For patients who respond poorly or incompletely to opioids, ketamine may be the answer.
In the middle of the past century, phencyclidine hydrochloride—called PCP or angel dust on the street—was developed to be a safe, effective anesthetic that did not cause cardiovascular and respiratory depression. However, its propensity to cause convulsions at high doses and long-lasting psychoactive side effects during emergence from anesthesia destroyed its potential.
Newer, cleaner drugs or biologics are replacing ketamine in the operative suite. Yet ketamine is finding a new place in clinical therapy. Ketamine, an N-methyl-D-aspartate (NMDA)–receptor antagonist, is becoming an option for perioperative pain management among patients with opioid tolerance, acute hyperalgesia, and chronic neuropathic pain.
Ketamine is the most potent clinically available, uncompetitive, open-channel NMDA-receptor blocker (it only works if the receptor is activated and the channel is open). Ketamine depresses the thalamus and limbic systems, preventing central nervous system centers from receiving or processing sensory input. This creates anesthesia, analgesia, and amnesia, and sometimes unpleasant psychomimetic effects or emergence phenomena
Some study results suggest that the oral route leads to few side effects. Topical formulations of ketamine or ketamine with other potential analgesics has been used for managing several painful conditions (eg, pelvic pain, pruritus) with mixed results.
Ketamine use in pain management evolved from its perioperative use.
In low doses, NMDA-receptor antagonists can provide analgesia and circumvent opioid-related tolerance, hyperalgesia, and allodynia. Randomized, placebo-controlled, double-blind clinical trials (RCTs) have found that perioperative subanesthetic doses of ketamine added to opioid analgesia improved pain scores and reduced opioid consumption by approximately 30% to 50%. Ketamine was given as an intermittent low-dose intravenous bolus or a continuous infusion. It reduced opioid-related nausea and vomiting and added no additional significant adverse effects.
Ketamine can also be given with morphine patient-controlled analgesia, contributing a morphine-sparing effect. Patients with chronic neuropathic pain, opioid dependence or tolerance, and acute hyperalgesia seem to benefit more
Acute sickle cell disease creates severe pain with a neuropathic element. Several published guidelines recommend using opioids as first-line treatment, but some patients are unresponsive to even high opioid doses.
Several of ketamine’s properties may prevent chronic pain from developing:
- Dampening of nociception
- Prevention or attenuation of hyperalgesia, allodynia, and tolerance
- Attenuating central sensitization and windup phenomenon from repeated noxious stimuli when previously nonpainful stimuli become exaggerated and painful.
Clinicians have used short-term subanesthetic doses of ketamine to treat neuropathic pain. Scheduled infusions over several days can improve pain scores in patients with chronic pain; a few studies report pain relief persisting for weeks following treatment, indicating that ketamine may be disease modifying.
Limited but increasing data support ketamine use in refractory cancer pain. Adding a small dose of ketamine to opioid therapy in a patient with opioid tolerance, called burst therapy, can improve pain management.
Most studies suggest, and experts believe, that ketamine use should be reserved for patients in whom opioids, anticonvulsants, or antidepressants have failed.