Ketamine Infusion for Comorbid PTSD and Chronic Pain

Low Dose Ketamine Infusion for Comorbid Posttraumatic Stress Disorder and Chronic Pain Patients

The purpose of the study is to investigate the effectiveness of low dose IV ketamine infusion in the treatment of patients with PTSD and comorbid chronic pain.

Hypothesis: A single ketamine infusion should be associated with significantly greater reduction in core PTSD symptom levels after the treatment and such an effect is not only due to its analgesic properties but also through unknown mechanism of action that maybe related to NMDA/AMPA receptor modulation.

Study Overview

• Status: Completed
• Conditions: PTSD; Chronic Pain
• Intervention / Treatment: Drug: A single low dose ketamine infusion as compared to the IV infusion of active placebo - ketorolac on chronic pain and PTSD symptoms.

Detailed Description

To date, treatment options (i.e. psychotherapy, antidepressant medications) for patients with PTSD, are relatively few, and considering their limited efficacy, novel therapies have gained interest among researchers and treatment providers alike. Among patients with chronic pain about one third suffer from comorbid PTSD, which further complicates their already challenging pharmacological regimens. Low dose ketamine infusion has shown promise in PTSD, and in treatment of chronic pain, however they have not been studied in comorbid population and under rigorous control conditions. The investigators compared the effects of a single dose of either ketamine (0.5 mg/kg) or ketorolac (15 mg) over a 40-minute of IV infusion in chronic pain patients with and without PTSD, in double blind, randomized study. Measures were collected before, during, 1 day and 7 days after the infusion.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • Ann Arbor VA Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Veterans with chronic pain as defined by having any chronic pain beyond 6 months in duration with and without PTSD diagnoses (participants must meet DSM-V criteria for current post-traumatic stress disorder (PTSD) and have received a diagnosis of PTSD greater than or equal to 3 months prior to assessment); they also will be either free of concomitant use of psychotropic and/or pain medications for at least 6 weeks or on stable doses of those medications within the last 6 weeks prior to randomization and for the duration of the study; if applicable, current frequency and duration of psychotherapy sessions must remain stable for at least 6 weeks prior to beginning of the study.

Exclusion Criteria:

Inability to speak English, inability or unwillingness to provide written informed consent; moderate-to-severe cognitive impairment (Mini-Mental State Examination scores<20 administered by a trained clinician); current or lifetime history of psychotic or bipolar disorder; current bulimia or anorexia nervosa, alcohol abuse or dependence in the previous 3 months; serious unstable medical illness or sleep apnea; HTN, prolonged QT interval, peptic ulcer disease or recent history of GI-bleed, renal insufficiency, active substance use disorder, active suicidal or homicidal ideation on presentation; pregnancy (confirmed by baseline lab test), the initiation of female hormonal treatments within 3 months of screening, or inability or unwillingness to use a medically accepted contraceptive method for the duration of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Chronic pain with PTSD+IV ketamine infusion	Drug: A single low dose ketamine infusion as compared to the IV infusion of active placebo - ketorolac on chronic pain and PTSD symptoms.; Subjects were randomized into 4 treatment groups: chronic pain subjects treated with ketorolac, chronic pain subjects treated with ketamine, chronic pain+PTSD subjects treated with ketorolac, and chronic pain+PTSD subjects treated with ketamine.
Active Comparator: Chronic pain with PTSD+IV ketorolac infusion	Drug: A single low dose ketamine infusion as compared to the IV infusion of active placebo - ketorolac on chronic pain and PTSD symptoms.; Subjects were randomized into 4 treatment groups: chronic pain subjects treated with ketorolac, chronic pain subjects treated with ketamine, chronic pain+PTSD subjects treated with ketorolac, and chronic pain+PTSD subjects treated with ketamine.
Experimental: Chronic pain without PTSD+IV ketamine infusion	Drug: A single low dose ketamine infusion as compared to the IV infusion of active placebo - ketorolac on chronic pain and PTSD symptoms.; Subjects were randomized into 4 treatment groups: chronic pain subjects treated with ketorolac, chronic pain subjects treated with ketamine, chronic pain+PTSD subjects treated with ketorolac, and chronic pain+PTSD subjects treated with ketamine.
Active Comparator: Chronic pain without PTSD+IV ketorolac infusion	Drug: A single low dose ketamine infusion as compared to the IV infusion of active placebo - ketorolac on chronic pain and PTSD symptoms.; Subjects were randomized into 4 treatment groups: chronic pain subjects treated with ketorolac, chronic pain subjects treated with ketamine, chronic pain+PTSD subjects treated with ketorolac, and chronic pain+PTSD subjects treated with ketamine.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impact of Event Scale-Revised (IES-R)	Severity of PTSD symptoms; items are rated on a 5-point scale ranging from 0 ("not at all") to 4 ("extremely"). The IES-R yields a total score (ranging from 0 to 88); higher scores mean worse symptoms	24 hrs post-infusion
Visual Analogue Scale (VAS)	Severity of chronic pain symptoms; using a ruler, the score is determined by measuring the distance (mm) on the 10-cm line between the "no pain" anchor and the patient's mark, providing a range of scores from 0-100; a higher score indicates greater pain intensity.	24 hrs post-infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impact of Event Scale-Revised (IES-R)	Severity of PTSD symptoms; items are rated on a 5-point scale ranging from 0 ("not at all") to 4 ("extremely"). The IES-R yields a total score (ranging from 0 to 88); higher scores mean worse symptoms	1 week post-infusion
Visual Analogue Scale (VAS)	Severity of chronic pain symptoms; using a ruler, the score is determined by measuring the distance (mm) on the 10-cm line between the "no pain" anchor and the patient's mark, providing a range of scores from 0-100; a higher score indicates greater pain intensity.	1 week post-infusion
Brief Pain Inventory (Short Form)	Severity of pain, impact of pain on daily function, location of pain, pain medications and amount of pain relief in the past 24 hours or the past week; No scoring algorithm, but "worst pain" or the arithmetic mean of the four severity items can be used as measures of pain severity (a range of 0-10, with 10 being worse scores); the arithmetic mean of the seven interference items can be used as a measure of pain interference (a range of 0-10, with 10 being worse scores). The total score is reported for severity items and interference items, which range from 0-40 and 0-70, respectively. Higher values represent worse outcome.	1 week post-infusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient-Rated Inventory of Side Effects (PRISE20)	Patient self report used to qualify side effects by identifying and evaluating the tolerability of each symptoms; 20 items; higher scores mean worse side effects	baseline-1 week post-infusion
Clinician-Administered Dissociative States Scale (CADSS)	Dissociative, psychotomimetic, and manic symptoms; 27-item scale with 19 subject-rated items and 8 items scored by an observer; higher scores mean worse present-state dissociative symptomatology	baseline-1 week post-infusion

Collaborators and Investigators

• Sponsor: VA Ann Arbor Healthcare System
• Collaborators: University of Michigan

Publications and helpful links

General Publications

• Sigtermans MJ, van Hilten JJ, Bauer MCR, Arbous SM, Marinus J, Sarton EY, Dahan A. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain. 2009 Oct;145(3):304-311. doi: 10.1016/j.pain.2009.06.023. Epub 2009 Jul 14.
• Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005 Jun;62(6):617-27. doi: 10.1001/archpsyc.62.6.617. Erratum In: Arch Gen Psychiatry. 2005 Jul;62(7):709. Merikangas, Kathleen R [added].
• Feder A, Parides MK, Murrough JW, Perez AM, Morgan JE, Saxena S, Kirkwood K, Aan Het Rot M, Lapidus KA, Wan LB, Iosifescu D, Charney DS. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2014 Jun;71(6):681-8. doi: 10.1001/jamapsychiatry.2014.62.
• Albott CS, Lim KO, Forbes MK, Erbes C, Tye SJ, Grabowski JG, Thuras P, Batres-Y-Carr TM, Wels J, Shiroma PR. Efficacy, Safety, and Durability of Repeated Ketamine Infusions for Comorbid Posttraumatic Stress Disorder and Treatment-Resistant Depression. J Clin Psychiatry. 2018 May/Jun;79(3):17m11634. doi: 10.4088/JCP.17m11634.
• Asmundson GJ, Bonin MF, Frombach IK, Norton GR. Evidence of a disposition toward fearfulness and vulnerability to posttraumatic stress in dysfunctional pain patients. Behav Res Ther. 2000 Aug;38(8):801-12. doi: 10.1016/s0005-7967(99)00101-1.
• Noppers I, Niesters M, Swartjes M, Bauer M, Aarts L, Geleijnse N, Mooren R, Dahan A, Sarton E. Absence of long-term analgesic effect from a short-term S-ketamine infusion on fibromyalgia pain: a randomized, prospective, double blind, active placebo-controlled trial. Eur J Pain. 2011 Oct;15(9):942-9. doi: 10.1016/j.ejpain.2011.03.008. Epub 2011 Apr 11.

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2018
• Primary Completion (Actual): June 4, 2019
• Study Completion (Actual): June 4, 2019

Study Registration Dates

• First Submitted: March 24, 2020
• First Submitted That Met QC Criteria: March 24, 2020
• First Posted (Actual): March 26, 2020

Study Record Updates

• Last Update Posted (Actual): December 22, 2020
• Last Update Submitted That Met QC Criteria: November 30, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: PTSD; chronic pain; ketamine infusion
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Chronic Pain; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Ketamine; Ketorolac
• Other Study ID Numbers: IRB-2017-1015

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Local IRB has conducted informed consent audit for the study and the investigators have been compliant with it.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No