Optimizing cancer pain management in resource-limited settings.

PURPOSE: Adequate cancer pain management (CPM) is challenging in resource-limited settings, where current international guideline recommendations are difficult to implement owing to constraints such as inadequate availability and accessibility of opioids, limited awareness of appropriate opioid use among patients and clinicians, and lack of guidance on how to translate the best evidence into clinical practice. The multinational and multidisciplinary CAncer Pain managEment in Resource-limited settings (CAPER) Working Group proposes a two-step initiative to bridge clinical practice gaps in CPM in resource-limited settings. METHODS: A thorough review of the literature, a steering committee meeting in February 2017, and post-meeting teleconference discussions contributed to the development of this initiative. As a first step, we developed practical evidence-based CPM algorithms to support healthcare providers (HCPs) in tailoring treatment according to availability of and access to resources. The second part of the initiative proposes a framework to support an effective implementation of the CPM algorithms that includes an educational program, a pilot implementation, and an advocacy plan. RESULTS: We developed CPM algorithms for first-line use, breakthrough cancer pain, opioid rotation, and refractory cancer pain based on the National Comprehensive Cancer Network guidelines and expert consensus. Our proposed educational program emphasizes the practical elements and illustrates how HCPs can provide optimal CPM according to evidence-based guidelines despite varied resource limitations. Pilot studies are proposed to demonstrate the effectiveness of the algorithms and the educational program, as well as for providing evidence to support a draft advocacy document, to lobby policymakers to improve availability and accessibility of analgesics in resource-limited settings. CONCLUSIONS: These practical evidence-informed algorithms and the implementation framework represent the first multinational step towards achieving optimal CPM in resource-limited settings.

[Neurolysis and Spinal Analgesia in Cancer Pain Management].

Cancer pain appears as a complex pain and often progressive.WhenWHO pain management strategy and/or palliative care failed to relieve their pain, patients are given high dose opioids or anonymous adjuvant drugs and have no chance to meet specialized pain treatment. This section briefly covers the outline of neurolysis and spinal analgesia for these cancer patients with severe pain. Purpose of nerve block and neurolysis are to block the incoming signal of pain in order to reduce pain, reduce analgesic dose, recover ADL, and finally to be discharged from the hospital. However, autonomic nervous system, sensory nerves, and motor function could be impaired at the same time. Careful selection of candidate should be considered by the pain specialists. Spinal analgesia is indicated when, conservative pain treatment failed to reduce pain, wide range or multiple pain area, and when contraindicated for neurolysis. Epidural analgesia is preferred for in-hospital treatment and intrathecal analgesia for home care settings. Many cancer pain patients' life expectancy is not long enough to postpone the indication of these invasive techniques. If you seek to maintain patients' quality of life(QOL), one should consider these procedures at some point, although it may not be indicated.

A Cancer-Pain Analgesia as Prolonging Strategy of Surviving Time after Failure of Adjuvant Chemotherapy in Patient with Progressive Bone-Metastatic Hepatocellular Carcinoma.

The hepatocellular carcinoma (HCC) with intrahepatic and bone metastasis shows poor survival of averagely 3 months. The bone metastasis and HCC itself might cause cancer-associated pain. An intrathecal (IT) analgesia might contribute to improve QOL and prolong surviving time (ST). A 71-year-old male presented with temperature and appetite loss continuing for 2 months. He looked pale and malaise. Computed tomography and tumor markers elevation confirmed diagnosis of HCC stage IV. To treat him, molecularly targeted therapy was started but abandoned because of side effects of life-threatening convulsions and loss of consciousness. Since this time, pain control strategy was planned as advance care plan. After dermal and oral opioids were administered, IT analgesia was introduced to conquer uncontrollable pelvic pain due to metastatic osteolytic lesions. Owing to IT analgesia against severe cancer-related pain, he had lived for 46 months. Comparing with reviews in which average ST is 3 months, this is the case with the longer ST in bone-metastatic HCC. From our experience, it must be emphasized that relieving cancer-related pain strategy for patients with progressive bone-metastatic HCC might contribute to prolong ST longer when adjuvant therapy has been failed.

[Intrathecal morphine treatment in advanced cancer pain patients].

For more than 20 years morphine for spinal analgesia in patients with refractory cancer pain has been one of the cornerstones for the management of chronic, medically intractable pain. In general, most types of cancer pain are treatable following the guideline of Cancer Pain Relief well established by the WHO. However, some patient are unable to tolerate pain only following the guideline and often suffer with side-effects from high doses of opioid and from prescribed multiple adjuvant drugs. Due to the proximity to the receptor sites, the therapeutic efficacy of intrathecal opioid application lasts longer and also reduces systemic side effects. Intrathecal drug application is cost effective and can significantly improve the quality of life in selected patients with limited life expectancy. However, an intensive training of physicians, careful patient selection, awareness of specific complications, and arrangement of social back-up medical system are essential to commence intrathecal morphine application using implantable access port. This article introduces the basic idea of intrathecal morphine therapy with implantable access port (not pumps) as cost effective, alternative therapy for cancer patient suffering from intractable pain.

Olprinone reduces ischemia/reperfusion-induced acute renal injury in rats through enhancement of cAMP.

Activated leukocytes are implicated in development of ischemia/reperfusion (I/R)-induced organ injuries. Phosphodiesterase 3 inhibitors have anti-inflammatory effects by preventing cyclic adenosine monophosphate (cAMP) degradation. We examined the effects of olprinone, a specific phosphodiesterase 3 inhibitor, on I/R-induced acute renal injury model in rats. Forty-five minute renal I/R was induced in uni-nephrectomized rats. Rats were divided into a vehicle group, an olprinone group, and a dibutyril (DB) cAMP group. Olprinone (0.2 microg/kg/minute) infusion began 30 min after reperfusion and continued for 3 h. DBcAMP (5 mg/kg), a stable analog of cAMP, was intraperitoneally administered 5 min after reperfusion to clarify the effect of cAMP in our model. Olprinone reduced the I/R-induced increases in serum levels of blood urea nitrogen and creatinine, and improved histological changes, including acute tubular necrosis in the outer medulla. Hemodynamic status was not affected by olprinone. I/R-induced a decrease in renal tissue blood flow, an increase in renal vascular permeability, and an enhancement of leukocyte activation, reflected by renal tissue levels of myeloperoxidase activity, and the tissue levels of cytokine-induced neutrophil chemoattractant (an equivalent of human interleukin 8) and tumor necrosis factor-alpha were all significantly decreased by olprinone. Olprinone also increased the renal tissue and plasma levels of cAMP in rats subjected to renal I/R. DBcAMP showed similar effects. Our results indicated that olprinone reduced the I/R-induced acute renal injury, probably by inhibiting leukocyte activation. The effects of olprinone could be explained through its action on cAMP levels.

[Parenteral opioids in end-of-life care in cancer patients].

The ethical obligation to relieve pain and other distressing symptoms in patients with cancer is now receiving increasing attention and concern in palliative and end-of-life care. The vast majority of patients with cancer pain are prescribed opioids in oral formulation. However, a patient at the end of his or her life often needs parenteral administration of opioids as the medical condition deteriorates, irrespective of using sedatives. Controlled release opioid preparations currently available in Japan are CR morphine sulphate, CR oxycodone and transdermal fentanyl patch. The opioids available in injectable preparations are morphine HCL and fentanyl citrate. Accordingly, not only the guideline for switching opioids, so-called "opioid rotation," but the guideline for changing the opioid administration route is also necessary in end-of-life care. The authors specifically indicate when and how to convert opioid administration from the oral to the parental route.

[Bisphosphonate as an adjuvant therapy for the pain of bone metastases, 3 cases].

Pain from bone metastases limits mobility and may cause pathological fractures that can seriously impair the patient's quality of life. Conservative treatments such as orthopedic fixation, radiotherapy, and opioids sometimes fail to give satisfactory pain relief. Bisphosphonates have been reported to reduce the severity of pain from bone metastasis due to breast cancer, prostate cancer, and multiple myeloma. Recent clinical reports demonstrated the effectiveness of bisphosphonates in reducing pain from bone metastases in various malignancies. This study presents 3 cases of refractory pain from bone metastases due to thyroid, colorectal and hepatocellular carcinoma. Primary treatment included orthopedic fixation, radiotherapy, and/or parenteral opioids that failed to reduce bone pain. Bisphosphonate therapy was considered at the start of pain control treatment using opioids. All 3 cases showed gradual reduction in pain after i.v. pamidronate administration and allowed physicians to control further pain with opioids. In 1 case, the patient was successfully withdrawn from opioids. The role of bisphosphonates in painful bone metastases remains unclear. However, recent encouraging reports have indicated that bisphosphonate may become one of the adjuvant treatments available to control refractory bone pain from various malignancies.

Blood pressure-lowering peptides from neo-fermented buckwheat sprouts: a new approach to estimating ACE-inhibitory activity.

Neo-fermented buckwheat sprouts (neo-FBS) contain angiotensin-converting enzyme (ACE) inhibitors and vasodilators with blood pressure-lowering (BPL) properties in spontaneously hypertensive rats (SHRs). In this study, we investigated antihypertensive mechanisms of six BPL peptides isolated from neo-FBS (FBPs) by a vasorelaxation assay and conventional in vitro, in vivo, and a new ex vivo ACE inhibitory assays. Some FBPs demonstrated moderate endothelium-dependent vasorelaxation in SHR thoracic aorta and all FBPs mildly inhibited ACE in vitro. Orally administered FBPs strongly inhibited ACE in SHR tissues. To investigate detailed ACE-inhibitory mechanism of FBPs in living body tissues, we performed the ex vivo assay by using endothelium-denuded thoracic aorta rings isolated from SHRs, which demonstrated that FBPs at low concentration effectively inhibited ACE in thoracic aorta tissue and suppressed angiotensin II-mediated vasoconstriction directly associated with BPL. These results indicate that the main BPL mechanism of FBP was ACE inhibition in living body tissues, suggesting that high FBP's bioavailability including absorption, tissue affinity, and tissue accumulation was responsible for the superior ACE inhibition in vivo. We propose that our ex vivo assay is an efficient and reliable method for evaluating ACE-inhibitory mechanism responsible for BPL activity in vivo.