Ketamine and Other Promising Opioid Alternatives

When it comes to addressing the kind of short-term pain associated with procedures like spinal surgery, opioids still tend to be the most effective option, according to Medhat Mikhael, MD, pain management specialist at MemorialCare Orange Coast Medical Center in Fountain Valley, CA.

However, opioids may provide insufficient relief for chronic pain, and the potential for addiction issues looms large, he said. The opioid crisis also causes many to feel conflicted about prescribing drugs to patients. A 2019 survey on drug use from the US Department of Health and Human Services (HHS) estimates 10.1 million people aged 12 and older misused opioids in the previous year, and two out of three drug overdose deaths involved an opioid.¹

“They work very well when it comes to acute pain like you have in many post-surgical situations,” Dr. Mikhael said. “But if you’re looking for relief for chronic pain, you need to keep addiction risk in mind. That’s why it’s important to turn to opioids only when truly necessary.”

One alternative that may be promising is ketamine. Research has shown that in controlled doses and environments, ketamine may offer a role in pain management, without some of the major concerns that opioids bring.²

Ketamine Background and Mechanisms

Ketamine is an NMDA receptor antagonist, along with several other commercially available drugs including memantine, amantadine, and dextromethorphan. Ketamine is an old drug: synthesized in 1962, approved by the FDA in 1970, and used as a field anesthetic during the war in Vietnam. It is still widely used as an anesthetic in human and veterinary practice, but it has gained notoriety as a recreational drug for its potentially dissociative effects.

According to Steven Richeimer, MD, chief of the division of pain medicine and professor of anesthesiology and psychiatry at the University of Southern California Keck School of Medicine, there are several mechanisms by which ketamine may mitigate pain. Research suggests it can:³

• reduce central sensitization

• reduce opioid-induced hyperalgesia

• reduce opioid tolerance

• inhibit serotonin and dopamine reuptake

• reduce pain-induced depression

Dosage Types and Risks

Dr. Richeimer noted that ketamine, in low doses, may be used postoperatively to reduce opioid use and decrease nausea and vomiting. In some cases, it provides primary post-op pain relief, particularly in patients who do not tolerate opioids.

Ketamine is also administered in infusion centers for patients with intractable pain from several conditions, including:

• chronic regional pain syndrome

• other neuropathic conditions

• refractory headache

Oral ketamine can be prescribed for pain management, but it is not commercially available; prescriptions must be sent to compounding pharmacies. Physicians who have not previously prescribed ketamine may want to work with a pain management specialist who is familiar with the drug.

Like any drug, especially powerful pain relievers, ketamine does have side effect risks. Dr. Richeimer said it should be avoided in patients with:

• severe cerebrovascular and cardiovascular diseases

• psychosis or delirium

• severe liver disease/hepatitis

• active substance abuse

• glaucoma/increased intraocular pressure

• hyperthyroidism or pheochromocytoma

Higher doses can cause people to fall into a dissociative “k-hole” that significantly impairs perception, which means it is unlikely ketamine would be prescribed as a standalone, long-term treatment for those with back pain.

Also, since it is a narcotic-classed drug, it does have an addiction risk. It is related to phencyclidine (PCP), and has been a party drug with the nickname “Special K.” For this reason, ketamine doses are often administered on-site in clinics or infusion centers, where patients can be supervised to make sure they are not experiencing dissociative side effects or showing signs of addiction.

Mental Health Applications

In addition to pain management, ketamine treatment might be beneficial for patients with spinal conditions as it may help alleviate mental health challenges such as depression.

According to a 2019 research review published in Systematic Reviews, a considerable portion of adults with low back pain suffer from depressive symptoms or depression.⁴ Researchers noted that this may put them at risk of poorer recovery and could necessitate more interventional healthcare. For example, a 2016 study in BMC Musculoskeletal Disorders found that depression among those with back pain can increase pain sensitivity, decrease quality of life, and negatively affect overall function and productivity.⁵

Recent research has highlighted how ketamine may be useful, even for treatment-resistant depression. For example, a 2020 study in Translational Psychiatry noted that even low doses can be beneficial because ketamine has a significant antidepressant effect.⁶

“Ketamine is a big topic in mental health, and for good reason,” said Keith Heinzerling, MD, internist and addiction medicine specialist at Providence Saint John’s Health Center in Santa Monica, CA. “The drug works very quickly, sometimes within hours. That’s compared to some antidepressants that may take weeks or even months to be effective.”

Addiction Risk

Although addiction to ketamine is possible — it is a controlled substance, Dr. Heinzerling said — it does not seem to have the significant addictive effect seen with opioids. Plus, its ability to act quickly for depression and pain means it may be able to be used on a short-term basis, similar to opioids.

“The best analogy is that you’re providing a reboot,” said Dr. Heinzerling. “Obviously, there are many considerations that go into use of ketamine, and it does have side effects, but if someone needs pain and antidepressant capability in an immediate way, ketamine is a promising option.”

Complementary Approaches

The choice in pain management obviously does not come down to opioids or ketamine, and even when the latter is more widely available as a pain management option for spinal issues, physicians are not likely to limit themselves to only those two options, according to Leia Rispoli, MD, an interventional pain management specialist and physiatrist at DISC Sports & Spine Center in Newport Beach, CA. In many cases, especially for older adults, a combination of approaches is important.

“Chronic low back pain is incredibly prevalent amongst the aging population, so there is constant growing interest and buzz in new treatment options, especially in the setting of the current opiate crisis,” she said. “These options can range from alternative medicine treatments, different classes of medications, injection, or minimally invasive surgical interventions.”

For ketamine to become part of a front-line treatment, more medical evidence is needed, especially from large, randomized controlled studies, she added. Along with that would need to be extensive training in terms of use.

“Ketamine as an opiate alternative may be a viable option, as long as the prescriber is comfortable with dosing, monitoring, and deciding which patients are good candidates for this option, while weighing its risks and benefits,” Dr. Rispoli said. “This option, just like many other potential new treatment options, will need more literature supporting its use and guidance in effective, safe dosing.”