Elizabeth Orr

A placebo-controlled randomized clinical trial of perioperative administration of gabapentin, rofecoxib and their combination for spontaneous and movement-evoked pain after abdominal hysterectomy

&NA; Current treatments for post‐injury movement‐evoked pain are inadequate. Non‐opioids may complement opioids, which preferentially reduce spontaneous pain, but most have incomplete efficacy as single agents. This trial evaluates efficacy of a gabapentin–rofecoxib combination following hysterectomy. In addition to IV‐PCA morphine, 110 patients received either placebo, gabapentin (1800 mg/day), rofecoxib (50 mg/day) or a gabapentin–rofecoxib combination (1800/50 mg/day) starting 1 h pre‐operatively for 72 h. Outcomes included pain at rest, evoked by sitting, peak expiration and cough, morphine consumption and peak expiratory flow (PEF). For placebo, gabapentin, rofecoxib and combination, 24 h pain (100 mm VAS) was: at rest—23.6 (P<0.05 vs. all treatments), 13.8, 14.4 and 12.1; during cough—50.7 (P<0.05 vs. all treatments), 41.5, 44.8 and 30.8; 48 h morphine consumption (mg) was: 130.4 (P<0.05 vs. all treatments), 81.7, 75.6 and 57.2 (P<0.05 vs. gabapentin and rofecoxib) and 48 h PEF (% baseline) was: 63.9 (P<0.05 vs. all treatments), 77.2, 76.7 and 87.5 (P<0.05 vs. gabapentin and rofecoxib). Adverse effects were similar in all groups except sedation which was more frequent with gabapentin. Combination and rofecoxib reduced pain interference with movement, mood and sleep (P<0.05) and combination was superior to gabapentin for all these three (P<0.05). These data suggest that a gabapentin–rofecoxib combination is superior to either single agent for postoperative pain. Other benefits include opioid sparing, reduced interference with movement, mood and sleep and increased PEF suggesting accelerated pulmonary recovery. Future research should identify optimal dose‐ratios for this and other analgesic combinations.

A randomized, double-blind, controlled trial of perioperative administration of gabapentin, meloxicam and their combination for spontaneous and movement-evoked pain after ambulatory laparoscopic cholecystectomy.

BACKGROUND: Hysterectomy and spinal surgery inpatient trials suggest favorable interactions between cyclooxgenase-2 inhibitors and gabapentin/pregabalin on postoperative days 1–2. We present the first trial of meloxicam-gabapentin combination after outpatient laparoscopic cholecystectomy. METHODS: This was a randomized, double-blind trial comparing daily oral administration of 1) meloxicam 15 mg, 2) gabapentin 1200–1600 mg, and 3) a combination of the two starting 1 h before until 2 days after surgery. Primary outcomes included day of surgery spontaneous and movement-evoked pain. Secondary outcomes included pain on Days 1, 2, and 30, adverse effects, opioid consumption, spirometry, pain-related interference, hospital discharge time, return to work time, and patient satisfaction. RESULTS: On the day of surgery, 60-min rest pain (0–10 numerical rating scale ± sd) was significantly lower (P < 0.05) with gabapentin alone (2.0 ± 1.6) versus meloxicam alone (3.6 ± 2.1). Observed pain differences between the combination (2.9 ± 2.1) and gabapentin alone were fairly small in favor of gabapentin alone (P > 0.05). Secondary analyses indicated that nausea was significantly less frequent with the combination (24%) versus the single-drug meloxicam (57%) only. CONCLUSION: Although nausea was reduced with combination therapy, this trial provides little or no support for the combined use of meloxicam and gabapentin for pain relief on the day of surgery. This suggests that perioperative analgesic polypharmacy may not always be necessary or appropriate.

The relationship between movement-evoked versus spontaneous pain and peak expiratory flow after abdominal hysterectomy

The pathogenesis of postoperative lung dysfunction implies a role for movement-evoked pain (e.g., splinting/hypoventilation because of pain avoidance). However, interactions between evoked pain and respiratory physiology are poorly understood. Thus, we examined the relationship between evoked versus spontaneous pain and one index of pulmonary function. In 25 patients having undergone a hysterectomy, visual analog scale ratings (100 mm) for spontaneous pain (REST) and pain during sitting (SIT), forced expiration (BLOW), and coughing (COUGH) were measured together with peak expiratory flow (PEF) at eight time points during postoperative Days 1 and 2. Secondary outcome measures included oxygen saturation and oxygen requirements. Pain was significantly correlated with PEF for COUGH, SIT, BLOW, and REST at eight, seven, four, and two of the eight studied time points, respectively. Mean visual analog scale scores [se] for COUGH (26.1 mm [1.7]) and SIT (21.5 mm [1.5]) were greater (P < 0.05) than REST (10.5 mm [0.8]), and COUGH was greater (P < 0.05) than BLOW (16.8 mm [1.3]). All pain measures diminished (P < 0.05), and PEF reductions improved (P < 0.05) across the study period. We hypothesize that the consistent negative correlation of COUGH-evoked pain with PEF is, in part, caused by avoidance of coughing, which ultimately limits deep inspiration, lung reexpansion, and clearance of secretions.

Chronobiological characteristics of postoperative pain : diurnal variation of both static and dynamic pain and effects of analgesic therapy

BackgroundPrevious postoperative investigations report morning peaks in analgesic administration. However, few studies have examined diurnal variation of both pain and analgesic consumption and little is known about dynamic pain in this context.MethodsThe diurnal pattern of postoperative pain is described using pain intensity and analgesic consumption data from a recently published hysterectomy trial.ResultsIn the presence of patient-controlled analgesia with morphine, pain at 8 a.m. was significantly higher (P < 0.05) than at noon, 4 p.m. or 8 p.m. on postoperative day one (for rest pain and pain evoked by sitting, forced expiration and cough) and on postoperative day two (for pain evoked by forced expiration and cough only). This temporal pattern was observed both with and without the co-administration of non-opioid analgesics (gabapentin and/or rofecoxib). Morphine use during the four hours preceding 8 a.m. on either postoperative day was not significantly lower than any of the other corresponding time intervals.ConclusionsBased on data from our post-hysterectomy analgesic clinical trial, static and dynamic pain in the morning appears to be more intense than pain later in the day. This pattern was observed in the presence of substantial nocturnal morphine use. Based on these and other previous observations, specifically designed investigations are needed to better characterize the clinical, neurohormonal and neurophysiological features of postoperative circadian pain variation - including pain during sleeping hours. If the above observations are replicated, future study of nocturnal sustained-release opioids as well as time-shifting the administration of non-opioid co-analgesic drugs to the very early morning may be warranted.RésuméContexteDes recherches postopératoires précédentes ont rapporté des pics matinaux dans l’administration d’antalgiques. Toutefois, peu d’études ont examiné les variations diurnes de la douleur et de la consommation d’antalgiques, et nous ne disposons que de très peu d’éléments concernant la douleur dynamique dans ce contexte.MéthodeL’évolution diurne de la douleur postopératoire est décrite en se basant sur des données concernant l’intensité de la douleur et la consommation d’antalgiques tirées d’une étude sur l’hystérectomie publiée récemment.RésultatsLors d’une analgésie contrôlée par le patient avec de la morphine, la douleur à 8 h était significativement plus élevée (P < 0,05) qu’à midi, 16 h et 20 h le premier jour postopératoire (pour la douleur au repos et la douleur provoquée par la position assise, l’expiration forcée et la toux) et le deuxième jour postopératoire (pour la douleur provoquée par l’expiration forcée et la toux uniquement). Cette évolution temporelle a été observée avec et sans co-administration d’antalgiques non opioÏ des (gabapentine et/ou rofecoxib). L’utilisation de morphine durant les quatre heures précédant 8h le premier et le second jour postopératoire n’a pas été significativement plus basse qu’à aucun autre intervalle de temps correspondant.ConclusionSur la base de données tirées de notre étude clinique antalgique post-hystérectomie, les douleurs statique et dynamique semblent être plus intenses le matin que plus tard dans la journée. Cette évolution a été observée malgré une utilisation nocturne importante de morphine. En se basant sur ces observations ainsi que sur d’autres qui les ont précédées, des recherches spécifiquement conçues sont nécessaires pour mieux caractériser les aspects cliniques, neuro-hormonaux et neurophysiologiques de la variation circadienne des douleurs postopératoires, y compris la douleur pendant le sommeil. Sis observations ci-dessus sont réitérées, une future étude d’opioÏdes à libération nocturne soutenue ainsi que le décalage de l’administration d’agents co-antalgiques non opioÏdes au petit matin pourraient être recommandés.

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.

interactions Between Pulmonary Performance and Movement-evoked Pain in the Immediate Postsurgical Period : implications for Perioperative Research and Treatment

Background and Objectives: Previous data suggest that movement‐evoked pain is more closely correlated with pulmonary performance than rest pain beyond 24 hours following lower abdominal surgery. Because adverse alterations in lung physiology are initiated intraoperatively and impact upon pulmonary morbidity, this study tests the hypothesis that movement‐evoked pain correlates negatively with pulmonary performance in the immediate postoperative period. Methods: We measured pain at rest and pain evoked by sitting, forced expiration, and coughing as well as peak expiratory flow (PEF), forced expiratory volume in 1 second, and forced vital capacity for the first 3 hours after laparoscopic cholecystectomy in 65 patients. Results: Immediately after surgery, all pain measures were significantly correlated with PEF with a medium effect size. Also, sitting‐evoked pain and cough‐evoked pain were significantly more intense than rest pain. Pain intensity improved significantly over the first 3 postoperative hours. Conclusions: Considering these and previous results, pulmonary function tests such as PEF should be considered for more routine use as functional surrogates of movement‐evoked pain in analgesic trials of thoracic and abdominal surgery. Mechanisms of immediate postoperative movement‐evoked pain may differ from those in effect at later time points after which tissue inflammation and spinal sensitization develop. Because pain adversely impacts upon postoperative rehabilitation, these results further imply that aggressive treatment of movement‐evoked pain could improve the outcome of postoperative rehabilitation measures if both are implemented very early after surgery.

Intraperitoneal ketorolac for post-cholecystectomy pain: a double-blind randomized-controlled trial

PurposeKetorolac is a parenterally active nonsteroidal anti-inflammatory drug with localized anti-inflammatory properties. We examine the postoperative analgesic efficacy of locally administered intraperitoneal (IP) ketorolac compared with intravenous (IV) ketorolac during laparoscopic cholecystectomy.MethodsWith institutional ethics approval, 120 patients undergoing elective laparoscopic cholecystectomy were randomized to receive intraoperative 1) IP ketorolac 30 mg + intravenous saline (IP group), 2) intraperitoneal saline + IV ketorolac 30 mg (IV group), or 3) intraperitoneal saline + intravenous saline (Control group) under standardized anesthesia. The primary and secondary outcomes were postoperative fentanyl requirements in the postanesthesia care unit and the time to first analgesic request, respectively. Other outcomes examined included abdominal pain (at rest and with coughing), shoulder pain, nausea, vomiting, and any other postoperative complications.ResultsOn average, patients receiving IP ketorolac required less (mean difference, 29 μg; 95% confidence interval [CI], 2 to 56; P = 0.04) fentanyl than patients in the Control group but a similar (mean difference, 16 μg; 95% CI, 12 to 43; P = 0.27) amount compared to patients in the IV group. There was an increase in the median (interquartile range [IQR]) time to first request in the IP group (43[30-52] min) compared with the Control group (35 [27-49]min; P = 0.04) but no difference between the IP group compared with the IV group (47 [40-75] min; P = 0.22). Shoulder pain and resting pain were reduced with IP and IV ketorolac compared with Control, but there was no difference between the IP and IV groups. No differences were observed in any other outcomes, side effects, or complications attributable to opioids or ketorolac at any time points.ConclusionThis study did not demonstrate any advantage for the off-label topical intraperitoneal administration of ketorolac in this surgical population. Intraperitoneal and IV ketorolac showed comparable analgesic efficacy following laparoscopic cholecystectomy.RésuméObjectifLe kétorolac est un agent anti-inflammatoire non stéroïdien à action parentérale et possédant des propriétés anti-inflammatoires localisées. Nous avons examiné l’efficacité analgésique postopératoire d’une administration intra-péritonéale (IP) locale de kétorolac par rapport à une administration intraveineuse (IV) pendant une cholécystectomie par laparoscopie.MéthodeAprès avoir obtenu le consentement du Comité d’éthique de notre institution, 120 patients subissant une cholécystectomie par laparoscopie non urgente ont été randomisés à recevoir en peropératoire l’un des trois traitements suivants: 1) 30 mg de kétorolac IP + une solution saline intraveineuse ip (groupe IP); 2) une solution saline intra-péritonéale + 30 mg de kétorolac IV iv (groupe IV); ou 3) une solution saline intra-péritonéale + une solution saline intraveineuse (groupe témoin) sous anesthésie standardisée. Les critères d’évaluation primaire et secondaire étaient les besoins postopératoires en fentanyl en salle de réveil et le délai jusqu’à la première demande d’analgésie, respectivement. Les autres critères d’évaluation ont examiné la douleur abdominale (au repos et en toussant), la douleur aux épaules, les nausées, les vomissements et toutes les autres complications postopératoires.RésultatsEn moyenne, les patients ayant reçu du kétorolac IP ont eu besoin de moins de fentanyl (différence moyenne, 29 μg; intervalle de confiance [IC] 95 %, 2 à 56; P = 0,04) que les patients du groupe témoin, mais une quantité semblable (différence moyenne, 16 µg; IC 95 %, 12 à 43; P = 0,27) à ceux du groupe IV. Nous avons observé une augmentation du temps moyen (écart interquartile [ÉIQ]) jusqu’à la première demande dans le groupe IP (43[30-52] min) par rapport au groupe témoin (35 [27-49] min; P = 0,04), mais aucune différence entre le groupe IP et le groupe IV (47 [40-75] min; P = 0,22). La douleur aux épaules et la douleur au repos étaient moindres dans les groupes kétorolac IP et IV par rapport au groupe témoin, mais aucune différence n’a été observée entre les groupes IP et IV. Aucune différence n’a été observée en ce qui touchait à nos autres critères, aux effets secondaires ou aux complications attribuables aux opioïdes ou au kétorolac et ce, à n’importe quel moment de notre analyse.ConclusionCette étude n’a pas démontré d’avantage à une administration intra-péritonéale topique non conforme de kétorolac dans cette population chirurgicale. Le kétorolac en administration intra-péritonéale et IV a montré une efficacité analgésique comparable après une cholécystectomie par laparoscopie.