Opioid-refractory Cancer Pain Research Articles

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.

For adults with opioid-refractory cancer pain, what are the benefits and harms of nabiximols (tetrahydrocannabinol (THC) and cannabidiol (CBD))?

For adults with opioid-refractory cancer pain, what are the benefits and harms of nabiximols (tetrahydrocannabinol (THC) and cannabidiol (CBD))?

Cannabis-based medicines and medical cannabis for adults with cancer pain.

Cannabis-based medicines and medical cannabis for adults with cancer pain.

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

The current clinical use of adjuvant analgesics for refractory cancer pain in Japan: a nationwide cross-sectional survey

Although adjuvant analgesics are used to treat opioid-refractory cancer pain, there is insufficient evidence to support this practice and limited data to guide the choice depending on cancer pain pathophysiology, dose titration and starting dose. This survey aimed to clarify the current use of adjuvant analgesics for treating opioid-refractory cancer pain. In this cross-sectional study, we sent an online survey questionnaire to 208 certified palliative care specialists. Primary outcomes were (i) effective pathophysiological mechanism of cancer pain and (ii) initiating doses and time period to the first response to each adjuvant analgesic therapy. In total, 87 (42%) palliative care specialists responded. Of all patients with cancer pain, 40% of patients (median) with refractory cancer pain were prescribed adjuvant analgesics. Additionally, 94.3, 93.1 and 86.2% of palliative care specialists found dexamethasone/betamethasone effective for neuropathic pain caused by tumor-related spinal cord compression, pregabalin effective for malignant painful radiculopathy and dexamethasone/betamethasone effective for brain tumor or leptomeningeal metastases-related headache, respectively. The median starting dose of pregabalin, dexamethasone/betamethasone, lidocaine and ketamine were 75, 4, 200, and 50mg/day, respectively, and the median time to the first response of those medications were 5, 3, 2 and 3days, respectively. Many palliative care specialists select adjuvant analgesics depending on the pathophysiological mechanism of cancer pain in each case. They used such adjuvant analgesics in low doses for cancer pain with short first-response periods.

An Open-Label, Analgesic Efficacy and Safety of Pituitary Radiosurgery for Patients With Opioid-Refractory Pain: Study Protocol for a Randomized Controlled Trial.

Hypophysectomy performed by craniotomy or percutaneous techniques leads to complete pain relief in more than 70% to 80% of cases for opioid refractory cancer pain. Radiosurgery could be an interesting alternative approach to reduce complications. To assess the analgesic efficacy compared with standard of care is the primary goal. The secondary objectives are to assess ophthalmic and endocrine tolerance, drug consumption, quality of life, and mechanisms of analgesic action. The trial is multicenter, randomized, prospective, and open-label with 2 parallel groups. This concerns patients in palliative care suffering from nociceptive or mixed cancer pain, refractory to standard opioid therapy. Participants will be randomly assigned to the control group receiving standards of care for pain according to recommendations, or to the experimental group receiving a pituitary GammaKnife (Elekta, Stockholm, Sweden) radiosurgery (160 Gy delivered in pituitary gland) associated with standards of care. Evaluation assessments will be taken at baseline, day0, day4, day7, day14, day28, day45, month3, and month6. We could expect pain improvement in 70% to 90% of cases at day4. In addition we will assess the safety of pituitary radiosurgery in a vulnerable population. The secondary endpoints could show decay of opioid consumption, good patient satisfaction, and improvement of the quality of life. The design of this study is potentially the most appropriate to demonstrate the efficacy and safety of radiosurgery for this new indication. New recommendations could be obtained in order to improve pain relief and quality of life.

Ketamine for cancer pain: what is the evidence?

In this review, we assess the benefit of ketamine in the treatment of terminal cancer pain that is refractory to opioid treatment and/or complicated by neuropathy. While randomized controlled trials consistently show lack of clinical efficacy of ketamine in treating cancer pain, a large number of open-label studies and case series show benefit. Ketamine is an N-methyl-D-aspartate receptor antagonist that at low-dose has effective analgesic properties. In cancer pain, ketamine is usually prescribed as adjuvant to opioid therapy when pain becomes opioid resistant or when neuropathic pain symptoms dominate the clinical picture. A literature search revealed four randomized controlled trials that examined the benefit of oral, subcutaneous or intravenous ketamine in opioid refractory cancer pain. None showed clinically relevant benefit in relieving pain or reducing opioid consumption. This suggests absence of evidence of benefit for ketamine as adjuvant analgesic in cancer pain. These findings contrast the benefit from ketamine observed in a large number of open-label studies and (retrospective) case series. We relate the opposite outcomes to methodological issues. The complete picture is such that there is still insufficient evidence to state with certainty that ketamine is not effective in cancer pain.

Intrathecal Ziconotide and Morphine for Pain Relief: A Case Series of Eight Patients with Refractory Cancer Pain, Including Five Cases of Neuropathic Pain

IntroductionStudies have shown that, at low doses and with careful titration, combination therapy with intrathecal ziconotide and morphine results in rapid control of opioid-refractory cancer pain. However, there is a lack of published data regarding the efficacy and safety of intrathecal ziconotide specifically for the treatment of neuropathic cancer pain.Case seriesCase reports of ziconotide intrathecal infusion in eight patients (age 45–71 years; 75% male) with chronic, uncontrolled cancer pain during therapy with intrathecal morphine plus bupivacaine were reviewed. Neuropathic pain was confirmed in five patients. Treatment was initiated with adjunctive ziconotide when pain ≥5 on a visual analog scale persisted in spite of 3 successive 20% dose increases of intrathecal morphine. Ziconotide was initiated at 0.5–1.0 µg/day, with mean increases of 0.5 µg every 4–7 days if required (maximum dose 10 µg/day; mean dose 4.9 µg/day). Pain intensity was reduced in all patients after 3–5 days. Of the eight patients, three died for reasons unrelated to ziconotide, three discontinued treatment due to adverse effects (predominantly psychoneurological disorders), and one patient is still receiving treatment. One patient discontinued ziconotide due to confusion and delirium. Due to continued lack of pain control with intrathecal morphine, intrathecal fentanyl was initiated; however, effective pain relief was not achieved with 1500 µg/day. Ziconotide was restarted and the patient then achieved pain control.ConclusionOn the basis of our clinical experience, we recommend adding ziconotide to intrathecal opioid-based therapy in cancer patients with neuropathic pain inadequately controlled by intrathecal morphine alone.FundingEisai, Spain.Electronic supplementary materialThe online version of this article (doi:10.1007/s40120-015-0035-z) contains supplementary material, which is available to authorized users.

Efficacy of lidocaine in patients receiving palliative care with opioid-refractory cancer pain with a neuropathic component: study protocol for a randomized controlled study.

BackgroundThe management of patients suffering from opioid-refractory cancer pain with a neuropathic component remains an important challenge for healthcare workers. Only one retrospective study specifically reported the use of intravenous (IV) lidocaine amongst the palliative care unit population, the study found that there was a positive response to this therapy. These preliminary uncontrolled results need to be confirmed by randomized controlled trials. The primary objective of this study is to assess the analgesic efficacy of IV lidocaine in patients in palliative care suffering from opioid-refractory cancer pain with a neuropathic component. The secondary objectives are to assess the tolerance of, symptomatology, and patient satisfaction with the therapeutic approach.Methods/DesignThis will be a multicenter, prospective, randomized, placebo-controlled, double-blind, two-parallel group study. It will take place in eight adult palliative care units across France. The main inclusion criteria are as follows: adult patients suffering from opioid-refractory cancer pain with a neuropathic component, and those receiving palliative care as defined by French Society of Palliative and Support Care. Participants will be randomized (1:1 allocation ratio) to one of two treatment groups: a) lidocaine-experimental group (intravenous lidocaine), or b) placebo-control group (intravenous saline solution). Evaluation assessments will be taken at baseline (T0 randomization), 40 minutes (T1), 120 minutes (T2), 12 hours (T3), 24 hours (T4), 48 hours (T5), and 14 days (T6) after baseline. The primary endpoint is change in the pain level between T0 and T1. The secondary endpoints are: changes in the pain level between T0 and other times, intensity of the neuropathic pain component, daily opioid consumption, symptoms (as classified by the MD Anderson Symptom Inventory), adverse events, and patient’s satisfaction (measured using the Pain Treatment Satisfaction Scale). A sample size of 200 individuals will be needed to obtain 90% power to detect a 25% difference in pain success at T1 between the two groups; pain success is classified as a 30% decrease in the pain level between T0 and T1 (10% of patients lost to follow-up expected).DiscussionThe randomized, double-blind, placebo-controlled design is the most appropriate design to demonstrate the efficacy of a new experimental intervention (Evidence-Based Medicine Working Group classification). National and international recommendations could be updated based on the findings of this study.Trial registrationCurrent controlled trials NCT02137954 (registration date: 7 May 2014).

Case Report: Efficacy and Tolerability of Ketamine in Opioid-Refractory Cancer Pain

ABSTRACTA 36-year-old female with metastatic breast cancer involving bones, liver, lung, and pleura/chest wall with worsening back pain received weight-based intravenous (IV) ketamine and was transitioned to oral ketamine for cancer-related neuropathic pain. She had responded poorly to outpatient pain regimen of oxycodone sustained and immediate release, hydromorphone, gabapentin, and duloxetine (approximate 480 mg total oral morphine equivalents [OME]), reporting an initial pain score of 10/10. She was started on hydromorphone parenteral patient-controlled analgesia (PCA) bolus dose in addition to her outpatient regimen. Despite escalating doses of opioids and the addition of a lidocaine 5% patch, the patient's pain remained uncontrolled 6 days after admission. On hospital day 7, utilizing a hospital weight-based ketamine protocol, the patient was started on subanesthetic doses of ketamine at 0.2 mg/kg/h (288 mg/24 h) and titrated over 2 days to 0.4 mg/kg/h (576 mg/24 h). Then, a 3-day rotation from intravenous to oral ketamine was initiated, and the patient was discharged on ketamine oral solution, 75 mg every 8 hours. When the patient's dose was increased to 0.4 mg/kg/h, adequate pain relief was charted by the nurse within 120 minutes, “patient pain free and resting comfortably.” Her pain continued to be well managed, with an average pain score of 5/10 with the ketamine continuous infusion and sustained with conversion to oral ketamine without any report of side effects. This was a 37% reduction in pain scores. With the patient's stabilized dose of ketamine, opioid requirements decreased by 61.4% (1017.5 mg reduction in total OME). The use of weight-based dosing of IV continuous infusion and transition to oral ketamine was effective and tolerable in the management of opioid-refractory, neuropathic cancer pain. It is hoped that this case report promotes a discussion regarding ketamine dosing in refractory neuropathic cancer pain.

Efficacy of oral ketamine against opioid-refractory cancer pain due to bone metastases: Four case reports.

161 Background: The use of oral ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is reported to be effective against opioid-refractory cancer pain. Only a few studies have been performed worldwide so far, and in Japan we have more difficulty evaluating it, as the insurance doesn’t cover the application of ketamine to the tumor pain unlike in some other countries. Here we present the successful treatment of four patients with severe cancer-related pain due to bone metastases, by oral administration of ketamine. Methods: Inclusion criteria were cancer pain refractory to standard opiates. After institutional approval and informed patient consent were obtained, the treatment started with 40mg/day of oral ketamine. The ketamine regimen was adjusted individually based on analgesia and any adverse effects. Results: Self-reported pain significantly improved. In addition, serious adverse effects such as nightmares were not observed. In one case, epidural anesthesia became unnecessary. In another case, base and rescue opiates regimen can decreased. Conclusions: Ketamine is considered one of the World Health Organization essential drugs for the management of refractory pain. By oral administration of ketamine the quality of life can be improved, so we consider that further studies should be performed.

Nabiximols for Opioid-Treated Cancer Patients With Poorly-Controlled Chronic Pain: A Randomized, Placebo-Controlled, Graded-Dose Trial

Patients with advanced cancer who have pain that responds poorly to opioid therapy pose a clinical challenge. Nabiximols (Nabiximols is the US Adopted Name [USAN] for Sativex [GW Pharma Ltd, Wiltshire, UK], which does not yet have an INN), a novel cannabinoid formulation, is undergoing investigation as add-on therapy for this population. In a randomized, double-blind, placebo-controlled, graded-dose study, patients with advanced cancer and opioid-refractory pain received placebo or nabiximols at a low dose (1–4 sprays/day), medium dose (6–10 sprays/day), or high dose (11–16 sprays/day). Average pain, worst pain and sleep disruption were measured daily during 5 weeks of treatment; other questionnaires measured quality of life and mood. A total of 360 patients were randomized; 263 completed. There were no baseline differences across groups. The 30% responder rate primary analysis was not significant for nabiximols versus placebo (overall P = .59). A secondary continuous responder analysis of average daily pain from baseline to end of study demonstrated that the proportion of patients reporting analgesia was greater for nabiximols than placebo overall (P = .035), and specifically in the low-dose (P = .008) and medium-dose (P = .039) groups. In the low-dose group, results were similar for mean average pain (P = .006), mean worst pain (P = .011), and mean sleep disruption (P = .003). Other questionnaires showed no significant group differences. Adverse events were dose-related and only the high-dose group compared unfavorably with placebo. This study supports the efficacy and safety of nabiximols at the 2 lower-dose levels and provides important dose information for future trials. PerspectiveNabiximols, a novel cannabinoid formulation, may be a useful add-on analgesic for patients with opioid-refractory cancer pain. A randomized, double-blind, placebo-controlled, graded-dose study demonstrated efficacy and safety at low and medium doses.

Ketamine Analgesic Effect by Continuous Intravenous Infusion in Refractory Cancer Pain: Considerations about the Clinical Research in Palliative Care

The literature has described the use of ketamine as an adjuvant treatment for opioid-refractory cancer pain. None of these studies have used the drug in a palliative care patient population. The primary objective of the study was to assess the efficacy of continuous intravenous infusion of ketamine in patients suffering from cancer pain refractory to opiates who had been admitted to palliative care units. Secondary objectives were to assess patients' satisfaction with and tolerance of ketamine. A randomized, double-blind, placebo-controlled study was designed, and the study setting included seven French adult palliative care units. Inclusion criteria were age ≥18 years, and cancer pain refractory to standard opiates. Evaluations were conducted at randomization (baseline), at ketamine or placebo introduction time (T0), and at 2 hours (T1), 24 hours (T2), and 48 hours (T3) after T0. The primary evaluation criterion was pain efficacy assessed using a patient self-rated Numeric Pain Intensity Scale (NPIS) at T1. The main secondary evaluation criteria were daily morphine dose, symptom evaluation (Edmonton Symptom Assessment Scale [ESAS]), and patient satisfaction (Pain Treatment Satisfaction Scale [PTSS]). Twenty patients were analyzed (11 received ketamine and 9 received placebo). Self-reported pain did not differ between the two groups, as the symptoms continued to evolve during the study period. The tolerance for ketamine was satisfactory. The present study did not confirm the efficacy of the ketamine-morphine combination in refractory cancer pain. The results suggest that specific populations could be "good responders" for this therapeutic approach. Further studies should be performed that take into account the difficulties of conducting clinical research in the palliative care context.