Ketamine was invented in 1962 as a very effective anesthetic for routine surgery. It works by blocking the neurotransmitter molecule glutamate from its NMDA receptor in brain neurons, and affects primarily the memory center in the hippocampal region of the brain, along with the prefrontal cortex abstract thought center. Ketamine is a medication that blocks the gluconate neurotransmitter receptor in one’s nervous system. It was soon discovered that this same medication used at very low doses had a remarkable antidepressant effects. Ketamine infusions create a cascade of events in the brain that affects certain neurotransmitter receptors and neurological pathways, and triggers rapid growth of normal neural conditions.
There is a large body of literature addressing the use of ketamine to help improve postoperative pain relief and reduce opioid requirements.
Perioperative ketamine decreased postoperative pain scores.
Most systematic reviews report that perioperative ketamine was well tolerated, with adverse effects being mild or absent. Most studies provided dichotomous data on central nervous system adverse events.14
Ketamine seems most beneficial when pain scores are high, suggesting that it is primarily useful for surgery associated with high levels of postoperative pain. Given that ketamine reduces opioid requirements, it may also be indicated for subgroups such as opioid tolerant or opioid-dependent patients.
Ketamine is widely used as a third-line drug for cancer pain, when the pain has not responded to opioid in combination with drugs such as nonsteroidal anti-inflammatory drugs, amitriptyline, and gabapentinoids. Published case reports demonstrate that ketamine is used for refractory pain in palliative care in many countries, and that treatment regimens differ widely using IV, subcutaneous, oral, intrathecal, and topical routes of administration.
There seem to be good arguments for keeping the ketamine dose low. Ketamine has dose-dependent adverse effects. Terminally ill cancer patients may have reduced hepatic function because of metastases and diminished liver perfusion. Hepatic impairment can cause reduced drug metabolism and significantly impaired clearance.
The evidence for efficacy and tolerability for ketamine in this setting is limited. It is undeniably challenging to conduct RCTs in this patient group. What then in theory could be the indications for ketamine treatment? When cancer pain or pain in a palliative care patient is refractory to opioid and adjuvant drugs, then ketamine may be an option. There are many reasons for pain in this patient group. Ketamine could be especially relevant when there are problems of opioid tolerance, a significant neuropathic pain component, inflammatory pain, depression, or any combination of these factors. In fact, this may be the pain patient group that is most likely to need a trial of ketamine and where the risk benefit ratio is the most beneficial. A trial of ketamine does not need to be lengthy and if there is no clear benefit, then ketamine treatment should be terminated.
Ketamine is increasingly being used as a third-line drug for refractory chronic noncancer pain. In this setting, it is commonly administered as intermittent IV infusions. Patients may be offered hospital admission and infusion treatment over several days. However, outpatient treatment seems to be on the increase, and in the United States, a large number of “ketamine clinics” have been established offering infusions for a variety of conditions, including chronic pain, depression, and other mood disorders. A Medscape report suggests that there may be more than 1000 such clinics currently operating in the United States. For chronic pain, these clinics offer a series of infusions on an outpatient basis, followed by “maintenance therapy” for example, involving monthly ketamine infusions. Although racemic ketamine is an inexpensive drug, patient costs associated with this treatment are high
Ketamine is a drug with complex mechanisms of action and many properties which make it interesting for pain management. However, treatment regimens differ widely and there are concerns regarding adverse effects. High doses of ketamine are reported to cause a range of adverse effects and should be avoided. Ketamine has low oral availability, and oral administration seems to be associated with a high rate of adverse effects. Spinal and epidural routes are not recommended because of issues of neurotoxicity. Although ketamine is a drug of addiction, safety data regarding long-term and/or intermittent treatment are lacking.
There is good evidence that ketamine in the perioperative setting reduces pain scores and opioid requirements. Adverse effects are mild or absent, and perioperative ketamine may decrease postoperative nausea and vomiting. It seems most beneficial for surgery associated with high levels of postoperative pain.
The evidence for the use of ketamine in palliative care is limited, and it is not possible to recommend any specific treatment regimen. However, despite the limited evidence, a trial of low-dose ketamine, adjuvant to opioid (morphine), may be warranted in refractory cancer pain or pain in palliative care.
The evidence regarding ketamine for chronic noncancer pain is extremely limited, and there is a lack of safety data concerning long-term or repeated treatments. Importantly, there seems to be no strong evidence for the current widespread use of intermittent ketamine infusions.