Ketamine hydrochloride intravenous and esketamine nasal spray (Spravato®)
Indication(s)
Ketamine hydrochloride (HCl) is indicated: (1) as the sole anesthetic agent for recommended diagnostic and surgical procedures; (2) for induction of anesthesia prior to administration of other general anesthetic agents; and (3) to supplement low potency agents.
Esketamine (Spravato®) is indicated: (1) in combination with a selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI), for treatment of major depressive disorder (MDD) in adults who have not responded adequately to at least two separate courses of different antidepressants, each of adequate dose and duration, in the current moderate to severe depressive episode; and (2) in combination with oral antidepressant therapy, as short-term treatment, for rapid reduction of depressive symptoms in adult patients with a moderate to severe episode of MDD, which according to clinical judgement requires urgent psychiatric care.
Formulary status
The Drug Advisory Committee (DAC) recommended the ketamine HCl injection be listed with prior authorization criteria on Musculoskeletal (02WS), Central Nervous System/Peripheral Nervous System (03WS), Psychotraumatic (22WS), Chronic Pain Disability (23WS) and Serious Injury (27WS) formularies for the following indications:
- Complex Regional Pain Syndrome (CRPS)
- Refractory Neuropathic Pain (NeP)/NeP spreading to larger areas
- Treatment-Resistant Depression (TRD)
The DAC also recommended esketamine (Spravato®) nasal spray be listed with prior authorization criteria only on WSIB formularies Psychotraumatic (22WS) and Serious Injury (27WS) for treatment-resistant depression (TRD)
Prior authorization criteria:
Complex Regional Pain Syndrome (ketamine HCl):
- Diagnosis of CRPS meeting the Budapest Criteria
- Failure or inadequate response to both appropriate non-pharmacological and pharmacological treatment (e.g., NSAIDS, bisphosphonates, NeP medications as described in 2014 CPS Consensus Statement on management of chronic NeP)
- Prior trial of prednisone in early inflammatory CRPS
- Average pain rating of at least 4 out of 10
Refractory NeP/NeP spreading to larger areas (ketamine HCl):
- A clear and clinically supported diagnosis of NeP
- Pain duration of at least three months
- Average pain rating of at least four out of 10
- Failure of initial non-pharmacological treatment
- Failure of adequate trials of at least three first and second-line pharmaceuticals at maximally tolerated effective doses (neuropathic pain medications as described in 2014 CPS Consensus Statement on management of chronic NeP)
For both CRPS and NeP:
- Patient has been screened for contraindications/precautions to IV ketamine
- IV ketamine should be administered in multidisciplinary settings that comply with the College of Physicians and Surgeons of Ontario (CPSO) requirements related to the parenteral administration of anaesthetics. A qualified specialist physician, after appropriate assessment by a multidisciplinary pain team providing ongoing monitoring of response, should administer IV ketamine.
- Oral ketamine should only be allowed short-term as a step-down from IV ketamine
Duration of approval: six months
Subsequent treatment request: based on response assessed using validated scoring tools
Treatment-resistant depression (with or without suicidal ideation; ketamine HCl and esketamine nasal spray)
- Lack of clinically meaningful improvement with at least two oral antidepressants at maximally tolerated effective doses and taken for adequate durations during the current/index depression episode
- Patient has been screened for contraindications/precautions to requested agent
- IV ketamine should be administered in multidisciplinary settings that comply with CPSO requirements related to the parenteral administration of anaesthetics. A qualified specialist physician, following appropriate psychiatric assessment by a psychiatrist who also is providing ongoing monitoring of response, should carry out administration of IV ketamine
- Esketamine should be used in combination with SSRI/SNRI and be administered under supervision of qualified health care professional according to the product monograph, following appropriate psychiatric assessment by an psychiatrist who also is providing ongoing monitoring of response
Duration of approval: six months
Subsequent treatment request: based on response assessed using validated scoring tools
The WSIB accepts the DAC recommendations for listing. For people with injuries or illnesses, ketamine IV and esketamine IN will be available through our specialty programs.
Recommendation highlights
- Ketamine is a NMDA [N-methyl-d-aspartate] receptor antagonist with potent anaesthetic effect. Ketamine interacts with opioid, monoaminergic and muscarinic receptors as well as voltage-sensitive calcium ion channels. Esketamine is the S-enantiomer of racemic ketamine.
- Ketamine is used for anaesthesia and various indications including pain and mental health disorders.
- An external, independent review completed in 2021 concluded that parenteral or epidural ketamine may be considered as an option for short-term analgesia in patients with chronic non-cancer pain refractory to conventional treatments. Additionally, parenteral ketamine was determined to be effective as an adjunctive therapy for TRD at reducing depression severity and suicidal ideation for up to seven days.
- The review also concluded that esketamine (in combination with a newly initiated antidepressant) showed significant improvement in depression scores, reduced relapse events and delayed relapse for patients with TRD.
- Evidence suggests that both ketamine and esketamine are safe when administered according to current practice guidelines and/or the product monograph. Adverse events were tolerable and transient in nature, and included anxiety, dysphoria, hallucinations, nausea, sedation and elevated blood pressure.
- A long-term (one year) study assessing the safety of esketamine nasal spray concluded that adverse effects were consistent with short-term studies.
- The American Academy of Pain Medicine and the American Society of Anesthesiologists’ 2018 Consensus Guidelines on the Use of Ketamine IV for Chronic Pain concluded that IV ketamine may be effective for CRPS, showing improvement in symptoms for up to 12 weeks. However, there was weak evidence for use in other conditions such as mixed NeP.
- The Canadian Network for Mood and Anxiety Treatments’ 2016 Guidelines for Management of Adults with Major Depressive Disorders concluded that IV ketamine is a fast-acting and effective antidepressant, but reserved its use as a third-line agent for severe symptoms, significant suicidal ideation or for TRD.
- Esketamine nasal spray is not currently mentioned in any guidelines, as the drug has only recently been marketed.
- Both ketamine injection and esketamine intranasal spray have special administration requirements; ketamine must be administered in a clinical setting under the care of health care professionals with knowledge and training in the administration of ketamine, along with appropriate safety and monitoring procedures in place. Patients, physicians and pharmacists must be enrolled in the JANSSEN JOURNEYTM program in order to receive, prescribe and dispense esketamine intranasal spray, respectively.
- Canadian Agency for Drugs and Technologies in Health (CADTH) published their review of esketamine in April 2021. They recommended it not be reimbursed for the treatment of MDD, primarily due to a lack of high-quality evidence and uncertain balance between benefits and harms, but did not specifically make a recommendation for TRD.
- Ketamine HCl and esketamine HCl nasal spray are not covered by the Ontario Drug Benefit Program.
- Based on published evidence, current guidelines, and an emerging need for the treatment CRPS, NeP and/or MDD/TRD in cases which are refractory to established therapies, the DAC recommended that injectable ketamine HCl and esketamine HCl nasal spray be listed with criteria. The WSIB will regularly review outcomes of treatment of all injured/ill people granted entitlement.
- Due to the lack of evidence, the DAC recommended that other routes of administration for ketamine HCl (e.g., topical) not be listed on any formulary.
Products available in Canada:
- Ketamine HCl 10mg/mL, 50mg/mL and 100mg/mL injection (Ketalar® and generics)
- Esketamine HCl 28mg nasal spray (Spravato®)