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A review on the recent application of ketamine in management of anesthesia, pain, and health care

Ketamine is considered as a promising drug for many clinical applications even after five decades since its discovery. Ketamine is a dissociative anesthetic agent with a variety of pharmacological effects from anesthetic induction and maintenance to analgesic and sedative depending on the consuming dose. It can be used solely or in combination with other co-adjuvant drugs, increasing their efficacy. Many therapeutic properties of ketamine have been attributed to its antagonism mechanism to N-Methyl-D-aspartate receptor. Identifying new properties of ketamine such as neuroprotective, antiinflammatory, and antitumor effects, on one hand, and taking advantage of subanesthetic regimens of ketamine, on the other hand, have resulted in a widespread use of ketamine in various clinical applications. Ketamine is solvable in aqueous and lipid solutions, providing convenient administration via multiple routes, including oral, nasal, rectal, intravenous, intramuscular, subcutaneous, transdermal, sublingual, and intraosseous administration. Application of ketamine has some advantages over other sedative and anesthetic agents. It produces bronchodilation status, allowing for most secure induction of anesthesia in patients with life-threatening asthma and intense acute bronchial constriction. Ketamine has an excellent hemodynamic profile, makes it the agent of choice for patients with unstable hemodynamics, such as shocked or hypotensive patients. Ketamine usage has been associated with a lower risk of respiratory depression and relatively more conserved airway reflexes. Although being an anesthetic agent, ketamine has been increasingly used in subanesthetic doses for acute and chronic pain as well as depression. Using ketamine in pre and postoperative pain management is well established. However, the studies on ketamine performance in pain management demonstrated contradicting results. On the other hand, various side effects along with no confirmatory data on long-term treatment demand great caution when using ketamine for treating complex chronic pains. The present study aimed to provide a general review on the recent applications of ketamine in anesthesia, pain management, and critical care.


Introduction
The unique properties of ketamine and its large versatility make it suitable to be used in prehospital medicine and emergency situations, and anesthetists and their assistants benefit its unique properties all over the world. [7] Ketamine satisfies many requirements of an ideal opioid alternative, including strong analgesia, [8][9][10] proper hemodynamic profile, very little inherent respiratory depression, and governable adverse effects. [11,12] As a dissociative anesthetic, ketamine provides deep analgesia with amnesia. [13] Compared to other anesthetic agents, ketamine usage results in lower risk of respiratory depression and relatively more conserved airway reflexes. [14] Currently, using ketamine for anesthesia is limited due to the factors such as incidence of various side effects (e.g. excitation, illusion, and panic attacks), the availability of new alternatives, its disturbing emergence reactions, and the potential to be abused by individuals. [15] For example, the application of ketamine in perioperative pain management is more common than using as an induction agent of general anesthesia. [16,17] Using ketamine as an anesthetic has been reported to be beneficial in certain cases such as in the prehospital setting, [2,7,13] in trauma patients with hemodynamic compromise, [14,18] in military services for wounded troops, and for children requiring sedation for painful or frightening procedures in the Emergency Department.
Over the past decade, several new clinical applications of ketamine have been explored by researchers. Some of the newer uses of ketamine include: using low-dose analgesic protocols to treat moderate to severe acute and chronic pain, [2,7,19] using for reactive airways disease, applications as a strong and rapid antidepressant in patients with high depression while therapy, [20] using as adjuvant therapy in local anesthetic nerve blocks, and applications as procedural sedation in normal and complex procedures among others. [7] Although being an anesthetic agent, using ketamine at low or subanesthetic doses is a very effective pain reliever for many painful conditions. It can also be applied as a potent adjunct in perioperative duration. [11] Anesthesiologists and other clinicians from various disciplines have used subanesthetic or low doses of ketamine to treat chronic pain syndromes which are resistant to therapy. [2] The analgesic [21] and antidepressant [22] characteristics of ketamine in subanesthetic doses have been explored by researchers of many countries. Although there is no decisive clinical proof supporting its use, a large number of clinicians, based on their observations of its positive effects during treatment, are using low-dose ketamine as an auxiliary analgesic for acute and chronic pain management. [23][24][25] Despite the great potential of ketamine in pain management, its various treatment regimens lead to concerns regarding adverse effects. [26] The adverse effects of ketamine vary based on the administered dose, and a range of the side effects has been related to using high doses of ketamine. [13,27,28] Despite the importance of prescription dose levels of ketamine in the occurrence of the side effects, there is no general consensus on dose or administration regimen. [5] The aim of the present study is to provide an overview of recent literature on the various applications of ketamine and its benefits and risks for patients in various clinical settings. It also summarizes the proposal doses of ketamine for many clinical settings.

Methods
In order to find relevant articles with the subject of this study, extensive research was performed on PubMed, Embase, and Google Scholar electronic databases as well as some other clinical websites and journals. The text words used in the search included "ketamine," "anesthesia," "ketamine side effects," "sub-anesthetic dose," "analgesia," "acute pain," "chronic pain," and "cancer pain." After finding the relevant articles, the information and data was extracted according to the objectives of the study. The bibliographies of obtained articles were investigated for new relevant publications that were missed in the initial search. Then, articles were reviewed and our criteria for selecting articles were applied. Only those articles were selected that were written in English and published after 2010.

Search Results
Totally, 784 records were obtained through searching databases and other sources, of which 195 duplicate records were removed. Of the remaining 589 records, 403 unrelated articles were excluded. The remaining 186 relevant articles were screened by their year of publication, and 98 records were excluded. After removing some other records, finally 84 related articles were selected in this review. The collected articles were categorized within four main groups including "pharmacology of ketamine," "ketamine as anesthetic drug," "ketamine for pain management," and "ketamine as an antidepressant." Figure 1 shows the flowchart of the selection steps of related articles for this study.

Structure of ketamine
Ketamine belongs to a group of compounds called arylcyclohexylamines. They consist of several substances with psychoactive impacts, which can be used either as medicals or drugs of abuse. The chemical structure of ketamine is (+/-) 2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone with the chemical formula of C13H16ClNO and a molecular weight of 274.4 g/mol. [15] It is a chiral compound, containing an asymmetric carbon atom and two optical isomers: R-(−)-isomer and S-(+) isomer [ Figure 2]. [29] The S-(+)-isomer is pharmacologically more active [30] and has more potent anesthetic and analgesic properties than the R-(-) isomer. [13,31] Pharmacology of ketamine Pharmacokinetics (PK) Ketamine has low protein-binding ability and is quickly solved in lipid and aqueous solutions. [13,30,32] This allows the ketamine to quickly transfer across the blood-brain barrier and increase the concentration there to 4-5 times of the concentration in the plasma. [7] This results in the rapid commencement of acute analgesic effect. [2] Ketamine is metabolized in the liver by cytochromes of CYP2B6, CYP3A4, and CYP2C9 to norketamine via ring hydroxylation and N-demethylation pathways, [33] and further metabolized into 4-, 5-, and 6-hydroxynorketamine by CYP2B6 and CYP2A6. As the main metabolite of ketamine, norketamine has less anesthetic potency than ketamine. [7,30] It is generated a few minutes after intravenous ketamine and reaches its peak levels within 30 min after administration. The norketamine is excreted through urine and bile after glucuronidation in the liver. [2,7] Ketamine and other related arylcyclohexylamines operate as noncompetitive antagonists at N-methyl-D-aspartate (NMDA) receptors. [2,28,30,34] Many therapeutic properties of ketamine such as anesthetic and analgesic as well as antidepressant properties have been attributed to this mechanism in the brain and dorsal horn neurons. [35] Ketamine interactions with other receptors [28,36] and cholinergic, monoamine, purinergic, and adrenoreceptor systems have also been reported. [30,37] Ketamine provokes the sympathetic nervous system, leading to increased cardiac output, blood pressure, and heart rate. [11] As a result, using ketamine for patients with ischemic heart disease requires major caution. [7] On the other hand, ketamine due to its effect of increasing blood pressure is often used in trauma patients with hemodynamic compromise. [14] Ketamine has negligible effects on central respiratory system, providing airway relaxation by targeting various receptors. [29,30] However, airway reflexes in children less than 12 months are unpredictable and uncertain. Moreover, a slight respiratory depressive effect during ketamine administration has been reported. Due to producing bronchodilation status, ketamine is preferred for patients with intensive asthma who require mechanical ventilation. Ketamine affects the central nervous system, producing a cataleptic state with strong analgesia and sedation. [7] It produces a unique dissociative state where the patient eyes are open but detached from the surroundings. [30] Route of administration Due to the solvability of ketamine in aqueous and lipid solutions, it could be conveniently administered via multiple routes. Clinical considerations are vital in selecting the route of administration to prevent suboptimal concentrations of the drug in the plasma. [38] The traditional routes for ketamine administration are intravenous or intramuscular, [5,39] which provides the highest percentages of bioavailability at 100% and 93%, respectively. [40] However, these routes are not always achievable in some circumstances (e.g. in some emergencies or in children and obese patients). There are a number of alternative routes for administering ketamine with acceptable outcomes including oral, nasal, rectal, transdermal, sublingual, subcutaneous, and intraosseous administration. [2,7,40,41] Intraosseous route has recently been shown to provide a rapid and safe method for ketamine administration. [42,43] This method is especially useful for geriatrics, remote administration, and preclinical emergency.

Therapeutic applications of ketamine
Ketamine as general anesthesia in the operating room The application of ketamine in the operating room dated back to nearly 50 years. Ketamine as an intravenous anesthetic agent produces a "dissociative anesthesia" and commonly used in hospital and prehospital environments for emergency situations. In the case of general anesthesia, a dose of 1-2 mg/kg intravenously is typically administered with a duration of action about 5-10 min of administration. [13] However, the same dose can be applied via rapid sequence induction, producing dissociative anesthesia about 1-2 min after administration. [7] Ketamine produces bronchodilation status, allowing for most secure induction of anesthesia in patients with life-threatening  asthma and intense acute bronchial constriction. [28] The role of ketamine in diminishing bronchospasm in the patients who suffer from respiratory distress has been well documented. It is reported that ketamine doses of 0.1-0.2 mg/kg pursued by an infusion of 0.15-2.5 mg/kg/h can be used in patients with refractory bronchospasm and intensive status of asthma. [29,30] Ketamine has many hemodynamic advantages over more traditional intravenous induction agents such as propofol or thiopentone, makes it the agent of choice for patients with unstable hemodynamics, such as shocked or hypotensive patients. [7,28] The application of ketamine for general anesthesia induction in caesarean operation has also been confirmed. It is reported that using ketamine 1.5 mg/kg in hypotensive and hypovolemic parturient such as uterine rupture or placental abruption prevents the increase of uterine tone and maternal awareness. No respiratory depression of neonates has been reported by this dose. [1] The successful application of ketamine as an alternative to etomidate in endotracheal intubation of patients with severe sepsis, [30] patients with traumatic brain injury, [44] and those with cardiac tamponade and restrictive pericarditis [33] has been documented. Moreover, it is reported that using ketamine as an alternative to sevoflurane in patients with congenital heart disease leads to better hemodynamic stability while and after the operation. [45] Administration of ketamine increases vascular resistance and therefore decreases the blood flow from the right heart to the left heart. As a result, it is considered as a preferable agent for inducing anesthesia in patients with congenital heart disease with right to left shunt, especially in children. [46] Moreover, ketamine improves oxygenation by increasing pulmonary blood flow. [26] It is shown that giving reduced doses of ketamine intravenously (0.25-0.5 mg/kg) before full induction of anesthesia results better preoxygenation in agitated patients. [47] Ketamine can be used solely or in combination with some hypnotics like benzodiazepines and propofol. It can be combined in low doses (0.5 mg/kg) with intravenous diazepam or midazolam, producing local and regional anesthesia in adults and children. [33] To maintain anesthesia, intravenous doses of 0.5 mg/kg, or 10 to 30 μg/kg/min continuous infusion can be applied. It is suggested that infusion to be discontinued 20 to 30 min before the completion of surgery. [7] Ketamine for pain management After five decades of its discovery, ketamine is considered as a promising drug for many clinical setting. Although being an anesthetic agent in doses between 1 and 4.5 mg/kg, ketamine has been increasingly used in subanesthetic doses for acute and chronic pain as well as depression.

Use in acute pains
Managing acute pain in patients is of great importance since insufficient management can increase the risk of chronic pain, reducing the quality of life among these patients. [9,48] In recent years, opioids have always been a part of acute pain management. However, using opioids increases the hyperalgesia possibility, resulting more analgesic requirements. Administration of low-dose ketamine can prevent sensitivity to opioids. [28] It is reported that ketamine can reduce the need for opioid consumption and the risk of post-surgical pain. [49,50] Moreover, it has been applied successfully to patients with weak response to traditional opioids.
The analgesic characteristics of ketamine are primarily established via the NMDA receptors located at the central nervous system, [51] and to some extent through opioid receptors. [52] Ketamine is especially preferred for patients with high pain scores, such as surgery patients who experience high levels of postoperative pain. [26] Clinical studies have examined the role of ketamine in multiple clinical scenarios.
Using ketamine has been reported to provide the same analgesia with opioids in war and accident injuries. [53] There are a large number of studies on using ketamine to provide analgesia in patients with burns and severe pain. [28,54] The application of ketamine in burn dressings, dressing changes or excisions, and grafting is very common and is shown to be practical and tolerable for pediatric patients with burns. [55] Despite all of these, the main advantage of using ketamine for patients with burns is that it maintains the normal function of the respiratory system and provides a good sedoanalgesia. [56] There is a large body of studies examined the effects of ketamine on peri and postoperative pain management. Many researchers have reported that perioperative ketamine alleviates pain severity after operation. [57][58][59][60] It has been shown that ketamine reduces the need for opioid consumption and results in less postoperative nausea. [57,60,61] Recently, a Cochrane review has also shown that prescribing subanesthetic ketamine can reduce postoperative morphine necessity and provide better outcomes for nausea and vomiting. [62] According to this review study, perioperative ketamine was well-tolerated by patients and no significant side effects were identified. A recent meta-analysis is reported that patients receiving continuous subanesthetic ketamine experienced considerably less pain than those treated by traditional opioid therapies. [63] There are a variety of dosing regimens for ketamine administration in various clinical scenarios. Higher doses are prescribed for induction of anesthesia with 1-4.5 mg/kg intravenously, rapid-sequence intubation with 1-2 mg/kg intravenously, and for procedural sedation with 0.5-1 mg/kg intravenously. [31] Lower doses of ketamine can be administered for pain management. Low-dose ketamine has various definitions based on the route of administration. In the case of intramuscular administration, a bolus dose of less than 2 mg/kg considered as low-dose, while for intravenous or epidural route, it is less than 1 mg/kg. Moreover, an intravenous infusion rate of ≤20 c/kg/min is considered as low-dose or subanesthetic ketamine. [64] Ketamine has dose-dependent side effects. Severe adverse effects have mostly occurred in high doses. However, occurring side effects in low doses, albeit at a lower incidence, is possible; thus, caution is advised when administering any doses of ketamine, especially in patients with cardiovascular disease.

Use in noncancer chronic pains
Central sensitization or neuropathic processes induced by prolonged nociceptive stimulation can result in chronic pains. The inhibition effect of ketamine on NMDA receptors can play a role in chronic pain management. [28] The reports on the clinical use of ketamine for chronic pain states dated back to late 1990s, where ketamine used to treat chronic neuropathic pain. [53] Since then, ketamine has been used in various chronic conditions, especially those with a neuropathic origin, and cancer pain. [65,66] Using ketamine in low doses results in robust analgesia for patients with neuropathic pain. This effect thought to be primarily as a result of blocking the NMDA receptor by ketamine. [67] The NMDAR, which is existing at spinal and supraspinal sites, is an excitatory glutamatergic receptor, participating in nociceptive signal transmissions.
The direct analgesic characteristic of ketamine along with its efficacy in hyperalgesia and opiate tolerance has accelerated its use in chronic pain conditions. However, clear evidence for ketamine efficiency in the management of chronic pains is scarce. The studies on ketamine performance in chronic pain treatment show contradicting results. On the other hand, various side effects along with no confirmatory data on long-term treatment demand great caution when using ketamine for treating complex chronic pains.
According to some studies, using ketamine have some short-term benefits for pain therapy in patients with chronic peripheral and central neuropathic pain, chronic regional pain syndrome, phantom and ischemic limb pain, chronic migraine, fibromyalgia, and visceral pain. [33] Moreover, ketamine has been used in patients with chronic pain, who poorly responded to standard analgesics and other treatments. [68] Intravenous infusions of ketamine have been increasingly used for refractory chronic pain. In these situations, patients may be received infusion treatment over several days. The used doses should be kept as low as possible. [26] It is reported that intravenous infusion of ketamine in the rate of 300 μg/kg over 3 h resulted in complete sedation of phantom limb pain. [69] Moreover, using low-dose intranasal ketamine has been reported to be beneficial in patients with neuropathic pain. [49] Using ketamine in patients with therapy-resistant severe neuropathic pain should be restricted due to the side effects like cardiovascular stimulation, psychedelic symptoms, and hepatotoxicity. [19] Use in cancer pains Ketamine is often administered together with other co-adjuvant drugs in palliative care practice, when the pain cannot be relieved by the use of opioids and other traditional drugs such as amitriptyline, gabapentinoids, and nonsteroidal antiinflammatory drugs. The use of ketamine together with opioids can improve the efficacy of cancer pain therapy. [26] Nowadays, ketamine is regarded as an essential adjuvant drug in palliative care in many countries. It could be administered in various regimens through oral, intravenous, intrathecal, subcutaneous, and topical routes of administration. Low-doses are preferable since ketamine has dose-dependent side effects. As a result, ketamine is always administered with low doses and increased to higher doses if required.
The oral doses can begin with 2-25 mg/3-4 times per day and increased up to 40-60 mg/4 times per day to produce sufficient analgesia. The intravenous and subcutaneous doses for analgesia are usually varied between 2.5-5 mg and 2.5-25 mg, respectively. [15,70] It is reported that oral ketamine may result in fewer side effects and provide stronger analgesia compared to subcutaneous ketamine. [71] The same study has argued that an intrathecal dose of 22.5 mg per day in combination to morphine resulted in pain relief of metastasis and urethral carcinoma patients who suffered from leg pain.
It is suggested that ketamine can produce antitumor effects by blocking the NMDA receptor. [72] Moreover, using ketamine as an adjunct to morphine has been reported to enhance the morphine efficacy in cancer pain therapy. [73] Ketamine is effective for the cases that cancer pain is refractory to opioids and adjuvant drugs. Conducting trials in cancer patients is undoubtedly challenging. This limited the sufficient evidence on the efficacy of ketamine in this group of patients. Although there are a variety of causes for pain among cancer patients, it could be articulated that ketamine is a drug of choice for the cases where opioid tolerance, inflammatory pain, neuropathic pain component, and depression or a combination of these factors are problematic. [26] It is favorable to evaluate the benefits against its risks and costs before using ketamine for treating cancer patients. Moreover, it is recommended that ketamine administration to be restricted until there are sufficient evidence on its safety.

Ketamine as an antidepressant
The antidepressant effect of ketamine has been recognized since its application in a clinical setting. [67] Ketamine has both antidepressant and analgesic effects. According to a recent study, the underlying mechanism for the antidepressant effect of ketamine may be attributed to hydroxynorketamine, which is a metabolite of ketamine. [74] The results of one meta-analysis showed that ketamine produced a high response rate and rapid effect in depressed patients. [75] Ketamine quickly effects, reducing depression within 2 h, while other conventional antidepressants require weeks to effect. [76,77] Several case studies also found similar results, stating that the intravenous administration of subanesthetic ketamine resulted in antidepressant effects about a few hours, and remained for 4 to 7 days after administration. [78,79] Ketamine has a great potential to be used for treatment-resistant depression; however, additional studies are needed on its mechanism of action, of action, long-term and the adverse effects.

Ketamine use limitations
Using ketamine has been associated with a high occurrence of nightmares, hallucinations, and other transient psychotic effects. The use of ketamine is not indicated in conditions such as hypertension, stroke, severe cardiac disease, preeclampsia or eclampsia, raised intracranial pressure, and acute porphyria. [80] Ketamine is also not recommended in newborns and patients with schizophrenia and raised intraocular pressure. [7,30] Oral administration of ketamine with high doses may lead to hepatic failures, ulcerative cystitis, and secondary renal damage. Moreover, epidural and spinal administration can increase the risk of toxicity and is not recommended. [30] Ketamine is a drug of abuse which can result in long-term memory disorders if frequently abused. [81] Conclusion Ketamine is a versatile drug, which through its complex mechanisms of action have been successfully used in a variety of clinical applications all over the world. Nowadays, the use of ketamine is not limited to anesthesia, but it is increasingly used for pain management and palliative care. It can be used solely or as an adjunct to other drugs. When used in low doses, ketamine produces a potent analgesic effect, making it a suitable alternative drug for the cases that pains are refractory to opioid and other adjuvant drugs.
Most of the main therapeutic properties of ketamine have been attributed to its antagonism mechanism to NMDA receptor; however, its interaction with other receptors has been explained. Ketamine is soluble in water and lipid solutions, allows it to be conveniently administered via multiple routes, including oral, nasal, rectal, intravenous, intramuscular, subcutaneous, transdermal, sublingual, and intraosseous administration. However, ketamine administers in a variety of regimens and there are serious concerns regarding adverse effects. High doses of ketamine have been associated with a range of adverse effects and are not recommended.
Using ketamine as an anesthetic has been reported to be beneficial in prehospital setting, in trauma patients with hemodynamic compromise, in military services for wounded troops, and for children requiring sedation for painful or frightening procedures in the Emergency Department.
The applications of ketamine in the perioperative setting have been associated with reduced pain scores, opioid requirements, and postoperative nausea and vomiting, without any considerable side effects. Moreover, good results have been established on using ketamine for surgery patients with high levels of postoperative pain.
The evidence regarding ketamine efficacy for chronic pain management is limited, and the studies demonstrated contradicting results. Generally, it could be concluded that although using ketamine may provide short-term benefits in chronic pain patients, there is not enough proof on its long-term benefits. However, the use of ketamine together with opioids can improve the efficacy of cancer pain therapy. Ketamine is a drug of choice for the cases where opioid tolerance, inflammatory pain, neuropathic pain component, and depression or a combination of these factors are problematic.