Ketamine is an anaesthetic drug discovered in the 1960s, it is known to produce a dissociative state with sedation, amnesia, and analgesia. Currently, ketamine is being actively studied for potential use in acute and chronic pain conditions.
The principle pharmacological action of ketamine is NMDA receptor antagonism. Given the role of NMDA receptor in nociceptive signaling, it is reasonable to postulate that ketamine possesses analgesic properties.
Acute pain procedures Most studies evaluating ketamine in an acute pain setting have focused on the perioperative environment and a few other specific painful disease states, such as sickle cell pain crises. For patients outside the perioperative setting, evidence is limited to mostly case reports. the evidence suggests that most patients who benefit from ketamine in the acute pain setting fall into several categories. the first group of patients is those who are undergoing painful surgery, after which the expected postoperative pain rating is considered to be in the severe range. Examples of surgical procedures in which the benefits seem to be the greatest include upper abdominal surgery and thoracic surgery; orthopedic limb, spine, intra-abdominal, and lower abdominal procedures also appear to be painful enough to warrant consideration of ketamine.
Opioid-tolerant and opioid-dependent patients are frequently cited as groups that should receive ketamine, primarily because it makes conceptual sense given the role of the NMDA receptor in hyperalgesia and opioid tolerance.
Evidence for ketamine in acute painful exacerbations of chronic diseases such as sickle cell disease and nonoperative trauma (eg, rib fractures) is limited to mostly case reports and small case series.
Studies have shown that perioperative ketamine use for more than 24 h has a modest but statistically significant reduction in the incidence of persistent post-surgical pain at 3 months after operation. Such beneficial effects were observed at 6 months but not 12 months after surgery.
Nonparenteral ketamine, especially intranasal ketamine (IN) that got the FDA approval very recently, is likely to continue to increase in use for acute exacerbations of chronic pain conditions.
Chronic pain procedures For spinal cord injury pain, there is weak evidence supporting ketamine infusions (0.42 mg/kg per hour to 0.4 mg/kg ranging from 17 minutes to 5 hours for 7 consecutive days) for short-term improvements in pain.
For CRPS, there is moderate evidence supporting ketamine infusions (22 mg/h for 4 days or 0.35 mg/kg per hour over 4 hours daily for 10 days) to provide improvements in pain for up to 12 weeks.
For mixed neuropathic pain, PLP, PHN, fibromyalgia, cancer pain, ischemic pain, migraine headache, and low-back pain, there was weak or no evidence supporting ketamine infusions for immediate improvements in pain.
Excluding CRPS, there was no evidence supporting ketamine infusions for intermediate or long-term improvements in pain.
Ketamine is often considered in management of these refractory cancer pain, although current evidence is insufficient to allow any conclusion on its effectiveness.S mall randomized controlled trials (RCTs) were able to show that addition of ketamine improves the effectiveness of morphine. There are also case reports showing effective analgesia in refractory cancer-related neuropathic pain using intrathecal ketamine infusions, even though the safety profile and potential neurotoxicity is not clear.
Adverse effects and pathophysiology Cardiovascular and Pulmonary Effects: Reviews have noted that ketamine has both a negative inotropic effect and simultaneous indirect sympathetic nervous system stimulation, which is due to systemic release of catecholamines, vagal nerve inhibition, inhibition of norepinephrine reuptake at peripheral nerves, and other mechanisms. In the pulmonary system, ketamine causes bronchodilation that appears to be due to circulating catecholamines. Pharyngeal and laryngeal reflexes are mostly preserved, as is respiratory function, and there are increased secretions.
Spinal Cord Effects: Several studies in animals suggest that ketamine may cause pathological changes when given intrathecally. Currently, the use of intrathecal ketamine is listed as a sixth-line adjuvant to be used in conjunction with other neuraxial analgesics in individuals with refractory cancer or other terminal chronic pain conditions.
Psychomimetic Adverse Effects: Reviews and meta-analyses of perioperative ketamine have come to different conclusions regarding ketamine’s adverse psychomimetic effects including hallucinations, visual disturbances, unpleasant dreams, and dysphoria, when it is used in subanesthetic doses.
Hepatic, Genitourinary, and Gastrointestinal Effects: There are few studies that directly address the issues of hepatotoxicity and cystitis with subanesthetic ketamine use. Data must be extrapolated from animal studies and studies in ketamine abusers. In humans, the incidence of hepatotoxicity and cystitis may be increased with higher doses and repeated exposure, although liver enzyme levels return to normal after discontinuation of the drug.
Ketamine-induced cystitis has been documented primarily in abusers of ketamine. It typically presents as painful hematuria, dysuria, frequency, and postmicturition pain. Treatment begins with cessation of ketamine use and may also consist of mucosal protective agents such as hyaluronic acid or anticholinergic drugs. More severe disease may require surgical intervention.
From a clinical practice perspective, oral ketamine has significant abuse potential and a high street value. For these reasons, in patients with a history of abuse or who are at high risk of abuse, the risks of prescribing it chronically in a community-based setting should be weighed against the potential benefits, and proper surveillance, similar to what is done for patients on chronic opioid therapy, should be used. More research should also be conducted regarding the long-term effects of ketamine.
The use of ketamine has skyrocketed for chronic pain and depression, but many questions remain unanswered.
In conclusion, despite its drawbacks, ketamine remains a powerful and inexpensive tool for practitioners who manage acute pain. We believe its use will continue to expand as more institutions treat increasingly challenging patients in the perioperative period as well as those with painful disease exacerbations while trying to combat the opioid epidemic. More research is needed to refine selection criteria for the treatment of acute pain and possible prevention of chronic pain, to determine the ideal dosing and treatment regimen to include coadministration of ketamine with opioids and adjuvants, and to better understand the long-term risks of ketamine in patients who receive serial treatments for frequent acute pain exacerbations.
Cohen SP, Bhatia A, Buvanendran A, et al. Consensus guidelines on the use of intravenous ketamine infusions for chronic pain from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med 2018;43:521–546.
Schwenk ES, Viscusi ER, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med 2018 Jul;43(5):456–466.
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