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The Use of Ketamine as an Adjunct to Treating Opioid Refractory Cancer-Related Pain in the Emergency Department

Brockett-Walker, Camille, DNP, FNP-BC, AGACNP-BC

Section Editor(s): Evans, Dian Dowling PhD, FNP-BC, ENP-C, FAANP, FAAN; Column Editor

Advanced Emergency Nursing Journal: April/June 2019 - Volume 41 - Issue 2 - p 101–106
doi: 10.1097/TME.0000000000000244
RESEARCH TO PRACTICE
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The Research to Practice column is designed to provide advanced practice registered nurses (APRNs) with an analysis of a current research topic with implications for practice change within the emergency care settings. This review examines a recent study conducted by K. J. Bowers, K. B. McAllister, M. Ray, and C. Heitz (2017) entitled “Ketamine as an adjunct to opioids for acute pain in the emergency department: A randomized controlled trial.” The authors conducted a randomized, double-blinded, placebo-controlled trial at a single academic emergency department (ED) to compare standard opioid pain control in the ED population to the use of ketamine in conjunction with opioids in the same population. Participants were randomized into either the ketamine group, receiving 0.1 mg/kg of ketamine in conjunction with an intravenous opioid, or to the control group, receiving an equivalent volume of normal saline in addition to an intravenous opioid. Participants were evaluated for adequacy of pain control, side effects, and level of sedation every 30 min up to the 120-min time point. Data revealed that patients receiving ketamine had a statistically significant lower mean pain score, 0.6512 (p = 0.0083), compared with patients in the control group. The data also showed that patient satisfaction with pain control was similar for the ketamine group and the control group. These and other associated findings have implications for APRN practice, including managing acute pain in the ED setting and preventing hospital admission of acute-on-chronic pain exacerbations in the ED.

Nell Hodgson Woodruff School of Nursing, Emory University, and Winship Cancer Institute, Emory Healthcare, Atlanta, Georgia.

Corresponding Author: Camille Brockett-Walker, DNP, FNP-BC, AGACNP-BC, Emory University Nell Hodgson Woodruff School of Nursing, 1520 Clifton Rd, Atlanta, GA 30322 (camille.brockett@emory.edu).

Disclosure: The author reports no conflicts of interest.

ADVANCE PRACTICE PROVIDERS working in the emergency department (ED) evaluate and treat cancer patients with a number of oncological related symptoms, from nausea, vomiting, dehydration, neutropenia, fever, to acute pain. Uncontrolled acute pain leads to 10%–41% of all ED visits among patients with cancer (Patel et al., 2017). The use of opioids to control pain is common among this population; however, 20% of these patients experience refractory pain after long-term opioid use and often present to the ED for pain control (Waldfogel, Nesbit, Cohen, & Dy, 2016). Literature has shown that pain is a common chief complaint of cancer patients who are admitted to the hospital, and often leads to prolonged hospital stays (Numico et al., 2015). The purpose of this article is to review and critique Bowers, McAllister, Ray, & Heitz's (2017) study entitled “Ketamine as an adjunct to opioids for acute pain in the emergency department: A randomized controlled trial,” through the context of a case in which a cancer patient presents to the ED with acute pain, concluding with how applying Bowers et al.'s findings can improve the cancer patient's care outcomes.

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THE CASE

Ms V is a 64-year-old Hispanic woman diagnosed with poorly differentiated metastatic adenocarcinoma of unknown primary source. Approximately 6 months prior to her cancer diagnosis, she developed pain in her lower back and right buttock, which radiated down her right leg. Over the following months, the patient had multiple ED workups with a concluding diagnosis of sciatica. However, due to progressively worsening pain, a computerized tomography (CT) scan was done, which revealed a sacral mass. Ms. V underwent a partial resection of the sacral mass and pathology was consistent with metastatic adenocarcinoma. CT of the chest, abdomen, and pelvis was done in the month following the surgical resection. Imaging showed a destructive S3/S4 mass along with a lytic lesion in the right superior pubic ramus. Irregular, partially enhancing soft tissue was also seen in the lower uterine segment involving both the myometrium and the endometrium. A nuclear medicine bone scan also redemonstrated the sacral lesion, and in addition, showed uptake in the anterior right third rib.

Ms V's treatment consisted of adjuvant/palliative radiation and chemotherapy. In past outpatient visits with her oncologist, she reported that, despite chemotherapy, the pain in her sacrum, chest, and back continued to progress. She was followed up by the palliative care service for pain management and was managed with morphine ER 90 mg orally every 8 hr, oxycodone 30 mg orally every 4 hr as needed for breakthrough pain, and gabapentin 600 mg orally every 8 hr.

Despite compliance with her usual pain medication regimen, Ms V presented to the ED with a 7-day history of increased pain to her right hip, which radiated down her right lower extremity. She also reported a loss of mobility of the affected leg, and although normally walked with a cane or walker, had been unable to ambulate even with assistive devices over the past 7 days. She denied any associated fever, chills, or trauma to the area.

Her vital signs were as follows: blood pressure, 132/62 mmHg; heart rate, 100 beats per minute; respiratory rate, 18 breaths per minute; temperature, 36.8°C; SpO2, 98% on room air; and a pain score of 10/10. The advanced practice registered nurse's (APRN)'s physical assessment revealed a neurological examination with cranial nerves II–XII grossly intact, sensory examination intact, bilateral upper extremity strength 5/5, left lower extremity strength 5/5, and right lower extremity strength decreased at 3/5 in dorsiflexion and plantar flexion. Her musculoskeletal examination revealed tenderness to palpation of the right hip with decreased flexion, extension, abduction, and adduction, and tenderness to palpation of midline lumbar spine and sacrum. Her lungs were clear to auscultation bilaterally, and her heart had a regular rate and rhythm. A plain view radiograph of the right hip was obtained that showed increased displacement of a previously seen fracture of the right superior inferior pubic rami and redemonstration of a vertically oriented fracture of the superior sacrum. The APRN consulted the orthopedic service who recommended pain management and non-weight-bearing activity. Given the overall poor prognosis of her metastatic process, no surgical intervention was recommended at that time. Ms V received a single dose of morphine 4 mg iv while in the ED with minimal relief of pain; therefore, the APRN consulted the medical oncology service, and the patient was admitted to the hospital for acute-on-chronic cancer-related pain.

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RESEARCH ARTICLE

Bowers, K. J., McAllister, K. B., Ray, M., & Heitz, C. (2017). Ketamine as an adjunct to opioids for acute pain in the emergency department: A randomized controlled trial. Academic Emergency Medicine, 24(6), 676–685.

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STUDY PURPOSE AND DESIGN

There were many objectives to Bowers et al.'s study; however, the overarching purpose was to compare standard opioid pain control in the ED population to the use of ketamine in conjunction with opioids in the same population. The study used a randomized, double-blinded, placebo-controlled design and was conducted in an academic affiliated Level I trauma center and tertiary care referral center. The study used a convenience sample of patients who were recruited between 2013 and 2015. Inclusion criteria were as follows: patients between the ages of 18 and 70 years; numerical pain scores reported as equal to or greater than 6–10, and patients deemed as requiring intravenous opioids by the treating ED provider. Exclusion criteria included as follows: patients with respiratory, hemodynamic, or neurologic compromise; history of ventilation, hemodialysis, cirrhosis, or hepatitis; active psychosis; clinical intoxication; allergy to study drug; chief complaint of headache or chest pain; pregnancy; lack of decision-making capacity; a pain score less than 6; and concern for narcotic abuse. Based on the inclusion and exclusion criteria, patients were identified from real-time chart reviews.

After recruitment, participants were randomized into either the ketamine group, receiving 0.1 mg/kg of ketamine administered over 1 min in conjunction with an intravenous opioid, or to the control group, receiving an equivalent volume of normal saline in addition to an intravenous opioid. Every 30 min up to the 120-min time point, patients were asked what their pain score was, if they needed more pain control, and assessed for any side effects and level of sedation. If patients reported the need for more pain medication, 0.05 mg/kg of morphine or an equivalent dose of another intravenous opioid was administered. Total opioid dose and the number of repeat doses were recorded at the end of 120 min. After 120 min, patient satisfaction with pain control was also recorded on a 4-point Likert scale.

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RESULTS AND DISCUSSION

A total of 116 patients met the inclusion and exclusion criteria. Sixty-three patients were randomized to the control group, receiving a normal saline placebo and intravenous opioid. Fifty-three patients were randomized to the ketamine group, receiving Ketamine in conjunction with an intravenous opioid. In analyzing the demographic variables, there were no statistically significant differences between the two groups. The primary outcomes measured were level of pain control and satisfaction with pain control among the control and ketamine groups.

Pain scores were taken at time (T)0, T30, T60, T90, and T120 min. In both the control and ketamine groups, pain scores decreased greater than three points on the numerical pain rating scale by T30 min. Analysis of the data revealed that patients receiving ketamine had a 0.6512 (p = 0.0083) lower mean pain score than patients in the control group. This difference was found to be statistically significant; however, the difference was not as large, as seen in previous studies.

Initial review of the data showed that patient satisfaction with pain control was similar for the ketamine group and the control group. The satisfaction scale ranged from 0, which was “completely unsatisfied,” to 3, being “very satisfied.” The final mean satisfaction score in the ketamine group was 2.66 and in the control group was 2.52. Of note, although not analyzed for statistical significance, the study also recorded the number of additional doses of opioid administered to each patient. The number of patients needing additional doses was less in the ketamine group, at 36 versus 53 in the control group.

Overall, the authors found low-dose ketamine to be an effective adjunctive treatment to opioids resulting in better pain control. However, the hypothesis that the use of ketamine would produce greater patient satisfaction with pain control compared with the placebo was not found. There was no statistically significant difference in satisfaction of pain control in either arm of the study.

Two limitations were identified by the authors of this study. Participants had a mixture of both acute and chronic pain complaints. Also, patients who were possibly opioid tolerant due to long-term opioid use were included in the study. All of these variables could potentially affect how participants reacted to ketamine as an adjunctive therapy. A second limitation is the subjective nature of patient-reported pain scores and satisfaction levels. These subjective reports may have been biased depending on the participants' perception of their care and attention received by medical staff.

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CAMILLE'S COMMENTS

The abuse and misuse of opioids in the United States has led to an opioid epidemic (American College of Emergency Physicians [ACEP], 2017). With pain accounting for a large number of ED encounters, ED providers must look to alternative approaches for pain management to combat the growing opioid epidemic. Furthermore, managing cancer-related pain in the midst of an opioid epidemic can be complex and challenging. The difficulty lies is effectively managing acute exacerbations of chronic pain in this patient population in order to prevent potential prolonged hospital stays, while also decreasing the potential for opioid misuse. The initiation of multimodal pain management is essential to treating cancer-related pain in the ED rather than the use of opioids alone (Paice, 2018). Although not widely used across the United States, evidence supports the use of ketamine as one of those alternative or adjunctive treatments.

In an evidence-based review of the use of ketamine for the treatment of pain, it was concluded that the efficacy of ketamine when used to treat chronic pain was moderate and a reasonable option when standard analgesic options have failed (Crumb, Bryant, & Atkinson, 2018). In a 2012 Cochrane review, there were two randomized controlled trials that studied the effectiveness of ketamine as an adjunct to opioids specifically in cancer patients with refractory pain. Both trials found the addition of ketamine to be effective in increasing pain control (Loveday & Sindt, 2015). A 2017 systematic review of the use of ketamine in the ED setting also concluded that, when used as an adjunct analgesic, ketamine had an opioid-sparing effect (Ghate, Clark, & Vaillancourt, 2018).

Albeit Bowers et al.'s study had some limitations, and their outcomes support ketamine usage in the ED setting. The design of the study was well conceived, but future randomized clinical trials on the use of ketamine in the ED should be designed to compare dosing as well as control for acute versus chronic pain and patient pain-related factors. First, ketamine doses reported throughout the literature are typically higher than the 0.1-mg/kg dose used in Bowers et al.'s study. Given that the ketamine group in Bowers et al.'s study had statistically significant lower pain scores than the control group with 0.1-mg/kg dosing, it is possible that higher ketamine dosing could yield even greater pain control without adverse effects when compared with use of opioids. Ketamine doses as high as 0.6 mg/kg have been shown to not only be effective for pain control, but also safe with minimal adverse effects on vital signs and level of sedation (Howard & Gisness, 2017).

Although Bowers et al.'s study primary aim was to determine the effect of ketamine on the treatment of acute pain in the ED, study participants also included those with chronic pain conditions and long-term outpatient opioid use. Therefore, the findings may actually vary based on whether patients were experiencing acute pain, exacerbation of chronic pain, or refractory pain from chronic opioid use. Ketamine can be used to treat pain arising from a variety of clinical conditions, including the management of malignant and nonmalignant chronic pain in patients who are already on high doses of opioid medication to achieve better pain control. Ketamine has also been shown to delay desensitization in patients with long-term opioid use and can resensitize opioid receptors in those with opioid refractory pain (Pourmand, Mazer-Amirshahi, Royall, Alhawas, & Shesser, 2017). Although shown to be beneficial in the management of acute and chronic pain, one might expect susceptibility or reaction to ketamine may be different in the two types of pain.

ED patients are medically diverse (Sobel & Steck, 2017) presenting with acute traumatic and nontraumatic pain as well as nonspecific chronic pain syndromes (ACEP, 2017). Research has shown that low-dose ketamine is an effective adjunct therapy that is safe and has the potential to reduce the use of opioids for pain control across multiple conditions and can potentially reduce hospital admissions for intractable pain, thereby reducing health care cost. However, further research is needed to better determine appropriate dosing and administration guidelines to reduce risks of adverse effects to ensure safe use, and to optimize patient outcomes.

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THE CASE REVISITED

Aware that low-dose ketamine can be used as an adjunctive therapy for managing acute, chronic, and refractory pain in the ED, the APRN ordered 0.1 mg/kg of intravenous ketamine in addition to 4 mg of intravenous morphine for Ms V. One hour later, she reported improved but continued pain and received one additional 4-mg dose of morphine. Thirty minutes later she reported her pain as being manageable with a pain score of 3/10 after a 120-minute length of stay in the ED. Ms V was offered admission for exacerbation of chronic pain; however, she refused, stating her pain level was at her baseline and that she would resume her usual pain medication regimen upon her discharge. To ensure she received the appropriate follow-up care, the palliative care service was contacted prior to her discharge. It was arranged for Ms V to be seen in the palliative care outpatient clinic the following day. Although no side effects were observed while in the ED, Ms V was educated about possible side effects from ketamine, which included nausea, dizziness, and disorientation. She was instructed to monitor herself for these side effects and to contact her palliative care physician or the ED for questions and concerns regarding her visit. Upon her discharge she also reported relief to the APRN at not having to be admitted to the hospital and stated that she was very satisfied with her ED care.

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CONCLUSION

Acute exacerbation of chronic pain is often a complication of malignant disease and the associated treatment. Poor pain management can lead to lengthy hospital admissions, which are costly to the health care system. Pain management is a fundamental and crucial component of emergency medicine practice. With the growing concern over opioid misuse and abuse, create challenges for cancer pain management. There is a growing body of evidence that supports the use of ketamine in the ED as an alternative and adjunctive treatment to traditional opioid use in patients with opioid refractory pain such as the cancer patient population. Although most of the evidence gives moderate strength to the use of ketamine for acute and opioid refractory pain, the conduction of more randomized controlled studies is needed to continue furthering support for its use in clinical practice.

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REFERENCES

American College of Emergency Physicians. (2017). “Sub-dissociative ketamine for analgesia.” Policy resource and education paper. Retrieved from https://acep.org/globalassets/new-pdfs/preps/prep—sub-dissociative-doseketamine-for-analgesia-120717.pdf
Bowers K. J., McAllister K. B., Ray M., Heitz C. (2017). Ketamine as an adjunct to opioids for acute pain in the emergency department: A randomized controlled trial. Academic Emergency Medicine, 24(6), 676–685.
Crumb M. W., Bryant C., Atkinson T. J. (2018). Emerging trends in pain medication management: Back to the future: A focus on ketamine. The American Journal of Medicine, 131(8), 883–886.
Ghate G., Clark E., Vaillancourt C. (2018). Systematic review of the use of low-dose ketamine for analgesia in the emergency department. CJEM, 20(1), 36–45.
Howard P. K., Gisness C. M. (2017). Is subdissociative ketamine as safe and effective as morphine for pain management in the emergency department? Advanced Emergency Nursing Journal, 39(2), 81–85.
Loveday B. A., Sindt J. (2015). Ketamine protocol for palliative care in cancer patients with refractory pain. Journal of the Advanced Practitioner in Oncology, 6(6), 555–561.
Numico G., Cristofano A., Mozzicafreddo A., Cursio O. E., Franco P., Courthod G., Silvestris N. (2015). Hospital admission of cancer patients: Avoidable practice or necessary care? PLoS One, 10(3), e0120827.
Paice J. A. (2018). Navigating cancer pain management in the midst of the opioid epidemic. Oncology (Williston Park), 32(8), 386–390, 403.
Patel P. M., Goodman L. F., Knepel S. A., Miller C. C., Azimi A., Phillips G., Hartman A. (2017). Evaluation of emergency department management of opioid-tolerant cancer patients with acute pain. Journal of Pain and Symptom Management, 54(4), 501–507.
Pourmand A., Mazer-Amirshahi M., Royall C., Alhawas R., Shesser R. (2017). Low dose ketamine use in the emergency department, a new direction in pain management. The American Journal of Emergency Medicine, 35(6), 918–921.
Sobel R. M., Steck A. R. (2017). Low dose ketamine in the age of opioids. The America Journal of Emergency Medicine, 35(6), 917–918.
Waldfogel J. M., Nesbit S., Cohen S. P., Dy S. M. (2016). Successful treatment of opioid-refractory cancer pain with short-course, low-dose ketamine. Journal of Pain & Palliative Care Pharmacotherapy, 30(4), 294–297.
Keywords:

ketamine; ketamine for cancer pain; ketamine in emergency care

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