial. Study period from November 2009 to July 2013. PATIENTS: Adults (>18 years) of American Society of Anesthesiologists' status 1 to 2 scheduled for abdominal hysterectomy. INTERVENTIONS: Patients were randomised to one of four study treatment groups: acetaminophen, meloxicam and gabapentin (AMG); acetaminophen and meloxicam; acetaminophen and gabapentin; and meloxicam and gabapentin. In addition to intravenous patient-controlled opioid analgesia, study treatments were administered for 48 h, starting 1 h preoperatively. MAIN OUTCOME MEASURES: The primary outcome was cough-evoked pain. Secondary outcomes included pain at rest, during sitting and peak expiration, opioid consumption, side effects, peak expiratory flow rate, timed up and go test (TUG), and modified Brief Pain Inventory (mBPI). RESULTS: Interim analysis indicated a minimal chance of demonstrating superiority of the triple regimen group over all three double regimen groups if the trial were to be recruited to planned sample size. Thus, the trial was prematurely terminated for futility. All four analgesic regimens were well tolerated. Exploratory analyses revealed consistent significant negative correlations between pain and TUG and between pain and interference with activity, walking and sleep. CONCLUSION: This trial failed to demonstrate substantial benefits with the addition of a third nonopioid analgesic to three different double-drug regimens. Further research is needed that will more definitively support expanding multimodal analgesic practices. Our results demonstrate consistent correlations between evoked pain and functional outcomes further emphasising the need for improved analgesic regimens that will accelerate postsurgical functional recovery. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Register 12723675.

Cardiopulmonary bypass does not affect plasma concentration of preoperatively administered gabapentin.

PURPOSE: Drug effects can be unpredictable during cardiac surgery due to factors that may influence drug concentration, such as extracorporeal oxygenation and hemodilution. The primary aim of the current investigation was to determine whether plasma gabapentin concentration is altered by cardiopulmonary bypass (CPB). METHODS: Following approval from the Research Ethics Board and written informed consent, we conducted this open-label prospective cohort investigation. A convenience sample of 16 patients, who were scheduled for coronary bypass surgery, received oral gabapentin 600 mg as follows: 90 min prior to induction of anesthesia, following tracheal extubation, and then every eight hours for a total of four doses. Plasma gabapentin concentration, as well as pain and sedation scores, were documented. RESULTS: Plasma gabapentin concentrations were unaltered during CPB (31.9 +/- 12.7 mumol.L(-1) prior to CPB, 35.6 +/- 12.9 to 37.2 +/- 9.6 mumol.L(-1) during CPB). However, using the current protocol, drug accumulation (reflected by increased drug concentrations) was observed following the third (58.2 +/- 19.5 micromol.L(-1)) and the fourth (71.9 +/- 34.3 micromol.L(-1)) doses. Pain and sedation scores and opioid requirements were comparable with those found in other studies. CONCLUSION: Plasma gabapentin concentration is unaltered during CPB following preoperative administration. Drug accumulation following third and fourth postoperative doses suggests the need for therapeutic drug monitoring in future trials. Gabapentin is well established as an effective adjunct analgesic in a number of surgical settings. Randomized controlled trials are necessary to evaluate analgesic efficacy, optimal dosing, and adverse effects in the setting of cardiac surgery.