Abstract
Abstract
Patients with advanced cancer often suffer from both severe pain and severe symptoms of depression. Use of traditional antidepressants is often limited by the short prognosis associated with advanced cancer. We present the case of a patient with neuropathic pain from advanced cancer and severe depression that responded dramatically to an intravenous infusion of ketamine resulting in decreased pain and resolution of severe depression symptoms.
Introduction
P
Ketamine is an alternative agent that has been studied for off-label use in both pain and depression.1,2,5–10 Ketamine is a rapidly acting dissociative anesthetic originally FDA-approved in 1970 for induction and maintenance of general anesthesia. 11 There are numerous uses for ketamine described in current literature, including severe pain, status asthmaticus, acute bronchospasm, procedural sedation, and depression.12–16
Ketamine acts on a variety of receptors, including cholinergic, serotonin, norepinephrine, dopamine receptors, L-type calcium and sodium channels, and opioid receptors.
17
The mechanism of action of ketamine for pain, including neuropathic pain, mainly occurs through N-methyl-
It is ketamine's rapid onset of action 21 and NMDA receptor antagonism (a purported mechanism in the pathophysiology of depression 22 ) that make it an attractive candidate for treatment of depression and/or pain in terminal patients. The antidepression effects seem to be short lived; however, this may be less of a limitation in patients nearing end of life. Cases of single doses or serial infusions of subanesthetic dose ketamine have been reported to produce a rapid antidepressant effect in treatment of depressive symptoms.6,10,23,24 Further randomized clinical trials have also demonstrated clinical success in the rapid treatment of depressive episodes. 8 In the setting of advanced cancer, one case report presents a patient that received burst doses of ketamine for the treatment of major depressive disorder. 2 Despite multiple studies suggesting that ketamine is effective for treatment of depressive episodes, there are currently no guidelines recommending the use of ketamine in the setting of depression at the end of life.
In this study, we report a case involving a patient with advanced thyroid cancer at a tertiary academic teaching hospital who received treatment for neuropathic pain and treatment-naïve, severe depression with a continuous intravenous (IV) infusion of ketamine.
Case Presentation
In 2016, a 64-year-old man with metastatic anaplastic thyroid cancer previously treated by surgical resection, chemotherapy, and radiation was admitted to University of California San Diego Health for syncope and hematochezia. His past medical history was significant for hypertension, hypothyroidism, atrial fibrillation, sleep apnea, and kidney stones. In the emergency department he was found to be hypovolemic with tachycardia, and suffering from acute kidney injury, thrombocytosis, leukocytosis, and an elevated lactate. Of note, the patient's QTc was 605 on methadone while receiving fluconazole, a potent cytochrome p450 inhibitor for oral thrush.
The Doris A. Howell Palliative Care Service was consulted on hospital day 3 to provide recommendations on the management of pain related to thyroid cancer, as well as to assist in defining goals of care. Upon evaluation the patient endorsed fatigue, weakness, odynophagia, anorexia, poor oral intake, and an unintended 35-pound weight loss over the preceding four months. Owing to this decline, his oncologist had recently held his tyrosine kinase inhibitor (lenvatanib) therapy at his last outpatient appointment before admission. As he reported spending most of his day in bed and needing increasing assistance with his activities of daily living, the palliative care team determined the patient had a Palliative Performance Status of 40% 25 and an Eastern Cooperative Oncology Group (ECOG) 26 performance grade of 3 (capable of limited self-care and confined to bed or chair >50% of waking hours), suggesting a prognosis of less than six months. 27
The patient endorsed posterior and lateral right neck pain moderate in severity at rest on his outpatient pain regimen but reported severe (8/10) odynophagia upon swallowing. He described the odynophagia as “burning” in nature, indicating a neuropathic component. His home pain regimen consisted of methadone 5 mg twice daily and oxycodone 5 mg by mouth every four hours as needed. The patient had been placed on methadone by his outpatient oncologist in response to a complaint of right lateral neck pain radiating down to his right shoulder. Per outpatient documentation, the radiating pain did improve after initiation of methadone. Upon evaluating his mood, the patient voiced a desire to stop all treatment and stated that he would, in fact, welcome a hastened death. Given his statements, palliative psychiatry was consulted on hospital day 4 to evaluate for depression and possible suicidality in the setting of terminal disease.
The palliative psychiatry team ascertained that the patient had neither a prior psychiatric history nor previous medication trials to treat depression. During the evaluation, the patient reiterated to the psychiatrist that he was “over it” and wished “to die.” He noted that the only other acceptable alternative would be to sleep indefinitely, that is, palliative sedation. He stated that his family did “not want him to suffer.” The patient's wife relayed her concerns about the patient's state of mind to a medical social worker stating, “He's just not himself anymore,” believing him to be depressed. The palliative psychiatrist diagnosed the patient with severe clinical depression after he scored a 24 out of possible 27 on the Patient Health Questionnaire 9 (PHQ 9). The PHQ 9 identifies patients with scores between 5 and 9 as having mild depression, scores between 10 and 19 as having moderate or moderately severe depression, and scores >20 as having a severe major depressive disorder.
Upon reassessment by the palliative care licensed clinical social worker (LCSW), the patient presented in severe psychological distress, clearly requesting that the palliative care team to hasten his death or put him “to sleep.” The patient expressed that he had lost hope that the medical teams would be able to address his symptoms and thus simply wanted to die. The LCSW inquired whether improving his physical symptoms might alter his desire for hastened death. The patient greeted this proposition with skepticism but eventually granted the palliative care team 24 hours in which to attempt to improve his pain control and mood with the ultimate goal of transferring him home with the support of hospice for his final days.
With such a brief window to address both severe neuropathic pain (8/10) and severe depression, the palliative care team elected to initiate a trial of IV ketamine at 0.2 mg/kg/h, as described in the UCSD Health “Guideline for Low-Dose Ketamine for Pain Management.” (The health system maintains a separate ketamine protocol exclusively for depression—UC San Diego Health “Injectable Low-dose Ketamine for Refractory Depression”—with different dosing [0.5 mg/kg IV nightly] and different monitoring requirements than that for pain.) It was our hypothesis that the ketamine regimen for pain would also yield improvement in his severe depression. In addition, we theorized that ketamine's NMDA antagonism might allow for the discontinuation of the patient's methadone, which as noted previously had significantly prolonged his QTc.
The continuous infusion of ketamine was initiated at 17:00 on hospital day 4. At that time, his pain was documented at 8/10. By 21:00 on hospital day 4, his pain score was a 3/10. Twenty-six hours (hospital day 5) after initiation of ketamine infusion, the patient achieved a documented pain score of 0/10. He did experience two spikes of pain as high as 7/10 during the ketamine infusion, which responded to 0.5 mg hydromorphone IV.
Upon reevaluation on hospital day 5, the patient was observed lying in bed, smiling, and stated that he was feeling better, a mood that was confirmed by his daughter at bedside. His daughter had played some music earlier that morning and remarked that the patient was feeling well enough and motivated enough to get out of his bed and dance with her. The patient did not ask the palliative care team for hastened death or for palliative sedation. Instead, he was joking with the team and engaging in conversation. His wife remarked, “This is my husband. Thank you for bringing him back.” The palliative psychiatrist's assessment was similar. She documented that the patient was “smiling with good eye contact,” with a stated mood of, “I feel better.” She found his affect “congruent with his mood,” and documented that he lacked “suicidal ideation or plan.”
The patient was discharged with home hospice on hospital day 6 after receiving a peripherally inserted central catheter to allow for continued ketamine infusion at home. The pain relief achieved by the ketamine infusion allowed the hospice team to discontinue his methadone. He continued to use oxycodone 5 mg orally (PO) as needed for breakthrough pain. The patient remained on the ketamine infusion until his peaceful death at home approximately two weeks later.
Discussion
Reported prevalence of major depressive disorder (MDD) in patients with advanced cancer varies widely, ranging between 15% and 48%.2,28 Many studies of depression in advanced cancer do not differentiate between the newly diagnosed, active treatment, or end-stage phases of cancer. 29 Symptoms of depression often overlap with those normally seen in cancer—lack of energy, sleep disturbance, concentration difficulties, anorexia, and weight loss—but other symptoms such as hopelessness and requests for hastened death are not considered part of the normal trajectory of cancer and increase suffering for patients and their loved ones.21,30 The oft-shortened life span associated with advanced cancer may limit the utility of traditional antidepressants, such as SSRIs and SNRIs, which can take weeks to achieve results in MDD. For this reason, palliative care providers have sought alternative treatments for depression in patients with advanced cancer.
The role for psychostimulants, such as methylphenidate, in treating depression in patients with advanced cancer has been previously described.31,32 Although rapidly effective for improvement of depression, often within days, methylphenidate does not provide any augmentation of pain relief, a frequent concomitant symptom in end-stage cancer.
There is a growing body of literature suggesting the efficacy of ketamine, a powerful noncompetitive NMDA-receptor antagonist, in treating severe depression in otherwise healthy patients. 6 Typical dosing regimens for depression are at subanesthetic doses (<0.5 mg/kg). 6 In the palliative care setting, ketamine has been long used in the treatment of neuropathic pain owing to its distinct NMDA-receptor antagonism. More recently, however, ketamine has been increasingly utilized in palliative care to rapidly ameliorate depression symptoms in patients with advanced cancer. Several articles, briefly reviewed as follows, have reported improvement in depression in patients with advanced cancer using PO, IV, and intramuscular (IM) administrations of ketamine.
Irwin and Iglewicz 21 reported two cases of rapid and sustained improvement in depression and anxiety in hospice patients with advanced cancer receiving a single oral dose of ketamine. Two patients each received 0.5 mg/kg of ketamine orally; both experienced subjective and objective improvement in depression and anxiety within hours of administration. The effects of the improvement were sustained over a period of weeks in both cases. Repeat dosing in one case was not as effective. No adverse effects were noted in either case. The article did not, however, address differences in pain control.
“Burst” IV dosing (0.5 mg/kg) >60 minutes in a patient with metastatic prostate cancer, as described by Stefanczyk-Sapieha et al., 2 yielded rapid improvements in depressions scores within hours. The antidepressant effect, however, was not sustained beyond 72 hours and was not attained to the same degree or duration upon repeat dosing. Side effects, including nondistressing visual hallucinations, did not require treatment.
Zanicotti et al. 28 published a case report of a 36-year-old woman with metastatic ovarian cancer receiving chemotherapy (carboplatin and gemcitabine) with long-standing MDD already on venlafaxine, quetiapine, and methadone who experienced significant relief of depressive symptoms within one hour after receiving the first injection of IM ketamine. This effect was sustained for six to seven days. Relief in pain was also described for this patient; however, it was for a shorter duration than relief from depression (around one day). The patient did not experience tachyphylaxis to the antidepressant effects with repeated IM dosing. It is thought that IM dosing may be more cost-effective as it obviates the need for an infusion pump and IV access. Side effects were generally mild (visual hallucinations and vivid dreams) and were treated with as needed benzodiazepines to the satisfaction of the patient.
In addition to scant data on the prevalence of depression in advanced cancer patients, even less data exist regarding the frequency with which cancer patients are appropriately treated for depression at the end of life. Thus, the “scope and magnitude of suffering due to unrecognized and inadequately treated depression in terminally ill cancer patients remains both unknown and unfortunate. 29 ”
A quotation from Cicely Saunders—“How people die remains in the memory of those who live on”—may lead us to believe that improved symptom control for patients at the end of life should confer benefits to (or at least be protective to) survivors, we have little objective data to prove it. The bulk of research on complicated grief focuses on caregiver-inherent risk factors (preexisting mental health issues/substance abuse or low levels of social support) or on the nature of the patient's illness (protracted, traumatic, and stigmatized) rather than on the caregiver's/family's perception of the patient's comfort at the time of death. 33
In this report, we present a case of an advanced cancer patient experiencing pain and depression symptoms so severe as to prompt requests for hastened death, who experienced rapid, significant, and sustained improvement in pain and depression symptoms with a continuous IV infusion of ketamine. This improvement transcended the inpatient setting, persisting as he transitioned to home with the support of hospice. The relief from depression symptoms allowed the patient to participate more fully in his last days and allowed his family to feel as though the time remaining was spent with someone they more fully recognized as their loved one.
The use of ketamine for depression in patients with advanced cancer remains supported by only case reports such as ours. A well-designed randomized study of continuous IV infusion of ketamine for patients with advanced cancer suffering from depression is needed to address ideal dosing. In addition, practitioners should be well versed in the mechanism, dosing, and potential side effects of any medication before its administration. Finally, given the relatively short periods of administration in patients with advanced cancer, it is unclear whether patients may experience tachyphylaxis with prolonged infusion.
Footnotes
Author Disclosure Statement
No competing financial interests exist.