Many nociceptive, inflammatory, and neuropathic pathways contribute to perioperative pain. Although opioids have long been a mainstay for perioperative analgesia, other non-opioid molecules, including dexmedetomidine, have been increasingly used as part of a multimodal analgesic plan to provide improved postoperative pain control, while minimizing opioid-related side effects.

Dexmedetomidine (DEX) is an alpha-2 adrenergic receptor agonist that can be directly applied to the peripheral nervous system, causing a dose-dependent inhibition of C- and Aα-fibers. Alpha-2 adrenergic receptors act on the locus ceruleus area, inhibiting nociceptive neurotransmission, through the posterior horn of the spinal cord. Alpha-2 adrenergic receptors also act on the presynaptic membrane, inhibiting the release of norepinephrine, which in turn induces hyperpolarization and inhibits the pain signals to the brain. Moreover, DEX promotes the release of acetylcholine from spinal interneurons; the resulting increased synthesis and release of nitric oxide could be involved in the regulation of analgesia. as such, DEX could be effectively applied for preoperative, intraoperative, and postoperative analgesia (iv, spinal canal, and nerve blocks). While there have not been any large-scale clinical trials conducted, the current body of evidence suggests that DEX is suitable for use as an adjuvant analgesic at all perioperative stages, keeping in mind its potential adverse effects, such as hypotension and bradycardia, which must be taken into consideration by clinicians.

Preoperative Dexmedetomidine Utilization Dexmedetomidine can be administered intravenously, intramuscularly, orally, buccally, and intranasally, in the preoperative setting. Buccal and intranasal administration have a high bioavailability and are more easily tolerated by patients due to noninvasiveness, making it an excellent choice for preoperative premedication in children. Intranasal DEX 1 μg/kg and 0.2 mg/kg midazolam, approximately 45–60 min before the induction of pediatric tonsillectomy and complete dental rehabilitation, resulted in the same sedation, with DEX markedly reducing the required dosage of postoperative analgesia drugs, suggesting that its preoperative administration reduces early postoperative pain in children and has a relatively prolonged duration as an adjuvant analgesic. In paediatric population, intranasal DEX (2 μg/kg) during myringotomy and pressure-equalizing tube placement reduced the need for additional analgesics, as well as perioperative pain levels. However, increasing the intranasal dose of DEX to 2 μg/kg led to a prolonged postoperative recovery time. Thus, the dose of intranasal DEX should not be more than 2 μg/kg during short procedures in children.

Intraoperative Dexmedetomidine: Intravenous Administration High doses of opioids (eg remifentanil) may induce hyperalgesia, which presents as a decreased mechanical hyperalgesia threshold, enhanced pain intensity, a shorter time to first postoperative analgesic requirement, and greater opioid consumption. An initial intravenous dose of DEX (1.0 μg/kg) in 10 min, followed by a continuous infusion of up to 0.7 μg/kg/h approximately 15 min before the induction of general anesthesia, may be a novel and effective treatment option for preventing or attenuating opioid-induced hyperalgesia. Some studies results reported that DEX led to a decreased requirement for opioid analgesics and inhaled anesthetics, and lessened the incidence of severe cardiovascular changes during traumatic phases of surgeries. In thoracic surgery, patients given DEX at a loading dose of 1 μg/kg for 10 min, followed by continuous infusion at 0.5 μg/kg/h until 30 min before the end of surgery, exhibited reduced resting and coughing numerical rating scale scores and a sufentanil-sparing effect during the first 24 h. Premedication with a single intravenous dose of 0.5 μg/kg DEX decreased the intraoperative propofol and postoperative analgesic requirements, and increased the postoperative satisfaction and Ramsay sedation scale scores considerably in patients undergoing direct laryngoscopic biopsy under total intravenous anesthesia. Additionally, it has been found that sensory block duration was prolonged by at least 34%, motor block duration was prolonged by at least 17%, and time to first analgesic request was increased by at least 53% when intravenous DEX was administered with spinal anesthesia. Further, its use was associated with a 3.7-fold increase in transient reversible bradycardia. Intravenous dexmedetomidine with a single-injection interscalene brachial plexus block for outpatient shoulder surgery reduced the pain and opioid consumption for up to 8 h postoperatively, without prolonging motor blockade, possibly being related to the central sedative and analgesic effects, and sensitization of the nervous system produced by the excited alpha-2 adrenergic receptor. DEX can be an effective baseline anaesthetic adjuvant for patients undergoing locoregional anesthesia for a broad range of surgical procedures, providing better patient satisfaction, lower opioid requirements, and less respiratory depression than placebo rescued with midazolam and fentanyl. Further, common adverse events associated with DEX, such as bradycardia and hypotension, are predominately mild to moderate in severity.

Intraoperative Dexmedetomidine Administration: Progress of Spinal Analgesia Patients, undergoing lower limb vascular surgery under lumbar epidural anesthesia (15 mL of levobupivacaine with 0.5 μg/kg DEX) exhibited a longer time to two-segment regression and total regression, compared to patients who received levobupivacaine and racemic bupivacaine alone. Nevertheless, DEX caused significant bradycardia, that required treatment. Epidural administration of 15 mL of 0.5% isobaric bupivacaine with 1 μg/kg DEX provided superior early onset of analgesia, superior intraoperative analgesia, stable cardio-respiratory parameters, prolonged postoperative analgesia, and increased patient comfort, compared to 15 mL of 0.5% isobaric bupivacaine with 2 μg/kg clonidine in patients undergoing lower limb orthopedic surgery. Intrathecal administration of 15 mg of 0.5% isobaric bupivacaine with 5 μg of DEX provided earlier onset of sensory and motor block with longer duration of analgesia and haemodynamic stability, compared to bupivacaine alone, in patients undergoing infraumbilical surgeries. In paediatric population, 1 μg/kg DEX, as an adjuvant to 1 mL/kg of 0.25% bupivacaine in caudal analgesia in patients, aged 2–10 years, undergoing infraumbilical surgeries, resulted in an increased duration of caudal analgesia and improved hemodynamic stability without an increase in adverse effects.

Intraoperative Dexmedetomidine Administration: Progress of Peripheral Nerve Block Analgesia A randomized, paired, triple-blind trial in 21 healthy volunteers who received bilateral saphenous nerve blocks with 20 mL of 0.5% ropivacaine and 1 mL of 100 μg/ml DEX in one thigh, and 20 mL of 0.5% ropivacaine and 1 mL of saline in the contralateral thigh showed that DEX prolonged the saphenous nerve block by a peripheral mechanism, but not necessarily to a clinically relevant extent. In another prospective, randomized, controlled, double-blind, crossover trial, 14 healthy volunteers received an ultrasound-guided tibial nerve block with a 10 mL solution containing 0.5% ropivacaine with 1 μg/kg DEX. the addition of DEX prolonged the duration of sensory blockade, without affecting onset time. Forty-five patients undergoing arthroscopic knee surgery received ultrasound-guided femoral nerve block with 25 mL of 0.5% bupivacaine combined with 25 μg, 50 μg, or 75 μg of DEX before the induction of general aneasthesia. the addition of 50 μg and 75 μg of DEX reduced the onset time, extended the duration of block, prolonged the time to the first postoperative request for rescue analgesia, and reduced postoperative morphine requirements. the 75 μg dose had the best analgesic profile, but was associated with an increased risk of hypotension. a study using DEX 100 μg as an adjuvant to 0.5% bupivacaine in ultrasound-guided combined femoral-sciatic nerve block in 30 patients undergoing below-knee surgery found a prolonged duration of analgesia. However, these patients also experienced significant bradycardia. In another study of 31 patients undergoing elective shoulder surgery under general anaesthesia with an interscalene block, adding 150 μg DEX to 0.5% ropivacaine increased the duration of the nerve block and improved postoperative pain. However, DEX dexreased heart rate, without influencing the blood pressure. a 79-year-old man with multiple cerebral infarcts, congestive heart failure, atrial flutter, and syncope was treated with an above-knee amputation under lumbar plexus and sciatic nerve block with the addition of 1 μg DEX to 0.33% ropivacaine. Complete nerve block was maintained for the full duration of the surgery, and analgesia was maintained for 26 h with haemodynamic stability and moderate sedation. the patient did not complain of pain or require any supplementary analgesics postoperatively, suggesting that DEX with ropivacaine for lumbar plexus and sciatic nerve block may be a feasible and safe technique for high-risk patients undergoing lower limb surgery. Thirty patients undergoing modified radical mastectomy received ultrasound-guided thoracic paravertebral blocks with the addition of 1 μg/kg DEX to 0.25% bupivacaine, and exhibited an improved quality and duration of analgesia, as well as an analgesic sparing effect with no serious side effects. Several reports concluded that 0.5 μg/kg DEX with 0.25% bupivacaine for transversus abdominis plane block in patients undergoing abdominal hysterectomy led to better pain control postoperatively, without any major side effects. In a double-blinded study, 60 adults undergoing thyroid surgeries received bilateral superficial cervical plexus block with the addition of 0.5 μg/kg DEX to 0.5% ropivacaine, and exhibited a significantly prolonged and better quality of postoperative analgesia and patient satisfaction.

Effects of Postoperative Dexmedetomidine Administration in Perioperative Pain Management A prospective, randomized, double-blind, controlled trial reported that the combination of 50 mg oxycodone and 0.5 μg/kg/h DEX for patient-controlled analgesia after video-assisted thoracoscopic lobectomy reduced oxycodone consumption, improved patient satisfaction, and provided better analgesia with fewer side effects (nausea and vomiting), compared with patient-controlled analgesia with oxycodone alone. Another study adding 0.5 μg/kg DEX and 1 μg/kg of neostigmine to 0.25% bupivacaine for epidural anesthesia in 20 patients undergoing orthopedic surgeries found synergism in the analgesic action and a decreased incidence of drug-related side effects. However, there was also an increased requirement of fluids to maintain blood pressure. Patients undergoing vaginal hysterectomies received intrathecal administration of 3 mL of 0.5% hyperbaric bupivacaine with 5 μg DEX in 0.5 mL of normal saline, exhibited a significantly longer duration of sensory block, and reduced doses of postoperative analgesic agents with comparable side effects when compared to the intrathecal administration of 3 mL of 0.5% hyperbaric bupivacaine with 2 mg midazolam in 0.4 mL and 0.1 mL normal saline. Adding 1 μg/kg DEX to 0.75% ropivacaine in 35 patients undergoing arthroscopic shoulder surgery with ultrasound-guided single-dose interscalene block prolonged the interscalene block, and provided better postoperative pain control during the first 24 h, compared to that produced by clonidine. the addition of 2 mL of 0.5 μg/kg DEX to 20 mL of 0.3% ropivacaine for ultrasound-guided bilateral transversus abdominis plane block for postoperative analgesia after abdominal hysterectomy surgery potentiated the analgesic properties of ropivacaine, reduced sufentanil consumption, and provided better pain control. Intra-articular injection of 1 μg/kg DEX at the end of arthroscopic knee surgery was reported to alleviate pain, reduce the postoperative need for narcotics as analgesics, and increase the time to first analgesic request after surgery. a prospective double-blinded study of 100 patients found that intraperitoneal instillations of 50 mL of 0.25% bupivacaine and 1 μg/kg DEX led to a prolonged duration of postoperative analgesia and a decreased requirement for postoperative rescue analgesics, compared to that with bupivacaine alone.

Conclusion In summary, dexmedetomidine plays its analgesic and adjuvant analgesic roles through multiple mechanisms in each stage of the perioperative period. the addition of dexmedetomidine to local anaesthetics is a promising new avenue to enhance their effectiveness. However, dexmedetomidine also has potential adverse effects such as hypotension and bradycardia that must be taken into consideration when administered. Therefore, clinical trials are needed to establish the safe optimal doses that provide the maximum benefit with minimum side effects. In addition, the successful application of epidural and subarachnoid analgesia suggests that dexmedetomidine has the potential to be used for the treatment of chronic pain and neuropathic pain, which is another potential avenue of study.

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