Table 2.

Ketamine administration details and its effectiveness on pain management based on route of administration.

Citation	Dosage of Ketamine (Including Duration)	How and When Was the Pain Measured?	Opioids Use and Dose	Does the Use of Ketamine Improve Pain Management?
Intramuscular
Abd El-Rahman, El Sherif et al. [23]	1 mg/kg	Time to first request analgesia, Visual Analog Scale (VAS) at rest (VAS-R) and on movement (VAS-M) Measured immediately postoperatively, 1, 2, 4, 6, 12, and 24 h postoperatively	Induction of anesthesia included 2 mg/kg fentanyl. Postoperative analgesia comprised patient-controlled anesthesia with an initial morphine bolus of 0.1 mg/kg once pain was expressed by the patient or if the VAS was ≥3, followed by a 1 mg bolus with a 15-min lockout time.	Yes, local wound ketamine instillation provided superior postoperative analgesia with a lower incidence of side effects in comparison with intramuscular ketamine and placebo following total thyroidectomy.
Kamal et al. [31]	0.5 mg/kg ketamine (Group II) or 1 mg/kg ketamine (Group III)	Using a modified Observer’s Assessment of Alertness/Sedation scale (where 6 = agitated to 0 = does not respond to deep stimulus), VAS, time to first request of IV-PCA (which is defined as the time between the end of operation and tracheal extubation to the first request for supplemental analgesics and its administration to the patient), and the cumulative consumption of morphine PCA in the 1st 48 h postoperatively Measured at baseline (upon admission to the surgical intensive care unit (SICU)) and 2, 4, 6, 12, 24, 36, and 48h postoperatively	Fentanyl 50 μg, 100 mg morphine, and an initial morphine bolus of 0.1 mg/kg once pain was expressed by the patient or if the VAS score was ≥3, followed by a 1 mg bolus with a 15-min lockout time.	Yes, ketamine-bupivacaine in thoracic paravertebral block controlled acute postoperative pain in a dose-dependent manner and decreased DN4 scores one month after breast cancer surgery.
Othman et al. [40]	1 mg/kg	VAS Measured and assessed at baseline, one hour, 2 h, 4 h, 6 h, 12 h, 24 h, and 48 h postoperatively	Anesthesia was induced for all participating patients with 2 μg/kg fentanyl, 2–3 mg/kg propofol, and 1.5 mg/kg lidocaine.	Yes, the addition of ketamine to the modified Pecs block prolonged the time to the first request for analgesia and reduced total opioid consumption without serious side effects in patients who underwent a modified radical mastectomy.
Rakhman et al. [41]	1 dose (25 mg ketamine or 1 mL saline) at 4 h preoperatively (K1 or P1); 2 doses (10 and 25 mg ketamine or 1 mL saline twice) at 11 and 4 h (K2 or P2); or 3 doses (5, 10, and 25 mg ketamine or 1 mL saline thrice) at 17, 11, and 4 h preoperatively (K3 or P3).	Numerical rating scale (0–10) Measured every 15 min during the first postoperative hour and every 30 min until discharge from the PACU. On the ward, pain scores and vital signs were recorded every 6 h.	IV midazolam (2 mg), propofol (1–2.5 mg/kg), fentanyl (2–5 g/kg), and rocuronium or vecuronium to facilitate endotracheal intubation. Postoperatively, all patients received morphine (1.5 mg/bolus) via IV PCA. During patients’ stay in the PACU, 4 additional boluses of morphine could be added beyond the PCA protocol by the PACU anesthesiologist upon patient request; further requests to relieve pain were fulfilled with 75 mg of IM diclofenac.	Yes, repeated and escalating subanesthetic doses of intramuscular ketamine administered hours before surgery were associated with lower acute pain scores and lower IV PCA morphine consumption for 48 h after tumor surgery in the studied patients. These doses and the mode of delivery were well tolerated.
Intrathecal
Abd El-Rahman, Mohamed et al. [22]	0.1 mg/kg ketamine in 1 mL volume	VAS Measured at 2, 4, 6, 12, 18, and 24 h postoperation	General anesthesia was induced with fentanyl 1.5 to 2 mg/kg. The morphine group received 10 mg of hyperbaric bupivacaine 0.5% in a 2 mL volume and 0.3 mg of morphine in a 1 mL volume intrathecally. The morphine + ketamine group received 0.3 mg of morphine. Rescue analgesia was represented by patient-controlled analgesia with intravenous morphine, with an initial bolus of 0.1 mg/kg	Yes, adding intrathecal ketamine 0.1 mg/kg to morphine 0.3 mg in patients who underwent major abdominal cancer surgery reduced the total postoperative morphine consumption in comparison with either drug alone, with overall good postoperative analgesia in all groups and no side effects apart from sedation.
Mohamed et al. [38]	0.1 mg/kg in a 1 mL volume	NRS, scored from 0–10 (where 0 = no pain and 10 = the worst pain imaginable) Measured immediately postoperatively, 2, 4, 6, 12, 18, and 24 h postoperatively	Intravenous morphine with an initial bolus of 0.1 mg/kg once pain was expressed by the patient, or if NRS was 3 or more (NRS ≥ 3). Total IV PCA morphine consumption (mg) in G1 was 9.16 ± 3.63, in G2 it was 8.66 ± 3.49, and in G3 it was 6.67 ± 2.8. General anesthesia was induced with fentanyl 1.5–2 µg/kg.	Yes, the combination of intrathecal dexmedetomidine and ketamine provided superior postoperative analgesia, prolonged the time to first request of rescue analgesia, and reduced the total consumption of PCA morphine without serious side effects compared to either drug alone.
Topical
Barton et al. [24]	20 mg (twice a day, in the morning and before bed, for the duration of 4 weeks)	Quality of Life Questionnaire—Chemotherapy-Induced Peripheral Neuropathy (QLQCIPN20 or CIPN-20), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire—CIPN20 (EORTC QLQ-CIPN20), Profile of Mood States (POMS), the Brief Pain Inventory (BPI), and the sensory neuropathy subsection of the NCI Common Terminology Criteria, version 3.0. Measured at baseline, before starting the study gel, and at 4 weeks	None	Yes, topical treatment with BAK-PLO appears to somewhat improve the symptoms of CIPN. This topical gel was well tolerated without evident systemic toxicity.
Gewandter et al. [28]	4g of KA cream (2% ketamine plus 4% amitriptyline) two times per day	NRS. Patients completed the seven-day daily pain, numbness, and tingling diary starting one week prior to entry into the study and at three and six weeks after study enrollment. The daily scores were averaged to calculate the pain, numbness, and tingling score for each data point. Measured 1 week prior to entry into study and 3 and 6 weeks after study enrollment	N/a	No, two percent ketamine plus 4% amitriptyline cream does not decrease CIPN symptoms in cancer survivors.
Oral
Fallon et al. [27]	The starting dosage was 40mg/d, with a maximum dosage of 400 mg/d. Patients continued to receive a stable dosage for 16 days	Sensory Component of the Short Form, McGill Pain Questionnaire Measured at baseline and 16 days	The median morphine equivalent daily dose for both arms was 0 mg.	No, ketamine was equivalent to a placebo for cancer-related neuropathic pain.
Ishizuka et al. [30]	10 mg of ketamine	Pain severity was evaluated through a verbal scale, in which patients used the following scores: no pain = 0, mild = 1, moderate = 2, and severe = 3. Measured for four weeks, with interviews on the 7th, 14th, 21st, and 28th days	Oral morphine, 10 mg every 6 h, adjusted to every four hours if needed. The dose of morphine was increased (5 mg) whenever necessary, in each weekly evaluation, during the study.	No, a reduction in the need for opioids, lower pain scores, or greater pain relief in patients taking S(+) ketamine was not observed when compared to the placebo group, which goes against the reports in the literature for racemic ketamine.
Lauretti, Lima et al. [35]	0.5 mg/kg at 12 h intervals	VAS Measured on days 1, 5, 10, 15, 20, and 30 after the test drug was introduced	The morphine regimen was adjusted individually to a maximal oral dose of 80–90 mg/day to keep the VAS pain score less than 4. All patients in all groups had free access to as much morphine as they needed, with a maximum dose of 80–90 mg/day. At that point, when patients reported pain (VAS a-4), despite taking 80–90 mg of oral morphine daily, the test drug was added as follows: the control group received 20 mg of additional oral morphine (10 mg at 12 h intervals)	Yes, low-dose ketamine and transdermal nitroglycerin were effective co-adjuvant analgesics. In conjunction with their opioid tolerance-sparing function, joint delivery of ketamine or nitric oxide donors with opiates may be of significant benefit in cancer pain management.
Subcutaneous infusion
Hardy et al. [29]	100, 300, or 500 mg were prepared by diluting ketamine hydrochloride 200 mg/2 mL in 24 h	BPI average pain score (reduction in BPI average pain score by greater than or equal to 2 points from baseline in the absence of more than four breakthrough doses of analgesia over the previous 24 h) Measured at the end of the 5-day study period	Minimum Daily Oral Dose of morphine, oxycodone, and hydromorphone was 60, 30, 8, and 20 mg, respectively. Minimum Parenteral Dose/24 Hours for morphine, oxycodone, hydromorphone, methadone, fentanyl, sufentanil, and alfentanil were 20 mg, 15 mg, 3 mg, 10 mg, 25 μg/h TTS or 600 μg SC/IV, 30 μg SC/IV, and 2 mg, respectively.	No, it had a strong placebo effect and failed to show any additional clinical benefit for ketamine when delivered subcutaneously in a dose-escalating regimen over 5 days, while significantly increasing toxicity.
Lauretti, Gomes et al. [34]	0.2 mg/kg epidural ketamine (2 mL)	VAS Measured within 25 days of observation (days 1, 2, 3, 8, 15, and 25)	The morphine regimen was adjusted individually to a maximal oral dose of 80–90 mg/day to keep the visual analog scale score less than 4. Pain was initially treated with epidural morphine 2 mg twice daily (12 hr intervals) to maintain the VAS below 4/10. Afterwards, VAS scores > 4/10 at any time were treated by adding the epidural study drug (2 mL), which was administered each morning, just after the 2 mg epidural morphine administration. The control group (CG) received 2 mg of epidural morphine (2 mL).	Yes, the association of low-dose epidural ketamine or neostigmine enhanced epidural morphine analgesia when administered in the early stages of terminal cancer pain therapy, without increasing the incidence of adverse effects, while ketamine also reduced the morphine requirement during the period of observation.
Intravenous
Chelly et al. [25]	10 mg (1 mL)	Numeric Rating Scale (NRS) Measured every six hours (±two hours) until discharge, although the patients were not awakened for pain assessment during the night. Postoperative morphine consumption was also recorded at 24 hr and 48 hr (morphine equivalent)	Morphine 1–2 mg IV was given every ten minutes as needed to control immediate postoperative pain until the patient had free access to a morphine set-up delivering a morphine bolus of 1 mg with an eight-minute lockout	Yes, paravertebral blocks combined with celecoxib and ketamine provide better immediate postoperative pain control and facilitate earlier functional recovery in patients undergoing an open radical prostatectomy when compared with PCA alone.
De Kock et al. [26]	Ketamine at the bolus dose of 0.25 mg/kg, followed by an infusion of 0.125 mg/kg per h (group 2), 0.5 mg/kg and 0.25 mg/kg per h (group 3), epidural ketamine 0.25 mg/kg and 0.125 mg/kg per h (group 4), or 0.5 mg/kg and 0.25 mg/kg per h (group 5)	The cumulative number of met and unmet PCA morphine demands, the pain VAS scores at rest, at cough, and at mobilization, and the area of hyperalgesia for punctate mechanical stimuli around the surgical incision. Measured by the cumulative number of met and unmet PCA morphine demands at 2, 6, 12, 24, 36, and 48 h. The pain VAS scores were assessed by a blinded observer at 15 min, 2, 6, 12, 24, 36, and 48 h	All the patients, in any group considered, received an epidural bolus, including sufentanil 2.5 mg. This was immediately followed by an infusion that included sufentanil 0.75 mg/h at a rate of 4 ± 5 mL/h. This epidural infusion was stopped at the end of surgery.	Yes, subanesthetic doses of IV ketamine (0.5 mg/kg bolus followed by 0.25 mg/kg per h) given during anesthesia reduce wound hyperalgesia and are a useful adjuvant in perioperative balanced analgesia. Moreover, the systemic route is clearly the preferential route.
Kang et al. [32]	Between induction and skin incision, patients received a 0.25 mL/kg (0.5 mg/kg of ketamine or normal saline) study drug bolus followed by continuous infusion at 0.06 mL/kg/h (0.12 mg/kg of ketamine or normal saline) until the end of surgery	Via telephone, the first question was whether the patient had surgery-related pain. If the answer was positive, the investigator asked for their NRSr and NRSd questions from the Numeric Rating Scale for pain Measured 1, 3, and 6 months after surgery	Anesthesia was induced by total intravenous anesthesia using target-controlled infusion with propofol and remifentanil to reach 5 μg/mL and 4 ng/mL of effect site concentration (Ce), respectively. In order to ensure adequate and similar anesthesia between the groups, propofol was titrated to maintain a target Bispectral Index value between 40 and 50, and the remifentanil infusion rate was titrated between 2 and 4 ng/mL in order to keep mean arterial pressure within 20% of baseline. 0.1 mg/kg of morphine sulfate was administered along with 0.075 mg of palonosetron HCl. It contained morphine sulfate 100 mg (20 mL) with 80 mL of normal saline (1 mg/mL morphine sulfate). The pump delivered 2 mL boluses with a lockout period of 5 min and a 4 h limit of 20 mL. If the NRS-11 was more than 4 despite using the PCA, rescue medication (4 mg of morphine sulfate) was injected intravenously by a nurse in the postanesthetic care unit (PACU) and the general ward. The PCA was discontinued 72 h postoperatively.	Yes; while intraoperative low-dose ketamine without postoperative infusion significantly reduced the incidence of PPSP up to 3 months after breast cancer surgery, it failed to reduce clinically significant PPSP and improve patients’ quality of life.
Kollender et al. [33]	Drug injections consisted of a solution that contained 1.5 mg morphine (group MO) or 1 mg morphine plus 5 mg ketamine/bolus (group MK).	VAS Measured every 15 min for the first 2 h, every 30 min for the next 2 h and every 6 h until the IV-PCA device was disconnected	Drug injections consisted of a solution that contained 1.5 mg morphine (group MO) or 1 mg morphine plus the test drug (group MK).	Yes, the use of subanesthetic ketamine plus 2/3 of the standard dose of morphine following bone and tissue resections results in (1) a lower and more stable pain score, (2) a 60% morphine sparing effect, and (3) a shorter period of postoperative IV-PCA dependence.
Lavand’homme et al. [36]	0.5 mg/kg bolus followed by continuous infusion at 0.25 mg/kg/h) was started before skin incision and discontinued at the end of the procedure	VAS and patient-controlled analgesia Measured by the cumulative number of met PCA or PCEA demands at 12, 24, 48, and 72 h and visual analog scale pain scores at rest, cough, and mobilization assessed by a blinded observer at 30, 60, 90, and 120 min and 24, 48, and 72 h	Tracheal intubation was performed with 2.5 μg sufentanil and other anesthetics.	Yes, combined with an antihyperalgesic dose of ketamine, intraoperative epidural analgesia provides effective preventive analgesia after major digestive surgery.
Mahran et al. [37]	0.5 mg/kg ketamine in 5 mL of normal saline syringe IV before induction of anesthesia, followed by ketamine infusion at a rate of 0.25 mg/kg/h till the end of the surgery (the end of skin closure).	VAS at rest and with movement Measured after 30 min and subsequently after 2, 4, 6, 12, and 24 h	General anesthesia was induced with fentanyl 1–2 µg/kg IV. Additional doses of fentanyl were given so as to maintain HR within 15% of the baseline value and systolic arterial blood pressure within 20% of the baseline value. After emergence from anesthesia, the patients were transferred to the recovery room, and a PCA device was connected to the IV route of the patient. A solution of morphine (1 mg/mL) was prepared for the PCA. The PCA device was set for all groups with a demand dose of 1 mL and a lockout interval of 10 min, without a continuous background infusion.	No, neither the use of preoperative IV ketamine 0.5 mg/kg nor the preoperative oral use of 150 mg pregabalin could reduce VAS scores in patients undergoing breast cancer surgery, but they were proven in this study to reduce postoperative opioid requirements, rendering them a good co-analgesic in multi-modal analgesia with a good safety profile.
Nesher et al. [39]	1 mg of morphine plus a 5 mg ketamine bolus (MK).	VAS Measured every 15 min for 4 h	For anesthesia, 1 mg/kg; medium-dose fentanyl, patients were connected to patient-controlled IV analgesia, delivering 1.5 mg of morphine plus saline solution (MO) or 1.0 mg of morphine plus the test drug (MK). MO patients used 6.8 mg/h (mean) and 5.5 mg/h of morphine during the first and second hours, respectively; MK patients used 3.7 mg/h and 2.8 mg/h, respectively.	Yes, subanesthetic ketamine combined with a 35%-lower morphine dose provided equivalent pain control compared to the standard morphine dose alone, with fewer adverse side effects and a 45% reduction in morphine consumption.
Shah et al. [42]	Pre-incisional ketamine dose of 0.5 mg/kg, two more ketamine doses (0.25 mg/kg) were administered at 20-min intervals.	VAS Measured immediately after tracheal extubation and at one, two, four, eight, and 24 h postoperatively	Morphine 1.5 mg, fentanyl 2 µg/kg. Rescue analgesia comprised additional fentanyl boluses (20 µg each; maximum total dose 3 µg/kg) followed by 3 mg morphine boluses (maximum total dose 0.2 mg/kg) if VAS was still ≥3	Yes, pre-emptive PECS-blocks supplemented with low-dose ketamine and dexmedetomidine comprise a practical and useful alternative technique to the standard opioid-based general anesthetic technique for MRM.