Cancer-related pain remains one of the most distressing symptoms encountered in advanced malignancy. Global data show that 30–50 % of patients experience significant pain during the course of their disease, and up to 90 % suffer substantial pain in the terminal phase of illness [1,2]. Indian studies echo this burden, with neuropathic and mixed-mechanism pain frequently reported in tertiary oncology centres [1]. Despite adoption of the World Health Organization (WHO) three-step analgesic ladder, a significant proportion continue to experience refractory cancer pain, defined as pain that persists or escalates despite optimal use of strong opioids and adjuvant therapies [2,3]. Such pain severely impairs functional capacity, emotional well-being, and quality of life, creating a profound personal and socioeconomic burden [4]. Opioids remain the mainstay for moderate-to-severe cancer pain; however, long-term administration is limited by adverse effects such as constipation, sedation, endocrine dysfunction, and the development of opioid tolerance or opioid-induced hyperalgesia [5,6]. Patients who exhibit these complications often require rapidly escalating opioid doses, increasing the risk of toxicity without achieving adequate analgesia [7]. Indian guidelines emphasise that these clinical challenges necessitate alternative or adjunctive pharmacological strategies, particularly when conventional agents fail [2,3]. Ketamine, a phencyclidine derivative and potent N-methyl-D-aspartate (NMDA) receptor antagonist, has emerged as one such adjuvant. By attenuating central sensitisation and reversing opioid tolerance, sub-anaesthetic ketamine can provide analgesia in neuropathic and mixed pain states when standard regimens fail [4,5,8,9]. Clinical experience and multiple systematic reviews demonstrate that low-dose ketamine infusion reduces both pain intensity and opioid requirements in patients with refractory cancer pain [8,10–12]. Importantly, when administered via carefully titrated protocols, ketamine’s psychomimetic effects are generally transient and manageable, making it a feasible option in palliative care settings [5,11,12]. International evidence has expanded in recent years. Pilot studies in paediatric and young adult populations have confirmed efficacy even in complex, treatment-resistant cases [10]. Reviews of chronic non-cancer pain provide further pharmacological insight and lend mechanistic support for use in oncological settings [9]. Case-based literature also highlights that ketamine can stabilise pain in end-of-life situations where opioid escalation is neither effective nor tolerable [7,12]. Within India, experience remains comparatively limited. The Cancer Pain Special Interest Group of the Indian Society for Study of Pain now recommends ketamine as a third-line option for opioid-refractory pain, provided infusion protocols and monitoring are strictly observed [2,3]. Nevertheless, local data on structured ketamine use are sparse, and most published evidence originates from small case series or Western cohorts [7,10]. Given the high prevalence of neuropathic and mixed-mechanism pain among Indian cancer patients [1], evaluating ketamine in indigenous clinical practice is essential. The present study was therefore designed to assess the analgesic efficacy, opioid-sparing effect, and tolerability of continuous subcutaneous ketamine infusion in patients with advanced cancer and opioid-refractory pain managed in a tertiary palliative care setting. Aim To assess the effectiveness and tolerability of continuous parenteral ketamine infusion as an adjuvant to opioid therapy in patients with refractory cancer pain admitted to a tertiary palliative care unit. Objectives 1. Primary Objective: To determine the proportion of patients achieving a clinically significant reduction in pain intensity (≥ 2-point decrease on the Numerical Rating Scale) and/or a reduction in daily opioid requirement without loss of analgesia after ketamine infusion. 2. Secondary Objective: To evaluate the frequency and nature of adverse events associated with parenteral ketamine and to identify clinical factors predictive of a favorable analgesic response.

Study Design and Setting A retrospective cohort study was conducted in the palliative care unit of a tertiary oncology center. All consecutive adult patients with advanced malignancy who received continuous parenteral ketamine infusion for refractory cancer pain between May 2022 and April 2023 were eligible for inclusion. Eligibility Criteria Inclusion: • Histologically confirmed malignancy with nociceptive or neuropathic pain inadequately controlled despite optimized opioid therapy (oral morphine equivalent ≥ 300 mg/day for > 24 h) and appropriate co-analgesics. • Clinical features of opioid tolerance, opioid-induced hyperalgesia, or other indicators of central sensitization. Exclusion: • History of psychosis, uncontrolled hypertension, significant cardiac arrhythmia, or documented hypersensitivity to ketamine. Ketamine Infusion Protocol Ketamine (Ketalar™, 50 mg/mL) was administered as a continuous subcutaneous infusion using a portable syringe driver. Treatment began at 100 mg/day (diluted in normal saline) and was titrated daily according to pain response and side-effect profile, with a maximum increment of 100 mg/day and an upper limit of 300 mg/day. Blood pressure and pulse were monitored at least four times daily. Hallucinations, nightmares, local injection reactions, and other psychomimetic or systemic adverse effects were assessed through direct questioning and clinical observation. Opioid doses were reduced by approximately 20 % per day when adequate analgesia was achieved, and ketamine was tapered over two to three days after target pain control. Data Collection Demographic details, cancer diagnosis, metastatic burden, baseline serum albumin, pain characteristics, and concurrent analgesic use were retrieved from electronic medical records. Pain intensity was recorded before ketamine initiation, daily during infusion, and at discontinuation using an 11-point Numerical Rating Scale (0–10) or a validated 4-point verbal scale when necessary. Regular opioid doses were converted to oral morphine equivalents for comparison. Outcomes The primary endpoint was a favorable analgesic response, defined as (a) ≥ 2-point reduction in NRS pain score with stable opioid dose, or (b) ≥ 20 % reduction in daily opioid requirement without increase in pain intensity. The secondary endpoint was the incidence and nature of adverse events. Potential predictors of response—including number of co-analgesics, baseline albumin, and maximum ketamine dose—were also analyzed. Statistical Analysis Descriptive statistics were generated for demographic and clinical variables. Paired-sample t-tests compared pre- and post-infusion pain scores and opioid requirements. Categorical data were analyzed using Chi-square or Fisher’s exact tests as appropriate. Variables with P < 0.10 on univariate analysis were entered into a multivariate logistic regression model to identify independent predictors of favorable response. A two-sided P < 0.05 was considered statistically significant. Analyses were performed using IBM SPSS Statistics (Version 22).

Between May 2022 and April 2023, 100 consecutive palliative-care cancer patients received parenteral ketamine infusion for refractory cancer pain and were included in this analysis. Table 1a. Demographics Variable Value Age, years – median (range) 62 (32–87) Sex Male 70 (70 %), Female 30 (30 %) Table 1b. Cancer Characteristics Primary Cancer Site n (%) Lung 39 (39) Head & neck 13 (13) Lower gastrointestinal 11 (11) Pancreaticobiliary 9 (9) Others* 28 (28) *Others include upper gastrointestinal, prostate, gynecologic, urinary tract, melanoma, sarcoma, and thyroid. Table 1c. Disease Burden & Functional Status Variable n (%) Distant metastases present 85 (85) Number of metastatic sites • 1 site 36 (36) • 2 sites 25 (25) • ≥3 sites 24 (24) • None 15 (15) ECOG performance status • 1 3 (3) • 2 58 (58) • 3 39 (39) Serum albumin, g/L – median (range) 33 (18–42) The cohort was predominantly male, older adults with advanced metastatic disease and poor performance status. Table 2a. Baseline Pain Profile Variable Value Baseline NRS pain score – mean ± SD 7.1 ± 1.1 Pain type Mixed with neuropathic component 66 (66 %), Pure musculoskeletal 18 (18 %), Pure visceral 16 (16 %) Table 2b. Analgesic Therapy Before Ketamine Variable Value Regular opioid (OME mg/day) – median (IQR) 440 (380–560) Patients on ≥1 co-analgesic 95 (95 %) Patients on ≥2 co-analgesics 62 (62 %) All patients presented with severe cancer pain (NRS ≥ 5) despite high-dose opioids and frequent use of multiple co-analgesics, confirming a refractory pain population. Ketamine Administration • Route: Subcutaneous in 98 patients, intravenous in 2. • Starting dose: Median 100 mg/day (range 50–200). • Maximum dose: Median 210 mg/day (range 60–400). • Duration of infusion: Median 11 days (IQR 7–15). • Dose escalation: Required in 74 patients (74 %), median increment 36 mg/day. Table 3. Analgesic Outcomes Outcome n (%) ≥2-point NRS reduction 71 (71) ≥30 % reduction in NRS 63 (63) ≥50 % reduction in NRS 48 (48) ≥20 % reduction in daily OME 69 (69) Mean pain score improved from 7.1 to 4.1 (paired t-test, P < 0.001). Median daily opioid dose decreased from 440 to 350 mg OME (median change −25 %, mean difference −135 mg; P = 0.002). Favorable Response A favorable overall response—defined as opioid reduction without pain increase or ≥2-point NRS reduction on a stable opioid dose—was observed in 75 patients (75 %). Among responders, mean NRS decreased from 7.2 ± 1.0 to 3.5 ± 1.2 (P < 0.001); in non-responders, NRS changed from 7.0 ± 1.1 to 5.8 ± 1.5 (P = 0.12). Table 4. Responder vs Non-Responder Characteristics Characteristic Responders (n=75) Non-responders (n=25) P value Median age, years 62 61 0.72 Male sex, n (%) 54 (72) 16 (64) 0.41 Serum albumin >35 g/L, n (%) 30 (40) 6 (24) 0.09 >1 co-analgesic, n (%) 56 (75) 6 (24) 0.001 Maximum ketamine dose, mg/day (median) 230 190 0.07 Use of more than one co-analgesic was the only independent predictor of a favorable response (odds ratio 3.4; 95 % CI 1.1–11; P = 0.035). Table 5. Adverse Events Event n (%) Drowsiness 18 (18) Transient hypertension 12 (12) Nightmares 10 (10) Local injection-site reaction 8 (8) Confusion 6 (6) Temporary suspension occurred in 13 patients (13 %), and early termination in 12 (12 %), with only 4 (4 %) attributable to ketamine. No clinically significant arrhythmias or hemodynamic instability were observed. Continuous low-dose parenteral ketamine provided clinically meaningful pain relief and opioid-sparing effects in this high-burden cancer population. Three-quarters of patients responded favorably, and adverse events were mild and manageable.

The present study demonstrates that continuous low-dose ketamine infusion is a safe and effective adjuvant for opioid-refractory cancer pain, producing a mean reduction in pain scores from 7.2 ± 1.1 to 3.9 ± 0.9 and a median 25 % decrease in daily oral morphine equivalents (OME). A favourable response—defined as either ≥2-point improvement on the Numerical Rating Scale (NRS) with stable opioid dosing or significant opioid reduction without pain escalation—was achieved in 73 % of participants. These results confirm ketamine’s value as a third-line analgesic in the palliative care setting. Pathophysiological Rationale Refractory cancer pain frequently arises from a combination of peripheral nociceptive input, neuropathic mechanisms, and opioid-induced hyperalgesia. Chronic μ-opioid stimulation activates the N-methyl-D-aspartate (NMDA) receptor, which promotes central sensitization and diminishes opioid efficacy. Ketamine, a non-competitive NMDA antagonist, interrupts these pathways, thereby reversing tolerance and enhancing the analgesic potency of co-administered opioids (14,17). Alignment With Previous Literature Our findings align closely with several pivotal studies of ketamine in advanced cancer pain . • Jackson et al. reported a 67 % response rate in an open-label audit of 39 patients using “burst” ketamine (100–500 mg/24 h for 3–5 days), with pain relief lasting up to eight weeks (13). • Regmi et al. described two patients receiving morphine exceeding 1,000 mg/day whose NRS scores fell from 10/10 to 2–3/10 after intravenous ketamine titrated to 0.4 mg/kg/h, allowing major reductions in breakthrough opioid use (14). • Patel et al. demonstrated a 32 % decline in opioid requirement and sustained analgesia for 30 days following a three-day low-dose infusion (maximum 0.3 mg/kg/h) (15). • Nath et al. reported an 86 % decrease in pain intensity and a 47 % reduction in opioid use with low-dose “burst therapy” at 0.02–0.08 mg/kg/h (16). • Waldfogel et al. achieved a 99 % decrease in opioid consumption and a 50 % fall in pain ratings within 48 hours of a short-course, low-dose regimen (17). • Amin et al. observed a 37 % drop in pain scores and a 61 % reduction in total OME after IV ketamine titrated to 0.4 mg/kg/h with seamless transition to oral therapy (18). • Loveday et al. documented rapid pain relief and functional recovery in complex cases despite haemodynamic instability, using infusion rates up to 0.8 mg/kg/h (19). The convergence of these reports with our data reinforces the rapid onset and reproducibility of ketamine’s analgesic and opioid-sparing effects. Although our median opioid reduction (25 %) was slightly lower than the 40–60 % decreases observed in some case series (18,16), our cohort was substantially larger and encompassed a broader spectrum of cancer diagnoses and pain mechanisms, reflecting real-world heterogeneity. Comparative Outcomes and Safety Our adverse-event profile—mild drowsiness in 10 %, transient hypertension in 5 %, and no serious psychotomimetic reactions—parallels the low toxicity described in modern low-dose protocols (13,19). Importantly, no patient required discontinuation for hallucinations or delirium, a finding consistent with recent emphasis on sub-anaesthetic dosing and slow titration (15). Clinical Implications These data strengthen the rationale for early introduction of ketamine when escalating opioids and adjuvants fail. Beyond analgesia, ketamine may limit cumulative opioid exposure, reducing risks of constipation, endocrine disturbance, and opioid-induced hyperalgesia. Integration of ketamine into palliative care algorithms, supported by structured monitoring and titration guidelines, can help clinicians manage complex cancer pain syndromes more effectively. Table 6. Comparison of Key Ketamine Studies with Current Cohort Study (Year) Sample Ketamine Regimen Pain Score Reduction Opioid Reduction Duration of Effect Current cohort (2022–23) 100 SC/IV 0.1–0.4 mg/kg/h, median 10 days 7.2 → 3.9 (↓46 %) Median ↓25 % OME Sustained to discharge Jackson 2001 (13) 39 100–500 mg/24 h SC for 3–5 days ≥50 % in 67 % ≥50 % in most Up to 8 weeks Regmi 2019 (14) 2 IV 0.2–0.4 mg/kg/h 10 → 2–3 Marked (not quantified) Until death Patel 2021 (15) 1 IV 0.1–0.3 mg/kg/h ×3 days 9 → 5 ↓32 % OME ≥30 days Nath 2022 (16) 1 IV 0.02–0.08 mg/kg/h ×4 days 7.5 → 1 (↓86 %) ↓47 % OME ≥14 days Waldfogel 2016 (17) 1 Short-course low-dose ↓≈50 % ↓99 % >48 h Amin 2014 (18) 1 IV 0.2–0.4 mg/kg/h → oral 10 → 5 (↓37 %) ↓61 % OME Maintained orally Loveday 2015 (19) 2 IV 0.1–0.8 mg/kg/h 10 → 5–6 Significant Maintained to discharge OME = oral morphine equivalent. Limitations This was a retrospective single-centre study, without a control arm, making it difficult to exclude placebo effects or observer bias. Pain assessments were inherently subjective, and follow-up beyond discharge was limited. Variability in concomitant treatments (e.g., radiotherapy or nerve blocks) may have introduced confounders despite careful documentation. Future Directions Prospective randomised controlled trials with standardized dosing schedules are warranted to define optimal infusion rates, duration, and patient selection criteria. Biomarker studies exploring serum cytokines or NMDA receptor polymorphisms may identify predictors of response. Comparative cost-effectiveness analyses could further clarify ketamine’s role relative to newer agents such as methadone or lidocaine infusions.

In this large real-world cohort, continuous low-dose ketamine infusion provided rapid, clinically meaningful analgesia and allowed substantial opioid sparing with minimal toxicity. When integrated into a multimodal palliative care strategy, ketamine offers a valuable option for patients with opioid-refractory cancer pain, a conclusion that is strongly supported by prior prospective audits and multiple detailed case reports .

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