The clinical use of ketamine for sedation, catalepsy, somatic analgesia, bronchodilation, and sympathetic nervous system stimulation began in 1970; however, its use has been limited mostly to pediatric and trauma anesthesia because it can cause side effects, especially the psychotropic effects.^[1] Because of its strong analgesic effect, ketamine has recently emerged as a promising adjunct for pain management as an alternative to narcotic medications to end the dreaded opioid epidemic. Ketamine works mainly as an N-methyl-D-aspartate (NMDA)- receptor antagonist but also enhances descending inhibition and has anti-inflammatory properties.^[1–5] The NMDA antagonism helps to attenuate central sensitization and palliate neuropathic pain, which are believed to play significant roles in the development and propagation of chronic pain states.^[6–8]

“To date, no protocol has been developed to standardize doses and duration of ketamine infusion because of the lack of quality studies and sufficient evidence.”

In recent years, a relatively large body of evidence has accumulated showing the beneficial effects of intravenous ketamine infusion in patients with chronic refractory pain states, including fibromyalgia, neuropathic pain, phantom limb pain, postherpetic neuralgia, complex regional pain syndromes (CRPS), diabetic neuropathy, sickle cell pain during acute crises, and central pain related to stroke or spinal cord injuries.^9–13 However, to date, no guideline has been developed for its use or a protocol to standardize doses and duration because of the lack of quality studies and sufficient evidence.

Infusion Protocols

Because of the potential side effects of tachyarrhythmias, hypertension, and psychomimetic effects, ketamine continuous infusion was, historically, mostly limited to intensive or intermediate care settings and thus associated with high costs. Ketamine, however, can be administered safely on a nonacute, inpatient ward. Following are the infusion protocols that have been implemented at the University of Chicago Medical Center and University of Virginia Health System. When used in subanesthetic doses, ketamine is considered safe and side effects are generally well tolerated1 or readily treatable. No major complications have occurred in our patients so far.

University of Chicago. Patients are admitted to the inpatient ward, where low-dose ketamine infusions outside of the intensive care unit are managed by the acute pain service staffed by faculty physicians trained in pain medicine and anesthesiology. Conditions commonly treated with intravenous ketamine infusions include neuropathic pain, CRPS, refractory headache or back pain in patients with Chiari malformations, refractory abdominal pain from inflammatory bowel disease or celiac artery compression syndrome, and pain related to vaso-occlusive sickle cell crisis. Infusions are dosed based on ideal body weight and started at 1 mcg/kg/min and titrated to effect or best tolerated dose without significant cardiovascular or central nervous system side effects up to a maximum dose of 5 mcg/kg/min for a course of 1–5 days. During this time, patients are closely monitored with routine vital signs of blood pressure, pulse, respiratory rate, pain score, and sedation level assessed 1 hour post dose following the first dose or dose increase and then every 4 hours and continuous pulse oximetry throughout infusion. The acute pain service is alerted for systolic blood pressure greater than 160 mm Hg, respiratory rate less than 10 breaths/min, any acute change in mental status (eg, blunted affect, emotional withdrawal, thought disorder, delirium), or any difficulty in arousal despite continuous stimulation. Laboratory test results and electrocardiograms are checked periodically upon the discretion of the acute pain service attending. Oxygen therapy via nasal cannula is available to maintain oxygen saturation above 92% with a bag valve mask available at the bedside in case of severe hypoxia. Supportive medications such as naloxone, lorazepam, and prochlorperazine are readily available. At time of initiation, strong consideration is given to decreasing or modifying opioid and nonopioid analgesics with concomitant use of ketamine intravenous infusions.

University of Virginia. At University of Virginia Health System, ketamine infusions are also performed on an inpatient ward and are also managed by the acute pain service by trained faculty. Conditions commonly treated with intravenous ketamine infusions include CRPS and refractory neuropathic pain of various causes. The infusion is typically started at 0.1 mg/kg/hr, then increased slowly as tolerated to 0.5–0.75 mg/kg/hr, with the entire course lasting for 5–7 days depending on a patient's response. During this time, patients are monitored closely, Laboratory test results and electrocardiogram checked periodically, and side effects treated in a timely fashion. Benzodiazepines have been used to minimize its psychotropic side effects. When used in subanesthetic doses, ketamine is considered safe, and side effects are generally well tolerated1 or readily treatable. No major complication has occurred in our patients so far. Similar to the University of Chicago, strong consideration is given to decreasing opioid analgesics.

Acute Pain

Ketamine given preoperatively, intraoperatively, or postoperatively has been shown to decrease postoperative pain and reduce perioperative opioid consumption in opioid-dependent patients.^[14–16] Ketamine infusions should be considered in the treatment of refractory acute pain after surgery or from trauma, in the intensive or intermediate care setting, as well as on the regular floor, especially for patients who are opioid tolerant. Including ketamine in the enhanced recovery after surgery protocols is likely beneficial.

Many questions still remain regarding ketamine. The incidence and degree of side effects from ketamine depend on dosage. The existing evidence also suggests that the analgesic effect of ketamine is both dose^[9] and duration^[1-2] dependent. However, no consensus exists on ketamine infusion protocols regarding dose, titration, infusion duration, and frequency of repeated infusions. Randomized controlled trials are needed to answer these questions. A consensus or guideline on ketamine infusions is needed, as well. A ketamine registry may be helpful to report complications.

Conclusion

Current evidence has shown that ketamine infusion is effective in treating chronic and acute refractory pain. It appears ketamine infusion treatment can be administered on the inpatient ward. A consensus or guideline on ketamine infusion is needed.

References

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