Ketamine is a medication approved by the U.S. Food and Drug Administration for anesthesia, generally for surgery or other medical procedures. Ketamine can also be used to treat acute pain in sickle cell disease patients.
How does ketamine work?
Sickle cell disease is a disease caused by a mutation in the gene that provides instructions to make hemoglobin, the protein in red blood cells that carries oxygen. The mutation causes red blood cells to form “sickle” shapes that stick to each other and the sides of small blood vessels.
This makes it difficult for these cells to pass through the smallest blood vessels and may block them. These blockages cause pain, inflammation, and vaso-occlusive crisis (VOC).
The precise mechanism of action of ketamine is not known, but scientists know that it binds to protein receptors in the brain, including the N-methyl-D-aspartate (NMDA) receptors and opioid receptors. The NMDA receptors are normally involved in the transmission of nerve signals, learning, and memory.
Ketamine is thought to cause anesthesia (a treatment that prevents patients from feeling pain) primarily through the blockage of the NMDA receptors, but this process is not well understood.
The binding of ketamine to opioid receptors, the receptors by which narcotic anesthetics such as morphine work, is not as strong as the binding to NMDA receptors. So it is not clear how much this binding explains the anesthetic effect of ketamine.
Ketamine in clinical trials
A retrospective study published in the journal Blood examined the records of 30 patients with sickle cell disease who had received a low dose of ketamine to treat episodes of acute pain. The aim was to determine whether ketamine could reduce the need to use opioid narcotics to manage pain. The results showed that the use of low-dose ketamine significantly reduced the need for opioids.
The results of a clinical trial published in the Scandinavian Journal of Pain examined whether low-dose ketamine is as effective as morphine in treating acute pain in children, ages 7 to 18. A total of 240 patients were randomly assigned to receive either morphine or ketamine infused into the bloodstream.
After the infusion, pain level was assessed at intervals to determine the time to maximum effect. The authors found that low-dose ketamine was as effective as morphine in treating acute pain in sickle cell disease patients.
A Phase 2 clinical trial (NCT02573714) is currently recruiting up to 160 children, ages four to 16 years, with sickle cell disease in Cameroon and Tanzania. The aim of this trial is to determine whether intranasal ketamine is safe and effective in reducing vaso-occlusive crises. The treatment group will receive intranasal ketamine in addition to the normal pain intervention. The placebo group will receive an intranasal salt solution. Pain level will be assessed at intervals following treatment by the faces pain scale-revised (FPS-R). The study had a target completion date of July 2019 which has passed but there has been no update to the clinical trial page since March 2019.
Another Phase 2 clinical trial (NCT03296345) was aiming to recruit 90 patients with sickle cell disease, ages 10-25, in California. The goal was to investigate the safety and tolerability of ketamine for the treatment of vaso-occlusive crises in emergency care facilities. The trial was to assess the effectiveness of the treatment in controlling pain and reducing hospitalization rates. Patients were to receive low-dose ketamine infused into the bloodstream in addition to their normal pain-relieving medication and were to be monitored for safety and side effects following treatment. The status of the trial is listed as unknown since it had a target completion date of December 2018 (which has passed) and there have been no updates to the clinical trial page since September of 2017 when the study began.
Another clinical trial (NCT03431285) has an unknown status. The study was going to recruit 264 adult patients with sickle cell disease in Saudi Arabia. Investigators hypothesized that the administration of ketamine early on would lead to a more rapid improvement in pain score and a reduced need for narcotics. The patients were to be randomly assigned to receive either morphine or ketamine infused into the bloodstream with pain being assessed for six hours following treatment. The study had an estimated completion date of February 2019 and no updates since February of 2018.
A Phase 3 clinical trial (NCT03502421) aimed to enroll 60 patients with sickle cell disease in Florida. One group of patients was to receive a continuous infusion of ketamine into the bloodstream in addition to Dilaudid, an opioid narcotic similar to morphine. The patients in the control group were to receive Dilaudid only. Pain level was to be assessed by the visual analog scale for three hours following the start of treatment, as well as the total amount of Dilaudid required to manage patients’ pain in either group. The study was withdrawn, however, due to a lack of Institutional Review Board (IRB) approval.
Finally, a more recent Phase 3 trial (NCT04150757) will soon be enrolling patients for a study in patients ages three to 25 with sickle cell disease. The study has a target enrollment of 40 participants who will receive intranasal ketamine as the first response to pain from VOCs. The study will compare the change in pain scores between patients who receive intranasal ketamine and those who elect not to.
Other information
Ketamine can cause some side effects such as confusion, nausea, blurred vision, dizziness, and coughing.
Last updated: Feb. 19, 2020
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