Efficacy of a propofol bolus against placebo to prevent cough at emergence from general anesthesia with desflurane: a randomized controlled trial.

PURPOSE: Emergence from anesthesia is a critical period and cough can result in adverse effects. Propofol inhibits airway reflexes and when infused it reduces cough more than inhalation anesthesia does. We evaluated the effect of a propofol bolus given at emergence on the incidence of coughing following a desflurane-based anesthesia. METHODS: One hundred and fifty-four patients scheduled for elective surgery were prospectively randomized to propofol (0.5 mg·kg-1) or normal saline (NS) administered at the end of the surgery at 1 minimum alveolar concentration (MAC) of desflurane. A "no touch" emergence technique was used until extubation. The primary outcome was the incidence of cough at the discontinuation of desflurane (T0) and reaching a MAC adjusted for age (MACage) of 0.15. Secondary outcomes included incidence and severity of cough until five minutes postextubation (T0-T5), time to extubation, nausea and vomiting, sedation, hemodynamic variations, postoperative hypoventilation, hypoxemia, and sore throat. RESULTS: We could not draw inferences on the incidence of cough between T0 and MACage of 0.15 because only 27/68 (40%) patients in the NS group and 13/73 (18%) patients in the propofol group regained consciousness before reaching a MACage of 0.15. There were no significant differences between the groups in coughing incidence and severity between T0 and T5 (NS group, 57/68 [84%] vs propofol group, 70/73 [96%] ). The mean time to extubation in the propofol group was prolonged by 3 min 27 sec (95% confidence interval, 1 min 7 sec to 4 min 47 sec; P < 0.001) and more vasopressors were used at emergence (P = 0.02). The incidence of respiratory complications, nausea and vomiting, agitation, and sedation were not different between groups. CONCLUSION: In the present trial, a propofol bolus administered at emergence did not reduce the incidence of cough occurring between T0 and T5 following a desflurane-based general anesthesia compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02932397); registered 13 October 2016.

RéSUMé: OBJECTIF: L'émergence de l'anesthésie est une période critique et la toux peut entraîner des effets indésirables. Le propofol inhibe les réflexes des voies aériennes et, lorsqu'il est perfusé, il est plus efficace pour réduire la toux que l'anesthésie inhalée. Nous avons évalué l'effet d'un bolus de propofol administré à l'émergence sur l'incidence de toux après une anesthésie à base de desflurane. MéTHODE: Cent cinquante-quatre patients devant bénéficier d'une chirurgie non urgente ont été randomisés prospectivement à recevoir du propofol (0,5 mg·kg−1) ou une solution physiologique de sérum salé (NS) administrée à la fin de la chirurgie lorsque la concentration alvéolaire minimale (MAC) de desflurane était de 1. Une technique d'émergence « sans contact ¼ a été utilisée jusqu'à l'extubation. Le critère d'évaluation principal était l'incidence de toux à l'arrêt du desflurane (T0) et à l'atteinte d'une MAC ajustée en fonction de l'âge (MACâge) de 0,15. Les critères d'évaluation secondaires comprenaient l'incidence et la gravité de la toux jusqu'à cinq minutes après l'extubation (T0-T5), le délai d'extubation, les nausées et vomissements, la sédation, les variations hémodynamiques, l'hypoventilation postopératoire, l'hypoxémie et les maux de gorge. RéSULTATS: Nous n'avons pas pu tirer de conclusions sur l'incidence de toux entre T0 et à une MACâge de 0,15 parce que seulement 27/68 (40 %) patients du groupe NS et 13/73 (18 %) patients du groupe propofol ont repris conscience avant d'atteindre une MACâge de 0,15. Il n'y avait aucune différence significative entre les groupes dans l'incidence et la gravité de la toux entre T0 et T5 (groupe NS, 57/68 [84 %] vs groupe propofol, 70/73 [96 %]). Le temps moyen d'extubation dans le groupe propofol a été prolongé de 3 min 27 sec (intervalle de confiance à 95 %, 1 min 7 sec à 4 min 47 sec; P < 0,001) et une plus grande quantité de vasopresseurs a été utilisée à l'émergence (P = 0,02). L'incidence de complications respiratoires, de nausées et vomissements, d'agitation, et de sédation n'était pas différente entre les groupes. CONCLUSION: Dans la présente étude, un bolus de propofol administré à l'émergence n'a pas réduit l'incidence de toux survenant entre T0 et T5 après une anesthésie générale à base de desflurane par rapport au placebo. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT02932397); enregistrée le 13 octobre 2016.

The Quebec Cannabis Registry: Investigating the Safety and Effectiveness of Medical Cannabis.

Objective: To investigate the safety and effectiveness of medical cannabis (MC) in the real-world clinical practice setting. Design: A 4-year prospective noncomparative registry of adult patients who initiated MC for a variety of indications. This paper reports on patients followed for up to 12 months, with interim visits at 3, 6, and 9 months after enrollment. Setting: Public or private outpatient clinics certified to authorize MC in the province of Quebec, Canada. Participants: Overall, 2991 adult (age ≥18 years) patients (mean age 51 years; 50.2% women) were enrolled between May 2015 and October 2018, with the last follow-up ending in May 2019. Interventions/Exposures: Cannabis products (dried, oil, or other) purchased from a Canadian licensed cannabis producer as authorized by physicians. Main Outcome Measures: The primary outcomes were self-reported pain severity, interference and relief (Brief Pain Inventory [BPI]), symptoms using the Revised Edmonton Symptom Assessment System (ESAS-r) and health-related quality of life dimensions (EQ-5D-5L) at baseline and each follow-up visit. The secondary outcomes were self-reported adverse events (AEs) and characteristics of cannabis treatment. Results: All patient-reported outcomes (BPI, ESAS-r, and EQ-5D-5L) showed a statistically significant improvement at 3 months (all p<0.01), which was maintained or further improved (for pain interference, tiredness, and well-being) over the remainder of the 12-month follow-up. Results also revealed clinically significant improvements in pain interference and tiredness, anxiety, and well-being from baseline. There were 79 AE reports (77 patients), 16 met the regulatory definition of seriousness, in which only 8 AEs were certainly or probably related to MC. Conclusions: MC directed by physicians appears to be safe and effective within 3 months of initiation for a variety of medical indications.

Predictors of Pain Reduction Among Fibromyalgia Patients Using Medical Cannabis: A Long-Term Prospective Cohort Study.

OBJECTIVE: Many patients with fibromyalgia (FM) report using cannabis as a strategy to improve pain. Given that pain often co-occurs with symptoms of anxiety and depression (i.e., negative affect) and sleep problems among patients with FM, improvements in these symptoms might indirectly contribute to reductions in pain intensity following cannabis use. The main objective of the study was to examine whether changes in pain intensity following initiation of medical cannabis among patients with FM could be attributed to concurrent changes (i.e., reductions) in negative affect and sleep problems. METHODS: This was a 12-month prospective cohort study among patients with FM (n = 323) initiating medical cannabis under the care of physicians. Patients were assessed at baseline, and follow-up assessment visits occurred every 3 months after initiation of medical cannabis. Patients' levels of pain intensity, negative affect, and sleep problems were assessed across all visits. RESULTS: Multilevel mediation analyses indicated that reductions in patients' levels of pain intensity were partly explained by concurrent reductions in sleep problems and negative affect (both P < 0.001). This remained significant even when accounting for patients' baseline characteristics or changes in medical cannabis directives over time (all P > 0.05). CONCLUSION: Our findings provide preliminary insight into the potential mechanisms of action underlying pain reductions among patients with FM who are using medical cannabis. Given the high attrition rate (i.e., 75%) observed in the present study at 12 months, our findings cannot be generalized to all patients with FM who are using medical cannabis.

Peak plasma concentration of total and free bupivacaine after erector spinae plane and pectointercostal fascial plane blocks.

PURPOSE: Erector spinae plane blocks (ESPB) and pectointercostal fascial (PIFB) plane blocks are novel interfascial blocks for which local anesthetic (LA) doses and concentrations necessary to achieve safe and effective analgesia are unknown. The goal of this prospective observational study was to provide the timing (Tmax) and concentration (Cmax) of maximum total and free plasma bupivacaine after ESPB in breast surgery and after PIFB in cardiac surgery patients. METHODS: Erector spinae plane blocks or PIFBs (18 patients per block; total, 36 patients) were performed with 2 mg⋅kg-1 of bupivacaine with epinephrine 5 µg⋅mL-1. Our principal outcomes were the mean or median Cmax of total and free plasma bupivacaine measured 10, 20, 30, 45, 60, 90, 180, and 240 min after LA injection using liquid chromatography with tandem mass spectrometry. RESULTS: For ESPB, the mean (standard deviation [SD]) total bupivacaine Cmax was 0.37 (0.12) µg⋅mL-1 (range, 0.19 to 0.64), and the median [interquartile range (IQR)] Tmax was 30 [50] min (range, 10-180). For ESPB, the mean (SD) free bupivacaine Cmax was 0.015 (0.017) µg⋅mL-1 (range, 0.003-0.067), and the median [IQR] Tmax was 30 [20] min (range, 10-120). After PIFB, mean plasma concentrations plateaued at 60-240 min. For PIFB, the mean (SD) total bupivacaine Cmax was 0.32 (0.21) µg⋅mL-1 (range, 0.14-0.95), with a median [IQR] Tmax of 120 [150] min (range, 30-240). For PIFB, the mean (SD) free bupivacaine Cmax was 0.019 (0.010) µg⋅mL-1 (range, 0.005-0.048), and the median [IQR] Tmax was 180 [120] min (range, 30-240). For both ESPB and PIFB, we observed no correlations between pharmacokinetic and demographic parameters. CONCLUSION: Total and free bupivacaine Cmax observed after ESPB and PIFB with 2 mg⋅kg-1 of bupivacaine with epinephrine 5 µg⋅mL-1 were five to twenty times lower than levels considered toxic in the literature.

RéSUMé: OBJECTIF: Les blocs des muscles érecteurs du rachis (ESP) et les blocs des plans fasciaux pecto-intercostaux (PIFB) sont de nouveaux blocs interfasciaux pour lesquels les doses et les concentrations d'anesthésique local (AL) nécessaires à obtenir une analgésie sécuritaire et efficace sont inconnues. L'objectif de cette étude observationnelle prospective était de déterminer le moment d'administration (Tmax) et la concentration (Cmax) de bupivacaïne plasmatique totale et plasmatique libre maximale après un bloc ESP pour chirurgie mammaire et après un PIFB chez les patients en chirurgie cardiaque. MéTHODE: Des blocs ESP ou PIFB (18 patients par bloc; total, 36 patients) ont été réalisés avec 2 mg⋅kg-1 de bupivacaïne et 5 µg⋅mL-1 d'épinéphrine. Nos principaux critères d'évaluation étaient la Cmax moyenne ou médiane de bupivacaïne plasmatique totale et libre mesurée 10, 20, 30, 45, 60, 90, 180 et 240 min après l'injection d'AL par chromatographie liquide avec spectrométrie de masse en tandem. RéSULTATS: Pour le bloc ESP, la Cmax de bupivacaïne totale moyenne (écart type [ET]) était de 0,37 (0,12) µg⋅mL-1 (plage, 0,19 à 0,64), et le Tmax médian [écart interquartile (ÉIQ)] était de 30 [50] min (intervalle, 10­180). Pour le bloc ESP, la Cmax de bupivacaïne libre moyenne (ET) était de 0,015 (0,017) µg⋅mL-1 (plage, 0,003­0,067), et le Tmax médian [ÉIQ] était de 30 [20] min (intervalle, 10­120). Après un PIFB, les concentrations plasmatiques moyennes ont plafonné à 60­240 min. Pour le bloc PIFB, la Cmax de bupivacaïne totale moyenne (ET) était de 0,32 (0,21) µg⋅mL-1 (plage, 0,14­0,95), et le Tmax médian [ÉIQ] était de 120 [150] min (intervalle, 30­240). Pour le bloc PIFB, la Cmax de bupivacaïne libre moyenne (ET) était de 0,019 (0,010) µg⋅mL-1 (plage, 0,005­0,048), et le Tmax médian [ÉIQ] était de 180 [120] min (intervalle, 30­240). Pour le bloc ESP et le PIFB, nous n'avons observé aucune corrélation entre les paramètres pharmacocinétiques et démographiques. CONCLUSION:  : Les Cmax de bupivacaïne totale et libre observées après un bloc ESP et PIFB avec 2 mg⋅kg-1 de bupivacaïne avec 5 µg⋅mL-1 d'épinéphrine étaient cinq à vingt fois plus faibles que les niveaux considérés comme toxiques dans la littérature.

Pectoral I Block Does Not Improve Postoperative Analgesia After Breast Cancer Surgery: A Randomized, Double-Blind, Dual-Centered Controlled Trial.

BACKGROUND AND OBJECTIVES: General anesthesia for breast surgery may be supplemented by using a regional anesthetic technique. We evaluated the efficacy of the first pectoral nerve block (Pecs I) in treating postoperative pain after breast cancer surgery. METHODS: A randomized, double-blind, dual-centered, placebo-controlled trial was performed. One hundred twenty-eight patients scheduled for unilateral breast cancer surgery were recruited. A multimodal analgesic regimen and surgeon-administered local anesthetic infiltration were used for all patients. Ultrasound-guided Pecs I was performed using bupivacaine or saline. The primary outcome was the patient pain score (numerical rating scale [NRS]) in the recovery unit 30 minutes after admission or just before the morphine administration (NRS ≥4/10). The secondary outcomes were postoperative opioid consumption (ie, in the recovery unit and after 24 hours). RESULTS: During recovery, no significant difference in NRS was observed between the bupivacaine (n = 62, 3.0 [1.0-4.0]) and placebo (n = 65, 3.0 [1.0-5.0]) groups (P = 0.55). However, the NRS was statistically significantly different, although not clinically significant, for patients undergoing major surgeries (mastectomies or tumorectomies with axillary clearance) (n = 29, 3.0 [0.0-4.0] vs 4.0 [2.0-5.0], P = 0.04). Morphine consumption during recovery did not differ (1.5 mg [0.0-6.0 mg] vs 3.0 mg [0.0-6.0 mg], P = 0.20), except in the major surgery subgroup (1.5 mg [0.0-6.0 mg] vs 6.0 mg [0.0-12.0 mg], P = 0.016). Intraoperative sufentanil and cumulative morphine consumption up to 24 hours did not differ between the 2 groups. Three patients experienced complications related to the Pecs I. CONCLUSIONS: Pecs I is not better than a saline placebo in the presence of multimodal analgesia for breast cancer surgery. However, its role in extended (major) breast surgery may warrant further investigation. CLINICAL TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov, identifier NCT01670448.

Medical cannabis: considerations for the anesthesiologist and pain physician.

PURPOSE: New regulations are in place at the federal and provincial levels in Canada regarding the way medical cannabis is to be controlled. We present them together with guidance for the safe use of medical cannabis and recent clinical trials on cannabis and pain. SOURCE: The new Canadian regulations on the use of medical cannabis, the provincial regulations, and the various cannabis products available from the Canadian Licensed Producers were reviewed from Health Canada, provincial licensing authorities, and the licensed producers website, respectively. Recent clinical trials on cannabis and pain were reviewed from the existing literature. PRINCIPAL FINDINGS: Health Canada has approved a new regulation on medical marijuana/cannabis, the Marihuana for Medical Purposes Regulations: The production of medical cannabis by individuals is illegal. Health Canada, however, has licensed authorized producers across the country, limiting the production to specific licenses of certain cannabis products. There are currently 26 authorized licensed producers from seven Canadian provinces offering more than 200 strains of marijuana. We provide guidance for the safe use of medical cannabis. The recent literature indicates that currently available cannabinoids are modestly effective analgesics that provide a safe, reasonable therapeutic option for managing chronic non-cancer-related pain. CONCLUSION: The science of medical cannabis and the need for education of healthcare professionals and patients require continued effort. Although cannabinoids work to decrease pain, there is still a need to confirm these beneficial effects clinically and to exploit them with acceptable benefit-to-risk ratios.

Endocannabinoids decrease neuropathic pain-related behavior in mice through the activation of one or both peripheral CB1 and CB2 receptors.

The two most studied endocannabinoids are anandamide (AEA), principally catalyzed by fatty-acid amide hydrolase (FAAH), and 2-arachidonoyl glycerol (2-AG), mainly hydrolyzed by monoacylglycerol lipase (MGL). Inhibitors targeting these two enzymes have been described, including URB597 and URB602, respectively. Several recent studies examining the contribution of CB1 and/or CB2 receptors on the peripheral antinociceptive effects of AEA, 2-AG, URB597 and URB602 in neuropathic pain conditions using either pharmacological tools or transgenic mice separately have been reported, but the exact mechanism is still uncertain. Mechanical allodynia and thermal hyperalgesia were evaluated in 436 male C57BL/6, cnr1KO and cnr2KO mice in the presence or absence of cannabinoid CB1 (AM251) or CB2 (AM630) receptor antagonists in a mouse model of neuropathic pain. Peripheral subcutaneous injections of AEA, 2-AG, WIN55,212-2 (WIN; a CB1/CB2 synthetic agonist), URB597 and URB602 significantly decreased mechanical allodynia and thermal hyperalgesia. These effects were inhibited by both cannabinoid antagonists AM251 and AM630 for treatments with 2-AG, WIN and URB602 but only by AM251 for treatments with AEA and URB597 in C57BL/6 mice. Furthermore, the antinociceptive effects for AEA and URB597 were observed in cnr2KO mice but absent in cnr1KO mice, whereas the effects of 2-AG, WIN and URB602 were altered in both of these transgenic mice. Complementary genetic and pharmacological approaches revealed that the anti-hyperalgesic effects of 2-AG and URB602 required both CB1 and CB2 receptors, but only CB2 receptors mediated its anti-allodynic actions. The antinociceptive properties of AEA and URB597 were mediated only by CB1 receptors.

Opioids and cannabinoids interactions: involvement in pain management.

Among several pharmacological properties, analgesia is the most common feature shared by either opioid or cannabinoid systems. Cannabinoids and opioids are distinct drug classes that have been historically used separately or in combination to treat different pain states. Indeed, it is widely known that activation of either opioid or cannabinoid systems produce antinociceptive properties in different pain models. Moreover, several biochemical, molecular and pharmacological studies support the existence of reciprocal interactions between both systems, suggesting a common underlying mechanism. Further studies have demonstrated that the endogenous opioid system could be involved in cannabinoid antinociception and recent data have also provided evidence for a role of the endogenous cannabinoid system in opioid antinociception. These interactions may lead to additive or even synergistic antinociceptive effects, emphasizing their clinical relevance in humans in order to enhance analgesic effects with lower doses and consequently fewer undesirable side effects. Thus, the present review is focused on bidirectional interactions between opioids and cannabinoids and their potent repercussions on pain modulation.

[The cannabinoid system and pain: a new therapeutic avenue?]. / Système cannabinoïde et douleur: quelle place en thérapeutique?

Pain is relatively refractory to most of the current analgesics, emphasizing the importance of identifying novel pharmacological agents. Thus, modulation of the cannabinoid system is a new therapeutic approach. This could be performed at several levels. For endogenous cannabinoids, it would be a modulation of their synthesis, release, cellular uptake, metabolism or interactions with cannabinoid receptors. Many recent clinical studies investigating the role of cannabinoids in various pain syndromes demonstrated overall positive results. Nevertheless, cannabis and cannabinoids as analgesic agents have not been yet unequivocally established. Targeting preferentially peripheral cannabinoid receptors to avoid unwanted psychotropic effects is a new interesting avenue requiring further investigation.

Pre-emptive antinociceptive effects of a synthetic cannabinoid in a model of neuropathic pain.

The antinociceptive effects of WIN55,212-2, a synthetic cannabinoid, were evaluated in the model of partial sciatic nerve ligation after daily subcutaneous administration of 0.1 mg/kg a week before and two weeks after surgery. Mechanical allodynia and thermal hyperalgesia were evaluated in 46 rats allocated to receive: (1) Vehicle (before surgery)-Vehicle (after surgery); (2) Vehicle-WIN55,212-2; (3) WIN55,212-2-Vehicle; (4) WIN55,212-2-WIN55,212-2; (5) AM251+vehicle; (6) AM251+WIN55,212-2; (7) AM630+vehicle; (8) AM630+WIN55,212-2; (9) Sham receiving vehicle; and (10) Sham receiving WIN55,212-2. The decreased in mechanical allodynia and thermal hyperalgesia by WIN55,212-2 was significantly greater when it was administered during one week before surgery. In conclusion, pre-emptive use of cannabinoids produced greater antinociceptive effects in a model of neuropathic pain and this effect is mediated by cannabinoid CB(1) and CB(2) receptors.