Opioids are the most commonly used medications for perioperative pan control. Recent studies evaluated the efficacy of nonopioids, such as ketamine, lidocaine, and naloxone, as perioperative infusion to decrease pain after surgery. Esmolol and Dexmedetomidine have also been investigated but these drugs have rarely been employed for perioperative pain management.

Noncompetetive N-methyl-D-aspartate glutamate(NMDA) receptor antagonist Sodium channel blocker Available as racemic ketamine which contains the S(+) and R(-) ketamine Half life of min Its metabolite norketamine has a longer half life and is one third as potent as the parent component

Analgesic properties at low doses Does not depress the laryngeal protective reflexes Does not suppress cardiovascular function in the presence of an intact CNS Less depression of ventilation compared to opioids May stimulate respiration Used in subanesthetic dose as an analgesic Plasma conc. 100 to 150 ng/ml produces analgesia Undesirable side effects :Cardiovascular excitation, psychomimetic side effects, tolerance, accumulation of metabolites, malaise

Most of the randomized controlled clinical studies on perioperative IV ketamine shows some beneficial effect. Cervical and lumbar spine surgery: Ketamine 1 mg/kg bolus 83 mcg/kg/h maintenance Resulted in lower pain scores less analgesic requirements and better satisfaction than patients who had saline infusion or those had lower dose of ketamine infusion(42 mcg/kg/h)

Major abdominal surgery Loading dose 0.5 mg/kg Maintenance 2 mcg/kg/min For 48 h after surgery Resulted in lower morphine consumption than patients with saline infusion.

Bilgin et al Compared ketamine bolus followed by an infusion with ketamine bolus alone either before surgical incision or at wound closure in gynecological laparotomy patients. The patients who had the ketamine bolus and infusion had lower pain scores and lower morphine consumption.

No beneficial effect of the ketamine infusion was noted when the general anesthetic consisted of total intravenous anesthesia with remifentanil and propofol infusion. The absence of beneficial effect may be related to the generous use of opioids intraoperatively.

The role of perioperative ketamine in preventing post amputation pain Loading dose 0.5 mg/kg Infusion 0.5 mg/kg/h for 72 h Was not effective in reducing morphine consumption or decreasing the stump allodynia At the 6 month follow up the incidence of phantom pain and stump pain was 47% in ketamine group compared to 71% and 35% in the control (saline) group.

A ketamine infusion appears to have a salutary effec on epidural analgesia The addition of ketamine infusion to epidural analgesia in patients who underwent surgery for rectal adenocarcinoma resulted in less patient-controlled analgesia, morphine requirements and reduced area of hyperalgesia. Interestingly the patients also had less residual pain until the sixth postoperative month.

Results: Large variations in clinical setting Small number of patients studied Different ketamine regimens Different rout of administration Some beneficial effects in low dose ketamine infusion Improve the efficacy of epidural analgesia Does not seem to have any effect when TIVA is used.

Lidocaine has peripheral and central effects for pain relief. It inhibits leukocyte migration and metabolic activation Decrease albumin extravasation in animal models of chemical peritonitis Centrally it has been shown to modify the neuronal responses in the dorsal horn and selectively suppress synaptic spinal transmission by decreasing C-fiber evoked activity in the spinal cord

Several studies showed the beneficial effect of IV lidocaine infusion Cassuto studied in abdominal surgery Patients underwent cholecystectomies IV bolus of 100 mg lidocaine Infusion at 2mg/min Starting at 30 min before surgery Patients had lower pain scores during the first day and significantly less meperidine during the first 2 postoperative days compared with saline infusion group.

Groudine studied lidocaine infusion in retropubic prostatectomy patients 1.5 mg/kg bolus 3mg/min infusion Continued until 1 h postoperatively Lower VAS Shorter return of bowel movement Shorter hospital stay But equal opioids consumption in both groups The same beneficial effects in Koppert study in major abdominal surgery

Two studies not only looked pain relief but the effect of lidocaine on markers of inflammation and immune response Significant attenuation of the plasma level of IL-1 IL-8 Complement C3a IL-1 ra CD11b P-selectin Platelet leukocyte aggregates

The beneficial effects of IV lidocaine infusion were not duplicated in patients who had a total hip replacement or coronary artery bypass graft.

IV lidocaine infusion appears not to be as effective as perioperative epidural analgesia

The beneficial effects of a perioperative infusion in abdominal surgery may be related to its ability to suppress inflammatory process secondary to surgery. Also it attenuates proinflammatory cytokines which induce peripheral and central nervous system sensitization leading to hyperalgesia. These effects are not seen when the trauma is minimal like ambulatory surgery. Also, when there is a moderate component of neuropathic pain such as total hip or thoracic surgery these effects are not seen.

Pure mu receptor antagonist. Use with morphine to decrease the incidence of side effects is intuitive. Possibility of reversing the analgesia from the opioid. Naloxone infusion has been utilized to decrease the incidence of nausea, vomiting, respiratory depression, and urinary retention after epidural and intratechal opioids.

A retrospective study in radical prostatectomy patients showed 0.8 to 1.7 mg intratechal morphine with 5 mcg.kg.h naloxone IV infusion provided excellent analgesia with infrequent and minor side effects. In a RCT Gan et al assigned 60 patients who underwent hysterectomy into three groups: PCA morphine with low dose naloxone, PCA morphine with saline infusion, and PCA morphine with high dose naloxone infusion. There was no difference in verbal rating score (VRS) for pain among the three groups, morphine use was significantly lower in the low dose group, respiratory depression, sedation score, hemodynamic parameters, were equal.

Some investigations noted the biphasic or dual modulatory effect of naloxone; The mechanism of analgesic effect of naloxone maybe related to the release of endorphins or displacement of endorphins from receptor sites not pertinent to analgesia, potentiation of the activity of opioid receptors is another possibility although this upregulation phenomenon has been demonstrated after prolonged(7days) naloxone infusion in animals.

At higher doses naloxone blocks the action of the released or displaced endorphin at the postsynaptic receptors.

There seems to be no added efficacy when naloxone is administered via IV PCA. THE LACK OF ADDED BENEFIT MAYBE DUE TO THE DIFFERENT PHARMACOKINETICS OF THE DRUG WHEN GIVEN INTERMITTENTLY. Naloxone has an alpha half-life of 4 min and a beta half-life of 55 min and a continuous infusion may have resulted in a constant plasma level resulting in a more consistent effect.

In summary, it appears that the present indication for IV naloxone infusion is to control the side effects of neuraxial opioids Only the study of Gan et al showed the efficacy of a low dose naloxone infusion in reducing opioid consumption.

Some surgeons infiltrate the surgical incision with local anesthetics at the end of the operation. Such practice only result in transient relief. For the effect to last longer, surgeons infuse the wound with local anesthetics after the surgery. These wound infusions have been employed in painful procedures such as thoracic, cardiac, breast, abdominal, gynecologic, cesarean section, and spinal surgeries. Studies showed the beneficial effects of local anesthetic wound infusion after thoracic operations.

A qualitative and quantitative review of the literature on local anesthetic wound infusions concluded that the available data consistently showed improved analgesia across a range of procedures, a very low technical failure rate, and zero reported toxicity. Patient compliance is acceptable and wound infection rate have not increased.