bs_bs_banner Pain Medicine 2013; *: **–** Wiley Periodicals, Inc. Effects of Low-Dose IV Ketamine on Peripheral and Central Pain from Major Limb Injuries Sustained in Combat Rosemary C. Polomano, PhD, RN, FAAN,*‡ Sciences, 418 Curie Blvd. RM 324, Philadelphia, PA Chester C. Buckenmaier III, MD,††‡‡ 1904, USA. Tel: 215-898-0934; Fax: 215-573-7507; Kyung H. Kwon, MSN, CRNP,†† E-mail: [email protected]. Alexandra L. Hanlon, PhD,† ¶¶ Christine Rupprecht, MSN, RN, Conflict of Interest/Disclosure: There are no perceived Cynthia Goldberg, MSN, RN-BC,§§ and conflicts of interests by any authors related to the Rollin M. Gallagher, MD, MPH§¶** conduct of this research. *Department of Biobehavioral Health Sciences Funding: This work was supported by institutional funding and the Defense and Veterans Center for †University of Pennsylvania School of Nursing, Integrative Pain Management. Philadelphia, Pennsylvania; Copyright Protection: Our team is comprised Departments of ‡Anesthesiology and Critical Care partly of military service members and employees of the US Government. This work was prepared (Secondary) and as part of our official duties. Title 17 United States Code (USC) 105 provides that “Copyright protection § Psychiatry and Anesthesiology and Critical Care, under this title is not available for any work of the University of Pennsylvania Perelman School of United States Government.” Title 17 USC 101 Medicine, Philadelphia, Pennsylvania; defines a US Government work as a work prepared by a military service member or employee ¶Pain Management, Veterans Health System, of the US Government as part of that person’s offi- Philadelphia, Pennsylvania; cial duties. Disclaimer: The views expressed in this presentation **Pain Policy Research and Primary Care, Penn Pain are those of the authors and do not necessarily reflect Medicine, Philadelphia, Pennsylvania; the official policy of the Department of the Army, the Department of Defense, or the United States ††Defense and Veterans Center for Integrative Pain Government. Management, Rockville, Maryland; ‡‡Department of Anesthesiology, Uniformed Services University of the Health Sciences, Bethesda, Abstract Maryland; Objective. Examine response patterns to low-dose §§Orthopedic Trauma & Physical Medicine and Rehab, intravenous (IV) ketamine continuous infusions on Walter Reed National Military Medical Center, multiple pain outcomes, and demonstrate effective- ness, safety, and tolerability of ketamine administra- Bethesda, Maryland; tion on general wards. ¶¶Inova Mount Vernon Hospital Pain Service, Design. Retrospective case series of consecutive Alexandria, Virginia, USA patients given low-dose IV ketamine continuous infusions. Reprint requests to: Rosemary C. Polomano, PhD, RN, FAAN, University of Pennsylvania School Setting. Walter Reed Army Medical Center, of Nursing, Department of Biobehavioral Health Washington, DC. 1 Polomano et al. Patients. Nineteen eligible inpatients with neuro- these effects are typically seen with higher anesthetic pathic pain from major limb injuries sustained in doses and infrequently with analgesic doses or low doses combat with inadequate pain control from multimo- of ketamine [10,11]. dal analgesia. Low-dose ketamine has been routinely administered as Interventions. A 3-day IV infusion of ketamine at part of multimodal analgesia for acute and chronic pain for doses Յ120 mg/kg/h. injured service members in the Afghanistan and Iraq wars sustaining major polytrauma including multiple limb Outcome Measures. Daily present (PPI), average trauma and amputations. At Walter Reed Army Medical (API), and worst (WPI) pain intensity (0–10), global Center (WRAMC—now closed), Washington, DC, and the pain relief (GPR) (1 “no relief” to 5 “complete relief”), newly established Walter Reed National Military Medical daily assessments of adverse events, and daily Center (WRNMMC), Bethesda, MD, low-dose ketamine opioid requirements measured during therapy. infusion was often added to multimodal analgesic regi- mens to maximize analgesia in particularly challenging Results. A significant reduction in PPI (P < 0.001) pain patients. Combat-injured service members who and improvement in GPR (P = 0.031) was noted over require multiple wound care procedures, residual limb revi- time. Higher baseline WPI (Ն7; N = 14) was associ- sions, and limb salvage operations for mangled limbs or ated with a significant decrease in WPI (P = 0.0388), those with persistent pain from major limb trauma who are but lower baseline WPI (N = 5) was not. Significant refractory to multimodal analgesic treatments may receive mean percent decreases in PPI with higher baseline low-dose ketamine as another therapeutic option. Few PPI (N = 8; P = 0.0078) and WPI with no phantom studies have systematically evaluated the short-term out- limb pain (PLP) (N = 10; P = 0.0436) were observed. comes associated with low-dose ketamine infusions to Mean percent increase in overall GPR was better for treat neuropathic pain from major limb injuries sustained in those reporting GPR scores Յ3(N= 13) in the first combat. The primary aim of this investigation was to 24 hours of therapy (P = 0.0153). While not signifi- examine patterns in short-term patient-reported pain out- cant, mean opioid requirement (IV morphine equiva- comes to continuous low-dose intravenous (IV) ketamine lents) decreased from 129.9 mgs Ϯ 137.3 on day 1 to infusions added to individualized standard multimodal 112.14 Ϯ 86.3 24 hours after therapy. analgesia regimens in a cohort of combat wounded with major limb injuries experiencing neuropathic pain. A sec- Conclusions. Low-dose ketamine infusions for ondary aim was to demonstrate the effectiveness, safety, complex combat injury pain were safe and effective, and tolerability of continuous low-dose IV ketamine (doses and demonstrated response patterns over time and of 120 mcg/kg/h or less) over 3 consecutive days on by baseline pain score stratification and presence or general care wards. absence of PLP. Key Words. Acute Pain; Ketamine; Chronic Pain Methods A retrospective review of hospital and Acute Pain Service (APS) records was conducted on a cohort of 19 hospital- ized combat wounded with major limb trauma experienc- Introduction ing acute and chronic pain with a component of neuropathic pain. All patients were treated in the context Ketamine, classified as a dissociative anesthetic, has been of usual care with outcomes collected on response to used for more than 40 years for procedural sedation and therapy. The study was approval by the WRAMC, Depart- surgical anesthesia. Growing interest in this agent, as an ment of Clinical Investigation, Human Use Committee, and adjunct analgesic for both acute and chronic pain, centers met the criteria for waiver of informed consent; however, on its unique pharmacological properties [1–4]. Specifi- only limited data collection procedures were allowed as cally, S(+)-ketamine exerts N-methyl-D-aspartate (NMDA) part of this study. As such, patient electronic medical antagonist effects from noncompetitive binding to the records were only followed for the duration and day after phencyclidine (PCP) site of the NMDA receptor [1,2]. This the treatment. A confounding variable in the study was receptor binding counteracts the excitatory effects of that nine (47.4%) had a surgical procedure either before or glutamate brought about by nociceptive and neuropathic after receiving the ketamine infusion. All research proce- pain transmission, and interactions with other sites such dures were in accordance and compliance with the Health as opioid receptors, muscarinic receptors, voltage-gated Insurance Portability and Accountability Act regulations Ca++ channels, and monoamine receptors [5]. Conse- and WRAMC’s policies and guidelines for the protection of quently, ketamine is believed to minimize early windup human subjects. associated with acute pain, suppress central sensitization, reduce the likelihood for NMDA receptor-mediated neuro- Sample and Setting plasticity, and perhaps prevent opioid hyperalgesia [6–9]. Its widespread use is tempered by the psychomimetic Patients who were part of this case series were hospital- effects associated with NMDA receptor antagonists, but ized patients at the former WRAMC who were currently 2 Low-Dose IV Ketamine being followed by the APS. Because this was a descriptive alpha) across four time points with our patient cohort was study examining trends in pain outcomes, a power analy- 0.71, which is above the acceptable threshold of 0.70 for sis was not conducted a priori to determine the sample limited item sets [15]. size. Data from 19 patients were available to investigators for analyses. For each 24-hour period of ketamine infusion therapy, the amount of scheduled and as needed opioid analgesics Study patients were consecutively selected after receiv- consumed was recorded. Daily requirements were con- ing continuous IV low-dose ketamine infusion when con- verted to IV morphine equivalents for each 24-hour period ventional therapy with multimodal analgesia including during therapy. All patients were assessed daily for eight opioids, nonopioids, adjuvant analgesics, and regional possible types of adverse events including sedation, anesthesia techniques were not effectively controlling nausea and/or vomiting, cardiovascular effects (e.g., episodes of acute pain and chronic persistent pain as hypotension, tachycardia, etc.), hallucinations, night evaluated by the APS attending physician. Patients who mares, vivid dreams, nystagmus, and allergic