Cancer Pain Research Articles

Efficacy and safety of fentanyl inhalant for the treatment of breakthrough cancer pain: a multicenter, randomized, double-blind, placebo-controlled trial

BackgroundBreakthrough cancer pain (BTcP) has a negative impact on patients’ quality of life, general activities, and is related to worse clinical outcomes. Fentanyl inhalant is a hand-held combination drug-device delivery system providing rapid, multi-dose (25μg/dose) administration of fentanyl via inhalation of a thermally generated aerosol. This multicenter, randomized, placebo-controlled, multiple-crossover, double-blind study evaluated the efficacy, safety, and tolerability of fentanyl inhalant in treating BTcP in opioid-tolerant patients.MethodsThe trial was conducted in opioid-tolerant cancer patients with 1 ~ 4 BTcP outbursts per day. Each patient was treated and observed for 6 episodes of BTcP (4 with fentanyl inhalant, 2 with placebo). During each episode of targeted BTcP, patients were allowed up to six inhalations, with an interval of at least 4 min between doses. Primary outcome was the time-weighted sum of PID (pain intensity difference) scores at 30 min (SPID30).ResultsA total of 335 BTcP episodes in 59 patients were treated. The mean SPID30 was -97.4 ± 48.43 for fentanyl inhalant-treated episodes, and -64.6 ± 40.25 for placebo-treated episodes (p < 0.001). Significant differences in PID for episodes treated with fentanyl inhalant versus placebo was seen as early as 4 min and maintained for up to 60 min. The percentage of episodes reported PI (pain intensity) scores ≤ 3, a ≥ 33% or ≥ 50% reduction in PI scores at 30 min, PR30 (pain relief scores at 30 min) and SPID60 favored fentanyl inhalant over placebo. Only 4.4% of BTcP episodes required rescue medication in fentanyl inhalant group. Most AEs were of mild or moderate severity and typical of opioid drugs.ConclusionTreatment with fentanyl inhalant was shown to be a promising therapeutic option for BTcP, with significant pain relief starting very soon after dosing. Confirmation of effectiveness requires a larger phase III trial.Trial registrationClinicalTrials.gov: NCT05531422 registered on 6 September 2022 after major amendment, NCT04713189 registered on 14 January 2021.

Palliative radiotherapy versus best supportive care in patients with painful hepatic cancer (CCTG HE1): a multicentre, open-label, randomised, controlled, phase 3 study

Palliative treatment options for painful hepatic cancer can be restricted due to patients eventually becoming refractory to standard treatment. The aim of this study was to determine whether radiotherapy improves hepatic pain from cancer. In this open-label, randomised, controlled, phase 3 trial (CCTG HE1) done in nine cancer centres across Canada, we included patients aged 18 years or older with hepatocellular carcinoma or liver metastases, who were refractory to standard treatment, with an Eastern Cooperative Oncology Group performance status of 0-3, with life expectancy of more than 3 months, and pain or discomfort at its worst in the past 24 hours on the Brief Pain Inventory (BPI) of at least 4 out of 10, which was stable for up to 7 days before randomisation. Patients were randomly assigned (1:1), via a minimisation method after stratification by centre and type of cancer (hepatocellular carcinoma vs liver metastases), to single-fraction radiotherapy (8 Gy) to the liver with 8 mg ondansetron (or equivalent) orally and 4 mg dexamethasone orally given 1-2 h before radiotherapy plus best supportive care (including non-opioid or opioid analgesia, or dexamethasone, or a combination of these) or best supportive care alone. The primary endpoint was improvement in patient-reported liver cancer pain or discomfort of at least 2 points on worst pain intensity on the BPI at 1 month after randomisation. All patients with both baseline and 1-month assessments were included in the primary endpoint analysis. Safety was assessed in all patients randomly assigned to treatment. This trial is registered with ClinicalTrials.gov, NCT02511522, and is complete. Between July 25, 2015, and June 2, 2022, 66 patients were screened and randomly assigned to radiotherapy plus best supportive care (n=33) or best supportive care (n=33). Median age was 65 years (IQR 57-72), 37 (56%) of 66 patients were male, 29 (44%) were female, 43 (65%) had liver metastases, and 23 (35%) had hepatocellular carcinoma (data on race and ethnicity were not collected). As of data cutoff (Sept 8, 2022), median follow-up was 3·2 months (95% CI 3·0-3·4). 24 (73%) of 33 in the radiotherapy plus best supportive care group and 18 (55%) of 33 in the best supportive care only group completed baseline and 1-month assessments. An improvement in hepatic pain of at least 2 points in worst pain intensity on the BPI at 1 month was seen in 16 (67%) of 24 patients in the radiotherapy plus best supportive care group versus four (22%) of 18 patients in the best supportive care group (p=0·0042). The most common grade 3-4 adverse events within 1 month after randomisation were abdominal pain (three [9%] of 33 in the radiotherapy group vs one [3%] of 33 in best supportive care group) and ascites (two [6%] vs one [3%]). No serious adverse events or treatment-related deaths were observed. Single-fraction radiotherapy plus best supportive care improved pain compared with best supportive care alone in patients with liver cancer, and could be considered a standard palliative treatment. Canadian Cancer Society.

Buprenorphine for the Treatment of Pain in Cancer Patients.

Opioids remain the cornerstone for the treatment of moderate to severe cancer pain. Due to benefits over full agonist opioids (FAO), buprenorphine has emerged as an alternative treatment. Buprenorphine is only approved for the treatment of pain that is chronic non-cancer. Cancer-related pain is often progressive with breakthrough pain. There is limited evidence for using short-acting FAO in combination with buprenorphine. There are concerns about withdrawal and the efficacy of pain control using buprenorphine. We hypothesize buprenorphine, in combination with short-acting FAOs, can adequately control cancer- related pain without causing withdrawal symptoms. Procedures/data/observations: Our prospective, single-arm, open-label study enrolls patients with cancer-related pain who are on buprenorphine in combination with an FAO at > 30 mg OME/day, either requiring long-acting pain relief or their pain is not controlled with an FAO alone. Our study is ongoing, with 15 patients enrolled and a target of 50. The patient's pain is self-assessed daily using a mobile application. Withdrawal is assessed regularly using a modified Clinical Opioid Withdrawal Scale (COWS) score. Buprenorphine appears to be effective for the treatment of cancer pain without causing withdrawal in combination with short-acting FAO >30 mg/day.

Cordotomy under general anesthesia for a pediatric palliative patient: illustrative case.

Computed tomography (CT)-guided cordotomy has been shown to be a safe and effective method for treating cancer pain in adults in a palliative care setting. Its effectiveness has been rarely reported in children. During cordotomy, patient feedback is considered essential. Unfortunately, in this report, the featured patient's age and demeanor precluded an awake cordotomy. The authors report the first case, to their knowledge, of percutaneous cordotomy with the patient under general anesthesia. An 11-year-old boy with osteosarcoma of the right pelvis presented with medically refractory unilateral nociceptive pain. The pain prevented ambulation, interfered with sleep, was the focus of his concern, and could not be relieved without sedation. A left percutaneous CT-guided cervical cordotomy while he was under general anesthesia was performed without complication and provided sufficient pain relief to allow ambulation and restorative sleep. Pain was no longer an issue for the patient and his family. CT-guided percutaneous cervical cordotomy can be accomplished in a pediatric patient under general anesthesia. The risks of cordotomy under general anesthesia without patient feedback must be weighed against the opportunity to improve palliative care. https://thejns.org/doi/abs/10.3171/CASE2427.

Validation of the Spanish Version of the Breakthrough Pain Assessment Tool in Patients With Cancer.

Assessment of breakthrough pain is essential for adequate management of cancer pain. The Breakthrough Pain Assessment Tool (BAT) has been proven to be a brief, multidimensional, and reliable questionnaire for the assessment of breakthrough cancer pain (BTCP). Currently, there are no validated instruments in Spanish that allow assessing BTCP. The objective of this study was to validate the Breakthrough Pain Assessment Tool - Spanish (BAT-S) version of the BAT in adult patients with cancer. The BAT-S was tested in a prospective observational study conducted in adult patients with cancer-related pain and treated in a comprehensive cancer center in Mexico. We conducted a forward-backward translation and cross-cultural equivalence test in the Spanish language. The psychometric properties in patients with cancer were assessed using factor analysis, reliability, and validity. To assess reliability, the Kappa test and the intra-class correlation coefficient were used. For consistency, Cronbach's alpha test was used. Seventy patients participated in the study; 140 questionnaires were analyzed. The Spanish translation was well accepted by participants. Reliability was comprised between 0.746 for "use of analgesics" and 1.00 for "pain location." Thirteen of the 14 items had values above 0.8, and 12 above 0.9. Cronbach´s alpha coefficient was 0.7. This study confirms that BAT-S is a valid and reliable questionnaire to assess breakthrough pain in Mexican patients with cancer. This newly validated tool may be used to facilitate clinical management of primarily Spanish-speaking patients with breakthrough cancer pain. This study describes a prospective observational study to assess the validity and reliability of the Breakthrough Pain Assessment Tool in its Spanish version. The results support the use of this newly validated tool to facilitate clinical management of primarily Spanish-speaking patients with breakthrough cancer pain.

1889P Addressing unmet needs in the management of persistent severe cancer pain: European expert recommendations

1889P Addressing unmet needs in the management of persistent severe cancer pain: European expert recommendations

1478P Dual single-nucleotide polymorphism biomarker combination to select opioid for cancer pain management

1478P Dual single-nucleotide polymorphism biomarker combination to select opioid for cancer pain management

LBA61 Conventional oral morphine vs. IV patient-controlled analgesia (IPCA) with either hydromorphone (HM) continuous infusion plus rescue dose (CIRD) or HM bolus-only (BO) for severe cancer pain: A randomized phase III study

LBA61 Conventional oral morphine vs. IV patient-controlled analgesia (IPCA) with either hydromorphone (HM) continuous infusion plus rescue dose (CIRD) or HM bolus-only (BO) for severe cancer pain: A randomized phase III study

Innovative Approaches to Severe Intractable Cancer Pain Due to Malignant Psoas Syndrome

Abstract Malignant psoas syndrome (MPS) is associated with proximal lumbosacral plexopathy and is characterized by severe intractable pain, despite multimodal medical treatment. Spinal dexmedetomidine and lumbar sympathetic nerve block in combination with pulsed radiofrequency (PRF) are rarely performed for intractable lumbosacral plexopathy pain. We present a combination of spinal dexmedetomidine lumbar sympathetic nerve block and caudal-epidural PRF in the management of MPS, refractory to medical and physical treatment. A 49-year-old female with recurrent lung adenocarcinoma was admitted with shooting pain on the right side over the psoas muscle with irradiation into the right groin and weakness of quadriceps at motion. She was managing her pain with a number of opioids, including oxycodone, morphine, fentanyl, and intramuscular meperidine. The total oral morphine equivalent opioid dose equaled 460 mg. At the first admission, we successfully palliated pain with spinal dexmedetomidine and simultaneously reduced the patient’s opioid addiction. On the second admission, lumbar sympathetic nerve block at L3 with additional caudal-epidural PRF led to a significant reduction in her thigh pain visual analog scale (VAS) score to 1–2/10. In addition, improvement in quadriceps functionality and sleep quality, along with a remarkable reduction in analgesic medicine doses, earned patients high satisfaction. Our patient passed away 6 months later with average VAS severity of 4/10. Spinal dexmedetomidine, caudal-epidural PRF, and lumbar sympathetic nerve block should be added as a therapeutic option to the treatment guidelines for the management of MPS, acquired due to lumbosacral plexopathy.

Spinal astrocyte-derived interleukin-17A promotes pain hypersensitivity in bone cancer mice

Spinal microglia and astrocytes are both involved in neuropathic and inflammatory pain, which may display sexual dimorphism. Here, we demonstrate that the sustained activation of spinal astrocytes and astrocyte-derived interleukin (IL)-17A promotes the progression of mouse bone cancer pain without sex difference. Chemogenetic or pharmacological inhibition of spinal astrocytes effectively ameliorates bone cancer-induced pain-like behaviors. In contrast, chemogenetic or optogenetic activation of spinal astrocytes triggers pain hypersensitivity, implying that bone cancer-induced astrocytic activation is involved in the development of bone cancer pain. IL-17A expression predominantly in spinal astrocytes, whereas its receptor IL-17 receptor A (IL-17RA) was mainly detected in neurons expressing VGLUT2 and PAX2, and a few in astrocytes expressing GFAP. Specific knockdown of IL-17A in spinal astrocytes blocked and delayed the development of bone cancer pain. IL-17A overexpression in spinal astrocytes directly induced thermal hyperalgesia and mechanical allodynia, which could be rescued by CaMKIIα inhibitor. Moreover, selective knockdown IL-17RA in spinal Vglut2+ or Vgat+ neurons, but not in astrocytes, significantly blocked the bone cancer-induced hyperalgesia. Together, our findings provide evidence for the crucial role of sex-independent astrocytic signaling in bone cancer pain. Targeting spinal astrocytes and IL-17A/IL-17RA-CaMKIIα signaling may offer new gender-inclusive therapeutic strategies for managing bone cancer pain.

1487P Telemonitoring system effectiveness for alleviating cancer pain in patients with advanced cancer

1487P Telemonitoring system effectiveness for alleviating cancer pain in patients with advanced cancer

Assessing Gender Differences for Non-Predictable Breakthrough Cancer Pain Phenomenon: A Secondary Analysis from IOPS-MS Study.

Breakthrough cancer pain (BTcP) is a temporary exacerbation of pain that "breaks through" a phase of adequate pain control by an opioid-based therapy. The non-predictable BTcP (NP-BTcP) subtype occurs in the absence of any specific activity. Evidence showed that gender differences exist in pain response sensitivity and clinical pain risk. This analysis aimed to signify the gender differences for the NP-BTcP phenomenon. This is a secondary analysis of the Italian Oncologic Pain multiSetting-Multicentric Survey (IOPS-MS), the largest study on BTcP. The subset of NP-BTcP cases for non-gender-specific cancer was considered. Univariable and multivariate analyses were conducted to identify gender differences for the NP-BTcP profile about its intensity, number of episodes per day, and type. A metastatic status-stratified analysis was performed to compare gender with the main clinical variables among the population with NP-BTcP. Males exhibited a higher occurrence of BTcP in the thorax region compared to females (15% vs 11%, respectively, p = 0.03). Males also had a higher onset of BTcP, a higher BTcP therapy dosage (33% vs 28%, p = 0.04, mean: 201 vs 186, p = 0.02) and a lower Karnofsky score (mean: 46.9 vs 49.2, p = 0.03) compared to females. Similar gender differences were found for metastatic patients in the BTcP site (14% vs 8.5%, respectively; p = 0.01), peak onset (33% vs 27%, p = 0.02), BTcP therapy dosage (199 vs 185, p=0.04), and Karnofsky score (mean 47.5 vs 50.4, p = 0.009). Phenotype 2 was more characterized by non-metastatic males (41% vs 23%, p = 0.020) while non-metastatic females presence was predominant among others. In this study, gender differences according to site, onset and dosage of BTcP were found. The phenotype characterization of BTcP needs to be further investigated for a possible useful function in the management of cancer-related pain in non-metastatic patients.

1479P Use of rescue opioids and pain control after ketamine initiation in refractory cancer pain: A multicentric observational study

1479P Use of rescue opioids and pain control after ketamine initiation in refractory cancer pain: A multicentric observational study

Pain Management in Animals with Oncological Disease: Opioids as Influencers of Immune and Tumor Cellular Balance.

Advancements in understanding pain physiopathology have historically challenged animals' absence of pain senses. Studies have demonstrated that animals have comparable neural pain pathways, suggesting that cats and dogs likely experience pain similarly to humans. Understanding brain circuits for effective pain control has been crucial to adjusting pain management to the patient's individual responses and current condition. The refinement of analgesic strategies is necessary to better cater to the patient's demands. Cancer pain management searches to ascertain analgesic protocols that enhance patient well-being by minimizing or abolishing pain and reducing its impact on the immune system and cancer cells. Due to their ability to reduce nerve sensitivity, opioids are the mainstay for managing moderate and severe acute pain; however, despite their association with tumor progression, specific opioid agents have immune-protective properties and are considered safe alternatives to analgesia for cancer patients.

Minimally Invasive Anterolateral Cervical Cordotomy for Intractable Cancer Pain Using Microtubular Retractors: A Single Institution Case Series.

As advancements in cancer treatments have allowed patients with a high burden of disease to live longer, the number of patients who present with debilitating refractory pain has increased. Anterolateral cordotomy has long been used for the treatment of intractable unilateral cancer pain using either an imaging-guided percutaneous approach or an open surgical approach. In this report, we describe a novel minimally invasive modification to the open surgical approach. It combines the benefits of both approaches by providing direct visualization for lesioning without the collateral tissue damage of an open approach. This retrospective study evaluated medical records, operative reports, and imaging studies of patients who underwent a minimally invasive cordotomy at a single institute between 2018 and 2022. The surgical technique involved a microscope-assisted C2 hemilaminectomy using microtubular retractors followed by dural opening and anterolateral cordotomy under direct visualization and with intraoperative neurophysiological monitoring. Eleven patients were included in the study. None were converted to an open approach, and no wound-related postoperative complications were observed. A clinically significant decrease in pain was observed after the procedure, and 10 of the 11 patients (91%) were ambulatory by the time of analysis. Compared with image-guided percutaneous cordotomy, anterolateral cervical cordotomy with microtubular retractors potentially improves the safety of the procedure through direct visualization while being less invasive than a conventional open approach. Our preliminary experience with this technique demonstrates the feasibility of the approach, as it was both safe and effective.

Involvement of HDAC2-mediated kcnq2/kcnq3 genes transcription repression activated by EREG/EGFR-ERK-Runx1 signaling in bone cancer pain

Bone cancer pain (BCP) represents a prevalent symptom among cancer patients with bone metastases, yet its underlying mechanisms remain elusive. This study investigated the transcriptional regulation mechanism of Kv7(KCNQ)/M potassium channels in DRG neurons and its involvement in the development of BCP in rats. We show that HDAC2-mediated transcriptional repression of kcnq2/kcnq3 genes, which encode Kv7(KCNQ)/M potassium channels in dorsal root ganglion (DRG), contributes to the sensitization of DRG neurons and the pathogenesis of BCP in rats. Also, HDAC2 requires the formation of a corepressor complex with MeCP2 and Sin3A to execute transcriptional regulation of kcnq2/kcnq3 genes. Moreover, EREG is identified as an upstream signal molecule for HDAC2-mediated kcnq2/kcnq3 genes transcription repression. Activation of EREG/EGFR-ERK-Runx1 signaling, followed by the induction of HDAC2-mediated transcriptional repression of kcnq2/kcnq3 genes in DRG neurons, leads to neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats. Consequently, the activation of EREG/EGFR-ERK-Runx1 signaling, along with the subsequent transcriptional repression of kcnq2/kcnq3 genes by HDAC2 in DRG neurons, underlies the sensitization of DRG neurons and the pathogenesis of BCP in rats. These findings uncover a potentially targetable mechanism contributing to bone metastasis-associated pain in cancer patients.

Factors influencing fidelity to guideline implementation strategies for improving pain care at cancer centres: a qualitative sub-study of the Stop Cancer PAIN Trial

BackgroundThe Stop Cancer PAIN Trial was a phase III pragmatic stepped wedge cluster randomised controlled trial which compared effectiveness of screening and guidelines with or without implementation strategies for improving pain in adults with cancer attending six Australian outpatient comprehensive cancer centres (n = 688). A system for pain screening was introduced before observation of a ‘control’ phase. Implementation strategies introduced in the ‘intervention’ phase included: (1) audit of adherence to guideline recommendations, with feedback to clinical teams; (2) health professional education via an email-administered ‘spaced education’ module; and (3) a patient education booklet and self-management resource. Selection of strategies was informed by the Capability, Opportunity and Motivation Behaviour (COM-B) Model (Michie et al., 2011) and evidence for each strategy’s stand-alone effectiveness. A consultant physician at each centre supported the intervention as a ‘clinical champion’. However, fidelity to the intervention was limited, and the Trial did not demonstrate effectiveness. This paper reports a sub-study of the Trial which aimed to identify factors inhibiting or enabling fidelity to inform future guideline implementation initiatives.MethodsThe qualitative sub-study enabled in-depth exploration of factors from the perspectives of personnel at each centre. Clinical champions, clinicians and clinic receptionists were invited to participate in semi-structured interviews. Analysis used a framework method and a largely deductive approach based on the COM-B Model.ResultsTwenty-four people participated, including 15 physicians, 8 nurses and 1 clinic receptionist. Coding against the COM-B Model identified ‘capability’ to be the most influential component, with ‘opportunity’ and ‘motivation’ playing largely subsidiary roles. Findings suggest that fidelity could have been improved by: considering the readiness for change of each clinical setting; better articulating the intervention’s value proposition; defining clinician roles and responsibilities, addressing perceptions that pain care falls beyond oncology clinicians’ scopes of practice; integrating the intervention within existing systems and processes; promoting patient-clinician partnerships; investing in clinical champions among senior nursing and junior medical personnel, supported by medical leaders; and planning for slow incremental change rather than rapid uptake.ConclusionsFuture guideline implementation interventions may require a ‘meta-implementation’ approach based on complex systems theory to successfully integrate multiple strategies.Trial registrationRegistry: Australian New Zealand Clinical Trials Registry; number: ACTRN 12615000064505; data: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspxid=367236&isReview=true.

Medical cannabis for refractory cancer-related pain in a specialised clinical service: a cross-sectional study

Background and objectivesCancer-related pain management in advanced stages presents a significant challenge that often requires a multidisciplinary approach. Although advancements in pharmacological and interventional therapies, a considerable number of patients...

Opioid Prescription Practices and Risk Management among Physicians in Morocco

The opioid crisis represents a major public health challenge globally, notably in the United States where it has resulted in significant morbidity and mortality. In Morocco, the patterns of opioid prescription and the factors influencing these practices are not well documented. This study aims to explore the socio-demographic characteristics, professional backgrounds, and opioid prescription practices among physicians in Morocco. Utilizing a cross-sectional survey design, data were collected from 123 physicians across various regions. The findings indicate that specialist doctors, particularly those in urban public sectors, are more likely to prescribe opioids, with codeine, tramadol, and morphine being the most common. These opioids are primarily prescribed for cancer pain, rheumatic pain, and post-operative pain. The study underscores the necessity of targeted interventions to address gaps in opioid prescription practices and to enhance risk management strategies among physicians.

Naldemedine-induced perforation of a diverticulum in the sigmoid colon of a patient with opioid-related constipation: a case report

BackgroundNaldemedine is an orally available peripherally acting μ-opioid receptor antagonist approved to treat opioid-induced constipation (OIC). It is contraindicated for patients with known or suspected gastrointestinal obstruction to protect against naldemedine-induced perforation. Here, we report a clinical case of suspected perforation of a diverticulum in the sigmoid colon associated with naldemedine.Case presentationThe patient was a 65-year-old man with a history of oral cancer who had been prescribed oxycodone (20 mg/day) for cancer pain. On day 0, the patient started naldemedine 0.2 mg once daily before bedtime for OIC. The dose of oxycodone was increased for pain control up to 60 mg/day. On day 35 of naldemedine treatment, the patient developed fever and abdominal pain, and his frequency of defecation had decreased. Initial laboratory results showed a C-reactive protein (CRP) level of 28.5 mg/dL and white blood cell (WBC) count of 13,500/µL. On day 37, the patient still had tenderness in his lower abdomen. Abdominal computed tomography revealed free air in the abdominal cavity suggesting an intestinal perforation. A Hartmann procedure was performed. Histopathological findings showed numerous diverticula in the sigmoid colon, some of which were perforated.ConclusionsThese results suggest that the effects of OIC may have compressed the intestinal tract, which was followed by naldemedine-activation of peristalsis, which led to the onset of intestinal perforation. In patients with pre-existing diverticular disease, we should monitor for increased WBC counts and CRP levels after the initiation of treatment with naldemedine, and consider performing appropriate tests early in the event of abdominal complaints.