There is tremendous confusion and controversy surrounding a very old drug called ketamine (Ketalar). The FDA first approved Ketalar in 1970 as an injectable anesthetic. It has advantages over existing anesthetics. It is fast acting. Excellent pain relieving properties make it ideal for badly burned patients who needed skin grafts or accident victims requiring orthopedic surgery. Research from Israel offers new insights into the drug’s mechanism of action against depression (Neuron, May 31, 2022). Ketamine side effects may also have unexpected benefits. This mother reports that her daughter got double duty from ketamine: antidepressant action and relief from chronic pain.
Antidepressant Action and Pain Control:
Q. My daughter, who has been seriously depressed and suffers terrible pain, is doing ketamine therapy. This has worked wonders. She needs 75 percent fewer pain medicines (which means she no longer needs opioids) and feels so much less depressed. This drug has been a life saver.
We were not surprised to learn that ketamine helped with depression. More about that shortly. We were surprised to read that this woman was getting relief from chronic pain. That led us to the medical literature and some confusing research.
Anesthesiologists have known for decades that ketamine is an amazing analgesic. In other words, it extremely helpful in the emergency room, the ICU and during surgery when patients have to undergo extremely painful procedures. That’s acute pain. A review suggests that it may also have a role in the treatment of chronic pain (Current Opinion in Anesthesiology, Oct. 2020):
“Ketamine may be particularly beneficial in management of burn patients, who often require multiple procedures over the course of their treatment. Ketamine’s role in the ongoing opioid crisis has been of particular interest, with multiple studies evaluating its potential role in managing both acute and chronic pain conditions. Ongoing studies examining the role of ketamine in treatment of depressions show promise as well.”
This analysis also noted that ketamine might be helpful for something called PPP (persistent postoperative pain). I was especially intrigued to learn that the authors reported:
“Oral ketamine was found to be safe, but the dose was limited to 1.0 mg/kg due to side effects and further studies are needed to determine efficacy.”
For reasons that are not entirely clear, there have been very few studies of oral ketamine.
Nerve (Neuropathic) Pain and Ketamine:
Doctors call it neuropathic pain (NP). Everyone else refers to it as nerve pain. It is terribly challenging for patients, family members and health professionals. NP is common, affecting as many as 10% of the population. Symptoms of neuropathic pain can include numbness, tingling or unbearable stabbing pains. Some NP patients describe it as a horrible burning sensation. There are many causes, including chemotherapy for cancer, diabetes, injury, shingles (postherpetic neuralgia) or injury to the spinal column.
Treatment is also challenging. NSAIDs like ibuprofen and naproxen aren’t very helpful. Antidepressants and anti-seizure drugs may help some people, but not everyone benefits and side effects can be problematic. What about ketamine?
A systematic review and meta-analysis published in the Journal of Pain Research (April 9, 2022) offers this assessment:
“Results showed that ketamine reduced significantly (ranging from 28% to 46%), neuropathic pain compared to the baseline pain in the control group; and its effects can last for up to two months after the end of treatment. Thus, ketamine could be an attractive option to both patients and care providers for the management of breakthrough pain episodes and for cases refractory to standard care.
Ketamine Side Effects:
“Although ketamine administration does not seem to cause serious adverse outcomes, our meta-analysis revealed a significant increase in psychedelic effects.
“This comprehensive meta-analysis of 18 RCTs [randomized controlled trials] provides current evidence for the addition of ketamine to the standard treatment of patients suffering from neuropathic pain. It confirms previous observations that ketamine can be safely administered to patients, although revealing a significant increase in psychedelic effects amongst these patients.”
Ketamine Clinics?
The use of ketamine for chronic pain is extremely controversial. An article in the journal Anesthesiology (July, 2020) describes the dilemma. It is titled:
Ketamine for Chronic Pain: Old Drug New Trick
“The use of ketamine for chronic pain and other maladies has drawn comparisons to the Wild West as use of these infusions is random and poorly regulated. Ketamine clinics are now commonplace, advertising treatment of depression, anxiety, bipolar disorder, posttraumatic stress disorder, and, of course, chronic pain. Websites for these clinics typically offer testimonials of miraculous responses. Initial consultations may be free, but the infusions are often a cash deal. On the other hand, scientific reviews universally lament the lack of definitive evidence of effectiveness for low-dose ketamine infusion, at least for chronic pain.”
The author goes on to conclude:
“There is little doubt that ketamine is exceedingly useful in the practice of anesthesia and now perhaps in the field of psychiatry. Despite these successes, we struggle to identify clear roles for ketamine in patients affected by chronic pain. The unbridled use of ketamine ‘for what ails you’ threatens to undermine the goal of understanding the proper uses of the drug, including long-term risks, before releasing it on large populations of patients.”
How Does Ketamine Work To Ease Depression?
Researchers have believed that antidepressants work by modifying brain neurotransmitters such as serotonin or norepinephrine. They can take several weeks to begin to exert an anti-depressant effect. That’s why ketamine is so unusual. It does not appear to work through serotonin or norepi. And the antidepressant activity can show up within hours instead of weeks and can last for days or even weeks after an IV infusion.
The authors of a new study suggest a novel mechanism of action (Neuron, May 31, 2022):
“The discovery that a single sub-anesthetic dose of ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor blocker, produces a rapid yet sustained antidepressant response, even in treatment-resistant patients, is one of the most significant improvements in the field of depression in over 60 years. Ketamine is effective for the treatment of suicidal ideation in emergency room settings, and its antidepressant effects have been demonstrated in many human and animal studies.”
The researchers have identified how ketamine might alter neuronal activity. The drug appears to stabilize potassium channels in glutamate-sensitive nerve cells.
The lead investigator says:
“In-depth knowledge of how antidepressants work might lead to a better understanding of depression and help improve existing treatments.”
Much more research needs to be done to truly understand how ketamine might work to ease depression. We hope this new paper stimulates others to duplicate and expand this work.
Surprising Ketamine Side Effects:
When drug companies test medications on animals they can measure lots of bodily functions. One thing they cannot do, however, is ask the animal how it is feeling. It came as a surprise to investigators to discover that Ketalar caused a “dissociative” brain reaction during recovery.
I have long had a personal interest in this drug because my advisor and professor of neuropharmacology at the Univeristy of Michigan was Edward Domino, MD. He was the lead author on the first published paper about ketamine in humans.
In 1965 Dr. Domino and his colleagues published a paper about an exciting new drug labeled CI-581 (Clinical Pharmacology and Therapeutics, May-June, 1965). It was, as far as I can tell, the first use of the term “dissociative anesthetic.” They described what they observed this way:
“The syndrome immediately following the administration of the drug was of interest. Usually the subject was asked to keep his eyes closed during the procedure. Within a minute after drug injection, the subject reported numbness of the entire body, although sensation to touch remained intact. After 1.0 mg. per kilogram or more of CI-581, the subject would open his eyes and at the same time lose contact with the environment…
Recovery: Odd Ketamine Side Effects:
Dr. Domino, et al, went on to describe surprising ketamine side effects during the return to consciousness:
“During the recovery period the subjects showed considerable variability in psychic reaction. Some were completely oriented in time and place and showed no significant changes. Others showed marked alteration in mood and affect, some becoming apprehensive and aggressive and others markedly withdrawn. Almost all the subjects felt entirely numb, and in extreme instances stated that they had no arms or legs, or that they were dead. If they were touched, however, or moved, such stimuli were perceived….Other reactions noted included feelings of estrangement or isolation, negativism, hostility, apathy, drowsiness, inebriation, hypnogenic states, and repetitive motor behavior.
“At times some of the subjects had vivid dreamlike experiences or frank hallucinations. Some of these involved the recall of television programs or motion pictures seen a few days before, or they were at home with their relatives, or were in outer space, and so on. Some of these phenomena were so real that the subjects could not be certain they had not actually occurred.
“Usually these psychological aberrations subsided completely within a half hour after awakening. The subjects gradually became well oriented and frequently expressed amazement at the experience; most found the experience pleasant and were willing to undergo a second experiment, although 2 refused to continue.”
The Pros of Ketamine:
Dr. Domino explained to me and the other grad students in the department of pharmacology at the Univeristy of Michigan that ketamine was remarkable because it produced “profound analgesia.” The unusual pain-relieving properties of the drug made it highly desirable for procedures that were terribly uncomfortable.
Dr. Domino noted that the experimental subjects who received the drug reported “changes in mood, body image, and affect, and some reported vivid dreams/or hallucinations.” These surprising ketamine side effects were of concern to clinicians and no doubt to the drug company developing ketamine.
We were told that if patients were put in special recovery rooms after surgery with the lights dimmed and with no physical stimulation from nurses, they would often reorient to their bodies more gradually. This allowed for the dissociative state to wear off without some of the complications initially reported after the coma of anesthesia began to wear off.
Other Ketamine Side Effects:
In his original paper in 1965 Dr. Domino reported that subjects experienced watery eyes and profuse sweating. Nystagmus (uncontrollable eye movements) was common along with visual disturbances. Other ketamine side effects include excessive salivation, indigestion, nausea and vomiting. Blood pressure can go up along with heart rate. Some people also note muscle twitching.
Although anesthesiologists still use ketamine in certain circumstances, it has lost favor over the decades. Part of the reason may be that the recovery process can be challenging for busy hospital routine. We suspect that the strange psychological side effects, including hallucinations, also worry some anesthesiologists.
Unexpected Benefits of Ketamine:
When a person feels suicidal, seconds count. Delays could mean a life lost. But what do health professionals have to offer in an emergency?
Until recently, there hasn’t been an effective, fast-acting medication to ease severe depression or counteract thoughts of suicide. Traditional antidepressants can take six weeks or longer to act. That’s why there is growing excitement about the use of ketamine to treat suicidal ideation.
Interrupting Suicidal Thoughts:
A study published in The American Journal of Psychiatry (online, Dec. 5, 2017) demonstrated that a ketamine infusion can banish suicidal thoughts within hours for some people. That’s remarkable.
In this trial, 80 people were randomized to receive either ketamine or a benzodiazepine called midazolam. In this double-blind research, both groups got their medicine by intravenous infusion. Not only did ketamine help ease major depression, it also reduced suicidal thoughts directly.
Longer Lasting Benefits:
One of the unexpected results of this single-infusion clinical trial was the persistence of the benefit. Most other research has suggested that ketamine loses its antidepressant activity after a week or two. In this study, the improvement lasted for at least six weeks.
The implications of this research are profound. Emergency rooms are overwhelmed with severely depressed patients. Hospitals frequently do not have enough beds to care for suicidal patients. They may be left in the waiting room or in the hallway for days until a room becomes available. Even then, treatments are slow to kick in.
Now that intravenous ketamine infusions have been shown to control suicidal thoughts, emergency physicians may feel justified in administering the drug to desperate patients on the spot. There is a downside, however. You cannot just give a suicidal patient ketamine and walk away. Such patients require intense supervision and continued care. Once the ketamine wears off, they could end up back where they started or worse if there is not monitoring and further treatment.
Ketamine: Not FDA Approved for Depression!
Ketamine is not approved by the FDA for treating chronic pain, depression or easing suicidal thoughts. As a result, many clinicians may be uncomfortable administering it. Only those who are experienced with such treatment should consider prescribing this off-label use.
This is not the first study of ketamine to show promise. A meta-analysis of five trials found that ketamine “showed a large and consistent decrease of suicidal ideation” (Neuroscience and Biobehavioral Reviews, June, 2017). Other reviews also report that ketamine has a significant effect on suicidal thoughts (American Journal of Psychiatry, online Oct. 3, 2017).
Enter Esketamine (Spravato):
Because ketamine can no longer be easily patented for depression or chronic pain, drug companies have not been willing to spend big bucks testing this old drug for new tricks. But one company was willing to develop a derivative compound called esketamine. they gave it the brand name Spravato. It is taken in the form of a nasal spray.
If you would like to learn more about this new antidepressant, here is a link:
What Should You Know about New Antidepressant Spravato?
FDA has approved a new antidepressant, esketamine. It will be available as Spravato nasal spray for people who have not responded to other drugs.
This drug is pricey, though. We suspect that insurance companies may not be enthusiastic about paying for it unless a patient has exhausted more traditional treatment.
Readers Respond to Ketamine:
We heard this from one reader who has received ketamine infusions:
“I feel frantically discouraged when I am too depressed to feel in control of my mind, body and ability to re-join life. So often, depressed people like me are shunted from hospital to hospital and given drugs that just don’t work. Ketamine is the only medicine that keeps me steady so I don’t want to jump off the nearest bridge.”
Lyn in Phoenix experienced nasty ketamine side effects:
“I was given ketamine by an anesthesiologist when he could not get into my veins for a colonoscopy. I did not come to afterwards. They sent me home anyway.
“My husband managed to get me in the house where I laid on the floor for twelve hours, throwing up occasionally. For the next three days I seemed to have Alzheimers. I kept asking the same questions over and over, I was told later. I could hardly get out of bed. My husband was concerned my brain was gone. This is a very dangerous drug. Stay away from it.”
Ketamine for Suicide vs. Surgery:
Lyn either got a very high dose by mistake or was super susceptible to ketamine. It was being used as an anesthetic during the colonoscopy procedure.
When the drug is used to treat suicidal thoughts and depression, the dose is much lower than that used for anesthesia. Still, study volunteers in the most recent study had some mild adverse reactions, especially elevated blood pressure and a spacey feeling during the infusion.
The scientists hope that further research on ketamine will lead to the development of new and better drugs that will act more quickly than current antidepressants to treat seriously suicidal people.
Want to Learn More?
If you would like to get the straight and skinny on the history of ketamine from the horse’s mouth, so to speak, check out this wonderful article by my old mentor, Edward Domino, MD (Anesthesiology, Sept. 2010). In it you will learn the back story on ketamine from a brilliant neuropharmacologist!
Could ketamine help prevent suicide in vulnerable individuals? That is the question we wrestle with in this article. Where is the FDA on this issue? Find out why we are again disappointed in the Food and Drug Administration at this link.
Share your own ketamine story below in the comment section.
