KETAMINE (KETALAR)
Ketamine (Ketalar) is a nonselective, noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor and acts by blocking excitatory glutamate receptors in the central nervous system. This produces sedation, amnesia, and analgesia. Ketamine (Ketalar) is a rapidly acting general anesthetic producing a dissociative anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally a transient and minimal respiratory depression. Intravenous (IV) ketamine (Ketalar) should be administered only by or under the supervision of individuals who are experienced with its use and potential complications.
Ketamine (Ketalar) is a known drug of abuse and is subject to control under the Federal Controlled Substances Act of 1970 as a schedule III drug. Although brief exposure to IV ketamine (Ketalar) in a hospital setting is not likely to cause addiction, the possibility of addiction exists, and individuals should be individually assessed for their risk. Ketamine (Ketalar) should be prescribed and administered with caution because of the risk of abuse. Tolerance and dependence may develop following prolonged administration of the drug.
PEER-REVIEWED LITERATURE
The first published human study involving ketamine (Ketalar) (Domino et al., 1965) was a phase I, open-label trial in which varying doses of ketamine (Ketalar) were administered IV to 20 individuals. Ten of the individuals also received a repeat dosing after awakening from the first dosing of ketamine (Ketalar). Vital signs, level of consciousness, and laboratory studies were monitored before and after receiving ketamine (Ketalar). Since the time of this study, there have been over 100 separate studies involving thousands of individuals in thousands of operative and diagnostic procedures.
OTHER CONDITIONS OR INDICATIONS
Acute/Chronic Pain
Many studies have been undertaken to evaluate the use of IV ketamine (Ketalar) for acute and/or chronic pain (where the individual's pain has lasted longer than 3 months). The conditions associated with the pain include, but are not limited to, migraines/headaches, neuropathic pain, perioperative pain, and fibromyalgia. The use of IV ketamine (Ketalar) for the treatment of acute and/or chronic pain is considered experimental/investigational.
Migraines cause over one million Emergency Department visit annually. There are many categories of pharmacological agents that can be used in the treatment of acute or chronic migraines. Some of these agents are opioids, corticosteroids, antihistamines, nonsteroidal anti-inflammatory drugs (NSAIDs), and migraine-specific drugs including triptans and ergotamine compounds. In an assessment of parenteral pharmacotherapies for use with acute migraines, the American Headache Society (Orr et al., 2016) concluded that no recommendation could be made regarding the role of ketamine (Ketalar) in the Emergency Department as there was insufficient evidence.
Neuropathic pain can be defined as pain that is initiated or caused by a focus in the nervous system, or by a dysfunction in the nervous system. Treatments for neuropathic pain can be targeted towards providing analgesia or the underlying cause of the pain. Since there may be more than one mechanism at work causing the pain, attempting to treat the pain can be complex. In a review of the current evidence on targeted pharmacotherapy for neuropathic pain (Granot et al. 2007) identified eight studies that evaluated the use of parenteral ketamine (Ketalar) for various types of neuropathic pain (spinal cord injury [SCI], complex regional pain syndrome [CRPS], nerve injury). All of the studies were done on too small a number of individuals to allow the results to be generalizable. The authors concluded that there was not enough clinical evidence to recommend any of the agents evaluated in the study with much certainty.
In The Cochrane Database of Systematic Reviews, Chaparro et al. (2013) identified 14 randomized controlled trials (RCTs) involving the use of ketamine (Ketalar) for the prevention of chronic pain after surgery. Thirteen of the 14 studies included too small a number of tested individuals to allow the results to be generalizable. The final study enrolled 352 individuals into the study, but only 25.9 percent of participants responded at 3 months and 10.2 percent at 6 months to chronic pain questionnaires, leading to attrition bias. In an updated article from The Cochrane Database of Systematic Reviews, Carley et al. (2021) identified 13 new RCTs. No treatment effect of ketamine (Ketalar) versus placebo was identified on the prevalence of any pain regardless of outcome timing (3 months, 6 months, or 12 months), duration of drug administration (one time dose, ≤24 hours, >24 hours), or type of surgical procedure in any of the 27 studies identified. Other systematic reviews and meta-analyses are mentioned in this review that reached the same conclusion.
Fibromyalgia is significant for chronic generalized musculoskeletal pain for which an inflammatory source or structural lesion cannot be identified. The pain in fibromyalgia has been associated with central sensitization. There may be more than one process that initiates the central sensitization, and one of these includes an NMDA receptor activation that ketamine (Ketalar) could block. In a study to evaluate the long-term effects from an infusion of ketamine (Ketalar) on fibromyalgia pain (Noppers et al., 2011), it was found that ketamine (Ketalar) produced a reduction of pain exceeding 50 percent in 15 minutes significantly more than midazolam did in the same time frame. At 180 minutes, 1 week, and 8 weeks, however, there was no significant difference between the two groups in reduction of pain. In a review of pharmacotherapy options for individuals with fibromyalgia (Clauw, 2008), ketamine (Ketalar) is not mentioned as an option for therapy.
Although many studies have been undertaken to evaluate the use of ketamine (Ketalar) for various acute and/or chronic pain syndrome, the long-term benefits have not been clearly demonstrated. The intense treatment protocols used in many studies would make the implementation of them difficult in practice. Optimal dosing and/or dosing regimens have not been established. Most of the studies enrolled too few individuals for the results to be generalizable. Many studies were not placebo-controlled, blinding was inadequate, or the placebo was saline as opposed to another active drug. Multiple studies documented adverse events with some leading to individuals dropping out of the studies. Schwenk et al. (2018)
acknowledged that the use of ketamine (Ketalar) outside of the operative or
intensive care unit setting is limited by the potential for adverse
cardiovascular and psychomimetic effects. Safe dose ranges for use have not
been established. High-quality studies comparing varying dose ranges of
ketamine (Ketalar) for individuals with acute pain conditions or comorbid
conditions have not been accomplished. The overall net health benefit of IV ketamine (Ketalar) for use in acute/chronic pain syndromes is considered experimental/investigational.
Psychiatric Disorders
Fewer than half of individuals who present for treatment of their initial episode of major depression will obtain remission. With each successive treatment, there is often less chance of an individual obtaining remission. There is no standardized definition of treatment-resistant depression (TRD). The term often refers to a major depressive episode that has not responded satisfactorily to two trials of AD therapies. There is also no standardized definition for describing the results to antidepressant (AD) therapy. Often no response is defined as less than 25 percent improvement from baseline on a depression rating scale. There are many therapies that can be used to treat TRD. These therapies can include augmentation of an AD with either another AD and/or other drug (e.g., lithium), cognitive behavioral therapy (CBT), repetitive transcranial magnetic stimulation, vagus nerve stimulation, or interpersonal psychotherapy. Each of these therapies has possible benefits and side effects. There are some individuals who will not attain a lasting remission from the currently available treatments.
In The Cochrane Database of Systematic Reviews, Caddy et al. (2015) searched the literature for RCTs involving the use of IV ketamine (Ketalar) for depression. Nine trials were identified, four of which specified that the participants had TRD. It was found that there was limited evidence that ketamine (Ketalar) was more efficacious than placebo, but the quality of evidence was limited by the risk of bias in the studies and too few individuals being enrolled in the studies for the results to be generalizable. There was low-quality evidence that ketamine (Ketalar) influences the individuals' depression after 24 hours, but limited evidence of an effect at 1 week, and even less evidence of an effect at 2 weeks. Limited data were found on documentation of suicidality, cognition, drop-out rates, or changes in quality of life, which would be important to know.
Obsessive-compulsive disorder (OCD) is a spectrum of disorders that can include obsessive thoughts, compulsive behaviors, and anxiety. Disorders that can be included in this group include eating disorders and substance use/abuse disorders. There is some literature published on studies evaluating the use of ketamine (Ketalar) in individuals with OCD. Many of the trials are proof-of-concept/pilot studies, single case studies, or include groups of individuals too small for the results to be generalized. Martinotti et al. (2021) reviewed the literature for studies involving the use of ketamine (Ketalar) and esketamine (Spravato) in multiple psychiatric disorders. In the studies evaluating the use of IV ketamine (Ketalar), if evaluated at all, the published trials document little effect of ketamine (Ketalar) on OCD beyond 1 week following the infusion(s). Long-term outcomes were not documented. One study also documented the onset of worsening anxiety and suicidal thinking. The overall net health benefit of IV ketamine (Ketalar) in psychiatric disorders is considered experimental/investigational.
Professional Guidelines
The American Headache Society published an article on the parenteral pharmacotherapy management of adults with acute migraine in the emergency department (Orr et al., 2016). Their conclusion was that no recommendation could be made regarding the role of IV ketamine (Ketalar). It was believed that the evidence for efficacy was insufficient.
The American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists published a joint set of consensus guidelines on the use of IV ketamine (Ketalar) for chronic pain (Cohen et al., 2018). They found the level of evidence for the use of IV ketamine (Ketalar) for SCI to be grade C with a low certainty. For the use of IV ketamine (Ketalar) for CRPS, the level of evidence was found to be grade B with low to moderate certainty for improvement in pain up to 12 weeks. For the use of IV ketamine (Ketalar) for other pain conditions (e.g., neuropathic pain, fibromyalgia, headache) the level of evidence was found to be grade D with low certainty.
The American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments published a consensus statement on the use of ketamine (Ketalar) in the treatment of mood disorders (Sanacora et al., 2017). They believed that ketamine (Ketalar) could be beneficial to some individuals with mood disorders, but it was important to consider that the published literature contained only studies with relatively small numbers of participants. There are many documented physical and psychotomimetic side effects that could prove dangerous to an individual receiving the drug. They believed that the literature did not demonstrate the safety and durability of ketamine (Ketalar) over time.
ESKETAMINE (SPRAVATO)
Esketamine (Spravato), the S-enantiomer of racemic ketamine, is a nonselective, noncompetitive antagonist of NMDA. The mechanism by which esketamine (Spravato) exerts its AD effect is unknown. Esketamine (Spravato) is a schedule III substance and may be subject to abuse and diversion. Esketamine (Spravato) should be prescribed and administered with caution because of the risk of abuse. Tolerance would be expected with prolonged use of esketamine (Spravato).
PEER-REVIEWED LITERATURE
Treatment-Resistant Depression (TRD): Short-Term Study
The safety and efficacy of esketamine (Spravato) was evaluated in a randomized, placebo-controlled, double-blind, multicenter, short-term (4-week), phase III study (Popova et al., 2019) in adult individuals 18 to 64 years old with TRD. Individuals in the study met Diagnostic and Statistical Manual of Mental Disorders, fifth edition text revision (DSM-5TR) criteria for major depressive disorder (MDD), and in the current depressive episode had not responded adequately to at least two different ADs of adequate dose and duration. Key exclusion criteria included substance use disorder, suicidal ideation or behavior, homicidal ideation or intent, MDD with psychotic features, borderline personality disorder, bipolar or related disorders, antisocial personality disorder, OCD, narcissistic personality disorder, psychotic disorder, histrionic personality disorder, autism, and intellectual disability. After discontinuing prior AD treatments, individuals in the study were randomly assigned to receive twice weekly doses of intranasal esketamine (Spravato) (flexible dose; 56 mg or 84 mg) or intranasal placebo. All individuals also received open-label concomitant treatment with a newly initiated daily oral AD (duloxetine, escitalopram, sertraline, or extended-release venlafaxine as determined by the investigator based on the individual's prior treatment history). Esketamine (Spravato) could be titrated up to 84 mg starting with the second dose based on investigator discretion. In the study, the primary efficacy measure was change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at the end of the 4-week double-blind induction phase. The MADRS is a 10-item clinician-rated scale used to assess severity of depressive symptoms. Scores on the MADRS range from 0 to 60, with higher scores indicating more severe depression. Esketamine (Spravato) plus a newly initiated oral AD demonstrated statistical superiority on the primary efficacy measure compared to placebo nasal spray plus a newly initiated oral AD. Clinically meaningful improvement was also observed earlier with the esketamine (Spravato) arm as compared to the placebo arm.
Treatment-Resistant Depression (TRD): Long-term Study
The time to relapse of depression was evaluated in a long-term, randomized, double-blind, parallel-group, multicenter maintenance-of-effect phase III study (Daly et al. 2019) in adults 18 to 64 years of age who were known remitters and responders to esketamine (Spravato). Individuals in this study were responders in one of two short-term controlled trials (the Popova et al. 2019 study and another 4-week study) or directly enrolled in the study in which they received flexibly dosed esketamine (Spravato) (56 mg or 84 mg twice weekly) plus daily oral AD in an initial 4-week phase. Key exclusion criteria included substance use
disorder, suicidal ideation or behavior, homicidal ideation or intent, MDD with
psychotic features, borderline personality disorder, bipolar or related
disorders, antisocial personality disorder, OCD,
narcissistic personality disorder, psychotic disorder, histrionic personality
disorder, autism, and intellectual disability. Stable remission was defined as a MADRS total score less than or equal to 12 for at least 3 of the last 4 weeks. Stable response was defined as a MADRS total score reduction from baseline of greater than or equal to 50 percent in the last 2 weeks but not in remission. A randomized withdrawal design was used to evaluate the time to relapse.
After an induction phase, individuals in the study entered a 12-week optimization phase during which the dosage of the study drug remained stable, but the frequency of dosing was reduced to once weekly for 4 weeks, then individualized to weekly or every 2 weeks based on the severity of the individuals' depressive symptoms. The oral AD was continued throughout the study. Relapse was defined as a MADRS total score greater than or equal to 22 for two consecutive assessments separated by 5 to 15 days, or hospitalization for worsening depression or any other clinically relevant event indicative of relapse.
Of the individuals in stable remission, 26.7 percent of individuals in the esketamine (Spravato) group and 45.3 percent of individuals in the placebo group experienced a relapse event during the optimization phase. Individuals who continued treatment with esketamine (Spravato) plus oral AD experienced a statistically significantly longer time to relapse of depressive symptoms than did individuals on placebo nasal spray plus an oral AD. Time to relapse was also significantly delayed in the stable responder population. These individuals experienced a statistically significantly longer time to relapse of depressive symptoms than individuals on placebo nasal spray plus oral AD as well.
Major Depressive Disorder (MDD): Short-Term Studies
ASPIRE I (Fu et al., 2020) and ASPIRE II (Ionescu et al., 2021) were identical phase III, short-term (4 week), randomized, double-blind, multicenter, placebo-controlled studies to evaluate the use of esketamine (Spravato) versus placebo in reducing MDD symptoms, including suicidal ideations. Individuals who met the DSM-5TR criteria for MDD without psychosis, age 18 to 64 years old, with moderate-to-severe MDD (MADRS score >28) with active suicidal ideation and intent received either esketamine (Spravato) or placebo twice weekly for 4 weeks. Key exclusion criteria included substance use
disorder, MDD with psychotic features, bipolar disorder, OCD, borderline personality disorder, and antisocial personality disorder. All individuals received comprehensive standard of care treatment including an inpatient psychiatric hospitalization and a newly initiated or optimized oral AD. The initial dosage of esketamine (Spravato) was 84 mg but could be reduced to 56 mg if the individual could not tolerate the higher dosage. The primary endpoint of the study was improvement in MADRS scores 24 hours after the treatment. There was a statistically significant improvement in the esketamine (Spravato) MADRS scores (−16.4 in ASPIRE I; −15.7 in ASPIRE II) versus the placebo group MADRS scores (−12.8 in ASPIRE I; −12.4 in ASPIRE II). The onset of improvement was earlier with esketamine (Spravato), at 4 hours, versus with placebo as well. Both groups had rapid reduction in the severity of their suicidality, but the difference between the groups was not statistically significant and was believed to be likely due to both groups receiving inpatient hospital care.
Professional Guidelines
The American Psychiatric Association last issued clinical practice guidelines for depression in 2010. Because esketamine (Spravato) was approved by the US Food and Drug Administration in 2019, the drug was not included in the most recent guidelines. There is therefore no published guideline from the American Psychiatric Association that contains recommendations on the use of esketamine (Spravato) for use in TRD.
The Institute for Clinical and Economic Review published a summary on the effectiveness and value of intranasal esketamine (Spravato) for the management of TRD (Agboola et al., 2020). They found that esketamine (Spravato) demonstrated superiority when combined with an AD as compared to an AD alone. Concerns about the safety of the long-term use of esketamine (Spravato) remain, however.
OFF-LABEL INDICATIONS
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company's off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
