Continuous Ketamine Infusion for Pain as an Opportunity for Psychotherapy for PTSD: A Case Series of Ketamine-Enhanced Psychotherapy for PTSD and Pain (KEP-P2)

Abstract

Two recent meta-analyses estimated the comorbidity of chronic pain and posttraumatic stress disorder (PTSD) in the general population to be approximately 10% [1, 2], but among military members, these comorbidity levels consistently rise to levels above 40% [3-6]. Patients having both conditions experience more intense pain and affective distress, higher levels of depression, greater levels of life interference/disability, and greater healthcare utilization when compared to those with either chronic pain or PTSD alone [1, 6]. There has been no investigation into the use of continuous ketamine, with co-occurring psychotherapy, in the treatment of military members suffering from both chronic pain and PTSD.The theorized effectiveness of ketamine is based on: (a) increased access to traumatic memory via enhanced synaptic connectivity; (b) decreased central sensitization via downregulation of the prefrontal cortex; and (c) enhanced extinction of previously paired pain-related memories (e.g., moving = pain; discussing trauma = pain). Therefore, we postulated that ketamine would facilitate the conditions for the modification of core maladaptive fears underlying PTSD and thereby enhance exposure-based PTSD psychotherapy (i.e., Ketamine-Enhanced Psychotherapy for PTSD and Pain, KEP-P2).This article documents 11 consecutive patients treated with intravenous ketamine and psychotherapy for co-occurring neuropathic pain and PTSD from July 2014 to December 2019. All patients in this series were diagnosed with chronic neuropathic pain who had: (i) previously failed multiple pain treatment modalities; (ii) currently manifested PTSD symptoms; and (iii) received ketamine infusion as a standard of care for the pain condition. Please reference the online supplement for more detailed information, including the treatment inspiration, all patient reports, discussion/conclusion, and limitations (see www.karger.com/doi/10.1159/000507095 for all supplementary material).Standard pain protocols began with subanesthetic doses of ketamine infusion at 2 μg/kg/min, and the dose was increased in 1–2 μg/kg/min increments every 3–4 h until a final dose of 11–15 μg/kg/min was achieved. The ketamine continued at this maximum dose for approximately 96 h on average. Psychotherapy was delivered via daily bedside psychotherapy sessions for approximately 90 min. The primary outcome measures were change in PTSD symptoms using the PTSD Checklist (-M/-C/-5) and change in pain intensity scores using the Numeric Pain Rating Scale (NPRS). Secondary outcome measures consisted of behavioral health utilization in the 1 year prior to and in the 1 year after the treatment.Table 1 summarizes the demographics and patient outcomes. The table shows the PTSD symptom scores (PCL) and pain rating scores (NPRS) seen before (pre) and after (post) 5 days of integrated behavioral health treatment during ketamine infusion. Seven out of the 11 patients showed clinically significant ≥35% pre-to-post reductions of PCL scores. Only 6 out of the 11 patients showed pre-to-post reductions in pain, but these were ≥25% in magnitude. Nonetheless, 5 patients did not show pain reductions, and 3 actually showed increases in pain ratings. A paired-samples t test showed a significant decrease (p = 0.003) in PCL scores (pre-treatment M = 55.33, SD = 11.52 to post-treatment M = 27.11, SD = 12.36) 95% CI (13.11, 43.33), Cohen’s d = 1.44. Although they cannot be directly compared, the effect size of KEP-P2 on PTSD symptoms is even larger than the recently published encouraging results for MDMA-assisted psychotherapy on PTSD symptoms (Cohen’s d = 0.8) [7].The more modest reductions in pain scores from pre-ketamine (M = 5.81, SD = 1.72) to post-ketamine (M = 4.63, SD = 2.34) were evident, but not significant (p = 0.087), 95% CI (–0.25, 3.16), Cohen’s d = 0.57. Although there was evidence of reduced behavioral health service utilization for many patients, the overall mean number of visits measured before (M = 26.8, SD = 26.52) and after treatment (M = 26, SD = 25.43) were not different (p = 0.820), 95% CI (–6.94, 8.54), Cohen’s d = 0.07.These results were obtained in patients who generally had received a number of behavioral health inventions prior to ketamine infusion, and post-treatment assessment clearly suggested that ketamine-enhanced treatment resulted in a clinically meaningful improvement in the lives of these patients.All patients in this case series were tolerant to full agonist opioids but were not tolerant to the analgesic and anti-PTSD effects of ketamine. In addition, the ketamine infusion was instituted as part of a pain management protocol to discontinue opioid use. Thus, our findings suggesting therapeutic benefits of ketamine to treat psychiatric symptoms of PTSD are not likely mediated by opiates.The biopsychosocial model of chronic pain illustrates the complex and variable interaction between biological factors (e.g., genetic, hormonal), psychological factors (e.g., pain catastrophizing, stress sensitivity), and social factors (e.g., abuse history, social support) that influence pain intensity and complicates its interaction with PTSD [8]. That is, the relationship between PTSD and chronic pain are both complicated and uniquely experienced.The KEP-P2 psychotherapeutic experience appears unique when compared with regular, trauma-focused psychotherapy in the absence of ketamine, most notably the experience of what were at times extreme visions/hallucinations. These altered states of consciousness appeared to play a key role in the therapeutic outcome (online suppl. material).Importantly, most of our patients had significant behavioral health engagement and psychotherapy in the year prior to ketamine, and yet 5 days of KEP-P2 seemed to achieve remarkable and sudden results and breakthroughs in terms of helping patients to focus on trauma memories. Nonetheless, most of these patients continued to receive psychotherapy after the KEP-P2 intervention.Our findings add to previous research showing that abbreviated forms of trauma-focused interventions for PTSD can be effective [9]. The current form of treatment supports an even shorter duration of psychotherapy enhanced by the pharmacological aid of ketamine. We suggest that the current data, though an observational case series, do support the idea of using medicines (i.e., ketamine) to facilitate the imaginal re-experiencing of traumatic memories under conditions where defensive functioning is reduced. Not only may this general approach lead to more effective treatments for PTSD, but ketamine may be uniquely enhancing the neuroplasticity necessary for fear extinction and new memory formation [10]. Randomized controlled trials are required to determine whether or not ketamine is efficacious to enhance PTSD psychotherapy outcomes as well as whether it is differentially effective for PTSD with or without pain comorbidity.We would like to express special thanks to Dr. John Vogel, the first to recognize the potential for and assist in the application of ketamine-enhanced psychotherapy. Additionally, this work would not have been possible without a dedicated group of physicians at Brooke Army Medical Center: Dr. Brandon Goff, Dr. Justin Boge, Dr. Joe Alderete, and Dr. Kevin Guthmiller.All patients provided clinical consent to receiving psychotherapy during their ketamine infusion. Outcomes and assessments were collected as part of the evaluation of this new integrated behavioral health care program. The local Human Research Protections Office provided a written determination that this case series was not part of a research protocol and therefore not subject to IRB review.B.M.K., J.D.R., J.R.J., R.J.K., and J.H.P. have no conflicts of interest to declare. J.H.K. is a consultant for Biogen, Idec, MA, Biomedisyn Corporation, Bionomics, Limited (Australia), Boehringer Ingelheim International, Concert Pharmaceuticals, Inc., Epiodyne, Inc., Heptares Therapeutics, Limited (UK), Janssen Research and Development, Otsuka America Pharmaceutical, Inc., Perception Neuroscience Holdings, Inc., Spring Care, Inc., Sunovion Pharmaceuticals, Inc., Takeda Industries, and Taisho Pharmaceutical Co., Ltd; is on the Scientific Advisory Board for Bioasis Technologies, Inc., Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc. (Clinical Advisory Board), BlackThorn Therapeutics, Inc., Cadent Therapeutics (Clinical Advisory Board), Cerevel Therapeutics, LLC, Lohocla Research Corporation, PsychoGenics, Inc.; holds stock options in Biohaven Pharmaceuticals, Sage Pharmaceuticals, and Spring Care, Inc; holds patents for Dopamine and Noradrenergic Reuptake Inhibitors in Treatment of Schizophrenia, US Patent No. 5,447,948 (issued Sep 5, 1995), and Glutamate Modulating Agents in the Treatment of Mental Disorders, US Patent No. 8,778,979 (issued Jul 15, 2014); and has filed the following patents: Seibyl JP, Krystal JH, Charney D.S. Dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia. US Patent #:5,447,948. September 5, 1995; Vladimir Coric, Krystal John H, Sanacora Gerard – Glutamate Modulating Agents in the Treatment of Mental Disorders US Patent No. 8,778,979 B2 Patent Issue Date: July 15, 2014. US Patent Application No. 15/695,164: Filing Date: 09/05/2017; Charney D, Krystal JH, Manji H, Matthew S, Zarate C: Intranasal Administration of Ketamine to Treat Depression United States Application No. 14/197,767 filed on March 5, 2014; United States application or Patent Cooperation Treaty (PCT) International application No. 14/306,382 filed on June 17, 2014; Zarate C, Charney DS, Manji HK, Mathew Sanjay J, Krystal, JH: Department of Veterans Affairs “Methods for Treating Suicidal Ideation,” Patent Application No. 14/197.767 filed on March 5, 2014 by Yale University Office of Cooperative Research; Arias A, Petrakis I, Krystal JH: Composition and methods to treat addiction. Provisional Use Patent Application no.61/973/961. April 2, 2014. Filed by Yale University Office of Cooperative Research; Chekroud A, Gueorguieva R, Krystal JH: “Treatment Selection for Major Depressive Disorder” (filing date 3rd June 2016, USPTO docket number Y0087.70116US00). Provisional patent submission by Yale University; Gihyun Yoon, Petrakis I, Krystal JH: Compounds, Compositions and Methods for Treating or Preventing Depression and Other Diseases. US. Provisional Patent Application No. 62/444,552, filed on January10, 2017 by Yale University Office of Cooperative Research OCR 7088 US01; Abdallah C, Krystal JH, Duman R, Sanacora G: Combination Therapy for Treating or Preventing Depression or Other Mood Diseases. US Provisional Patent Application No. 62/719,935 filed on August 20, 2018 by Yale University Office of Cooperative Research OCR 7451 US01. The views expressed in this article are solely those of the authors and do not reflect an endorsement by or the official policy of the US Army, the Department of Defense, the Department of Veterans Affairs, or the US Government.The authors have no funding sources to declare.B.M.K., J.D.R., J.R.J., R.J.K., J.H.P. and J.H.K. all made substantial contributions to the conception of the work, participated in the drafting and revision of the intellectual content, participated in the interpretation of data for the work, and approved the final version to be published. Additionally, B.M.K., J.R.J., and R.J.K. made substantial contribution to the acquisition and analysis of data for the work.

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