Abstract
Background:
Ketamine is an N-methyl-D-aspartate receptor antagonist traditionally used for dissociative sedation that has also been used for the treatment of pain. Ketamine can have a higher bioavailability when administered intranasally.
Objective:
To present a case in which intranasal (IN) ketamine was used for unpredictable, episodic, cancer-related neuropathic pain.
Case Presentation:
We present a 49-year-old patient with metastatic adenocarcinoma of the lung who presented to our outpatient palliative care clinic with uncontrolled severe episodic neuropathic pain of the lower extremity.
Case Management:
We prescribed compounded racemic ketamine 20–30 mg intranasally as needed at the onset of severe episodes of breakthrough pain, in addition to scheduled use of oral methadone and a buprenorphine patch for long-acting pain management.
Case Outcome:
The patient reported a decrease in frequency, intensity, and duration of episodic breakthrough pain with use of IN ketamine without any reported negative adverse effects.
Conclusion:
Low-dose compounded racemic IN ketamine may be a useful and safe adjunct in alleviating severe breakthrough pain in cancer patients in the outpatient setting.
Introduction
Ketamine acts as a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor as well exerting effects at several other receptors, including mu-, kappa-, and delta-opioid receptors, muscarinic and nicotinic receptors, serotonin receptors, dopaminergic receptors, and neuronal sodium channels that contribute to its analgesic effect. 1 In palliative care, ketamine has been used as a coanalgesic for refractory cancer pain and is on the World Health Organization’s Essential Drugs List for patients who no longer respond to high doses of opioids or have predictable breakthrough pain. 2 While oral ketamine is commonly used in palliative care practice, oral bioavailability is low at 15–23% 2 compared to intranasal (IN) ketamine, which has a bioavailability of 50% and avoids first-pass metabolism. 3
The S-ketamine isomer esketamine has been developed, studied, and FDA approved for management of refractory major depressive disorder4–6 and has been studied in cancer patients. 7 However, use is currently restricted to specialized providers and facilities where monitoring can be continued after administration. Esketamine is generally available only for the management of treatment-resistant depression rather than pain management. Intravenous infusions of ketamine for pain are available but may be logistically difficult or not regionally available for advanced cancer patients with limited ambulation. Compounded racemic ketamine, on the contrary, is available orally or intranasally as an off-label adjunct for pain management and can be administered by patients and families at home.
In this article, we report on our experience using compounded racemic ketamine intranasally to alleviate severe bouts of breakthrough neuropathic pain in a patient suffering from metastatic lung cancer.
Case Description
A 49-year-old male presented to the outpatient palliative care clinic for management of refractory pain related to adenocarcinoma of the lung that had metastasized to bone. While the patient had been diagnosed about one year prior to consultation, he had not been having substantial pain until about three months prior to his first palliative care clinic visit. At that time, he started developing episodic periods of severe pain of the entire left lower extremity that was described as sharp, burning, and electric. Episodes of pain occurred on average four times daily without provoking factors and lasted about 1–2 hours. Because the patient was having symptoms at home, he was unable to be formally examined during the reported episodes. Based on the description of symptoms, it was felt that there was an episodic neuropathic component to the patient’s pain. The patient also had what appeared to be a constant, lower-intensity achy pain in the right femur, which ultimately correlated with bony metastasis on the PET scan.
Prior to his first palliative care clinic visit, the patient’s oncology team had titrated his pain regimen to hydromorphone 4 mg orally four times daily as needed for breakthrough pain and fentanyl 75 mcg/hr patch every 72 hours. Two weeks prior to his first palliative clinic visit, the patient was started on methadone 5 mg three times daily as well. The patient felt that this regimen helped with the lower-grade constant leg pain but did not work fast enough to ameliorate the severe episodic pain, which seemed to be neuropathic in nature. The patient was also undergoing radiation therapy to the left femur.
The patient’s exam was notable primarily for mild difficulty walking and bearing weight on the left leg due to pain and required ambulation with a cane. His palliative performance scale was 60%, and he displayed moderate generalized sarcopenia. He had some mild tenderness over the left femur but did not display any objective strength or sensory deficit throughout the bilateral lower extremities. He was neurovascularly intact and did not have any evidence of swelling or deep vein thrombosis. There were no red flag signs or symptoms suggestive of acute spinal cord compression.
With the first clinic visit, the patient was started on compounded racemic ketamine 20 mg IN three times daily as needed to be used at the onset of episodic pain in addition to lorazepam 1 mg orally as needed to address severe emotional distress during episodes. Initial ketamine dosing was chosen based on relative equivalency to parental weight-based dosing of 0.3 mg/kg for acute pain and at the lower end of IN dosing reported in some other studies.3,8,9 Compounded racemic ketamine was dispensed as a 100 mg/mL solution that the patient was able to self-administer from a syringe with a mucosal atomization device. Each spray was 0.1 mL of volume and dispensed 10 mg of ketamine. As insurance did not cover the compounded racemic ketamine, the patient’s out-of-pocket cost for 30 mL was about $100 from a local compounding pharmacy. The patient and his significant other were both counseled on the administration of IN ketamine, potential side effects, and symptoms that would warrant seeking emergent medical evaluation. His methadone was continued without change. His fentanyl patch was discontinued in favor of a buprenorphine 10 mcg/hr patch weekly with the intended long-term goal of cross-tapering off methadone over time as buprenorphine dosing would be increased and ultimately become his solo long-acting agent. His previously prescribed hydromorphone 4 mg four times daily as needed for breakthrough pain was continued as well. He also started on duloxetine 30 mg daily. He also continued with plans for outpatient radiation therapy.
Over the subsequent days, he reported no adverse effects and about 50% improvement in severity and duration of episodes, so ketamine was increased to 30 mg IN as needed at the onset of episodic pain. On his subsequent visit two weeks later, he reported substantial improvement with only one episode per day of severe breakthrough pain lasting about 15 minutes after self-administering ketamine. He ultimately did not use the available benzodiazepine during the painful episodes and used hydromorphone more for his constant pain than during episodic breakthrough pain. His methadone dosing remained unchanged, and his buprenorphine was titrated to 20 mcg/hr patch weekly and duloxetine titrated to 60 mg daily. The patient reported a gradual improvement in his constant bony pain as well. The patient reported some vivid but pleasant dreams after initiating ketamine.
One month after the initial visit, the patient was no longer having any episodes of intense neuropathic pain. While the IN ketamine seemed to be abortive for intense episodic pain early in our management plan, his frequency of painful episodes gradually decreased in frequency and intensity. This was attributed to ongoing use of methadone, buprenorphine, duloxetine, response to radiation treatment, and potentially to cumulative effect of IN ketamine. He was no longer requiring ketamine for breakthrough pain. His baseline constant bony pain was well controlled without change in dosing of his methadone and buprenorphine patch. The patient had progression of metastatic burden despite carboplatin + pemetrexed + cemiplimab. After further goals of care discussion with palliative medicine and oncology, the patient elected to proceed with docetaxel and ramucirumab. Unfortunately, the patient had continued progression of metastatic burden, most notably in the abdomen, diaphragm, and retroperitoneal space, which caused severe abdominal pain. He ultimately transitioned to hospice, and methadone was titrated. He died comfortably at home.
Discussion
IN administration of medication has been studied across a wide variety of medical conditions and is particularly promising in the treatment of pain in palliative care patients. 10 It has been regarded as a more efficient alternative for the administration of analgesic drugs due to rapid onset of action, simplicity, and minimal inconvenience in administration. 11 While IN ketamine has been studied and FDA-approved in the treatment of refractory major depressive disorder, there is evidence to suggest that it is useful in the treatment of breakthrough pain in patients with cancer, 12 neuropathic pain, 13 as well as in other conditions such as acute traumatic limb injury 11 and acute headache. 8 While there appears to be evidence in favor of the use of IN ketamine in monitored and inpatient care settings, there appears to be a paucity of reports on the use of patient-administered IN ketamine in an ambulatory setting.
Based on our positive experience with the use of compounded IN racemic ketamine, we propose that more study is warranted in the use of IN ketamine in the ambulatory cancer pain population. While our patient may have had substantial benefit from radiation, buprenorphine patch, methadone, and duloxetine for overall management of his neuropathic pain, he appeared to have faster resolution of his intense episodes of breakthrough pain with the use of IN ketamine.
Moreover, the patient did not seem to have any deleterious effects due to ketamine. While he did self-report abnormal dreams, the dreams were reported to be calming rather than concerning to the patient. We attribute our lack of adverse effects to the relatively low dose of IN ketamine 30 mg up to three times daily. It is important to note that there is an FDA alert regarding five cases between 2016 and 2021 of severe psychiatric disturbances such as delusion, dissociation, and panic attack with use of compounded racemic IN ketamine. Prescribed doses associated with those cases were reportedly in the range of 3–6 sprays of 125–200 mg/mL compounded ketamine. 14 For comparison, our patient was receiving a maximum of 3 sprays of 10 mg/mL compounded ketamine.
Conclusion
Our case demonstrates that low-dose compounded IN ketamine can be an effective, safe, and promising adjunct in managing cancer-related pain, particularly in outpatient palliative care settings. Given its rapid onset of action and ease of administration, it can be effective in treating unpredictable and episodic pain, which is often challenging to control with standard outpatient medication regimens. We recommend further investigation with randomized controlled studies to assess the efficacy and safety of IN ketamine for cancer-related episodic pain.