In a randomised, crossover, placebo‑controlled study of healthy adults, a single low dose (20 mg) of ketamine reduced pain perception and attenuated mean blood pressure responses to a cold pressor test but did not change muscle sympathetic nerve activity burst frequency. This dissociation suggests ketamine lowers pressor responses via mechanisms other than suppression of MSNA, informing clinical risk–benefit considerations.
Key points Low dose ketamine is a leading medication used to provide analgesia in pre‐hospital and hospital settings. Low dose ketamine is increasingly used off‐label to treat conditions such as depression. In animals, ketamine stimulates the sympathetic nervous system and increases blood pressure, but these physiological consequences have not been studied in conscious humans. Our data suggest that low dose ketamine administration blunts pain perception and reduces blood pressure, but not muscle sympathetic nerve activity burst frequency, responses during a cold pressor test in healthy humans. These mechanistic, physiological results inform risk‐benefit analysis for clinicians administering low dose ketamine in humans. AbstractLow dose ketamine is an effective analgesic medication. However, our knowledge of the effects of ketamine on autonomic cardiovascular regulation is primarily limited to animal experiments. Notably, it is unknown if low dose ketamine influences autonomic cardiovascular responses during painful stimuli in humans. We tested the hypothesis that low dose ketamine blunts perceived pain, and blunts subsequent sympathetic and cardiovascular responses during an experimental noxious stimulus. Twenty‐two adults (10F/12M; 27 ± 6 years; 26 ± 3 kg m−2, mean ± SD) completed this randomized, crossover, placebo‐controlled trial during two laboratory visits. During each visit, participants completed cold pressor tests (CPT; hand in ∼0.4°C ice bath for 2 min) pre‐ and 5 min post‐drug administration (20 mg ketamine or saline). We compared pain perception (100 mm visual analogue scale), muscle sympathetic nerve activity (MSNA; microneurography, 12 paired recordings), and beat‐to‐beat blood pressure (BP; photoplethysmography) during the pre‐ and post‐drug CPTs separately using paired, two‐tailed t tests. For the pre‐drug CPT, perceived pain (P = 0.4378), MSNA burst frequency responses (P = 0.7375), and mean BP responses (P = 0.6457) were not different between trials. For the post‐drug CPT, ketamine compared to placebo administration attenuated perceived pain (P < 0.0001) and mean BP responses (P = 0.0047), but did not attenuate MSNA burst frequency responses (P = 0.3662). Finally, during the post‐drug CPT, there was a moderate relation between cardiac output and BP responses after placebo administration (r = 0.53, P = 0.0121), but this relation was effectively absent after ketamine administration (r = −0.12, P = 0.5885). These data suggest that low dose ketamine administration attenuates perceived pain and pressor, but not MSNA burst frequency, responses during a CPT.
Pain is highly prevalent among people with cancer and often remains undertreated despite conventional management, with the World Health Organization estimating that 55–66% of patients experience greater-than-moderate pain even when managed in specialist units. Opioids are the standard therapy for cancer pain but carry a narrow therapeutic window, problematic side effects (for example nausea, constipation, sedation, neuroexcitation) and the potential for escalating doses due to tolerance and opioid-induced hyperalgesia. This clinical challenge motivates interest in non-opioid adjuvants. This paper reports a single-patient case study in which low-dose ketamine (LDK) infusion was used as an adjunct to high-dose opioid therapy for refractory cancer-related pain. The study aims to describe the protocol, monitor analgesic efficacy and opioid-sparing effects, and record adverse events and vital signs during and after the infusion period, with follow-up of pain scores and opioid use for 30 days after treatment.
This report is a single-case, observational study carried out under institutional review board approval in a palliative care setting. Patel and colleagues describe a 55-year-old male with metastatic prostate cancer (Gleason 9) and severe mixed neuropathic and somatic pain from bone metastases, who was receiving multiple concomitant medications including high-dose opioids totalling 458.8 morphine milligram equivalents (MME) per day. The patient had multiple comorbidities (including atrial fibrillation, hypertension, obesity and sleep apnoea) and prior limitations on non-steroidal anti-inflammatory use. The intervention followed a local LDK protocol (<0.5 mg/kg) established in 2019. The infusion formulation was ketamine (100 mg in 100 mL D5W, 1 mg/mL) with a maximum push dose of 50 mg over 1 minute. The active infusion described in the case was a 3-day titration: 0.1 mg/kg/hr on Day 1, 0.2 mg/kg/hr on Day 2, and 0.3 mg/kg/hr on Day 3. Pain was assessed with the Numerical Rating Scale (NRS), recorded every 4 hours while on infusion, and observational data collected within the first 24 hours of infusion on pain characteristics, vital signs, respiratory depression, tolerance and satisfaction. Opioid consumption (MME) and pain intensity were compared for the 30 days before, during and for 30 days after the ketamine infusion. The extracted text notes some inconsistency about duration (a 3-day infusion protocol is described in Methods while the Discussion refers to a 5-day period), and the exact duration of post-infusion monitoring is 30 days for pain and opioid use comparisons. The patient subsequently died and the authors report that informed consent could not be obtained because next of kin were untraceable.
Before ketamine, the patient consistently reported severe pain (9/10 on the NRS) while receiving an equianalgesic opioid dose averaging 458.8 MME/day. During the described LDK titration, the patient reported a reduction in pain to an average of 5/10 on the NRS. This improvement coincided with a reported 32.43% reduction in overall opioid use during the infusion period. Over the 30 days following the ketamine infusion, average pain was reported as 4.75/10, which the authors describe as approximately a 50% reduction from baseline. Opioid prescribing changes after the infusion included a reduction to 310 MME/day overall, cessation of transdermal fentanyl and a 16.67% reduction in methadone use (as reported by the authors). No ketamine-related adverse effects commonly associated with higher doses (for example hallucinations or marked agitation) were reported in this patient. The authors state that no additional adverse events were noted. Vital signs and respiratory status were monitored during infusion, but the extracted text does not provide detailed numerical data on those measures in the Results section beyond noting monitoring and no recorded complications. The text also reports an observed improvement in the patient's mood after infusion, with a nurse note describing the patient as being in “great spirits.”
Patel and colleagues interpret the case as illustrative of the potential utility of low-dose ketamine as an adjunct to opioids in palliative care for refractory cancer pain. They situate their findings within broader concerns about under-treatment of cancer pain and the harms of escalating opioid therapy, and note that LDK may both reduce pain intensity and allow opioid sparing. The authors discuss mechanistic rationale: ketamine is an NMDA receptor antagonist that can reduce central sensitisation to pain and may potentiate opioid receptor effects, thereby prolonging opioid-induced analgesia. They also raise the possibility that ketamine's anti-depressive effects might contribute to perceived pain relief, suggesting an emotional component to its analgesic action. The authors acknowledge the limited evidence base: prior studies they cite are small, heterogeneous in intervention and outcome measures, and do not yet establish optimal titration regimens. They note the single-case nature of their report and implicitly that generalisability is limited. Safety data are limited to this one patient, who did not experience reported psychotomimetic side effects, but the authors call for further titrated dose trials across pain scenarios to better characterise efficacy and safety. Ethical constraints are described: the patient died and informed consent could not be obtained from next of kin despite attempts, which the authors disclose as part of study limitations. Finally, they suggest that LDK warrants further investigation as a potentially simple and effective adjunctive analgesic in palliative settings, while emphasising the need for additional research to determine efficacy, dosing schedules and administration routes.
This single, selective case suggests that intravenous low-dose ketamine infusion (<0.5 mg/kg) used as an adjunct to high-dose opioids was associated with meaningful short-term reductions in pain scores and opioid requirements in a patient with advanced metastatic prostate cancer. Patel and colleagues argue that, although promising, these observations require confirmation in larger, controlled studies to define optimal dosing and to establish safety and generalisability in palliative care populations.
Pain is the most common symptom for patients diagnosed with cancer; the World Health Organization (WHO) cites that 55-66% of cancer patients experienced greater than moderate pain despite treatment in a pain management unit. While opioids remain to be the mainstay of cancer pain treatment, patients on these medications endure exacerbating side effects and complications. Additionally, due to opioid tolerance, or reduced responsiveness, 10-fold increases in opioid doses are common in chronic pain management. This rapid increase in dosages is problematic due to the narrow therapeutic range of opioids and their high-risk side effects, such as nausea/ vomiting, constipation, sedation, drowsiness, and neurological effects such as neuroexcitation, myoclonus, and urinary retention. The need for non-opioid treatment options for patients undergoing acute, chronic and obstinate pain is of great importance; one alternative is low-dose ketamine (LDK) infusion.
Low-dose ketamine as an adjuvant for pain control in a cancer patient: a case report Here we report a case with Metastatic Prostate Cancer (Gleason 9 Adenocarcinoma), where LDK was used following an initial opioid-based pain management treatment to better manage pain and reduce complications from high-dose opioid use. We present the following article in accordance with the CARE Reporting Checklist (available at).
The current case study received approval from the institutional review board. The patient, a 55-year-old male, presented with a 2-year history of Metastatic Prostate Cancer (Gleason 9 Adenocarcinoma) and was referred to the palliative care for secondary unmanageable lower back pain and local hip pain. The etiology of the neuropathic and somatic pain was from bone metastasis that was confirmed with imaging studies. The patient had a history of atrial fibrillation with a rapid ventricular response, dyslipidemia, hypertension, obesity, heart palpitations, sleep apnea, stroke, as well as prostate cancer which metastasized to the bone. The patient was prescribed a myriad of medications including Atorvastatin (Lipitor), Bisacodyl (Dulcolax), Gabapentin, Metoprolol (Toprol XR), as well as several opioid painkillers, such as fentanyl, oxycodone, and hydromorphone. The use of NSAIDs such as Ketorolac was limited due to the potential onset of GI bleeding and acute renal failure. The patient also had recurring issues with constipation, a likely side effect of the opioid medications he was taking. As a result of the opioid-induced constipation, the patient was given a bowel regimen of Senna 8.6 mg PO nightly, Miralax 17 g POM daily, Bisacodyl suppository and tablet 10 mg, and Dexamethasone 6 mg PO daily. The main criteria used to assess the patient's pain was the Numerical Rating Scale (NRS), which was incorporated into the Physical Exam. The patient consistently reported a 9/10 on the NRS as well as frequent bouts of constipation. An obvious diagnostic challenge faced during the study was the subjective nature of the NRS. The patient was receiving 458.8 morphine milligram equivalents (MME) per day (Table); however, was still reporting an average pain of 9/10 on the NRS. Clinical judgement for the patient was to not drastically increase the patient's opioid usage due to present adverse effects, such as nausea, constipation, urinary retention, lethargy, and ascending drug tolerance. To avoid undesirable effects of high dosage opioids, patient was considered for the LDK infusion. The patient under observation was deemed to have been on the maximum dosages of certain opioids and was at risk of acquiring opioid-induced hyperanalgesia. As a result, LDK infusions were deemed appropriate and potential benefits were clearly observed in this case. TablePatient total opioid usage [opioid oral morphine milligram equivalent (MME)] averaged (I) 30 days before LDK infusion, (II) during LDK infusion, (III) 30 days after ketamine infusion. Opioid oral morphine milligram equivalent (MME) was calculating by taking the average total daily dose of a drug and multiplying it by a drug-specific conversion factor. The conversion factors that were used are as following: Hydromorphone, IV; Oxycodone, PO; Fentanyl, Transdermal Patch; Methadone, PO {1-20 mg, 21-40 mg, 41-60 mg, > 61 mgA local LDK infusion protocol has been established in 2019 under federal and institutional guidelines and allowed the use of intravenous LDK titration (<0.5 mg/kg) as an adjunct to opioid treatment (Table). Under these guidelines, the standard concentration of the continuous infusion of Ketamine (Ketalar) was 100 mg in dextrose 5% 100 mL (1 mg/mL) with the maximum push dose being 50 mg/mL over 1 minute. The 3-day infusion was doses as following: 0.1 mg/kg/hr on Day 1, followed by 0.2 mg/kg/hr on Day 2, followed by 0.3 mg/kg/hr on Day 3 (Figure). Observational data was collected within the first 24 hours of LDK infusion regarding pain characteristics, pain score assessment, vitals, respiratory depression, tolerance and overall satisfaction. The pain intensity and regular opioid dose before starting and upon stopping Ketamine infusion was also compared for 30 days. Additionally, the NRS was routinely monitored every 4 hours while the patient was on the LDK infusion (Figure). Prior to undergoing the LDK infusion, the patient reported a pain level of 9 on the NRS, with 10 being identified as "maximal pain". Despite being in substantial pain, the patient was undergoing Palliative Care treatment of the Equianalgesic Dose of 458.8 MME. After 3 subsequent daily infusions, the patient had experienced a daily alleviation of pain to the level of 5 on the NRS. These results manifested alongside a 32.43% reduction in opioid usage. The most significant results were evident further after the termination of the Ketamine Infusion. Over a period of 30 days following the Ketamine Infusion, the patient reported an average pain level of 4.75 on the NRS, an approximately 50% reduction in pain from the start of the Ketamine Infusion. The patient was closely monitored for ketamine side effects, especially within the first hour following each infusion. Common side effects include hallucinations and feelings of agitation; however, the patient did not report any of these adverse effects. On the other hand, the patient reported feeling less total pain following LDK administration. Additionally, opioid usage dropped to 310 MME a 16.67% drop in Methadone use and a complete termination of Fentanyl use. Overall, the results obtained point toward the effectiveness of LDK infusions in a Palliative Care setting. These infusions not only alleviated symptoms of pain, but also allowed for a reduction in the use of opioids, and alleviation of possible opioid dependence and associated side effects. No additional adverse events were noted. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Due to the fact that the patient under observation had passed away, informed consent was unable to be obtained. Patient's next of kin were untraceable despite the authors' great efforts to obtain their consent.
Onset of acute pain is a significant issue at all points of the cancer continuum and can occur because of malignant conditions or the treatment plan. Earlier studies confirm that more than 50% of all patients with cancer experience moderate to severe pain. The prevalence of pain in cancer survivors is estimated to be 40%, while close to twothirds of those with advanced disease live with pain. Cancer pain management, an often-neglected component of oncological care, is closely associated to the development of the modern hospice measures, and palliative care. Additionally, the levels of pain experienced are often difficult to assess due to concerns of patients. In a study involving cancer patients (n=270), difficulty in properly medicating patients was found to be from patient concerns including fear of addiction, reluctancy to complain, and side effects of medications. Cancer patients are frequently resorted to opioid use for pain management. These patients may suffer from under-treatment for their pain and/or adverse opioid use outcomes including unnecessary and persistent opioid use. Moreover, patients with cancer-related pain are underrepresented in the opioid literature despite high opioid exposure. While progress has been made in the management of cancer pain, under-treatment persists and does have significant negative impacts on the quality of life of patients. The need for non-opioid analgesics for patients undergoing treatment for acute, chronic, and obstinate pain, calls for safer and more efficacious alternatives. This report illustrates the potential benefits of using ketamine as an adjunct to high dose opioid usage in the palliative care setting. The patient under observation was dealing with metastatic prostate cancer which had spread throughout his pelvic bones. There were multiple fractures seen on CT on 9/21/2019, indicating the severity of the metastatic disease. The patient, prior to receiving LDK infusions for a 5-day period, was progressively noted to have dampened spirits due to the disease and poor prognosis. The patient, prior to having cancer, was a very active and enthusiastic individual; the inability to participate in sports such as hiking depressed the patient's mood immensely. A hospital note written by one of the nurses after the LDK infusion mentioned that the patient was in "great spirits", portraying the potential benefit of low-dose ketamine in palliative care settings. Ketamine has been shown to have anti-depressive actions in addition to its ability to relieve pain. An interesting question then arises as to whether Ketamine's actions on NMDA receptors specifically target physical pain, or whether there is an emotional component to its analgesic effect, as well. Ketamine is a well-known N-methyl-D-Aspartate (NMDA) receptor antagonist, and its analgesic effect is attributed by blocking NMDA receptor induced pain sensitization. Ketamine induces analgesia by prolonging the effect of opioid stimulation by improving the sensitization of opioid receptors. There is increasing evidence that LDK has been progressing as a relatively simple, reliable and robust pain reliever in various painful conditions. The majority of cancer patients with advanced disease have severe pain which significantly impairs health-related quality of life. Despite the current emphasis on multimodal analgesic therapy, the potential treatment for pain almost always includes opioids when dealing with advanced stage cancer patients. Given the side effects and dependency issues, there is a strong need of alternate medications. Recent studies have shown that LDK as an adjuvant to opioids significantly reduces the intensity of pain in cancer patients. The data from these cancer pain control studies exhibit few subjects and involve heterogeneous interventions and outcome measures assessed by different pain assessment tools. Additionally, LDK titrated dose trials are still needed in multiple pain scenarios before it can be declared as a safe analgesic. Upon administration on the LDK infusion, the patient's pain has dropped significantly and averaged between 4-5 on the Pain Numerical Rating Scale for weeks following the treatment. Additionally, the patients need for opioids has decreased dramatically.
Cancer pain management, an often neglected component of oncological care, is closely associated to the development of modern hospice measures and palliative care. Cancer patients are frequently resorted to opioid use for pain management, sometimes suffering from under-treatment for their pain and/or adverse opioid use outcomes, including unnecessary and persistent opioid use. This is a very selective case of a patient where LDK infusion was shown to be efficacious at reducing pain when opioids and standard pain medications were not satisfactory. While ketamine use in managing post-operative pain is common, LDK infusion (<0.5 mg/kg) also shows further potential to deliver excellent outcomes in pain management for cancer patients while simultaneously curbing the myriad of potential side effects of opioids through minimizing their usage. Although additional research is still required to determine the efficacy, optimal dosing schedules, administration routes of LDK infusion, it is hard to underscore the untapped potential of this new treatment in palliative medicine.
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