Ketamine Infusion for Comorbid PTSD and Chronic Pain

• ClinicalTrials.gov Identifier: NCT04322968
• Recruitment Status: Completed
• First Posted: March 26, 2020
• Results First Posted: December 22, 2020
• Last Update Posted: December 22, 2020
• Sponsor: VA Ann Arbor Healthcare System
• Collaborator: University of Michigan
• Information provided by (Responsible Party): VA Ann Arbor Healthcare System

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
PTSD; Chronic Pain	Drug: A single low dose ketamine infusion as compared to the IV infusion of active placebo - ketorolac on chronic pain and PTSD symptoms.	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 41 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Patient with and without PTSD were randomized to receive either ketamine or ketorolac. Single IV infusion of ketamine hydrochloride (0.5 mg/kg) was administered over 40 minutes. Ketorolac 15 mg was reconstituted in 500 cc of normal saline administered over 40 minutes.
• Masking: Double (Participant, Outcomes Assessor)
• Masking Description: All study personnel, including rater, patients, and data analysts, were blinded to randomization order. Only the anesthesiologist performing the infusion was not blinded in order to prepare for possible side effects of each medication.
• Primary Purpose: Treatment
• Official Title: Low Dose Ketamine Infusion for Comorbid Posttraumatic Stress Disorder and Chronic Pain Patients
• Actual Study Start Date: January 9, 2018
• Actual Primary Completion Date: June 4, 2019
• Actual Study Completion Date: June 4, 2019

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Impact of Event Scale-Revised (IES-R) [ Time Frame: 24 hrs post-infusion ]
   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
2. Visual Analogue Scale (VAS) [ Time Frame: 24 hrs post-infusion ]
   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.

Secondary Outcome Measures :

1. Impact of Event Scale-Revised (IES-R) [ Time Frame: 1 week post-infusion ]
   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
2. Visual Analogue Scale (VAS) [ Time Frame: 1 week post-infusion ]
   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.
3. Brief Pain Inventory (Short Form) [ Time Frame: 1 week post-infusion ]
   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.

Other Outcome Measures:

1. Patient-Rated Inventory of Side Effects (PRISE20) [ Time Frame: baseline-1 week post-infusion ]
   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
2. Clinician-Administered Dissociative States Scale (CADSS) [ Time Frame: baseline-1 week post-infusion ]
   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

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Michigan

Ann Arbor VA Medical Center

Ann Arbor, Michigan, United States, 48105

Sponsors and Collaborators

VA Ann Arbor Healthcare System

University of Michigan

  Study Documents (Full-Text)

Documents provided by VA Ann Arbor Healthcare System:

Study Protocol  [PDF] October 9, 2020

Statistical Analysis Plan  [PDF] October 9, 2020

More Information

Publications:

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.

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.

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.

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.

• Responsible Party: VA Ann Arbor Healthcare System
• ClinicalTrials.gov Identifier: NCT04322968
• Other Study ID Numbers: IRB-2017-1015
• First Posted: March 26, 2020
• Results First Posted: December 22, 2020
• Last Update Posted: December 22, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

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

• 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

Keywords provided by VA Ann Arbor Healthcare System:

PTSD; chronic pain; ketamine infusion

Additional relevant MeSH terms:

Chronic Pain; Pain; Neurologic Manifestations; Ketorolac; Ketamine; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Central Nervous System Depressants; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Enzyme Inhibitors