Bakgrund: Användningen av höga doser av opioider under generell anestesi är numera mycket vanligt. Biverkningar orsakade av opioider är väl känt inom anestesin och sjukvården och senare evidens tyder på att opioider även kan bidra till smärtutveckling. Av denna anledning har studier de senaste 20 åren ifrågasatt användningen av opioider och intresset för att minska opioidbehovet och utveckla opioidfria metoder för anestesi har växt. Syfte: Att beskriva opioidfri analgesi i generell anestesi, och hur detta påverkar den perioperativa smärtupplevelsen, jämfört med patienter i generell anestesi som fått traditionell smärtlindring med opioider. Metod: En litteraturöversikt med systematisk ansats. Artikelsökningen genomfördes i PubMed, Cinahl och Scopus. Resultatet sammanställdes utifrån 15 granskade artiklar med kvantitativ design. Resultat: Litteraturöversikten visar att det finns ett stort antal läkemedel som kan användas inom opioidfri anestesi, samt deras för- och nackdelar för smärtupplevelsen jämfört opioider. De protokoll som användes vid opioidbaserad anestesi eller för opioidsparande anestesi är inte standardiserade och därför är det inte möjligt att syntetisera resultatet och ställa olika metoder mot varandra i denna litteraturöversikt. De flesta artiklar visade att det går att minska intraoperativt och postoperativt opioidbehov för patienter och ändå erbjuda likvärdig smärtlindring. De patienter som fick en opioidfri eller opioidsparande anestesi hade inte en försämrad perioperativ smärtupplevelse. Den mängd metoder som beskrevs indikerar att analgesi kan anpassas efter patientens individuella förutsättningar. Slutsats: Litteraturöversikten visade att olika läkemedel och metoder kan användas för att ge analgesi till patienten vid opioidfri anestesi samt dess effekt på smärtupplevelsen kontra opioider. De flesta alternativa läkemedel som används i artiklarna gav ett mer gynnsamt eller likvärdigt utfall för patienten. Genom utveckling av fler metoder för analgesi under anestesi kan anestesin i större omfattning utgå från individens behov och förutsättningar, vilket bidrar till en mer personcentrerad vård. Litteraturöversiktens resultat visar på en stor spridning och det är därför svårt att bedöma vilka läkemedel som är bäst lämpade. Det krävs således mer forskning inom detta ämne för att möjliggöra jämförelser och utarbeta protokoll som gör opioidfri anestesi till etablerad och säker metod för patienten. / Background: High dose opioids during general anesthesia are frequently used. The side effects caused by opioids are well known in anesthesia and healthcare and recent evidence implies opioides can contribute to the development of pain. For this reason, studies over the past 20 years have questioned the use of opioids and an interest has grown in reducing the need of opioids and developing opioid-free methods for anesthesia. Aim: To describe opioid-free analgesia in general anesthesia, and how this affects the perioperative pain experience, compared to patients in general anesthesia who have received traditional opioid-based pain relief. Method: A literature study with systematic approach. The article search was performed in PubMed, Cinahl and Scopus. The result was compiled based on 15 reviewed articles with quantitative design. Result: The literature review shows that there are a large number of drugs that can be used in opioid-free anesthesia and the advantages and disadvantages of these drugs versus opioids. The protocols used for opioid-based anesthesia or for opioid-saving anesthesia are not standardized and therefore it is not possible to synthesize the results or set different methods against each other in this review. Most articles found that it is possible to reduce the intraoperative and postoperative need of opioid for patients and still offer equivalent pain relief. The patients receiving opioid-free or opioid-sparing anesthesia did not suffer a worsened pain-related experience. The amount of methods described indicates that the analgesia can be customized accordingly to the patient's individual circumstances. Conclusion: The literature review described various drugs and methods that can be used to give analgesia to the patient during opioid-free anesthesia and the effect on the pain-related experience. Most of the alternative drugs used in the articles gave a more favorable or equivalent outcome for the patient. By developing more methods for analgesia during anesthesia, it is in a greater extent possible to adjust the anesthesia depending on the individuals needs, which contributes to a more person-centered care. The result shows a wide spread and it is therefore difficult to assess which drugs are best suited. Thus, more research is required in this subject to prepare protocols that make opioid-free anesthesia an established and safe method for the patient.

Opioids, such as oxycodone, morphine, and fentanyl, are commonly used medications in the treatment of moderate to severe pain. In spite of their efficacious analgesic properties, their increased prescribing rates by physicians and inherent abuse-related effects have led to the ongoing opioid epidemic. Their clinical utility is limited by the risk of adverse dose-dependent side effects, such as constipation and respiratory depression, and the development of tolerance and dependence. Opioid-sparing adjunctive therapies are sought to address these issues by reducing the dose of opioid needed to achieve analgesia through alternative non-opioidergic mechanisms and as a result, reduce the incidence of the previously mentioned side effects. Serotonin type-2C receptor agonists have demonstrated antinociceptive efficacy in preclinical models of chronic pain. Lorcaserin is a selective 5-HT2C receptor agonist and was reported to attenuate the abuse-related effects of oxycodone. The antinociceptive properties of 5-HT2C receptor agonists and their potential to alter the abuse-related effects of commonly abused drugs suggest that lorcaserin may be a potential opioid-sparing therapeutic. The goal of these studies was to evaluate the utility of lorcaserin, in combination with opioids, in a preclinical model of acute pain. Based on previous studies demonstrating the antinociceptive activity of 5-HT2C agonists, the hypotheses for these studies were that lorcaserin would increase the acute antinociceptive effects of opioids and would attenuate the development of tolerance associated with chronic opioid consumption. The results demonstrate that the acute antinociceptive effects and the time-course of activity of opioids were enhanced by doses of lorcaserin. These effects were mediated through activation of the 5-HT2C receptor and were not blocked by administration of naloxone. Additionally, the acute effects of lorcaserin to increase opioid potency and time course was not mediated through changes in opioid distribution in the blood or central tissues. Opioid tolerance was evaluated in vivo, and tolerance was developed using two methods of treatment: an acute (single dose administration) model of tolerance and a multiple-injection model. Testing the effect of lorcaserin in these models was important because current research suggests that the mechanisms that underlie both models of tolerance are distinct from one another. The results demonstrate that lorcaserin significantly blocked the development of acute tolerance in the whole animal and on a single cell level in dorsal root ganglion cell cultures. In the multiple-day tolerance model, lorcaserin partially attenuated the development of opioid antinociceptive tolerance. Chronic administration of an opioid is associated with desensitization of the MOR, and the effect of lorcaserin on opioid tolerance may be mediated through changes in MOR functional activity. Upon further investigation using agonist-stimulated [35S]GTPyS, the results showed that lorcaserin altered basal binding of [35S]GTPyS but not agonist-stimulated binding in mice that received chronic opioid treatment. These data suggest that the effect of lorcaserin on opioid tolerance, in the multiple-injection model, is not mediated through changes in MOR functional activity. Collectively, the tolerance studies suggest that the effect of 5-HT2C receptor activation by lorcaserin has differential effects on the stages of opioid tolerances and further supports the notion that the mechanisms that underlie the stages of opioid tolerance are distinct. Given the efficacy of lorcaserin to increase the acute antinociceptive effects of opioids and its ability to impair the development of opioid tolerance, collectively, these data suggest that lorcaserin may be a useful opioid-sparing adjunctive therapy.

Gabapentin is an anticonvulsant that has become a treatment option for several indications that are not approved by Health Canada. Commonly, gabapentin is prescribed for neuropathic pain and anxiety disorders. The objective of this dissertation was to evaluate the efficacy of gabapentin for reducing pre-operative anxiety, post-operative pain and opioid consumption. The initial study examined regimens of pre-operative and post-operative gabapentin given to patients undergoing total knee arthroplasty. Patients that received gabapentin postoperatively used significantly less morphine at 24 hrs, 36 hrs and 48 hrs (p<0.05). Furthermore these patients had significantly better active-assisted knee flexion on postoperative day (POD) 2, POD 3, with a trend toward better flexion on POD 4. Next, we examined whether: 1) gabapentin administration reduces pain and opioid use after total hip arthroplasty using a multimodal analgesic regimen that included spinal anesthesia; and whether 2) preoperative administration of gabapentin is more effective than postoperative administration. Our results demonstrated that whether a 600 mg dose of gabapentin was given preoperatively or postoperatively, patients’ postoperative morphine consumption or pain scores were not reduced in hospital nor was there a reduction in pain 6 months after hip arthroplasty. The third study found that a single dose of 600 mg of gabapentin was not sufficient to reduce preoperative anxiety in patients prior to hip arthroplasty. In contrast, the final study demonstrated that 1200mg of gabapentin reduced pre-operative anxiety and pain catastrophizing in female patients with moderate to high levels of preoperative anxiety prior to major surgery, but also increased preoperative and early postoperative sedation. Our findings demonstrate the efficacy of perioperative gabapentin with respect to preoperative anxiety reduction and decreasing morphine consumption after surgery. Future studies that focus on the optimal dose and duration of perioperative gabapentin, with the aim of improving functional outcomes and decreasing the incidence and severity chronic post-surgical pain are warranted.

Gabapentin is an anticonvulsant that has become a treatment option for several indications that are not approved by Health Canada. Commonly, gabapentin is prescribed for neuropathic pain and anxiety disorders. The objective of this dissertation was to evaluate the efficacy of gabapentin for reducing pre-operative anxiety, post-operative pain and opioid consumption. The initial study examined regimens of pre-operative and post-operative gabapentin given to patients undergoing total knee arthroplasty. Patients that received gabapentin postoperatively used significantly less morphine at 24 hrs, 36 hrs and 48 hrs (p<0.05). Furthermore these patients had significantly better active-assisted knee flexion on postoperative day (POD) 2, POD 3, with a trend toward better flexion on POD 4. Next, we examined whether: 1) gabapentin administration reduces pain and opioid use after total hip arthroplasty using a multimodal analgesic regimen that included spinal anesthesia; and whether 2) preoperative administration of gabapentin is more effective than postoperative administration. Our results demonstrated that whether a 600 mg dose of gabapentin was given preoperatively or postoperatively, patients’ postoperative morphine consumption or pain scores were not reduced in hospital nor was there a reduction in pain 6 months after hip arthroplasty. The third study found that a single dose of 600 mg of gabapentin was not sufficient to reduce preoperative anxiety in patients prior to hip arthroplasty. In contrast, the final study demonstrated that 1200mg of gabapentin reduced pre-operative anxiety and pain catastrophizing in female patients with moderate to high levels of preoperative anxiety prior to major surgery, but also increased preoperative and early postoperative sedation. Our findings demonstrate the efficacy of perioperative gabapentin with respect to preoperative anxiety reduction and decreasing morphine consumption after surgery. Future studies that focus on the optimal dose and duration of perioperative gabapentin, with the aim of improving functional outcomes and decreasing the incidence and severity chronic post-surgical pain are warranted.

Aspiration of gastric content and delayed or failed intubation are the leading causes of anesthesia-related mortality and morbidity. In the recovery period, airway obstruction with subsequent hypoxia is a relatively common cause of morbidity, and is highly associated to the amount of opioids administered, especially in obese patients. The overall aim of this thesis was to study these risk factors for airway complications and postoperative hypoxia in obese patients, and to evaluate possible strategies for their prevention. In Study I, intubation times and incidence of failed intubation in obese patients were compared between direct laryngoscopy and videolaryngoscopy with the Stortz® C-MAC™. In Studies II and III, the effect of esmolol vs. remifentanil on the esophageal junction, and the possible analgesic properties of low-dose esmolol vs. placebo were evaluated using high-resolution manometry and the cold pressor test, respectively. Finally, in Study IV, the possible opioid-sparing effect of esmolol after laparoscopic gastric bypass surgery was evaluated. The use of videlaryngoscopy did not shorten intubation times, however appeared to reduce the incidence of failed intubation. Our results also show that esmolol has a favorable profile, compared to remifentanil, with regard to the protection against passive regurgitation and aspiration of gastric content. No analgesic effect of low-dose esmolol was however demonstrated. The intraoperative administration of esmolol instead of remifentanil also did not reduce the requirement of morphine for treatment of post-operative pain. The use of Stortz® C-MAC™ may be recommended for intubation of obese patients. Further studies are however required to clarify the possible role of esmolol in anesthesia.