Depression is frequently associated with chronic pain. The use of antidepressants for pain management has often been thought of as a "two-fer": Pain scores can be decreased while accompanying depression is treated. Now, esketamine, a new formulation of a ketamine enantiomer, is being marketed for depression as Spravato (Janssen Pharmaceuticals).1
In landmark studies, Kim et al2 and Daly et al3 demonstrated that esketamine, the S(+)enantiomer of ketamine, significantly reduced depressive symptoms in patient who suffered from major depression and associated pain. Major improvements were demonstrated with few complications.
Pharmacology
Esketamine is the S(+)enantiomer of ketamine. Arketamine is the R(-)enantiomer of ketamine, which is less potent than racemic ketamine or esketamine with respect to anesthetic and analgesic potency. Arketamine binds to the sigma receptor, which may play a role in hallucinations and lowering of the seizure threshold as compared with both racemic ketamine and esketamine. However, it may be a more potent antidepressant because it binds strongly to the [alpha]-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor whereas an esketamine metabolite, hydroxynorketamine, binds weakly to the AMPA receptor and is thought to be responsible for the antidepressant effect of esketamine.
A unique aspect of esketamine is the nasal route of administration. Although patients have been snorting drugs since the 15th century (eg, snuff) and inhaling gas vapors since ancient Greece, the nasal route of drug administration has unique advantages and disadvantages. Delivery of medication into the nasal cavity allows for uptake through the rich vascular mucosa of the nares and through the cribriform plate, allowing for a very fast onset of action. However, patients with sinus problems or chronic and acute infections may have irregular uptake, and issues with worsening of the underlying condition, because the forced inhalation may alter the natural drainage pattern. Patients with a history of cocaine abuse may have altered nasal mucosa and irregular uptake.
Adverse Effects
The 5 most common side effects reported in the package insert during treatment were dysgeusia, vertigo, dissociation, somnolence, and dizziness.1 Most of these were considered mild to moderate and generally resolved in the same day.
Serious complications, although very rare, include autonomic nervous system "imbalance," disorientation, hypothermia, lacunar stroke (ie, ischemic lesion, day 1, 6 hours after dosing), sedation, simple partial seizures, and suicidal ideation.
Transient blood pressure increases were observed with esketamine on treatment days; the maximum value was reached at 40 minutes after the start of administration, in most cases, and typically returned to the predose range by 1.5 hours after administration.
One patient in the treatment group experienced treatment-emergent transient hypertension, defined as a systolic blood pressure of 180 mm Hg or higher and/or a diastolic blood pressure of 110 mm Hg or higher. None of the patients in the standard antidepressant and placebo groups experienced systolic hypertension. Diastolic hypertension occurred in 2 esketamine-treated patients and did not occur in the antidepressant- and placebo-treated patients during the maintenance phase. No clinically significant changes in electrocardiographic findings were observed during the study. No evidence of a distinct withdrawal syndrome was observed during the 2 weeks after cessation of esketamine nasal spray as assessed by the 20-item Physician Withdrawal Checklist.
Ketamine cystitis is a known issue.4 Chronic cystitis has been reported in patient who are ketamine abusers. Although hydration and diuresis may help avoid the issue, it is clearly something that needs to be fully addressed in patients who will be on esketamine for a considerable period. A 2.5% reported incidence is worrisome.
Cost Issues
The cost factor of esketamine versus IV ketamine is dramatic. The Red Book price of intranasal esketamine is $590 to $885 per treatment.5 In contrast, an equivalent dose of generic IV ketamine is $6 to $12.
A Unique Opportunity
As many pain practitioners have noted, persuading insurance companies to pay for ketamine therapy for chronic pain problems has been exceedingly difficult. If depression can be fully documented, then esketamine therapy may be used in these patients.
Conclusion
Esketamine, an antidepressant, decreased the risk of relapse among patients who achieved stable remission and to an even greater degree among those who achieved stable response compared with antidepressant and placebo treatment alone. The most common adverse events are mild but reported less in patients receiving with an antidepressant or placebo alone. This is a major advance in depression therapy, and unlike other antidepressant medications, the effectiveness is manifested quickly in comparison to other agents that may require weeks before any improvement is demonstrated.
References