Should Subanesthetic Ketamine be Considered When Managing Opioid Refractory Cancer Pain?

In the cancer pain setting, ketamine has been typically employed as a co-analgesic for opioid refractory and neuropathic pain. One controversial topic is whether subanesthetic ketamine be considered when managing opioid refractory cancer pain. In this "Controversies in Palliative Care" article, three clinicians independently answer this question. Specifically, each clinician provides a synopsis of the key studies that inform their thought processes, share practical advice on their clinical approach, and highlight the opportunities for future research. Three independent clinicians reported a divergence of opinion regarding the usefulness of subanesthetic ketamine for managing opioid refractory cancer pain. All investigators acknowledged the lack of high-quality trials. All agreed on the need for adequately powered trials, the development of standardized methodology, and the exploration of any patient sub-populations that may benefit from ketamine for cancer related pain.

Caudal Neuraxial Blocks for Pain Relief From Pelvic Neuropathy Caused by Extensive Diffuse Large B-cell Lymphoma.

Central neuraxial blocks can be a vital therapeutic tool for neuropathic pain, but they are infrequently implemented for pain management in cancer patients. Upon a literature review, further data on the role or efficacy of central nerve blocks for neuropathic cancer pain would be beneficial. Additionally, evidence-based guidelines and practices are lacking regarding additional interventions for neuropathic pain relief, a common manifestation of cancer burden. Here, we report the case of a 29-year-old male patient who presented in the ED with intractable neuropathic pain from extensive diffuse large B-cell lymphoma. The patient demonstrated left lower extremity pain, fevers, chills, and tenderness with erythema over the site of his port-a-catheter on his chest. The patient was also hypotensive, despite IV fluid resuscitation. Recent imaging showed a hypermetabolic soft tissue mass in the left upper quadrant of the abdomen. There was also extensive cancer spread in the peripheral pelvis, presacral region, and within multiple sacral foramina, with a secondary perineural spread of the tumor. The patient previously positively responded to a caudal nerve block at an outpatient pain clinic. The patient was admitted to the ICU for three days, and following the resolution of sepsis, the patient received caudal and sciatic nerve blocks on admission day 8. Upon further imaging showing metastasis to the brain, the patient was discharged to inpatient hospice on hospitalization day 10 following a palliative conversation with the patient and family.

Topical Diclofenac to Manage Opioid-Refractory Pain in a Rare Pancreatic Fibrosarcoma.

Pancreatic cancer is often diagnosed at an advanced stage and is frequently associated with severe pain. Traditional pain management in this condition may be improved with the use of topical diclofenac. A 39-year-old man with advanced pancreatic fibrosarcoma metastatic to the thoracic spine presented to the hospital with severe abdominal pain refractory to escalating doses of opioids. A celiac plexus block produced significant, yet inadequate, pain reduction. Satisfactory pain control and opioid de-escalation were ultimately achieved with the application of topical diclofenac gel to an area of bony metastasis. This case illustrates the potential for pain control using topical diclofenac in patients with pancreatic soft tissue tumors and vertebral metastases. Topical diclofenac may exert antitumoral effects and targeted application may improve absorption, leading to improved pain control. The use of topical diclofenac for pain management in metastatic pancreatic cancer presents an interesting tool that should be considered in similar cases.

Effectiveness of Low-Dose Ketamine Infusion in Opioid Refractory Cancer Pain: A Case Report.

Most patients with advanced cancer experience debilitating pain, which significantly affects their quality of life and has both physical and psychological implications. Opioids have been the mainstay of treatment for chronic cancer pain, but some people develop serious adverse effects or may become refractory to opioid use. There is always a need and search for alternative non-opioid analgesics with an acceptable safety profile, and one such drug is ketamine. In this era of evolving analgesic therapeutics, ketamine has been noted to have favourable results. Ketamine, a phencyclidine analogue, is an N-methyl-D-aspartate antagonist (NMDA), and it has been shown to have an analgesic effect at sub-anaesthetic doses by blocking NMDA-induced pain sensitization and enhancing opioid receptor sensitization. This is a case report of a 46-year-old Indian female with recurrent metastatic adenocarcinoma endometrium (International Federation of Obstetrics and Gynecology (FIGO) Grade II) involving the vaginal vault, rectum, and adrenal glands, along with para-rectal, bilateral iliac, and retroperitoneal nodal metastases, in which ketamine infusion was used successfully to alleviate the pain that was initially not controlled with an incremental dose of opioids. The patient presented with progressive pain in the peri-anal region, rated 8/10 on the Numerical Pain Rating Scale (NRS), following which she was treated with escalating doses of intravenous (IV) fentanyl, but with little to no relief. In view of the patient's opioid-resistant pain, she was started on a low-dose ketamine IV infusion (50 mg in 50 ml of 0.9% NS) as "burst therapy," at infusion rates of 0.02 mg/kg/hr-0.08 mg/kg/hr, with adequate pain relief occurring at 0.08 mg/kg/hr. Literature suggests weight-based dosing of ketamine ranging from 0.06 mg/kg/hr to 0.8 mg/kg/hr was previously used to achieve satisfactory results. In this patient, even lower doses were effectively used to achieve optimum long-term analgesia, cause an upliftment in the patient's overall mood and quality of life, and cause a significant reduction in opioid usage. However, further research is required to assess the efficacy of ketamine at such doses and its effect on opioid consumption. This case report will promote further study regarding optimum IV ketamine dosing and administration in the management of opioid-refractory pain in cancer patients, especially in the Indian population.

A Case Report of Subanesthetic Ketamine Bolus and Infusion for Opioid Refractory Cancer Pain.

Opioids and traditional adjuvant medications are frequently prescribed for the management of moderate to severe cancer pain with good effect. However, there are many cases, in which patients experience severe opioid refractory cancer pain. Ketamine is being used more frequently in the hospice and palliative setting to manage opioid refractory pain, although high-quality evidence regarding its effectiveness is lacking. It seems certain patients respond favorably to ketamine, while others experience no effect. Studies have not yet identified factors associated with a favorable response to ketamine. We present a case describing the successful treatment of high-dose opioid refractory cancer pain with a subanesthetic ketamine infusion and propose the novel use of a preinfusion test bolus of ketamine to identify patients who are likely to respond favorably to an infusion.

IMPORTANCE trial: a provisional study-design of a single-center, phase II, double-blinded, placebo-controlled, randomized, 4-week study to compare the efficacy and safety of intranasal esketamine in chronic opioid refractory pain.

Background:  Cancer is the second leading cause of death globally. Up to 86% of advanced cancer patients experience significant pain, while 10-20% live in chronic pain. Besides, increasing prescription of opioids resulted in 33,000 deaths in the US in 2015. Both reduce patients' functional status and quality of life. While cancer survival rates are increasing, therapeutic options for chronic opioid refractory pain are still limited. Esketamine is the s-enantiomer of ketamine, with superior analgesic effect and less psychotomimetic side effects. Intranasal esketamine was approved by the FDA for treatment-resistant depression. However, its use in chronic cancer pain has never been tested. Therefore, we propose a phase II, randomized, placebo-controlled trial to evaluate the efficacy and safety of intranasal esketamine in chronic opioid refractory cancer pain. Methods and analysis: We will recruit 120 subjects with chronic opioid refractory pain, defined as pain lasting more than 3 months despite optimal therapy with high dose opioids (>60 mg morphine equivalent dose/day) and optimal adjuvant therapy. Subjects will be randomized into two groups: intranasal esketamine (56mg) and placebo. Treatment will be administered twice a week for four consecutive weeks. The primary outcome is defined as reduction in the Numeric Pain Rating Scale (NPRS) after first application. Secondary outcomes include NPRS reduction after four weeks, the number of daily morphine rescue doses, functional status and satisfaction, and depression. Conclusion: This study may extend therapeutic options in patients with chronic pain, thus improving their quality of life and reducing opioid use. Trial registration: Clinical Trials.gov, NCT04666623. Registered on 14 December 2020.

Dexmedetomidine as an Option for Opioid Refractory Pain in the Hospice Setting.

Background: Opioid refractory pain is a common problem in pain management. Dexmedetomidine is suggested to have opioid-sparing effects, with well-described use in surgical and intensive care unit settings. Some authors advocate its benefit in reducing delirium. Its effects are thought to be exhibited through agonism of pre- and postsynpatic α2-receptors in the central nervous system. It is more selective on α2-receptors than clonidine, accounting for its relatively lower incidence of hypotension. Its use in sedation is favored because it does not depress the respiratory system. The main side effects reported include bradycardia. Case Description: Twenty-eight-year-old woman with triple negative left breast cancer and a locally destructive tumor was admitted to hospice after exhausting her disease-directed therapy options. Her chief complaint was a throbbing, burning pain to the left chest wall, lower back, and bilateral lower extremities, rated 8/10 on a 10-point verbal scale. Multiple pharmacologic agents for pain, including patient-controlled analgesia infusions with adjuvant methadone and steroids, had failed to provide consistent pain management. Symptoms were difficult to control in the home setting, and she required multiple admissions to our inpatient hospice unit for pain management. She also developed episodes of delirium shortly after hospice admission. We attributed her symptoms to rapid disease progression. After failed pain control with opioids, ketamine, and lidocaine, we trialed a dexmedetomidine infusion. While on the infusion, her pain rating decreased to 0/10 and she had no delirium. Pain recurred soon after cessation of the infusion, initially rated 6/10. Conclusion: Dexmedetomidine is safe for opioid refractory pain in the hospice inpatient setting. However, its effects may not be sustained. There is potential for use in end-of-life care, with added benefit for possible control of delirium.

Successful Treatment of Opioid-Refractory Cancer Pain with Short-Course, Low-Dose Ketamine.

Opioids remain the mainstay of treatment for severe cancer pain, but up to 20% of patients have persistent or refractory pain despite rapid and aggressive opioid titration, or develop refractory pain after long-term opioid use. In these scenarios, alternative agents and mechanisms for analgesia should be considered. This case report describes a 28-year-old man with metastatic pancreatic neuroendocrine cancer with severe, intractable pain despite high-dose opioids including methadone and a hydromorphone patient-controlled analgesia (PCA). After treatment with short-course, low-dose ketamine, his opioid requirements decreased by 99% and pain ratings by 50%, with the majority of this decrease occurring in the first 48 hours. As this patient's pain and opioid regimen escalated, he likely experienced some component of central sensitization and hyperalgesia. Administration of ketamine reduced opioid consumption by 99% and potentially "reset" neuronal hyperexcitability and reduced pain signaling, allowing for improved pain control.

Intensive symptom control of opioid-refractory dyspnea in congestive heart failure: Role of milrinone in the palliative care unit.

OBJECTIVE: We describe an exemplary case of congestive heart failure (CHF) symptoms controlled with milrinone. We also analyze the benefits and risks of milrinone administration in an unmonitored setting. METHOD: We describe the case of a patient with refractory leukemia and end-stage CHF who developed severe dyspnea after discontinuation of milrinone. At that point, despite starting opioids, she had been severely dyspneic and anxious, requiring admission to the palliative care unit (PCU) for symptom control. After negotiation with hospital administrators, milrinone was administered in an unmonitored setting such as the PCU. A multidisciplinary team approach was also provided. RESULTS: Milrinone produced a dramatic improvement in the patient's symptom scores and performance status. The patient was eventually discharged to home hospice on a milrinone infusion with excellent symptom control. SIGNIFICANCE OF RESULTS: This case suggests that milrinone may be of benefit for short-term inpatient administration for dyspnea management, even in unmonitored settings and consequently during hospice in do-not-resuscitate (DNR) patients. This strategy may reduce costs and readmissions to the hospital related to end-stage CHF.