A mechanism based understanding of cancer pain and development of novel strategies of cancer pain treatment

As advances in cancer detection and treatment have increased the life expectancy of cancer patients, more attention to improving patient quality of life is needed. The World Health Organization (WHO) has proposed a structured approach to drug selection for cancer pain, known as the "WHO analgesic ladder". This approach is capable of providing adequate relief to 70-90% of patients. However, the remaining 10-30% of patients are difficult to treat. The development of optimal analgesics for cancer pain has been hampered by the lack of understanding of basic mechanisms that contribute to cancer pain, which is due in part to the lack of appropriate animal models. Recently, preclinical models of bone cancer pain have been developed. These models have begun to provide insight into the mechanisms by which tumors cause pain and how cancer pain-related sensory information is processed. Once the mechanism by which cancer induces pain is elucidated, this would lead to the identification of molecular targets and the development of mechanism based therapies, which improve the quality of life of all those who suffer from cancer pain.     

Mechanisms underlying generation of cancer pain

As advances in cancer detection and treatment have increased the life expectancy of cancer patients, more attention to improving patient's quality of life (QOL) is needed. Among symptoms accompanying cancer, pain has strong impact on QOL. Most of cancer patients will experience moderate to severe pain and/or neuropathy during the course of their disease. Cancer pain can arise from different processes, either by direct tumor infiltration/involvement, or toxicity relating to chemotherapy used to treat cancer. The World Health Organization (WHO) has proposed a structured approach to drug selection for cancer pain, known as the "WHO analgesic ladder". However, several types of pain including bone cancer pain and chemotherapy-induced painful peripheral neuropathy are difficult to treat. The development of optimal analgesics for cancer pain has been hampered by the lack of understanding basic mechanisms that contribute to cancer pain. Recently, preclinical models of bone cancer pain and paclitaxel-induced painful peripheral neuropathy have been developed. These models have begun to provide insight into the mechanisms by which cancer pain is induced and how cancer pain-related sensory information is processed. In this paper, we review mechanism of cancer pain.     

Morfina como primeiro medicamento para tratamento da dor de câncer

Background and objectives

The medications used according to the recommendation of the World Health Organization do not promote pain relief in a number of patients with cancer pain. The aim of this study was to evaluate the use of morphine as first medication for the treatment of moderate cancer pain in patients with advanced and/or metastatic disease, as an option to the recommendations of the World Health Organization analgesic ladder.

Method

Sixty patients without opioid therapy, with ≥18 years of age, were randomized into two groups. G1 patients received medication according to the analgesic ladder and started treatment with non‐opioids in the first, weak opioids in the second, and strong opioids in the third step; G2 patients received morphine as first analgesic medication. The efficacy and tolerability of initial use of morphine were evaluated every two weeks for three months.

Results

The groups were similar with respect to demographic data. There was no significant difference between the groups regarding pain intensity, quality of life, physical capacity, satisfaction with treatment, need for complementation and dose of morphine. In G1 there was a higher incidence of nausea (p = 0.0088), drowsiness (p = 0.0005), constipation (p = 0.0071) and dizziness (p = 0.0376) in the second visit and drowsiness (p = 0.05) in the third.

Conclusions

The use of morphine as first medication for pain treatment did not promote better analgesic effect than the ladder recommended by World Health Organization, with higher incidence of adverse effects.     

Epidural and intrathecal analgesia for cancer pain

The three-step analgesic ladder approach developed by the World Health Organization works well in treating the vast majority (70–90%) of patients suffering from pain related to cancer. In those patients who do not get pain relief by this three-step approach, intraspinal agents can be a fourth step in managing pain of malignant origin. Although morphine is the only opioid approved by the US Food and Drug Administration for intraspinal use, many different opioid analgesics are used intraspinally, including hydromorphone, fentanyl, sufentanil, meperidine and methadone in the treatment of cancer pain. Many non-opioid agents have also been used intraspinally either alone or in combination with opioids in the treatment of intractable cancer pain. This chapter summarizes the clinical use of these agents with some practical points.     

73例四肢转移性骨肿瘤的疗效观察

目的探讨四肢转移性骨肿瘤的诊断、治疗与预防的方法。 方法前瞻性收集2010年1月至2015年12月四肢转移性骨肿瘤73例,年龄23~83岁,平均（56±8）岁。男性31例,女性42例,病理性骨折11例。其中肺癌转移20例,乳腺癌转移15例,肾癌转移15例,甲状腺癌转移10例,肝癌转移9例、结肠癌转移1例,子宫平滑肌肉瘤转移1例,直肠平滑肌肉瘤转移1例,胰腺癌转移1例。20例拒绝手术,选择保守治疗,另53例行手术治疗。手术方式包括瘤段切除假体置换术,病灶刮除植骨术,截肢术等。随访患者术后肢体功能情况、疼痛减轻情况、生存率等。 结果随访时间6~72个月,平均（26±19）个月。53例手术患者术后骨痛均明显减轻,肢体功能恢复均良好。20例保守治疗患者肢体功能较差,患肢疼痛较重。 结论骨转移性肿瘤的诊断应根据患者的年龄、主诉、影像学表现和病理检查进行综合判断,在治疗方法上,应首先评估患者有无手术指征,建议使用KPS标准,进而选择手术治疗或是保守治疗。对转移性骨肿瘤,应以减轻患者痛苦、恢复患肢功能,提高生活质量为目的。病理性骨折的预防尤为重要,一旦发生骨折,则增加痛苦,影响生活质量。     

Quality of Life Improvement after Videothoracoscopic Splanchnicectomy in Chronic Pancreatitis Patients: Case Control Study

The authors report on the effectiveness of videothoracoscopic splanchnicectomy (VSPL) as a method of pain treatment in patients with chronic pancreatitis (CP). A minimally invasive technique, VSPL is used in CP as an alternative method of pain treatment. The aim of the investigation was to evaluate by a prospective, semirandomized case-control study the influence of VSPL on the quality of life and the level of pain suffered by patients with CP. The study groups consisted of 32 patients who underwent VSPL between March 2000 and January 2001 and a control group of 32 CP patients who received conservative treatment. The effect of the therapy on subjective pain measures and multiparametric quality of life was measured before VSPL and throughout the first year thereafter. In the follow-up period there was a significant decrease in intensity of pain and an improvement in the quality of life of the patients—most significantly concerning emotional well-being and functioning in everyday life. We conclude that the VSPL is a safe, effective, and minimally invasive procedure and recommend that it be used in such cases.     

Thoracoscopic splanchnicectomy for pain relief in unresectable pancreatic cancer

HYPOTHESIS: Unilateral truncal thoracoscopic splanchnicectomy (TS) provides safe and effective treatment for pain relief in patients with unresectable pancreatic cancer. DESIGN: Before-and-after trial of 24 patients undergoing 25 TS procedures. SETTING: Surgical unit at a university teaching hospital. PATIENTS: A consecutive sample of 24 patients with severe pain due to unresectable (primary or recurrent) pancreatic cancer refractory to drug therapy and with a life expectancy of less than 6 months. INTERVENTION: The key point of the reported operation is intrathoracic carbon dioxide insufflation, which allows a more distal division of the greater splanchnic nerve and a 2-port technique. MAIN OUTCOME MEASURES: Pain and the effect of this symptom on quality of life were assessed before and after TS using a 10-point visual analog pain scale (VAS) and the Nottingham Health Profile questionnaire, respectively. RESULTS: Four TS procedures were technical failures because of pleural adhesions. One patient required a contralateral procedure 12 weeks after TS. Mean (+/- SD) preoperative VAS basal score was 7.4 +/- 1.7. Twenty-four hours after TS, it was reduced to 0.6 +/- 1.0. Significant reduction of VAS scores persisted over the first 3 months after TS (P<.001). Recurrence of pain of low intensity (mean VAS basal score, 4.2) was observed in 8 patients. Significant improvement (P<.001) in each area covered by the Nottingham Health Profile questionnaire was reported at 1 month after TS. CONCLUSION: Thoracoscopic splanchnicectomy offered substantial short-term relief of pain in patients with unresectable pancreatic cancer, and significantly ameliorated the quality of their residual life.     

Brief review: Neuraxial analgesia in refractory malignant pain

Purpose

This narrative review aims to inform health care practitioners of the current literature surrounding the use of intrathecal (IT) and epidural analgesia in cancer patients with refractory pain at end of life. Topics discussed and reviewed include: patient selection, treatment planning, procedure, equipment, medications, complications, policies and procedures, as well as directions for future research.

Principal findings

Cancer pain is inadequately treated in an estimated 10% of patients with malignant pain despite the implementation of the World Health Organization three-step analgesic ladder. This has prompted some to advocate for the addition of a fourth step that would include neuraxial interventions. There is moderate evidence supporting the safety and efficacy of IT drug therapy in cancer patients with refractory pain. A detailed assessment and interdisciplinary team approach is necessary to develop and implement care plans for patients requiring neuraxial analgesia. Neuraxial analgesia can significantly improve pain and reduce side effects, but this must be balanced against the increased complexity of care and the risk of uncommon but serious complications.

Conclusion

Neuraxial drug delivery gives clinicians more options to manage refractory pain at end of life and should be offered to patients with intractable cancer pain. Teams should be interprofessional with clear delineation of roles and responsibilities. They should discuss advanced discharge planning with the patient prior to implantation as well as provide on-call support.     

Opioids in cancer and chronic non-cancer pain therapy – indications and controversies

Indications for strong opioids for cancer-related pain as well as for chronic non-cancer pain are that non-opioid drugs, and other less risky therapies, fail and that the pain is opioid-sensitive. The WHO analgesic ladder principle continues to serve as an excellent educational tool in the efforts by WHO in collaboration with the World Federation of Societies of Anaesthesiologists (WFSA) and The International Association for the Study of Pain (IASP) to increase knowledge of pharmacological pain therapy and increase availability of essential opioid analgesics world-wide. Opioids differ in pharmacodynamics and pharmacokinetics, and patients have different pharmacogenetics and pain mechanisms. Sequential trials of the increasing numbers of available opioid drugs are therefore appropriate when oral morphine fails. Controversies continue concerning diagnosis and handling of opioid-insensitive pain in cancer and chronic non-cancer pain, opioid-induced neurotoxicities, risks of tolerance, addiction, pseudo-addiction, and methods for improving effectiveness and decreasing adverse effects of long-term opioid therapy, treating breakthrough pain with immediate release oral and transmucosal opioids. Consensus guidelines have recently been developed in the Nordic countries concerning the ethical practice of palliative sedation when opioids and other pain-relieving therapies fail in patients soon to die. Guidelines for long-term treatment with strong opioids of chronic non-cancer-related pain are also being developed in the Nordic countries, where very diverging traditions for the usage of such therapy still exist.     

Peripheral nerve blocks for cancer pain

Pain is a common symptom in patients with advanced cancer, but in the majority of patients the pain is well controlled with conservative management techniques. In a small proportion of patients (5–10%) more invasive analgesia regimens are required, including the use of peripheral nerve blocks, where pain arises within the territory of a major peripheral nerve or plexus. These blocks may be single-shot injections of long-acting local anaesthetic performed using standard approaches to the nerve. More commonly, perineural or plexus infusions are employed using special nerve sheath catheters through which infusions of local anaesthetic drugs are administered for weeks or even months, according to the severity of the pain and the patient's life expectancy. Placing the catheters and controlling the infusion can be technically demanding and the catheters require careful attention to detail to avoid infection, blockage or accidental removal throughout the duration of the infusion.Despite the difficulties of inserting and maintaining a successful peripheral nerve catheter infusion, the quality of analgesia available from such techniques can result in a major improvement in the quality of life for the patient. These techniques should be considered at an early stage in patients where pain management within the territory of an appropriate nerve or plexus is difficult.     

居家镇痛治疗对中晚期癌症患者生活质量的影响

目的探讨居家镇痛对中晚期癌症患者生活质量的影响。方法对57例中晚期癌症患者以定期上门探访、电话随访为主要服务形式执行规范的居家镇痛治疗。结果疼痛缓解率92．98％,居家镇痛治疗1个月后患者整体生活质量及各个功能评分显著高于居家镇痛治疗前（均P〈0．05）。结论居家镇痛治疗能显著提高大多数患者生活质量,减轻其躯体疼痛,为中晚期癌痛患者一种较好的治疗方式。     

乳腺癌术后疼痛及镇痛方法的研究进展

背景 乳腺癌为女性患者常见的一种恶性肿瘤,手术治疗是主要的治疗措施.乳腺癌术后疼痛具有独特的疾病特点,并且可以成为一种慢性疼痛长期影响患者的生活质量,一直是临床亟待解决的问题. 目的 阐述乳腺癌术后疼痛及镇痛方法的研究进展,为疼痛的预防和治疗提供参考. 内容 综述乳腺癌术后疼痛及其镇痛方法的研究现状. 趋向 进一步探讨乳腺癌术后疼痛综合征的治疗方法,以明确有效的防治措施.     

Single arm phase II study of oral vitamin B12 for the treatment of musculoskeletal symptoms associated with aromatase inhibitors in women with early stage breast cancer

Breast cancer patients receiving endocrine therapy with aromatase Inhibitors (AIs) often experience musculoskeletal and joint‐related side effects. The purpose of this study was to evaluate the effect of Vitamin B12 supplements on musculoskeletal symptoms such as pain and arthralgias induced by AIs and to correlate response with serum and inflammatory biomarkers. Upon receiving approval by the Institutional Review Board (IRB), the majority of the patients consented into the study were treated at the Texas Tech Breast Care Center. Included were patients who had a diagnosis of invasive breast cancer (Stages I‐III), and were experiencing significant musculoskeletal symptoms associated to AIs. Only patients with an average pain score ≥ 4, as assessed by the Brief Pain Inventory‐Short Form (BPI‐SF) questionnaire, were included in the study. Participants received 2500 mcg of sublingual vitamin B12 daily for 90 days. Assessments at baseline and at 3 months included: BPI‐SF pain scores, the impact on quality of life determined by Functional Assessment of Cancer Therapy–Endocrine Symptoms (FACT‐ES), and correlative serum markers relative to baseline (a pre‐post study). A total of forty‐one patients were enrolled. Average pain scores were improved by 34% (P < .0001) at 3 months compared to baseline. In addition, a 23% improvement in worst pain was noted (P = .0003). Analysis of the results for the FACT‐ES scoring showed improvement on all scales. No significant adverse events were observed. Decrease in pain score was correlated with increased serum B12 levels. This study suggests that Vitamin B12 reduces pain and improves quality of life for patients taking AIs who experienced AI‐related musculoskeletal symptoms. If confirmed in large randomized prospective trials, Vitamin B12 would be a safe and cost‐effective option for the treatment of AI‐related musculoskeletal symptoms.     

Thoracoscopic splanchnicectomy--a method of pain palliation in non-resectable pancreatic cancer and chronic pancreatitis

Severe upper abdominal pain is a dominant and distressing feature in advanced pancreatic cancer and in chronic pancreatitis. A way of palliation needs to be practiced in the non-resectable pancreatic cancer in order to control the pain. Between the many methods of palliation the thoracoscopic splanchnicectomy seems to be the best due its simplicity, no risk to the patient and the good results. In the Center of General Surgery and Liver Transplantation from Fundeni Clinical Institute we have practiced 50 thoracoscopic splanchnicectomies in a number of 49 patients during a period of 3 years. The morbidity was 2% and the mortality 0. We noticed a significant improvement in the pain score, the quality of sleep and the overall quality of life and consecutively a quick social reintegration of these patients. The quality of life is greatly improved (with a significant reduction of the pain score in 92% of the cases) after this minimally invasive procedure, a fact the qualifies this procedure as the technique of choice in these patients.     

髌股疼痛综合征病因及治疗的新进展

髌股疼痛综合征是膝关节疼痛中最常见诊断之一，常见于青春期和成年期活动量较大患者。髌股疼痛是由各种解剖，生物力学，心理，社会和行为等多种因素综合作用产生，如髌骨位置异常、双下肢生物力学不良、髋关节运动学改变、股四头肌失衡、髌股内侧支持带损伤、髂胫束过紧等。目前以保守治疗为主，保守治疗方法包括运动疗法、髌骨扎贴、髌骨支具、足矫形垫等，保守治疗失败之后，可以考虑手术治疗。     

前列腺癌骨转移性疼痛的综合治疗

目的 :探讨晚期前列腺癌骨转移性疼痛的综合治疗方法。　方法 :16例确诊为前列腺癌且有多个部位骨转移病灶伴有疼痛的患者 ,采用口服抗雄激素药物治疗的同时 ,辅以核素89Sr静脉内注射治疗和部分病灶放射治疗。　结果 :治疗后 ,疼痛缓解率 3个月为 75 .6 % ,6个月为 80 .5 % ,9个月为 6 3.4 % ;骨转移病灶数量明显减少。结论 :经过综合治疗后 ,本组晚期前列腺癌伴骨转移性疼痛的患者疼痛获得较为满意的缓解、甚至消失 ,从而改善了患者的生活质量。     

Feasibility of virtual reality-delivered pain psychology therapy for cancer-related neuropathic pain: a pilot randomised controlled trial

Virtual reality-delivered psychological therapies have recently been investigated as non-pharmacological management for acute and chronic pain. However, no virtual reality pain therapy software existed that met the needs of cancer patients with neuropathic pain. We created a bespoke virtual reality-delivered pain therapy software programme to help cancer patients manage neuropathic pain incorporating guided visualisation and progressive muscle relaxation techniques, whilst minimising the risk of cybersickness in this vulnerable patient population. This randomised controlled pilot study evaluated the feasibility, acceptability, recruitment rates and risk of cybersickness of this pain therapy software programme. Clinical outcomes including opioid consumption, pain severity, pain interference and global quality of life scores were secondary aims. Of 87 eligible cancer patients with neuropathic pain, 39 were recruited (47%), allocated to either the intervention (20 patients, virtual reality pain therapy software programme) or control (19 patients, viewing virtual reality videos). Four patients withdrew before the 3-month follow-up (all in the control group). Pre-existing dizziness (Spearman ρ 0.37, p = 0.02) and pre-existing nausea (Spearman ρ 0.81, p < 0.001) were significantly associated with risk of cybersickness in both groups. Patients in the intervention group reported less cybersickness, as well as tolerated and completed all therapy sessions. At 1- and 3-month follow-up, there were trends in the intervention group towards reductions in: oral morphine equivalent daily dose opioid consumption (−8 mg and −4 mg; vs. control: 0 mg and +15 mg respectively); modified Brief Pain Inventory pain severity (−0.4, −0.8; vs. control +0.4, −0.3); and pain interference (−0.9, −1.8; vs. control −0.2, −0.3) scores. The global quality of life subscale from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 was not significantly changed between groups at 1 and 3 months (intervention: −5, −8; vs. control: +3, +4). This newly created virtual reality-delivered pain therapy software programme was shown to be feasible and acceptable to cancer patients with neuropathic pain. These results will aid the design of a definitive multicentre randomised controlled trial.     

Plasma concentrations of meperidine and normeperidine following continuous intrathecal meperidine in patients with neuropathic cancer pain

BACKGROUND: Intrathecal administration of meperidine, an opioid with local anesthetic activity, can induce analgesia in patients with intractable cancer pain. However, continuous intrathecal administration may result in the accumulation of normeperidine, responsible for central nervous system toxicity. METHODS: Ten patients with neuropathic cancer pain, not responding to conventional opioid therapy, were treated with continuous intrathecal administration of meperidine. In all patients, plasma concentrations of meperidine and normeperidine were measured the first days after the start of treatment. Visual analog scale scores were recorded to evaluate pain relief. Quality of life was assessed before and 3 weeks following the start of intrathecal treatment. RESULTS: In three patients the plasma concentrations of meperidine and normeperidine increased rapidly. In one patient the plasma normeperidine concentration was higher than the meperidine concentration. One patient demonstrated transient symptoms suggestive for central nervous system excitation. Three weeks following the start of treatment, seven patients were available for evaluation of their quality of life. Pain relief and overall quality of life improved during the intrathecal treatment. CONCLUSION: We conclude that continuous intrathecal administration of meperidine alone, or in combination with clonidine, can provide significant pain relief in patients with poor pain control despite pharmacological treatment. However, accumulation of meperidine and normeperidine resulting in central nervous system toxicity may occur during this treatment.     

可切除胰头癌的治疗进展

胰腺癌是消化系统中恶性程度最高的肿瘤,远期预后极差.胰腺癌中胰头癌所占比例最高,所以胰头癌的治疗是胰腺癌治疗中的重点.根治性胰十二指肠切除术是胰头癌患者得以治愈的希望,同时也是患者长期生存的最重要的治疗方式.选择恰当的手术方式及技巧可以提高肿瘤根治性切除的几率,降低术后并发症;再结合适时、适当的辅助治疗,可能会改善可切除胰头癌患者术后生存质量并延长生存期.     

Swelling of the legs and feet

There are many different causes of leg and foot swelling, some are benign and transient, others can be debilitating and progressive. Correct diagnosis and early treatment is crucial as conservative measures are most effective before the condition is allowed to progress. Current waiting times in the UK National Health Service (NHS) after the Covid-19 pandemic are leading to delays in care for people with chronic leg swelling. Delayed or inadequate treatment for these patients can lead to irreversible tissue damage, an episode of cellulitis, and progression to leg ulceration. There is in addition a significant impact on quality of life associated with living with the pain, anxiety, and reduced mobility. The causes of acute and chronic leg and foot swelling are outlined. Diagnosis and treatment of the common causes of leg and foot swelling in the Western adult population are discussed. The mainstay of treatment for most of these conditions relies on physical therapy and graduated elastic compression garments or elastic Velcro wraps as many do not have a cure.