Safe and Effective Treatment of Refractory Cancer Pain with Chronic Oral Ketamine: A Case Series

Abstract

Introduction:

A growing body of evidence supports the off-label use of subanesthetic or low-dose oral ketamine for chronic pain. However, the safety and efficacy of long-term treatment remain unclear. This case series describes one palliative care (PC) clinic’s experience using long-term oral ketamine to treat refractory cancer pain.

Methods:

All patients (n = 3) treated with oral ketamine in one PC clinic between 2022 and 2024 for adult cancer pain were reviewed. Pain scores were collected using the Edmonton Symptom Assessment Scale numeric rating scale as part of routine follow-up visits.

Results:

All patients reported improvement in cancer-related pain with the addition of oral ketamine. The total daily dose ranged from 30 mg to 320 mg. One patient experienced mild dissociative effects and dizziness, which resolved after decreasing the total daily dose. Treatment was maintained beyond 3 months in 2/3 cases, and the longest course of therapy was 18 months. The most significant logistical challenge was related to supply chain issues limiting availability at community pharmacies.

Conclusion:

Chronic treatment with oral ketamine as a coanalgesic for refractory cancer pain was well tolerated. All patients reported improved pain scores with the addition of oral ketamine. Ongoing research is needed to further describe the risks and benefits of long-term oral ketamine treatment.

Introduction

Ketamine, first described as an intravenous anesthetic in 1966, is a nonselective, noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. ¹ The NMDA receptor plays a significant role in the development of chronic pain, especially neuropathic pain, where prolonged receptor stimulation causes upregulation, leading to a state of central sensitization. ² This phenomenon is characterized by a discrepancy between the amount of tissue damage and the intensity of pain experienced, explained by aberrant pain processing in the central nervous system. ³ Patients often experience allodynia (pain produced by a nonnoxious stimulus) and hyperalgesia (enhanced intensity of pain sensation). ⁴ Ketamine’s action at the NMDA receptor is hypothesized to treat pain associated with central sensitization.

Table 1.

Patient Characteristics, Diagnoses, Pain Treatments, and Outcomes

Patient	Age (years)	Sex	Cancer type	Baseline OME/day (mg) a	Baseline coanalgesia	Baseline pain score	Nadir pain score	Most recent ketamine regimen	Most recent coanalgesia	Most recent pain score	Adverse reaction(s)	Total duration (months)
LB	75	F	Lung	384	Methadone 10 mg TID Hydromorphone 12 mg every 3HR PRN	7/10	3–4/10	10 mg daily	Methadone 10 mg QAM, 5 mg QHS Hydromorphone IR 12 mg PRN (rarely)	3–4/10	Lightheaded Forgetful Fatigue	2.5
LG	64	M	Multiple myeloma	768	Methadone 40 mg TID Hydromorphone 24 mg every 3HR PRN	9/10	7/10	80 mg every 6HR	Methadone 50 mg TID Hydromorphone IR 32 mg every 3HR PRN Morphine ER 100 mg every 12HR Morphine and Bupivacaine IT pump	7–8/10	None	18
BW	63	M	Plasma cell neoplasm	N/A	Buprenorphine-Naloxone 8/2 mg TID Nortriptyline 50 mg daily Topiramate 50 mg BID	8/10	4/10	50 mg TID	Buprenorphine-Naloxone 8 mg/2 mg TID Hydromorphone IR 2 mg every 4HR PRN Nortriptyline 50 mg daily	7/10	Mild dizziness	15

a

Methadone was excluded in the calculation of oral morphine equivalent due to variable methadone dose conversion guidelines.

Abbreviations: BID, twice daily; ER, extended-release; F, female; HR, hours; IR, immediate release; IT, intrathecal; M, male; mg, milligram; N/A, not applicable; OME, oral morphine equivalent; PRN, as needed; QAM, every morning; QHS, at bedtime; TID, three times daily.

In 1970, Ketalar® was the first intravenous preparation of ketamine approved by the Food and Drug Administration (FDA). ⁵ Spravato®, an intranasal esketamine, was FDA-approved for refractory depression in 2019. ⁶ Subanesthetic or low-dose oral ketamine has been used off-label by pain specialists for decades. ⁷

In the outpatient setting, ketamine can either be prescribed in the injectable formulation to be ingested orally or as one of several oral formulations prepared by a compounding pharmacy, including capsules, troches, and oral suspensions. Oral ketamine has a more favorable safety profile than intravenous ketamine because of its association with lower plasma levels and its active metabolite, norketamine, a product of extensive first-pass metabolism. ⁸ Regardless of the route of administration, ketamine can cause sedation, somnolence, dizziness, dissociative experiences, nausea, abnormal liver function tests, tachycardia, and hypertension. ⁹

To our knowledge, the safety and efficacy of long-term oral ketamine in the treatment of cancer-related pain have not been established. The following cases describe three patients who were prescribed oral ketamine to treat chronic cancer pain in the ambulatory palliative care (PC) setting.

Case Series

We retrospectively reviewed all patients (n = 3) in our PC clinic whose cancer pain was treated with oral ketamine between June 1, 2022, and June 1, 2024 (Table 1). During this period, 1540 patients were seen. The clinic is embedded within a cancer center affiliated with a large, tertiary, academic medical center in New Haven, CT. Prescribers work closely with a PC-trained clinical pharmacist.

All patients were initially dosed with oral ketamine 10 mg every 6 hours per expert guidance from the Center to Advance Palliative Care. ¹⁰ Pain scores were collected as part of the Edmonton Symptom Assessment Scale (ESAS), ¹¹ administered at every clinic visit. Patients were initially prescribed injectable ketamine to be ingested orally, with subsequent changes in dosage formulation made based on patient preferences and pharmacy availability.

Case #1

LB was a 75-year-old female with a history of multiple sclerosis and epidermal growth factor receptor-positive nonsmall-cell lung cancer. Her cancer was initially treated with osimertinib, with bevacizumab added later due to progression. Pathological fractures in her thoracic spine were treated with vertebroplasty without any improvement. She experienced refractory right lower thoracic nociceptive pain exacerbated by sitting, standing, and walking. Despite treatment with methadone 10 mg three times daily and hydromorphone immediate release (IR) 12 mg every 3 hours as needed (PRN), she consistently rated her pain 7/10. Oral ketamine was initiated as her pain was not responsive to escalating doses of opioids, which were causing significant fatigue.

On day 1 of ketamine treatment, the patient reported mild lightheadedness. On subsequent days, she experienced increased daytime somnolence and forgetfulness. She did not experience hallucinations, dissociative effects, or confusion. After a week, she reported a significant decrease in pain scores to 3–4/10. She did not use any hydromorphone IR for 3 consecutive days, so methadone was decreased to 15 mg in the morning and 10 mg at night. Her pain scores remained 3–4/10 after week 2, and her hydromorphone IR use resumed at about once daily. Her caregiver then disclosed that she only required ketamine 10 mg once daily, 1–2 doses of hydromorphone IR per week, and was foregoing some of her methadone doses as she was comfortable by week 3. Her drowsiness improved, but fatigue was persistent throughout therapy, which her oncologist attributed to her advanced cancer and immunotherapy treatment. She accepted this trade-off as she prioritized improved pain control. She died 10 weeks after initiation of oral ketamine from progression of her lung cancer.

Case #2

LG is a 64-year-old male with a history of IgG kappa multiple myeloma with controlled response on B-cell maturation antigen (BCMA)-targeted bispecific T cell engager (Celgene BiTE). ¹² In addition, he also has a history of depression, anxiety, and opioid use disorder in remission. Magnetic resonance imaging of his thoracic and lumbar spine demonstrated multiple lytic lesions and a subacute L1 compression fracture. The patient’s oral opioid requirement increased considerably since his cancer diagnosis in 2018 to a regimen of hydromorphone IR 24 mg every 3 hours and methadone 40 mg three times daily. He reported persistent back pain due to compression fractures and severe kyphosis, which limits his daily function and ambulation. Surgical intervention was deemed too risky. Oral ketamine was initiated, as his pain was not responsive to escalating doses of opioids. One week after oral ketamine initiation, the patient reported a decrease in his pain score from 9/10 to 7/10. The ketamine dose was titrated weekly to a dose of 40 mg every 6 hours by week 4 and then to a dose of 80 mg every 6 hours by month 7. The patient reported improved function and mobility with these increases.

The patient was admitted to the hospital three times during a six-month period (months 4 through 9 of ketamine treatment) after running out of his opioids early in the setting of uncontrolled back pain. During each admission, hydromorphone patient-controlled analgesia (PCA) was initiated on day 1 with minimal relief. Then ketamine PCA was initiated at 0.2 mg/kg/hr on days 2 or 3 for uncontrolled pain. In each instance, ketamine PCA was delayed to allow time to assess his opioid needs. Once it was determined that reasonable increases in opioid doses were not effective, ketamine was resumed intravenously, as the oral formulation is not approved for inpatient use at our institution. Both hydromorphone and ketamine PCAs were discontinued before discharge, and oral ketamine was resumed at the prehospital dose. At each discharge, safety measures were implemented and escalated with each admission, including mandating the use of a lockbox, requiring his caregiver to manage his medications, and prescribing no more than 7 days of controlled substances at a time. His pain scores remained between 7–8/10.

During the third admission, after several interdisciplinary discussions between oncology, PC, acute pain service, and neurosurgery, an intrathecal drug delivery system was implanted in response to recurrent admissions for pain crises and an unsustainable oral opioid regimen. Oral ketamine was continued as he reported it to be the most effective medication for his pain. As part of his multimodal treatment plan, he follows closely with our PC psychologist for ongoing cognitive-behavioral therapy. He has been treated with oral ketamine for more than 18 months while he undergoes oral opioid weaning and further intrathecal morphine and bupivacaine titration. He has not been hospitalized for the past 6 months.

Case #3

BW is a 63-year-old male with a history of monoclonal gammopathy of undetermined significance and plasma cell neoplasm complicated by severe peripheral neuropathy. His pain was refractory to several neuropathic pain agents, including gabapentinoids, antispasmodics, duloxetine, topical agents, medical cannabis, and scrambler device therapy. His pain was initially treated by hematology with morphine extended-release (ER) 30 mg every 12 hours. Upon referral to the PC clinic, this was rotated to buprenorphine-naloxone after the patient requested to stop full agonist opioid therapy because of concerns about his balance and constipation. Oral ketamine was initiated to better target his neuropathic pain due to lack of response to first-line agents.

After 1 week of oral ketamine, his pain score decreased from 8/10 to 6/10. Ketamine was further titrated to 30 mg every 6 hours, resulting in a decrease in pain score to 4/10 three weeks later. He reported a dissociative experience described as “feeling out of my body,” which lasted one hour and was associated with mild dizziness for the following few days. The ketamine dose was decreased to 25 mg every 6 hours with improvement in dizziness and resolution of dissociative symptoms. A month later, the dose was increased to 35 mg, which he tolerated well. The patient reported taking ketamine only three times per day due to the burdens of four times daily dosing. Two months later, the ketamine dose was increased to 40 mg three times daily and then to 50 mg after another two months. Unfortunately, as his plasma cell neoplasm continued to progress through several lines of therapy, his neuropathy worsened. Although his pain scores gradually increased to 7/10, he described an improved level of function. Hydromorphone IR 2 mg every 4 hours PRN was added for severe breakthrough pain during month 9 of ketamine therapy, and currently, the patient is on month 15 of oral ketamine therapy.

Discussion

As a potent, noncompetitive NMDA receptor antagonist, ketamine is an effective adjuvant in the treatment of refractory cancer pain.^13–16 In this case series, we describe three patients with complex, cancer-related pain refractory to high doses of opioids and multimodal therapies who were treated with oral ketamine between 2.5 to 18 months. Patients were prescribed total daily doses between 30 mg and 320 mg.

The current evidence supporting the use of oral ketamine for cancer pain includes only a handful of prospective studies and mostly consists of case reports. ¹⁴ Lauretti et al. randomized 60 participants with uncontrolled cancer pain on oral morphine to receive either additional morphine, nitroglycerin, ketamine, or dipyrone. The ketamine group was the only one to have consistently improved pain with decreased doses of morphine. ¹⁵ Another randomized clinical trial, Fallon et al. found that oral ketamine was no more effective than placebo in treating patients with cancer-related neuropathic pain, most of whom had chronic, chemotherapy-induced neuropathy. ¹⁶ However, the authors acknowledged that there may be subgroups of patients, like those with central sensitization, who may benefit from oral ketamine. Notably, 74.7% of the patients studied were cancer survivors, decreasing the generalizability to our study population of patients with active cancer.

Marchetti et al. retrospectively reviewed 55 patients who were initiated on intravenous ketamine in the hospital and then continued oral ketamine on discharge and found that pain was reduced in two-thirds of treated patients. ¹⁷ However, patients were only treated for up to three months, and the study excluded patients with cancer pain. We found only one case report describing a single patient who was successfully treated with oral ketamine beyond three months. ¹⁸ Our case series builds on this work, as two of our three patients have continued ketamine treatment for longer than 1 year.

After initiating oral ketamine treatment, all three of our patients reported improved pain scores. The minimum clinically important difference for ESAS pain scores has been established as a 1-point change, ¹⁹ further supporting our results. Our case series highlights several important clinical observations. First, we noted that although patients LG and BW reported decreased pain scores with the addition of ketamine, they subsequently required additional opioids and, in LG’s case, an intrathecal drug delivery device. We hypothesize that this was due to the progressive nature of neuropathy in plasma cell neoplasm and multiple myeloma rather than ketamine treatment failure. ²⁰ Second, LG reported ketamine to be more effective than opioids in treating his pain. Notably, he was the only patient with comorbid depression. Ketamine affects multiple neurobiological pathways shared between depression and pain, ²¹ making it difficult to exclude the possibility that his improved pain was confounded by ketamine’s independent effect on his mood. Third, we noted a significant decrease in LB’s opioid usage. It is difficult to accurately report the true decrease in her daily oral morphine equivalents, given her inconsistent use of her ER and IR opioids.

We assessed the safety of chronic ketamine treatment through clinical monitoring of adverse effects and routine bloodwork collected as part of oncologic treatment. Mild psychotomimetic effects were observed in one patient with a dose of 30 mg every 6 hours and resolved when decreased to 25 mg every 6 hours. There were no reported adverse gastrointestinal, hepatic, or cardiac effects.

Logistically, we encountered several challenges in prescribing oral ketamine for refractory cancer pain. First, ketamine is manufactured as an injectable formulation or a bulk powder that can be compounded. When the injectable formulation is dispensed, patients must draw up concentrated injectables and administer them orally, which may confuse patients and retail pharmacists. Prescribers, clinical pharmacists (if available), and retail pharmacists must thoroughly educate patients on appropriate dosing and safe administration. Second, access to injectable and compounded ketamine is highly dependent on the supply chain, which may delay treatment when ketamine is unavailable. This requires additional time and effort from clinicians to locate a pharmacy whose contracted wholesaler can obtain it. Lastly, ketamine may not be available for oral use in certain settings (hospitals, extended care facilities, etc.) due to its off-label status. This disrupts the continuity of therapy when patients transition between care settings, i.e., from the hospital to home. Cumulatively, these challenges may discourage clinicians from prescribing ketamine. However, we worked within these challenges to help our patients access oral ketamine in the outpatient setting.

Our case series has several limitations. Our retrospective design and small sample size limit its generalizability. Additionally, we relied on clinical documentation of pain and adverse effects without a standard protocol. It is challenging to accurately compare the responses to ketamine treatment between participants because of differences in their cancer types, expected pain trajectories, and ketamine formulations. We attempted to address selection bias by reporting all patients treated with oral ketamine between 2022 and 2024. Lastly, we did not formally assess our patients for allodynia or central sensitization.

In conclusion, chronic oral ketamine treatment can be used safely as an adjunct to opioids in the management of refractory cancer pain. Given the complexity and expertise required to safely prescribe it, clinical use should remain limited to PC or pain specialists. Additional research is needed to confirm the safety and efficacy of chronic oral ketamine in the treatment of cancer pain, preferably using appropriately powered randomized control trials.