Understanding the Off-Label Use of Ketamine

Understanding the Off-Label Use of Ketamine

Ketamine (N-methyl-D-aspartate receptor antagonist) is a dissociative anesthetic used to induce and maintain anesthesia during surgery. It is a Schedule III controlled substance and is therefore regulated by the FDA. The FDA first approved ketamine in 1970 for use as a “sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation.” 

Currently, the use of ketamine in anesthesia is fading in preference for safer and more efficacious anesthetics. However, it remains the anesthesia of choice in low and middle-income countries. 

The FDA has approved esketamine (an S version of ketamine) for managing treatment-resistant depression (TRD) and suicidal ideation. The use of ketamine for any other indication is therefore considered off-label. Increasingly, people are turning to ketamine for off-label uses, such as managing chronic pain and mood disorders. 

What Is the “Off-Label” Use of Ketamine?

Off-label drug use (OLDU) refers to the practice of prescribing drugs that are already approved by the FDA and marketed but for an indication that has not received FDA approval. Hence, that indication becomes an off-label indication since it has not been listed in the drug-labeling information as required by the FDA. This applies to ketamine as well as other drugs. Off-label also applies to the use of a medication in a population (such as pediatric) or dosage that has not been approved by the FDA. 

The FDA regulates all drugs that are marketed commercially. The Food, Drug, and Cosmetic Act of 1938 required that all marketed drugs should be safe. However, the  Kefauver-Harris Amendment of 1962 required that drugs should be both safe and effective. Consequently, the FDA is obligated to only approve medications that are both safe and effective for certain specific indications. This forms the basis for on-label prescribing. That said, the FDA does not control how medications can be prescribed by healthcare providers once they have been released to the market. It is the prerogative of the physician to determine the indication, dosage, and form in which to prescribe approved medications. 

The off-label use of drugs can be motivated by the following factors:

  • The drugs have not been studied in a particular population (such as pediatric)
  • When a terminal or life-threatening condition is not responding to other medications
  • When a medication is in the same class as other drugs that have been approved for that indication or when two conditions share pathological characteristics

Why is Ketamine Used “Off-Label”?

Ketamine’s patent expired in 2002. This means that there is minimal profitability attached to funding further ketamine research. A company would need to invest millions of dollars in seeking a patent for a new compound before seeing a return on investment.

In 2013, Jensen pharmaceuticals, a subsidiary of Johnson & Johnson, isolated one of the active components of ketamine—esketamine—and patented it. This company has so far managed to fund two published studies that support FDA approval for the use of ketamine in managing treatment-resistant depression and acute suicidal ideation. 

Usually, a company will devote time to study a drug’s effectiveness in addressing a specific symptom or disease. Once they have met the threshold set by the FDA for safety and efficacy, the drug can then receive FDA approval and be considered “on-label”. 

Companies will be willing to fund research based on a projected return on investment, the prevalence of the symptom or disease, and the price they expect to charge should the drug gain approval. 

Ketamine is not the only drug that has off-label uses. A 2001 study showed that 1 in every 5 (21%) prescriptions are for off-label indications. Professor Caleb Alexander, a practicing epidemiologist, notes that “off-label use is so common, that virtually every drug has been used off-label in some circumstances.”

Are Physicians Prohibited From Prescribing Ketamine Off-Label?

While it is illegal for drug manufacturers to promote drugs for off-label use, physicians are not under similar restrictions. Healthcare providers are at liberty to prescribe ketamine (and other drugs) for off-label indications whenever they deem fit. However, they should not be affiliated with or work directly for the drug’s manufacturer. 

Off-label use of ketamine in the EU is allowed “after attempting all evidence-based antidepressant strategies outlined in clinical guidelines.” The Royal College of Psychiatrists in the UK issued a statement in 2017 to address the use of ketamine in the treatment of depression. The statement issued caution when using ketamine to treat depression due to unknown long-term side effects; it also called for further research in this area. In Canada, Ketamine is classified as a Schedule I drug. However, it can be prescribed off-label for the treatment of TRD. In 2020, Health Canada approved the use of Spravato (esketamine) as an antidepressant.

Ketamine for Chronic Pain: Off-Label Use

Recent studies have shown that ketamine can effectively manage chronic pain. One study showed that ketamine, administered in subanesthetic doses, offers adequate analgesia with improved safety profiles, given the reduced dosages. Ketamine also has an opioid-sparing ability that reduces opioid-induced hyperalgesia. It is no surprise that several ketamine clinics have been established around the U.S. to offer ketamine as an alternative pain management therapy. 

Ketamine for Treatment-Resistant Depression: Off-Label Use

Recent studies have shown that subanesthetic doses of ketamine produce antidepressant benefits in patients with severe mood disorders that are not responsive to standard therapies. 

One review published in 2015 involved seven trials that had 147 patients who had been treated with ketamine. The participants had been diagnosed with major depressive disorder and bipolar disease. Ketamine was found to have a strong but transient effect, and the researchers advised circumspection. “The fleeting nature of ketamine’s therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.”

However, a previous review that was published in 2014 showed marked benefits for the off-label use of ketamine. Most studies that were analyzed in the review demonstrated that ketamine had rapid antidepressant effects in patients with treatment-resistant depression (TRD). Ketamine provided rapid significant clinical improvement and also reduced suicidality. This also confirmed the role of glutamate in the pathophysiology (disease process) of TRD. 

Ketamine Clinics—Are They Legal?

Ketamine clinics are legal in the U.S. They offer ketamine treatment primarily for off-label indications. 

Ketamine for Non-Anaesthetic Indication” (Knai)

The off-label use of ketamine is also referred to as “ketamine for non-anesthetic indication” (KNAI).  Currently, ketamine is being used off-label to treat various mood and pain disorders in outpatient clinics that are now referred to as ketamine clinics. 

At these clinics, patients are usually offered ketamine infusions which may last anywhere from 45 minutes to 5 hours, depending on the individual and the condition being treated. Ketamine clinics may offer ketamine for any of the following conditions:

  • Chronic pain
  • Severe depression
  • Anxiety
  • Migraines 
  • Post-Traumatic Stress Disorder (PTSD)

Conclusion

Preliminary evidence has shown that ketamine has robust and fast-acting analgesic and antidepressant effects, which need further exploration. As much as the off-label use of ketamine in managing severe depression and chronic pain is promising, caution needs to be exercised since the potential adverse effects of long-term use have not been investigated. 

That said, mood disorders and chronic pain contribute significantly to the global burden of disease, and so expedited research to validate the effectiveness of this potentially transformative treatment is highly warranted. 

Several ongoing studies (NCT01945047, NCT03113968, and NCT00088699) seek to fill these knowledge gaps. It would also be helpful to have a registry of patients who are receiving ketamine for off-label use. This would help with regular follow-up to establish long-term safety and effectiveness. 

 

 

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