The Efficacy of Ketamine in the Palliative Care Setting: A Comprehensive Review of the Literature

Goldman and colleagues place this review in the context of substantial unmet need for rapid-acting treatments of psychological and physical symptoms in palliative care. The background emphasises that depression is common and difficult to diagnose in patients with life‑threatening illness, that standard monoaminergic antidepressants often take four to six weeks to work (a timeframe commonly longer than patients’ remaining life expectancy), and that psychostimulants used for faster relief have limitations such as tolerance and a range of side effects. Ketamine, an NMDA receptor antagonist, has attracted interest because it modulates the glutamatergic system and can produce antidepressant effects within minutes to hours, with single-dose effects reported to last up to about two weeks outside palliative settings. Ketamine’s analgesic properties and potential to reduce opioid requirements are also noted as clinically relevant for palliative populations where uncontrolled pain is frequent. This review therefore set out to examine the evidence specifically for ketamine’s efficacy as an antidepressant and as an analgesic in palliative care patients. The authors aimed to collate clinical trials, case reports and randomized controlled trials addressing these two outcomes, describe patterns relating to dose and route of administration, and identify gaps needing further research so that clinicians and investigators can better understand when ketamine might be useful in palliative contexts.

The literature search was conducted using PubMed, Google Scholar and the point‑of‑care resource UpToDate. Goldman and colleagues state that all articles identified were reviewed by the first author. The review applied the World Health Organization definition of a ‘‘palliative care patient’’ (any person with a life‑threatening illness) when selecting studies for inclusion. The extracted text does not list the exact keywords used for the searches. For the depression question the initial search yielded 6,022 human‑subject articles, which were narrowed to 439 by restricting to clinical trials, case reports and randomized controlled trials; after assessment for relevance to the palliative population and to ketamine treatment protocols, 11 studies were included. These comprised one randomized controlled trial (RCT), one retrospective chart review, one open‑label trial and eight case reports; three additional relevant clinical trials were noted as ongoing. For the analgesia question the authors limited inclusion to RCTs. An initial pool of 298 human studies was narrowed to 49 RCTs; after excluding postsurgical pain studies and screening for the relevant palliative population and protocols, five RCTs remained and were included. Where available, the review reports key dosing regimens, routes of administration and outcome measurement timepoints from the included studies.

Depression: Across the 11 included studies addressing depression in palliative care, all reported some antidepressant benefit from ketamine. The sole RCT (Fan et al.) compared a single IV ketamine dose (0.5 mg/kg) with midazolam (0.05 mg/kg) and found significantly lower suicidal ideation on days 1 and 3 (p < 0.05) and a significant antidepressant effect evident on day 1 with peak effect on that first day; the effect had faded by day 7. A retrospective chart review (Iglewicz et al.) reported net positive effects on depressive symptoms at days 0–1 and 2–3 (p < 0.001) and 4–7 (p < 0.05); 93% of patients showed benefit on days 0–3, and among 22 single‑dose responders about half showed fading between days 2 and 7. Single‑dose case reports using oral, IM or subcutaneous routes documented rapid reductions in depression (for example, oral 0.5 mg/kg in two hospice patients produced HRSD reductions at 120 minutes and at days), but fading often occurred within weeks. Multiple‑dose data included an open‑label trial (Irwin et al.) of nightly oral ketamine 0.5 mg/kg for 28 days in 14 patients (8 completers): 57% of the initial cohort improved, median time to response was 10.5 days, and the antidepressant effect was sustained through day 28 (p = 0.001). Other small case series and single‑patient reports described varying regimens (oral 0.25 mg/kg q8h; IM 1 mg/kg six treatments; subcutaneous 0.5 mg/kg followed by daily oral maintenance) with reported benefits ranging from days to months in individual cases. Intravenous administration generally produced faster onset (minutes to hours) than oral regimens, though some oral studies reported early benefit and one larger oral study only saw benefit by day 14. Analgesia: Five RCTs of ketamine for cancer‑related pain in palliative care produced mixed results. Three trials reported significant analgesic effects: Lauretti et al. (epidural ketamine 0.2 mg/kg) found longer duration with pain scores <4/10 compared with control (p = 0.049) and lower morphine consumption over 25 days (p = 0.003). Mercadante et al. (double‑blind crossover, IV boluses 0.25 and 0.5 mg/kg) reported favourable pain outcomes in opioid‑resistant patients, with psychological adverse effects manageable by diazepam. Yang et al. (intrathecal ketamine 1 mg BID added to intrathecal morphine) observed lower morphine requirements and lower pain scores in the morphine+ketamine phase (both p < 0.05). Two larger RCTs found no significant analgesic benefit. Hardy et al. enrolled 185 patients and compared subcutaneous ketamine (100–500 mg/day) with saline over 3–5 days; there was no significant difference in pain outcomes (p = 0.55), and adverse effects were nearly twice as common with ketamine. Salas et al. randomised 20 patients to IV morphine+ketamine (0.5–1.0 mg/kg) versus morphine+placebo and found no differences in pain scores or morphine consumption at 0, 2, 24 and 48 hours. Across the analgesia trials the authors note common adverse effects among ketamine recipients—constipation (n = 42), nausea/vomiting (n = 40) and somnolence (n = 39) in the pooled reports. The review highlights that studies administering ketamine epidurally or intrathecally tended to show benefit, whereas subcutaneous or intravenous routes more often did not, and that dosing heterogeneity and possible underdosing were raised as explanations for null findings in some trials. The five analgesia RCTs together enrolled 283 patients in total, with the two negative trials accounting for 205 of those participants.

Goldman and colleagues interpret the assembled evidence as supportive of ketamine’s antidepressant efficacy in palliative care across varied dosing schedules and routes, but they emphasise important limitations. Rapid onset of antidepressant effect was a consistent finding for parenteral administration, while oral regimens showed more variable timing; single parenteral doses commonly demonstrated fading of effect by about day 6–7, whereas daily dosing regimens produced the most sustained alleviation, including one 28‑day open‑label study with effect maintained through the trial. The authors discuss practical trade‑offs: although parenteral dosing may act faster, oral administration could be preferable for hospice patients who wish to remain at home, and a strategy of initiating parenteral dosing then switching to oral has been trialled in a small study. Safety and long‑term data are limited. Adverse effects occurred in single‑ and multiple‑dose studies, and the review finds no consensus on whether repeat dosing worsens or ameliorates tolerability. The authors note that long‑term safety was not extensively assessed; they cite preclinical and other research raising concerns such as potential tumour‑promoting effects via mTOR upregulation in some cancers, haemodynamic side effects and addiction risk, and therefore recommend caution. For analgesia the RCT evidence is inconclusive: older and smaller studies—particularly those using epidural or intrathecal administration—reported analgesic benefit including reduced opioid requirements, but two more recent and larger RCTs did not find significant effects. The largest negative trial enrolled 185 patients and found no benefit when ketamine was used as an adjuvant to opioids. The authors highlight heterogeneity in study populations, dosing and routes of administration, and the relatively small total sample size (N = 283) across analgesia RCTs, as reasons why firm conclusions cannot yet be drawn. Finally, the review suggests areas for future work identified by the authors: larger, well‑designed RCTs to clarify ketamine’s antidepressant and analgesic roles in palliative care; investigation of optimal dosing and routes (including whether intrathecal/epidural approaches are more effective for pain); assessment of long‑term safety; and development of screening methods to identify patients most likely to benefit, particularly those with comorbid depression and pain who might derive the greatest overall symptom relief.