USPHS: Ketamine: Old Dog, New Tricks?

Keith Warshany, PharmD, PhC, BCPS, NCPSLCDR US Public Health Service

Pharmacist Practitioner, PGY1 Residency Program Director, Deputy Chief PharmacistCrownpoint Healthcare Facility (Indian Health Service), Crownpoint NM

JOINT FEDERALPHARMACY SEMINARFEDERAL PHARMACY: SHARING THE VISION IN PHARMACY

Target Audience: Pharmacists

ACPE#: 0202-0000-19-186-L01-P

Activity Type: Knowledge-based

ACPE Information

The American Pharmacist Association is accredited by the Accreditation Council for Pharmacy

Education as a provider of continuing pharmacy education.

Keith Warshany declares no conflicts of interest, real or apparent, and no financial interests in any

company, product, or service mentioned in this program, including grants, employment, gifts, stock

holdings, and honoraria.”

Financial Disclosures

Describe the pharmacology of ketamine

Evaluate the evidence supporting FDA approved indications and off-

label use of sub-anesthetic ketamine

Learning Objectives

1) With respect to pharmacology, the antidepressant effects of ketamine

have been conclusively demonstrated to be the result of:

a. Antagonism at the NMDA receptor

b. Agonism at the mu-opioid receptor

c. Neuroplasticity and synaptogenesis

d. There is currently no clear explanation for ketamine’s antidepressant effect

Self-Assessment

2) With regard to clinical efficacy, data most robustly support ketamine’s

utility in the treatment of:

a) Neuropathic pain states

b) Opioid-resistant pain in palliative care

c) Suicidal ideation

d) Suicidal behavior

Self-Assessment

3) The recently FDA-approved esketamine intranasal spray:

a) Has demonstrated safety in studies that followed patients for up to 2 years of

treatment

b) Has been shown to have a lower risk of abuse than conventional ketamine

formulations

c) Is indicated for use in treatment resistant depression as an adjunct to oral

antidepressant therapy

d) Is indicated for use in bipolar depression type II as an adjunct to oral therapy

Self-Assessment

Initial FDA approval in 1970

Designed as a better tolerated alternative to phencyclidine (PCP)

Racemic mixture:

arketamine vs. esketamine

Pharmacodynamic effects:

Anesthetic and analgesic

Anti-hyperalgesic

Anti-allodynic

Antidepressant

Ketamine

Am J Psychiatry. 2015 Oct;172(10):950-66.

Neural Plast. 2017;2017:4605971.

Complex and not completely understood

Uncompetitive N-methyl-D-aspartate receptor (NMDA)

receptor antagonist

NMDA receptor:

Ligand gated channels with multiple binding sites:

Glutamate

Glycine OR d-serine

Ion-gated channel

Role of magnesium

Ketamine – Pharmacology

Am J Psychiatry. 2015 Oct;172(10):950-66.

Neural Plast. 2017;2017:4605971.

Blockage of NMDA receptor ion-channels results in downstream

activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

(AMPA) receptors

Other effects (possibly) include:

Monoamine reuptake inhibition

Enhancement of presynaptic glutamate release

Synaptogenesis

Synaptic versus extra-synaptic NMDA receptors

Implications for plasticity versus toxicity?

Ketamine – Pharmacology

Am J Psychiatry. 2015 Oct;172(10):950-66.

Neural Plast. 2017;2017:4605971.

“The right dose differentiates a poison and a remedy.”

Paracelsus

“All substances are poisons”

Generally well tolerated with low incidence of major adverse events

BUT….this statement is based on one-time / infrequent administration

Hemodynamic instability

Hypertension, tachycardia

Psychotomimetic & dissociative effects

Confusion/blurred vision

Dizziness, nausea / vomiting

Ketamine – Side Effects

Lancet Psychiatry. 2018 Jan;5(1):65-78.

Pain Manag Nurs. 2017 Dec;18(6):372-377.

Int J Neuropsychopharmacol. 2016 Apr 20;19(4).

▪ Existing treatments

lacking for chronic pain

and depression

▪ Rapid onset of action

▪ Encouraging short term

results in some studies

▪ Limited long term safety / efficacy data

▪ Known abuse potential

▪ Potential to exacerbate psychotic symptoms

▪ Some clinical data equivocal

Both Sides of the Story

FOR AGAINST

Major depressive disorder

(MDD)

Treatment Resistant

Depression (TRD)

Acute suicidality

Bipolar disorder

Palliative care

Acute and perioperative pain

Chronic noncancer pain

Complex regional pain

syndrome

Localized neuropathic pain

Cocaine addiction

Ketamine: Potential Uses

Ketamine is the only NMDA antagonist with clinical data to support an

antidepressant effect

Number and quality of studies is poor and heterogeneous

Most studies consider single infusions and effects become non-

statistically significant after 7d

Dosing:

0.5 mg/kg IV is most common, range: 0.1 to 1 mg/kg

Given over 40 minutes, range 2 – 100 minutes

Possible adjunctive treatment to electroconvulsive therapy (ECT)

Depression

Cochrane Database Syst Rev. 2015 Sep 23;(9):CD011612.

J Clin Psychiatry. 2017 Jul;78(7):e852-e857.

Lancet Psychiatry. 2017 May;4(5):365-377.

New Drug Approval:

March 2019

4 studies were submitted to

FDA for consideration

Risk Evaluation and

Mitigation Strategy (REMS)

Esketamine Intranasal

3 short term efficacy trials (~ 4 weeks),1 long term relapse trial (cumulative n~300)

All studies:

Added esketamine/placebo to a background of oral antidepressant therapy

Observed small (~4 point) decreases on the Montgomery-Asberg Depression Rating Scale (MADRS)

Note: MADRS is a 60 point scale

Notably, 2 of the 3 short term efficacy trials did not meet statistical significance

Clinical significance?

Number Needed to Treat (NNT) < 10 for both response and remission

Study drug was, generally, well-tolerated

Esketamine Intranasal in TRD

JAMA Psychiatry. 2018 Feb 1;75(2):139-148.

Am J Psychiatry. 2019; 176:428–438.

JAMA Psychiatry. 2019;76(9):893-903.

Int J Neuropsychopharmacol. 2019 Jul 10.

US FDA Briefing

Study population was not representative of patients with treatment

resistant depression

Relapse study was used to support efficacy

Benefits beyond the initial rapid onset of esketamine could be mostly

attributed to oral antidepressant

Esketamine - Criticisms

Am J Psychiatry. 2019 Jun 1;176(6):422-424.

Withdrawal phenomenon?

Higher relapse rates with esketamine discontinuation than with

conventional antidepressants

3 suicides occurred within 20 days of esketamine discontinuation

No safety or efficacy data exist beyond 1 year of treatment

Dosing schedule with chronic use is unclear

PI: twice weekly x 4 weeks, then once weekly x 4 weeks, then once

q1-2 weeks

Esketamine - Criticisms

Am J Psychiatry. 2019 Jun 1;176(6):422-424.

Suicide

Source: CDC Source: VA National Suicide Data Report 2005-2016

Ketamine meta-analysis of patient-level data from 10 studies, n=167

All patients experienced (+) active or passive suicidal ideation at baseline

Single dose of ketamine (specific doses not specified) versus control (saline or

midazolam, study-dependent)

Rapidly and significantly reduced suicidality on validated physician-

administered and self-reported scales

Treatment effect remained significant at day 3 but not at day 7

Randomized trial of intranasal esketamine produced similar results,

though with less durability in response

Acute Suicidality

Am J Psychiatry. 2018 Feb 1;175(2):150-158.

Am J Psychiatry. 2018 Jul 1;175(7):620-630.

Only studied for depressive symptoms (NOT for mania)

At least 2 small randomized crossover studies (combined n=33) have

shown decreases in MADRS scores

Single infusion of ketamine 0.5mg/kg

Reductions in depression scores sustained for 3 days

Low quality evidence

Bipolar Disorder

Ment Health Clin. 2017 Jan; 7(1): 16–23.

Downstream effects of NMDA receptor antagonism:

Attenuation of pain signals in the CNS

Diminished hyperalgesia

Decreased central sensitization

Decreased opioid tolerance

Pain

Pain Rep. 2018 Aug 9;3(5):e674.

Pain

Indication Findings Quality of Evidence

Acute perioperative

pain

-Decreased pain scores

-Decreased post-op opioids

-Increased time to first opioid request

-Decreased N/V

-No reduced risk of developing chronic post-op pain

Moderate

Opioid-resistant pain in

palliative care

-Keep the dose low (~1mg/kg/day), avoid intrathecal

or epidural routes of admin

- Primary evidence is case series data

Weak

Chronic noncancer pain -Higher quality data suggests benefit but there isn’t a

lot of it!

-Huge variability in doses, schedules, methodology,

study design

-No studies exceed 12 weeks

-In complex regional pain syndrome (CRPS), pain

improved but function did not

Weak to Moderate

Pain Rep. 2018 Aug 9;3(5):e674.

Topical ketamine

Advantages of topical treatments include fewer side effects and drug-

drug interactions compared to systemic treatment

Disadvantages include high cost of therapy and need for compounding

pharmacies

Small studies have evaluated ketamine, alone or in combination with

other agents, for a variety of neuropathic pain conditions

Presently, there is little evidence to support systematic use

Localized Neuropathic Pain

Curr Pain Headache Rep. 2017 Mar;21(3):15.

RCT, n=55

Single infusion of ketamine 0.5mg/kg vs midazolam control, followed

by 5 week course of mindfulness based relapse prevention

Abstinence maintained in 48.2% of ketamine vs 10.7% in control group

(statistically significant)

Likelihood of relapse and self-reported craving was also significantly

lower in ketamine group

Infusions were well tolerated

Cocaine Addiction

Am J Psychiatry. 2019 Jun 24:appiajp201918101123.

American Psychiatric Association

Indication: Mood disorders

Recommended dose: 0.5 mg/kg over 40 minutes

Frequency: not more than 2-3 infusions weekly

Duration: Not to exceed 4 weeks (“Short-term repeated infusions”)

Concerns: gaps in long term safety and efficacy

Guidelines/Consensus Statements

JAMA Psychiatry. 2017 Apr 1;74(4):399-405.

American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain

Medicine, and the American Society of Anesthesiologists

Indication:

Surgical pain, including opioid dependent individuals, (Grade B)

Sickle cell pain (+/- opioid dependent), comorbid sleep apnea (Grade C)

PCA adjunct to opioid (Grade B)

Recommended dose (IV):

Bolus <0.35mg/kg

Continuous not to exceed 1mg/kg/hr

Guidelines / Consensus Statements

Reg Anesth Pain Med. 2018 Jul;43(5):456-466.

Contraindications:

Poorly controlled CVD

Pregnancy

Psychosis

Hepatic impairment (mod – severe)

Elevated ICP / IOP

Active substance abuse

American Society of Regional Anesthesia and Pain Medicine, the American

Academy of Pain Medicine, and the American Society of Anesthesiologists

Indication: Chronic pain

Recommended dose:

80mg IV over at least 2 hours

Some evidence suggests higher doses are more effective and extend pain relief

No specific recommendations for frequency/duration

Guidelines / Consensus Statements

Reg Anesth Pain Med. 2018 Jul;43(5):521-546.

Positive treatment response:

30% decrease in pain

Patient satisfaction

20% reduction in opioid use

Positive response on

disability scale

Ketamine is an agent with a complicated pharmacological profile

whose well-established pharmacodynamic effects make it a seemingly

attractive candidate for a variety of psych and pain disorders

Ketamine provides rapid relief of depression, suicidal ideation and pain

but the durability of ketamine response appears to be highly variable

Take-Aways

Data on the efficacy of ketamine is generally limited by inconsistent

study design and variability with regard to indication for use, dose,

interval/frequency, and route of administration

Ketamine has a well established potential for misuse and a very limited

amount of data exist regarding the efficacy and safety of chronic long-

term use of ketamine

Take-Aways

1) With respect to pharmacology, the antidepressant effects of ketamine

have been conclusively demonstrated to be the result of:

a. Antagonism at the NMDA receptor

b. Agonism at the mu-opioid receptor

c. Neuroplasticity and synaptogenesis

d. There is no clear explanation for ketamine’s antidepressant effect

Self-Assessment

2) With regard to clinical efficacy, data most robustly support ketamine’s

utility in the treatment of:

a) Neuropathic pain states

b) Opioid-resistant pain in palliative care

c) Suicidal ideation

d) Suicidal behavior

Self-Assessment

3) The recently FDA-approved esketamine intranasal spray:

a) Has demonstrated safety in studies that followed patients for up to 2 years of

treatment

b) Has been shown to have a lower risk of abuse than conventional ketamine

formulations

c) Is indicated for use in treatment resistant depression as an adjunct to oral

antidepressant therapy

d) Is indicated for use in bipolar depression type II as an adjunct to oral therapy

Self-Assessment

Allen CA, Ivester JR Jr. Ketamine for Pain Management-Side Effects & Potential Adverse Events. Pain Manag Nurs. 2017 Dec;18(6):372-377.

Anderson IM, Blamire A, Branton T, et al. Ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT): a multicentre, double-blind, randomised, parallel-group, superiority trial. Lancet Psychiatry. 2017 May;4(5):365-377.

Andrade C. Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency?. J Clin Psychiatry. 2017 Jul;78(7):e852-e857.

Bell RF, Kalso EA. Ketamine for pain management. Pain Rep. 2018 Aug 9;3(5):e674.

Caddy C, Amit BH, McCloud TL, et al. Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database Syst Rev. 2015 Sep 23;(9):CD011612.

Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry. 2018 Jul 1;175(7):620-630.

Casale R, Symeonidou Z, Bartolo M. Topical Treatments for Localized Neuropathic Pain. Curr Pain Headache Rep. 2017 Mar;21(3):15.

Cohen SP, Bhatia A, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018 Jul;43(5):521-546.

Dakwar E, Nunes EV, Hart CL, et al. A Single Ketamine Infusion Combined With Mindfulness-Based Behavioral Modification to Treat Cocaine Dependence: A Randomized Clinical Trial. Am J Psychiatry. 2019 Jun 24:appiajp201918101123.

Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Feb 1;75(2):139-148.

Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019 Jul 10.

Grady SE, Marsh TA, Tenhouse A, et al. Ketamine for the treatment of major depressive disorder and bipolar depression: A review of the literature. Ment Health Clin. 2017 Jan; 7(1): 16–23.

References 1

Huang YJ, Lane HY, Lin CH. New Treatment Strategies of Depression: Based on Mechanisms Related to Neuroplasticity. Neural Plast. 2017;2017:4605971.

Newport DJ, Carpenter LL, McDonald WM, et al. Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression. Am J Psychiatry. 2015

Oct;172(10):950-66.

Popova V, Daly EJ, Trivedi M, et al. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant

Depression: A Randomized Double-Blind Active-Controlled Study. Am J Psychiatry. 2019 Jun 1;176(6):428-438.

Sanacora G, Frye MA, McDonald W, et al. A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry. 2017 Apr 1;74(4):399-405.

Schatzberg AF. A Word to the Wise About Intranasal Esketamine. Am J Psychiatry. 2019 Jun 1;176(6):422-424.

Schwenk ES, Viscusi ER, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of

Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018 Jul;43(5):456-466.

Short B, Fong J, Galvez V, et al. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018 Jan;5(1):65-78.

US Food and Drug Administration: Briefing information for the Feb 12, 2019 joint meeting of the Psychopharmacologic Drugs Advisory Committee (PDAC) and the Drug Safety and

Risk Management Advisory Committee (DSaRM). Available from:

https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM630970.pdf

Wilkinson ST, Ballard ED, Bloch MH, et al. The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-

Analysis. Am J Psychiatry. 2018 Feb 1;175(2):150-158.

Xu Y, Hackett M, Carter G, et al. Effects of Low-Dose and Very Low-Dose Ketamine among Patients with Major Depression: a Systematic Review and Meta-Analysis. Int J

Neuropsychopharmacol. 2016 Apr 20;19(4).

References 2

Closing Remarks

Keith Warshany, PharmD, PhC, BCPS, NCPSLCDR US Public Health Service

keith.warshany@ihs.gov

JOINT FEDERAL

PHARMACY SEMINARFEDERAL PHARMACY: SHARING THE VISION IN PHARMACY