Neuropathic pain in cancer: systematic review, performance of screening tools and analysis of symptom profiles.

BACKGROUND: The objectives of this study were to evaluate the methodological quality of rigorous neuropathic pain assessment tools in applicable clinical studies, and determine the performance of screening tools for identifying neuropathic pain in patients with cancer. METHODS: Systematic literature search identified studies reporting use of Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), Douleur Neuropathique en 4 (DN4) or painDETECT (PDQ) in cancer patients with a clinical diagnosis of neuropathic or not neuropathic pain. Individual patient data were requested to examine descriptor item profiles. RESULTS: Six studies recruited a total of 2301 cancer patients of which 1564 (68%) reported pain. Overall accuracy of screening tools ranged from 73 to 94%. There was variation in description and rigour of clinical assessment, particularly related to the rigour of clinical judgement of pain as the reference standard. Individual data from 1351 patients showed large variation in the selection of neuropathic pain descriptor items by cancer patients with neuropathic pain. LANSS and DN4 items characterized a significantly different neuropathic pain symptom profile from non-neuropathic pain in both tumour- and treatment-related cancer pain aetiologies. CONCLUSIONS: We identified concordance between the clinician diagnosis and screening tool outcomes for LANSS, DN4 and PDQ in patients with cancer pain. Shortcomings in relation to standardized clinician assessment are likely to account for variation in screening tool sensitivity, which should include the use of the neuropathic pain grading system. Further research is needed to standardize and improve clinical assessment in patients with cancer pain. Until the standardization of clinical diagnosis for neuropathic cancer pain has been validated, screening tools offer a practical approach to identify potential cases of neuropathic cancer pain.

The evidence of neuraxial administration of analgesics for cancer-related pain: a systematic review.

BACKGROUND: The present systematic review analysed the existing evidence of analgesic efficacy and side effects of opioids without and with adjuvant analgesics delivered by neuraxial route (epidural and subarachnoid) in adult patients with cancer. METHODS: Search strategy was elaborated with words related to cancer, pain, neuraxial route, analgesic and side effects. The search was performed in PubMed, EMBASE, and Cochrane for the period until February 2014. Studies were analysed according to methods, results, quality of evidence, and strength of recommendation. RESULTS: The number of abstracts retrieved was 2147, and 84 articles were selected for full reading. The final selection comprised nine articles regarding randomised controlled trials (RCTs) divided in four groups: neuraxial combinations of opioid and adjuvant analgesic compared with neuraxial administration of opioid alone (n = 4); single neuraxial drug in bolus compared with continuous administration (n = 2); single neuraxial drug compared with neuraxial placebo (n = 1); and neuraxial opioid combined with or without adjuvant analgesic compared with other comprehensive medical management than neuraxial analgesics (n = 2). The RCTs presented clinical and methodological diversity that precluded a meta-analysis. They also presented several limitations, which reduced study internal validity. However, they demonstrated better pain control for all interventions analysed. Side effects were described, but there were few significant differences in favour of the tested interventions. CONCLUSION: Heterogeneous characteristics and several methodological limitations of the studies resulted in evidence of low quality and a weak recommendation for neuraxial administration of opioids with or without adjuvant analgesics in adult patients with cancer.

Breakthrough pain in patients with multiple myeloma: a secondary analysis of IOPS MS study.

OBJECTIVE: The aim of this study was to characterize breakthrough pain (BTcP) in patients with multiple myeloma (MM). PATIENTS AND METHODS: This was a secondary analysis of a large multicenter study of patients with BTcP. Background pain intensity and opioid doses were recorded. The BTcP characteristics, including the number of BTcP episodes, intensity, onset, duration, predictability, and interference with daily activities were recorded. Opioids prescribed for BTcP, time to achieve a meaningful pain relief after taking a medication, adverse effects, and patients' satisfaction were assessed. RESULTS: Fifty-four patients with MM were examined. In comparison with other tumors, in patients with MM BTcP was more predictable (p=0.04), with the predominant trigger being the physical activity (p<0.001). Other BTcP characteristics, pattern of opioids used for background pain and BTcP, satisfaction and adverse effects did not differ. CONCLUSIONS: Patients with MM have their own peculiarities. Given the peculiar involvement of the skeleton, BTcP was highly predictable and triggered by movement.

Salivary gland dysfunction ('dry mouth') in patients with cancer: a consensus statement.

A group of interested professionals was convened to develop some evidence-based recommendations on the management of salivary gland dysfunction (SGD) in oncology patients. A Medline search was performed to identify the literature on SGD. The abstracts of all identified papers were read, and the full texts of all relevant papers were reviewed. The evidence was graded according to the Scottish Intercollegiate Guidelines Network grading system for recommendations in evidence-based guidelines. The summary of the main recommendations are: (1) patients with cancer should be regularly assessed for SGD (grade of recommendation - D); (2) the management of SGD should be individualised (D); (3) consideration should be given to strategies to prevent the development of radiation-induced SGD (C); (4) consideration should be given to treatment of the cause(s) of the SGD (C); (5) the treatment of choice for the symptomatic management of SGD is use of an appropriate saliva stimulant (C); (6) consideration should be given to prevention of the complications of the SGD (D); (7) consideration should be given to treatment of the complications of the SGD (D); and (8) patients with SGD should be regularly reassessed (D).

Clinical and financial analysis of an acute palliative care unit in an oncological department.

The aim of this article is to describe the clinical activity and medical intervention of an acute model of palliative care unit (APC), as well as the reimbursement procedures and economic viability. A sample of 504 patients admitted at an APC in 1 year was surveyed. Indications for admission, pain and symptom intensity, analgesic treatments, procedures, instrumental examinations and modalities of discharge were recorded. For each patient, tariff for reimbursement was calculated according to the existent disease related grouping (DRG) system. The mean age was 62 years, and 246 patients were males. The mean hospital stay was 5.4 days. Pain control was the most frequent indication for admission. All patients had laboratory tests and several instrumental examinations. Almost all patients were prescribed one or more opioids at significant doses, and different routes of administration, as well as medication as needed. 59 patients received blood cell transfusions and 34 interventional procedures. Only 40 patients died in the unit, 11 of them being sedated at the end of life. Treatment efficacy was considered optimal and mild in 264 and 226 patients respectively. A mean of 3019 euros for admission was reimbursed by the Health Care System. APCs are of paramount importance within an oncological department, as they provide effective and intensive treatments during the entire course of disease, providing a simultaneous and integrated approach. Our findings also suggest both a cost and quality incentive for oncological departments to develop APC.

Breakthrough cancer pain: The importance of the right treatment at the right time.

BACKGROUND: Confusion remains over the definition of breakthrough cancer pain (BTcP) potentially leading to delayed diagnosis and treatment. METHODS: An on-line survey was conducted in four EU countries among relevant healthcare professionals and cancer patients diagnosed with BTcP. The roles of healthcare professionals (HCPs) were examined and their knowledge and use of available medications recorded. Patients were questioned on how BTcP affected their lives and on the medications they had received/were receiving. RESULTS: There was a 'time lag' of 58 and 13 weeks in Germany and Spain respectively between the initial diagnosis of BTcP and its treatment. Four in ten oncologists across the four countries considered themselves not fully confident in their choice of the appropriate therapy. A quarter of patients in Germany, Italy and Spain and four in ten in France were treated only with increased dosages of the therapy already prescribed for their background pain - often morphine. Almost another quarter received morphine in addition to their treatment for background pain. Oncologists indicated a need for faster-acting treatments revealing a potential lack of awareness of rapid onset oral opioids and patients expressed a desire for more effective pain relief and better psychological support. CONCLUSIONS: There is a need for a universal definition of BTcP to facilitate earlier and more accurate diagnosis. It is essential that BTcP is treated immediately on diagnosis with therapies that more closely mirror its temporal characteristics to ensure that patients' desire for more effective pain relief is fulfilled. SIGNIFICANCE: Many cancer patients suffered episodes of BTcP needlessly over many months due to missed diagnosis. Even after diagnosis, many physicians were not fully confident in their choice of 'rescue' therapy which perhaps is not surprising given the very low level of awareness of treatment guidelines, both national and international.

Rapid switching from morphine to methadone in cancer patients with poor response to morphine.

PURPOSE: The aim of this study was to evidence the clinical effects of an abrupt substitution of morphine with methadone using a fixed ratio of 1:5 in patients for whom limiting adverse effects occurred before adequate analgesia was achieved with oral morphine. PATIENTS AND METHODS: A cross-sectional prospective study was carried out on 24 consecutive patients who were switched from oral morphine to oral methadone because they experienced substantial adverse effects that limited further increase in morphine dose. A fixed conversion morphine-to-methadone ratio of 5:1 was chosen. Subsequently, doses were changed according to clinical need, with frequent visits or phone contacts. Pain and symptom intensity, preswitching doses of morphine, initial and subsequent doses of methadone, and survival were recorded. RESULTS: A significant decrease in pain and symptom intensity was found within 24 hours after the substitution took place. The switching was effective in most patients (19 of 24), although five patients required alternative treatments. No significant changes in methadone dose were reported in the 3 days after switching. Methadone dose was significantly higher in patients who had lower preswitching doses of morphine and vice versa. No relevant complications were reported. CONCLUSION: A rapid substitution of morphine with methadone using an initial fixed ratio of 5:1 is a safe and effective method for improving the balance between analgesia and adverse effects in cancer patients with poor morphine response. An appropriate system of patient monitoring is necessary, because further changes in dose may be required according to clinical needs.

Morphine versus methadone in the pain treatment of advanced-cancer patients followed up at home.

PURPOSE: The aim of this study was to evaluate the analgesic and adverse effects and the doses of methadone in comparison to morphine. PATIENTS AND METHODS: A prospective randomized study was performed in a sample of 40 patients with advanced cancer who required strong opioids for their pain management. Patients were treated with sustained-release morphine or methadone in doses titrated against the effect administered two or three times daily according to clinical need. Opioid doses, adjuvant medications, symptoms associated with opioid therapy, pain intensity, and pain mechanisms were recorded. The opioid escalation indices in percentage (OEI%) and milligrams (OEImg) were calculated. The effective analgesic score (EAS) that monitors the analgesic consumption-pain ratio was also calculated at fixed weekly intervals. RESULTS: differences in pain intensity were found. Patients treated with methadone reported values of OEI significantly less than those observed in patients treated with morphine. Seven patients in the methadone group maintained the same initial dosage until death, whereas only one patient in the morphine group did not require opioid dose escalation. A more stable analgesia in time in patients treated with methadone was shown by the low number of gaps in EASs reported. Symptom frequencies and intensities were similar in the two groups. CONCLUSION: Methadone is a drug of indisputable value in the treatment of cancer pain, and an unbalanced focus on the risks of inappropriate use rather than the benefits should not compromise the use of a relevant alternative to morphine in the management of cancer pain.

Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study.

PURPOSE: To evaluate the clinical benefits of switching from morphine to oral methadone in patients who experience poor analgesia or adverse effects from morphine. PATIENTS AND METHODS: Fifty-two consecutive cancer patients receiving oral morphine but with uncontrolled pain and/or moderate to severe opioid adverse effects were switched to oral methadone administered every 8 hours using different dose ratios. Intensity of pain and adverse effects were assessed daily, and the symptom distress score (DS) was calculated before and after switching. RESULTS: Data were analyzed for 50 patients. Switching was considered effective in 80% of the patients; results were achieved in an average of 3.65 days. In the 10 patients who switched to methadone because of uncontrolled pain, a significant reduction in pain intensity (P <.005) and an average of a 33% increase in methadone doses necessary (P <.01) were found after an average of 3.5 days. DS significantly decreased from an average of 8.4 to 4.5 (P <.0005). In the 32 patients switching because of uncontrolled pain and morphine-related adverse effects, significant improvement was found in pain intensity (P <.0005), nausea and vomiting (P <.03), constipation (P <.001), and drowsiness (P <.01), but a significant increase in the methadone dose of an average of 20% (P <.004) was required. CONCLUSION: In most patients with cancer pain referred for poor pain control and/or adverse effects, switching to oral methadone is a valid therapeutic option. In the clinical setting of poor pain control, higher doses of methadone are necessary with respect to the equianalgesic calculated dose ratios previously published.

Strategies to manage the adverse effects of oral morphine: an evidence-based report.

Successful pain management with opioids requires that adequate analgesia be achieved without excessive adverse effects. By these criteria, a substantial minority of patients treated with oral morphine (10% to 30%) do not have a successful outcome because of (1) excessive adverse effects, (2) inadequate analgesia, or (3) a combination of both excessive adverse effects along with inadequate analgesia. The management of excessive adverse effects remains a major clinical challenge. Multiple approaches have been described to address this problem. The clinical challenge of selecting the best option is enhanced by the lack of definitive, evidence-based comparative data. Indeed, this aspect of opioid therapeutics has become a focus of substantial controversy. This study presents evidence-based recommendations for clinical-practice formulated by an Expert Working Group of the European Association of Palliative Care (EAPC) Research NETWORK: These recommendations highlight the need for careful evaluation to distinguish between morphine adverse effects from comorbidity, dehydration, or drug interactions, and initial consideration of dose reduction (possibly by the addition of a co analgesic). If side effects persist, the clinician should consider options of symptomatic management of the adverse effect, opioid rotation, or switching route of systemic administration. The approaches are described and guidelines are provided to aid in selecting between therapeutic options.

Evidence of peripheral nerve blocks for cancer-related pain: a systematic review.

The European Association for Palliative Care has initiated a comprehensive program to achieve an over-all review of the evidence of multiple cancer pain management strategies in order to extend the current guideline for treatment of cancer pain. The present systematic review analyzed the existing evidence of analgesic efficacy for peripheral nerve blocks in adult patients with cancer. A search strategy was elaborated with words related to cancer, pain, peripheral nerve and block. The search was performed in PubMed, EMBASE, and Cochrane for the period until February 2014. The number of abstracts retrieved was 155. No controlled studies were identified. Sixteen papers presented a total of 79 cases. The blocks applied were paravertebral blocks (10 cases), blocks in the head region (2 cases), plexus blocks (13 cases), intercostal blocks (43 cases) and others (11 cases). In general, most cases reported good pain relief and no side effects. The use of peripheral blocks is based upon anecdotal evidence. However, this review only demonstrates the lack of studies, which does not equal a lack of effectiveness.

Spinal neuronal correlates of tapentadol analgesia in cancer pain: a back-translational approach.

BACKGROUND: Pain is a common and highly debilitating complication for cancer patients significantly compromising their quality of life. Cancer-induced bone pain involves a complex interplay of multiple mechanisms including both inflammatory and neuropathic processes and also some unique changes. Strong opioids are a mainstay of treatments but side effects are problematic and can compromise optimal pain control. Tapentadol is a novel dual-action drug, both stimulating inhibitory µ-opioid receptors (MOR) and mediating noradrenaline reuptake inhibition (NRI) leading to activation of the inhibitory α-2 adrenoceptor. It has been demonstrated to treat effectively both acute and chronic pain. We here demonstrate the efficacy in a model of cancer-induced bone pain. METHODS: MRMT-1 mammary carcinoma cells were inoculated into the tibia of 6-week-old rats and 2 weeks after, the neuronal responses to a wide range of peripheral stimulation were evaluated. The recordings were made from wide-dynamic range neurons in lamina V of the dorsal horn before and after administration of tapentadol as well as antagonists of the two mechanisms, naloxone or atipamezole. RESULTS: We found marked inhibitions of the neuronal activity with efficacy against mechanical, thermal and electrically evoked activity following tapentadol administration. In addition, the effects of the drug were fully reversible by naloxone and partly by atipamezole, supporting the idea of MOR-NRI dual actions. CONCLUSIONS: These findings add to the mechanistic understanding of cancer-induced bone pain and support the sparse clinical data indicating a possible use of the drug as a therapeutic alternative for cancer patients with metastatic pain complication.

Pan-European, open-label dose titration study of fentanyl buccal tablet in patients with breakthrough cancer pain.

BACKGROUND: Fentanyl buccal tablet (FBT), a rapid onset opioid used to treat breakthrough cancer pain, must be titrated to an effective dose that provides adequate analgesia and minimizes undesirable events. This open-label, randomized study compared the percentage of patients achieving an effective dose of FBT when starting titration at 100 or 200 µg. METHODS: Opioid-tolerant patients with chronic cancer-related pain who experienced up to four breakthrough pain episodes daily were randomized to a starting dose of 100 or 200 µg for the titration period. The dose was increased until an effective dose (100, 200, 400, 600 or 800 µg) providing adequate analgesia with acceptable adverse events was achieved. Patients achieving an effective dose entered a treatment period during which they treated up to eight breakthrough pain episodes with their effective dose. RESULTS: A total of 442 patients from 135 sites in seven European countries were screened. Non-inferiority was established with the percentage of patients achieving an effective dose starting titration at 200 µg (81.4%) compared with the 100-µg (75.2%) starting dose. The most common effective doses of FBT were 200 µg (39.6%) and 400 µg (26.9%). No new safety concerns were identified with use of FBT at doses up to 800 µg per episode. CONCLUSIONS: This study involving a real clinical practice setting showed a similar percentage of patients safely achieving an effective dose by titration starting with 100 versus 200 µg of FBT.

The use of anti-inflammatory drugs in cancer pain.

The role of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer pain has been well established in the treatment of mild pain and also alone or in association with opioids for the treatment of moderate to severe pain. Acutely, NSAIDs may be more than mild analgesics, and may provide additional analgesia when combined with opioids. However, NSAIDs have ceiling effects and there is no therapeutic gain from increasing dosages beyond those recommended. As there is no clearly superior NSAID, the choice should be based on experience and the toxicity profile that probably relates to the COX-1:COX-2 ratio. Among the older drugs, ibuprofen seems to have these properties.Non-steroidal anti-inflammatory drugs have been shown to have an opioid-sparing effect. Although the value of a simple narcotic-sparing effect may be questioned in cancer pain treatment, the use of NSAIDs may be useful when the increase in opioid dosage determine the occurrence of opioid toxicity. Like opioids, NSAIDs should not be considered analgesics for a specific type or cause of pain. There is a lack of evidence for any difference between different routes of NSAIDs administration. The long-term toxicity of NSAIDs in cancer pain is poorly defined due to a lack of studies. A variety of strategies have been used in an attempt to reduce the risks associated with NSAID therapy. Those NSAIDs that are weak COX-1 inhibitors may be preferred. In addition, concomitant administration of misoprostol is recommended in patients at increased risk for upper gastrointestinal complications.

Anaemia in cancer: pathophysiology and treatment.

Anaemia in cancer patients is multifactorial and may occur as a either a direct effect of the cancer, as a result of the cancer treatment itself, or due to chemical factors produced by the cancer. The clinical symptoms of anaemia vary according to the individual's capacity to respond to blood loss or reduced red cell production. The haematological features in anaemic patients depend on the different types of malignant disease. Clinical and laboratory evaluation, and examination of the bone marrow can provide important diagnostic clues in many cases. Decisions are commonly made based on subjective consideration rather than on objective data. Blood transfusion involves many hazards, some of which may be reduced or avoided. Erythropoietin (EPO) treatment has been found to be effective in preventing anaemia and in reducing the need for blood transfusions, although it would be useful to identify high-risk patient subgroups who would benefit most from this expensive treatment. In advanced cancer patients the use of blood transfusion should be evaluated on an individual basis, according to the presence of distressing symptoms and life expectancy. These measures are unlikely to have an effect in irreversible and progressive bleeding states.

Predictive factors and opioid responsiveness in cancer pain.

The management of cancer pain not readily responsive to morphine is often problematic. Several factors can interfere with an appropriate analgesic opioid response in the course of the illness, including the progression of the disease and tolerance, the appearance of intractable side-effects, type and temporal pattern of pain, morphine metabolites, pharmacokinetic and pharmacodynamic factors, as well as individual factors. Different methodologies capable of accurately predicting or monitoring opioid response have been proposed in an attempt to allow researchers to 'speak a common language'. Tolerance is a component of the concept of opioid responsiveness. However, the assessment of analgesic tolerance in cancer patients is constrained by numerous difficulties because of the changes in the noxious stimuli with increasing activity in nociceptive pathways.