Is Ketamine an Opioid?

By Pat Anson, PNN Editor

A drug used to treat depression and pain is being touted as possible solution to the opioid crisis.

This week a South Carolina drug maker said it would partner with a medical device company to sell ketamine in take home medication bags that can be administered by an ambulatory pain pump. The idea is to give patients recovering from surgery a safer alternative to opioids.

“We are proud to partner with InfuTronix Solutions to deliver opioid-free pain medication to patients across the country,” Nephron Pharmaceuticals CEO Lou Kennedy said in a statement. “The overuse of opioids is a crisis in America. Non-narcotic pain management is a cost-saving way that companies like ours can help save lives.”

Non-narcotic? Opioid-free?

That’s not what a team of researchers at Stanford University concluded last year after studying how ketamine works in the brain. In a small clinical study, they gave a dozen patients diagnosed with depression a combination of ketamine and naltrexone – an opioid-receptor blocker. To their surprise, naltrexone stopped ketamine from working as an antidepressant.

In effect, the researchers discovered that ketamine works just like oxycodone, hydrocodone and other painkillers – by activating opioid receptors in the brain. 

“Everything that I was taught, and everything that I’ve always taught my students — all of the evidence supports the fact that ketamine is not an opioid,” said lead author Boris Heifets, MD, a clinical assistant professor of anesthesiology, perioperative and pain medicine. “I was really surprised at the results.”

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“And the results were so clear that we ended the study early to avoid exposing additional patients to the ineffective combination treatment,” said co-lead author Nolan Williams, MD, a clinical assistant professor of psychiatry and behavioral science.

The Stanford research, published in The American Journal of Psychiatry, caught psychiatrists and pain management experts by surprise. Some urged caution about the long-term use of ketamine until more can be learned about potential side effects such as addiction. Some depressed patients taken off ketamine have shown signs of withdrawal and became suicidal.

“Given the rapid relapse and potential suicide risk, it is hard to know what to recommend to clinicians. Should they really continue to use the agent beyond an acute course? For how long? In whom?” Alan Schatzberg, MD, a Stanford professor of psychiatry and behavioral sciences, warned in a commentary. “The drug’s opioid properties need to be considered when considering how best to use it.”

‘A Black Eye to Ketamine’

Talk like that has given ketamine a bad rap, according to experts at Johns Hopkins University School of Medicine. They’ve published a commentary of their own, defending the use of ketamine as a necessary treatment for depression that doesn’t respond to typical antidepressants.

“A (Stanford) study done late last year delivered a black eye to ketamine, and as a result of the coverage, there was a wholesale acceptance by both potential patients and physicians that ketamine is an opioid,” says Adam Kaplin, MD, an assistant professor of psychiatry and behavioral sciences at Johns Hopkins.

“This is most worrisome if people continue to think this way, particularly in the wake of the opioid epidemic; clinicians won’t refer patients for a treatment, despite that it has been shown to be incredibly effective for many patients with treatment-resistant depression.”

Kaplin says there is ample evidence that ketamine sticks to NMDA receptors in the brain that are involved in learning and memory. Because these NMDA receptors are found together with opioid receptors, Kaplin says it’s no surprise that the can meddle with one another, like interference picked up on a phone call or static on the radio.

“This interference and cross-talk does not mean that ketamine is an opioid, and to wrongly label it as such could eventually keep patients from essential antidepressant medications that could make a huge difference in their quality of life,” said Kaplin, who plans on opening a ketamine clinic.

The debate over whether ketamine is an opioid comes at a time when its use is expanding.  Ketamine was approved by the FDA in 1970 solely as a surgical anesthetic to be taken intravenously or by injection. But a growing number of clinics now offer off-label infusions of ketamine to treat depression, post-traumatic stress disorder and difficult chronic pain conditions such as Complex Regional Pain Syndrome (CRPS).

Demand has grown so much there are reports of ketamine shortages. Although ketamine itself is inexpensive, the infusions can cost several hundred dollars and are not covered by insurance.

Ketamine Nasal Spray

Not until this year did the Food and Drug Administration approve the use of ketamine to treat depression, when it okayed a nasal spray (Spravato) made by Janssen Pharmaceuticals that contains a ketamine compound.

The FDA approved Spravato even though 2 out of 3 short term trials failed to prove its effectiveness. The spray was effective in a longer trial, but only when taken with a conventional antidepressant.

Because of the risk of abuse and side effects, Spravato can only be administered in a doctor’s office, where patients can be observed for two hours after taking a dose. A single dose will cost about $900.

The FDA has called the herbal supplement kratom an opioid because it acts on opioid receptors, but the agency has not taken that step with ketamine. Given current attitudes about opioids, it’s fair to say the FDA would have never approved Spravato if it was considered an opiate.

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In addition to its medical uses, ketamine is used as a recreational party drug – known as “Special K” -- because it can cause hallucinations and intense dream-like states.

Whether taken to get high or to treat pain and depression, it’s clear that ketamine is a potent drug that has both harms and benefits. And experts say it needs to be viewed with caution until we know with more certainty how it works.

“Unfortunately, when one approaches ketamine as another antidepressant rather than a drug of abuse, this type of trap is easy to fall into, and in the end, such mistakes can be catastrophic,” Schatzberg said in his commentary. “We have witnessed four decades of supposedly new and safer opioids that have turned out often to be, if anything, even more abusable and lethal."

Researchers Say Chronic Pain Changes Brain Chemistry

By Pat Anson, Editor

A new study by UK researchers raises an intriguing question: Does chronic pain change brain chemistry and make pain more tolerable?

The answer is yes, according to a small study at the University of Manchester. Researchers there used Positron Emission Tomography imaging (PET scans) to measure the spread of opioid receptors in the brains of 17 arthritis sufferers and nine healthy control subjects

When they applied heat to the skin of study participants to induce pain, researchers found that the more opioid receptors they had, the higher their ability was to withstand pain. The number of opioid receptors was highest in arthritis sufferers, suggesting their brain chemistry had changed in response to chronic pain.

"As far as we are aware, this is the first time that these changes have been associated with increased resilience to pain and shown to be adaptive,” said Dr. Christopher Brown. "Although the mechanisms of these adaptive changes are unknown, if we can understand how we can enhance them, we may find ways of naturally increasing resilience to pain without the side effects associated with many pain killing drugs."

image courtesy of university of manchester

image courtesy of university of manchester

It’s been known for a long time that we have receptors in our brains that respond to natural endogenous opioids such as endorphins. Those same receptors also respond to opioid pain medications.

Some people seem to cope better with pain than others, and knowing more about their resilience and coping mechanisms may lead to the development of new ways of treating pain.

"This is very exciting because it changes the way we think about chronic pain,” said Anthony Jones, a professor and director of the Manchester Pain Consortium. "There is generally a rather negative and fatalistic view of chronic pain. This study shows that although the group as a whole are more physiologically vulnerable, the whole pain system is very flexible and that individuals can adaptively upregulate their resilience to pain.

"It may be that some simple interventions can further enhance this natural process, and designing smart molecules or simple non-drug interventions to do a similar thing is potentially attractive."

Researchers at Stanford University in California have also been studying this subject, trying to learn why some chronic pain sufferers are more resilient to pain.

I think this study emphasizes some very important points about pain resilience,” said Dr. Drew Sturgeon, a fellow in the Stanford University Pain Management Center and Stanford Systems Neuroscience and Pain Laboratory. “If you think about chronic pain as something that poses a constant challenge and requires frequent adaptation, it makes sense that we would see changes in the brain that correspond with this process.  We see it frequently from a psychological standpoint, where people are able to learn and develop better strategies for coping with pain and reduce their fear and negative thoughts about pain after dealing with it for a while.”

Sturgeon and his colleagues say resilience may also stem from an enhanced ability to enjoy the rewarding parts of life – which makes it easier to cope with pain.  

“The idea would be that if a person had more opioid receptors available they would be more sensitive to the good stuff in life, and therefore more motivated by pleasurable experiences, such as spending time with friends, exercising -- rewards that get us back on the road to living a meaningful life,” said Beth Darnall, PhD, a pain psychologist, clinical associate professor at Stanford University and author of Less Pain, Fewer Pills.

“Theoretically, people who are known to be resilient probably have more endogenous opioids -- or they have made choices in life to optimize their experience of endogenous opioids and therefore have honed an internal reward system.”

Whatever the cause of resilience, many patients hope further studies will uncover new ways of treating pain.

"As a patient who suffers chronic pain from osteoarthritis, I am extremely interested in this research. I feel I have developed coping mechanisms to deal with my pain over the years, yet still have to take opioid medication to relieve my symptoms,” said Val Derbyshire. “The notion of enhancing the natural opiates in the brain, such as endorphins, as a response to pain, seems to me to be infinitely preferable to long term medication with opiate drugs.”

The University of Manchester study is being published in Pain, the official journal of the International Association of the Study of Pain.