Using combination of opioid analgesics and analgesics with different mechanism of action the investigators can decrease the consumption of opioid analgesics and their side effects. The investigators will use opioid analgesic fentanyl alone or in combination with dexmedetomidine or lidocaine.The participants scheduled for laparoscopic intestine resection will be divided in three groups: in the first group, the participants will receive single boluses of fentanyl, in the second group, the participants will receive continuous infusion of lidocaine and single boluses of fentanyl, and in the third group, the participants will receive continuous infusion of dexmedetomidine and single boluses of fentanyl. Participants with intraoperative infusion od dexmedetomidine or lidocaine will need less boluses of fentanyl during the operation and less opioid analgesics after the operation in comparison to those who will receive only fentanyl boluses. Better cognitive function after the operation is expected in participants receiving dexmedetomidine infusion. There will be minimal incidence of neuropathic pain because of minimal surgical injury of peripheral nerves in all groups of patients.

Introduction: The consumption of opioid analgetics and their side effects can be minimized by using the combination of opioid analgesics and analgesics with different mechanism of action. The investigators will use opioid analgesic fentanyl alone or in combination with dexmedetomidine or lidocaine. Dexmedetomidine is alpha 2 adrenergic receptor agonist and is used more and more during anesthesia because of its anesthetic and analgesic effects as it preserves mental status and decreases the consumption of analgesics. Lidocaine is a local anesthetic and antiarrhythmic drug which decreases opioid consumption as well.

The participants scheduled for laparoscopic intestine resection will be divided in three groups: in the first group, the participants will receive single boluses of fentanyl, in the second group, the participants will receive continuous infusion of lidocaine and single boluses of fentanyl, and in the third group, the participants will receive continuous infusion of dexmedetomidine and single boluses of fentanyl.

Hypothesis: Participants with intraoperative infusion od dexmedetomidine or lidocaine will need less boluses of fentanyl during the operation and less opioid analgesics after the operation in comparison to those who will receive only fentanyl boluses. Better cognitive function after the operation in participants receiving dexmedetomidine infusion is expected. There will be minimal incidence of neuropathic pain because of minimal surgical injury of peripheral nerves in all groups.

Justification: Lidocaine and dexmedetomidine are analgesics with different mechanism of action in comparison to opioid analgesics. Their use during the operation decreases the consumption of opioids intra- and postoperatively. Dexmedetomidine has beneficial effect on cognitive function and that is why the investigators expect preserved cognitive function in participants after the operation. Because of minimal surgical injury and, therefore, minimal probability of peripheral nerve injury, the investigators expect low incidence of neuropathic pain in all groups.

Methods: The investigators will include 60 participants in the study, between 35 to 85 years old, ASA 2 - 3 (American Society of Anesthesiologists, ASA) undergoing a planned laparoscopic intestine resection. The participants will be randomized into three groups. In the first group, fentanyl boluses will be adimistred during the operation, in the second, infusion of lidocaine will be added to fentanyl, and in the third, the infusion of dexmedetomidine will be added to fentanyl. The investigators will record opioid consumption during the operation and two days after the operation. The investigators will use mini mental test for evaluation of cognitive function before the operation and at the transfer of the participant postoperatively to the surgical ward, in order to explore the influence of analgesics used on cognitive function. Two months after the operation the degree of neuropathic pain will be evaluated with pain questionnaire. The data will be statistically evaluated.

Expected results: Participants with intraoperative infusion of lidocaine and dexmedetomidine will need less opioid analgesics during and after the operation in comparison to the group with fentanyl boluses only. The investigators expect better cognitive function after the operation in participants with dexmedetomidine infusion. Because of the minimal surgery injury to the peripheral nerves low incidence of neuropathic pain is expected in all groups.

Study design and methods Inclusion criteria: In our study the investigators will include patients aged 35 to 85, ASA 2-3 (according to the classification of American Society of Anesthesiologists), undergoing a planned laparoscopic intestine resection at the Department of Abdominal Surgery at the University Medical Centre Ljubljana. Included participants will sign the consensus for participating in the study after exact explanation and conversation, as well as consensus for anesthesia and surgery.

Exclusion criteria: Participants with allergies to alpha 2 receptor agonists, uncontrolled arterial hypertension, 2nd and 3rd degree atrioventricular block, alcohol and illegal drugs abusers, patients with clinically important neurological, cardiovascular, respiratory (COPD, emphysema), renal, liver, and gastrointestinal disease, will be excluded from our study. The investigators will also exclude pregnant women and patients younger than 18 years due to their physiological particularities.

Data collection: The participants will be prepared for the operation as usual according to the operative protocol. Cognitive function is going to be assessed with a mini mental test before the operation.

After inserting the peripheral venous line, the induction will be performed with analgesic fentanyl (2 mcg/kg) and sedative propofol (1,5-2,5 mg/kg). Muscle relaxant rocuronium will be used for easier intubation (0,6 mg/kg; standard dose). The participants will be controlled mechanically ventilated with tidal volumes 6-8 ml/kg. Anesthesia will be maintained with intravenous anesthetic propofol in doses between 4 - 6 mg/kg/h according to bispectral index value (bispectral index, BIS, Vista), which will be kept between 40 and 55, the interval suitable for surgical depth of anesthesia. Normothermia and normocapnia will be maintained. The fluids will be warmed to 39°C via Hotline, the body temperature and expired CO2 will be measured. Mean arterial blood pressure will be maintained within ± 25 % baseline value. When mean arterial blood pressure will decrease more than 25% from the baseline value, a bolus of a vasoactive drug will be used.

Beside the standard monitoring (electrocardiogram, pulse oximetry, indirect blood pressure management, capnometry), the investigators will use ANI (analgesia nociception index) monitoring for the pain measurement. ANI values will be maintained between 50 and 70 and between those valuse good analgesia is provided. Muscle relaxation will be measured with TOF (train of four) and will be maintained on the level of deep muscle relaxation, that is TOF 0 and PTC 1 - 2 (posttetanic count).

Before the operation the investigators will randomize the participants into the three groups, which will distinguish according to analgesia used. All participants will get intravenous bolus of fentanyl (2 mcg/kg, standard dose) before the incision. All of them will receive bolus of fentanyl when ANI will drop below 50 during the operation (2 mcg/kg, recommended standard dose, first group). Participants in the second group will receive infusion of lidocaine (1,5 mg/kg/h), and participants in the third group infusion of dexmedetomidine (0,5 µg/kg/h). The consumption of fentanyl and propofol will be measured during the operation. The infusion of lidocaine and dexmedetomidine will be stopped 10 minutes before the end of the operation. Propofol infusion will be stopped at the end of the final suture. After the operation all participants will receive postoperative infusion of piritramide delivered with PCA (patient control analgesia). If the pain according to the visual analog scale (VAS) will be more than 3, the participants will be given a bolus of the peripheral acting analgesic or opioid (paracetamol, metamizol, piritramide). VAS will be reevaluated two days after the operation, as well as the consumption of other opioids and other analgesics. Cognitive function will be evaluated again on the second day with mini mental test, or at the transfer of the participant to the surgical ward with the discontinuation of the opioids and when they will be afebrile. Neuropathic pain will be evaluated with the pain questionnaire two months after the operation.

Statistical analysis: Collected data will be presented using descriptive statistics such as mean, median and standard deviation. The use of the opioids and other analgesics will be compared using paired Student t-test or other suitable nonparametric tests (eg. ANOVA), depending on the type of data used.

Correlation of different factors will be determined using Pearson/Spearman correlation coefficient. Deviation from normal distribution of data will be tested with a chi-squared test. Predictive value will be determined using logistic regression.

Expected results: The investigators assume that there will be less opioid consumption in participants receiving lidocaine or dexmedetomidine infusion during the operation and the following two days compared to participants who received fentanyl boluses only. In participants with intraoperative infusion of dexmedetomidine the investigators expect preserved cognitive function. Low incidence of neuropathic pain is expected two months after the operation in all groups because of minimal peripheral nerve injury during operation.

Inclusion Criteria:

• patients aged 35 to 85,
• ASA 2-3 (according to the classification of American Society of Anesthesiologists),
• undergoing a planned laparoscopic intestine resection at the Department of Abdominal Surgery at the University Medical Centre Ljubljana.

Exclusion Criteria:

• allergies to alpha 2 receptor agonists,
• uncontrolled arterial hypertension,
• 2nd and 3rd degree atrioventricular block,
• alcohol and illegal drugs abusers,
• patients with clinically important neurological, cardiovascular, respiratory (COPD, emphysema), renal, liver, and gastrointestinal disease,
• pregnant women,
• patients younger than 18 years-

2 months

Limitations of our study is that we have not evaluated inflammatory response on the cellular level. This should be investigated in the future studies to establish if dexmedetomidine and lidocaine have clinically important anti-inflammatory effect.