Paul Farquhar-Smith

Chemotherapy-induced neuropathic pain.

Purpose of reviewTo discuss the importance, clinical features, possible pathology and treatments of chemotherapy-induced neuropathic pain. Newer biological agents such as bortezomib will be considered in greater detail. Recent findingsChemotherapy-induced peripheral neuropathy (CIPN) is a frequent complication of common anticancer therapies. It may lead to treatment compromise, significantly adds to the symptom burden and interferes with quality of life of cancer survivors. Recent investigations have identified processes involved in CIPN which may give some insight for the development of novel treatments. CIPN induced by different anticancer therapies may be heterogeneous and present as distinct neuropathic pains. Recent work has focussed on the newer anticancer drugs such as bortezomib. Contemporaneous studies have failed to find good evidence for the use of several common antineuropathic agents and further research is required. SummaryPainful CIPN remains under recognized and undertreated. It is an important cause of pain during cancer treatment and is a common pain in the cancer survivor. Difficulties in assessment and limitations in treatment contribute to management problems. Improvements in education (patient and clinician), assessment and treatment would potentially reduce the often debilitating effects of painful CIPN.

Pain in cancer survivors

Cancer and its treatment exert a heavy psychological and physical toll. Of the myriad symptoms which result, pain is common, encountered in between 30% and 60% of cancer survivors. Pain in cancer survivors is a major and growing problem, impeding the recovery and rehabilitation of patients who have beaten cancer and negatively impacting on cancer patients’ quality of life, work prospects and mental health. Persistent pain in cancer survivors remains challenging to treat successfully. Pain can arise both due to the underlying disease and the various treatments the patient has been subjected to. Chemotherapy causes painful chemotherapy-induced peripheral neuropathy (CIPN), radiotherapy can produce late effect radiation toxicity and surgery may lead to the development of persistent post-surgical pain syndromes. This review explores a selection of the common causes of persistent pain in cancer survivors, detailing our current understanding of the pathophysiology and outlining both the clinical manifestations of individual pain states and the treatment options available.

Adverse event reporting in randomised controlled trials of neuropathic pain: considerations for future practice.

Summary Improving adverse event reporting and developing standardize methods for collection of data will facilitate comparisons of information across trials of neuropathic pain. ABSTRACT High‐quality information on the potential benefit and harm of a drug is required for patients and clinicians to make informed treatment decisions and to enable cost‐effectiveness modeling to be undertaken. This systematic review describes the collection and reporting of adverse event data as presented in published clinical trials of neuropathic pain for the evaluation of antidepressant or antiepileptic drugs. A total of 74 studies in 16,323 patients published between 1965 and 2012 were identified, of which 43 were published from 2004 onwards. The review found that methods used to collect adverse event data, the frequency of collection, and the selection criteria used by authors for reporting adverse events vary substantially, and these events are often inadequately reported. Consequently, a potential synthesis of valuable harm information across trials is hampered. We make recommendations regarding the reporting of methods used to collect, assess, select, and present adverse event data in publications. Through the Core Outcome Measures in Effectiveness Trials (COMET) initiative, core outcome sets (which include effectiveness and harm) are developed by disease condition. To facilitate data synthesis for adverse events of drug therapies, we suggest that core outcome sets for harms could be developed by therapeutic class (ie, individualized for each class of drug). To improve comparability of information across trials collection methods need to be standardized for patient reports (spontaneous or prompted) and active surveillance (clinical examinations and laboratory tests). Uniform methods for presenting summary information regarding recurrent events, duration and timing of events requires further research.

Is tapentadol different from classical opioids? A review of the evidence

Tapentadol is a single molecule able to deliver analgesia by two distinct mechanisms, a feature which differentiates it from many other analgesics. Pre-clinical data demonstrate two mechanisms of action: mu-opioid receptor agonist activity and noradrenaline re-uptake inhibition. From these, one may predict that tapentadol would be applicable across a broad spectrum of pain from nociceptive to neuropathic. The evidence in animal models suggests that norepinephrine re-uptake inhibition (NRI) is a key mechanism and may even predominate over opioid actions in chronic (and especially neuropathic) pain states, reinforcing that tapentadol is different to classical opioids and may, therefore, be an a priori choice for the treatment of neuropathic and mixed pain. The clinical studies and subsequent practice experience and surveillance support the concept of opioid and non-opioid mechanisms of action. The reduced incidence of some of the typical opioid-induced side effects, compared to equianalgesic doses of classical opioids, supports the hypothesis that tapentadol analgesia is only partially mediated by opioid agonist mechanisms. Both the pre-clinical and clinical profiles appear to be differentiated from those of classical opioids.

Adverse event reporting in randomised trials of neuropathic pain: challenges for clinical usefulness of safety data

Background Monitoring the safety of therapies is of paramount importance in protecting patients from harm and enabling risk-benefit assessment. The recording and reporting of measures of efficacy has received considerable attention and while by no means perfect, has advanced further than the parallel assessment of harm. The stimulus for this study came from a commissioned effectiveness and cost-effectiveness review of treatments for neuropathic pain in patients (the CEAN study) [1]. CEAN noted that the completeness of adverse event (AE) reporting varied between trials and some expert opinion was required where primary data were insufficient for modeling cost-effectiveness. Further, clinicians indicated that trials sometimes failed to provide adequate information for clinical decision-making and informing patients.

Opioids and cancer: friend or foe?

Purpose of reviewMost cancer patients experience pain and many will require opioids. However, the effects of opioids on cancer progression, metastasis, and recurrence is increasingly being questioned. There is evidence that opioids affect immune system function, angiogenesis, apoptosis, and invasion in a potentially deleterious manner. This review will examine the preclinical and clinical evidence. Recent findingsRecent clinical data have struggled to find robust evidence that opioids promote cancer progression. Although most study has involved morphine, differential effects of other opioids on immune function and cancer are revealing a more complex picture. SummaryAlthough there is a biologically plausible story, evidence for the action of opioids on cancer is mixed. Indeed, it may even be that in the chronic setting morphine has a beneficial effect on outcome in certain cancer types. This review critically examines and evaluates the evidence for the action of opioids on the processes involved in cancer progression. In the light of the uncertainty of opioid effect on cancer, any decision making should be tempered by knowing that stress and pain undoubtedly contribute to cancer progression.

The Characteristics and Quality of Randomized Controlled Trials in Neuropathic Pain A Descriptive Study Based on a Systematic Review

Background:Evidence from randomized controlled trials is regarded as the gold standard in clinical research and yet the quality of the conduct and reporting of trials is variable, even post-Consolidated Standards of Reporting Trials. This study arose from a systematic review and cost-effectiveness analysis of treatment for neuropathic pain. The aim was to provide a description of the included trials and investigate trends in study characteristics and measures of quality over time. Methods:The review provided data regarding study characteristics (patients, place, time, drugs, outcomes), methodological factors (sample size calculations, randomization, reporting baseline patient data, withdrawals, intention-to-treat (ITT), and statistical analysis (completeness and correctness of reporting of results, methods of analysis). Results:A total of 131 trials from 1969 to 2007 were included. Of these, 63% were parallel-group designs, the remainder were cross-over; 73% were placebo-controlled. Several trial features increased or improved over time: trial size, quality (using Jadad score), presentation of baseline data by group, reporting of power calculations, use of visual analogue score or numerical rating scale scales to assess pain, completeness of reporting of statistical results, use of modeling to allow for baseline pain scores. The proportion of withdrawals was constant over time with a mean of 14.3%. The proportion of studies stating the analysis as ITT, increased over time, but inspection of papers indicated that the proportion confirmed as ITT was unchanged. Conclusions:There have been a number of improvements regarding the quality and reporting of randomized controlled trials in neuropathic pain, but some failings remain that at best make some results difficult to interpret and at worst lead to bias.

Anaphylaxis to Patent Blue V: a case series.

Blue dyes such as Patent Blue V (PBV) have been used in medical procedures for decades, and in the United Kingdom they are routinely utilised in sentinel lymph node biopsy (SLNB) for staging the axilla in early breast cancer. However, it has long been recognised that such dyes are associated with anaphylaxis. It has recently been estimated in a prospective study that allergy to PBV occurs with a frequency of 0.9%. Since repeated SLNB (and therefore further exposure to PBV) is increasingly being advocated for the small proportion of patients who develop a local (in-breast) recurrence, and because anaphylaxis can be life-threatening, it is important that those individuals that are allergic to PBV are recognised on their first medical exposure. The measurement of serum mast-cell tryptase (MCT) and skin prick test (SPT) are used in the investigation of suspected anaphylaxis because positive results are supportive of type-1 mediated hypersensitivity. Here we report the clinical features, MCT results and SPT results that pertain to a series of four patients referred to our drug allergy clinic with suspected anaphylaxis following SLNB. We recommend that all patients that show clinical evidence of allergy following exposure to PBV are referred to a specialist drug allergy service for further evaluation to investigate the cause.

Extended-release gabapentin in post-herpetic neuralgia

Introduction: In early 2011, the FDA gave approval to a new preparation of gabapentin, licensed for the treatment of post-herpetic neuralgia (PHN). Gabapentin is commonly used worldwide for multiple indications, which include neuropathic pain. The new drug combines generic gabapentin with a polymeric delivery system allowing for extended release and is licensed to be given only as a once-daily dosing regimen. Areas covered: The article aims to review the available evidence relating to the pharmacokinetics, tolerability and efficacy of extended-release gabapentin (GpER). It addresses the current state of the drugs progress through regulation and the intention of its manufacturer for the market. Expert opinion: Although GpER has been approved by the FDA for once-daily use in PHN, there is a relative paucity of data for both its efficacy and the optimum dosing schedule (once or twice a day). There are no data directly comparing GpER with the immediate-release preparation or other first-line treatments for PHN. Therefore, the true status of GpER as a treatment option needs to be enhanced with additional experimental evidence for its efficacy and favourable side-effect profile.

Thirty-day mortality in critical care outreach patients with cancer: An investigative study of predictive factors related to outreach referral episodes

AIM To establish factors that predict outcome in critically ill, deteriorating cancer patients through critical care outreach referral episodes, characteristics and care reviews. METHODS A population-based prospective and retrospective study was undertaken with analysis exploring predictive factors regarding critically ill cancer patients referred to a critical care outreach team. Data collected included: diagnosis; presenting problem; early warning scores at referral and at deterioration; physiological and observation data; admission to critical care, length of stay; 30-day mortality; limitation of care including precipitating DNAR orders and documentation of not for CCU admission/intervention). RESULTS Data were collected on 407 episodes from 318 patients over a period of 8 months from 2006 to 2007. Outreach initiated decisions to limit care with medical teams in 32.2% (n=103/318) of all patients. Early warning scores were not predictive of outcome. A high heart rate at referral (HR), a high potassium, low SpO2 at time of deterioration were independently predictive of 30-day mortality. The logistic regression (LR) model, using these three variables correctly predicts the 30-day outcome of 71% of the patients, demonstrating a relatively high predictability in this patient population. The odds of mortality increase with a higher potassium, heart rate and as the oxygen saturation at deterioration (DSpO(2)) worsen. Management factors included limitation of care, which is highly associated with 30-day mortality. Cancer patients recently receiving chemotherapy may have an increased mortality once admitted to critical care. Being a haemato-oncology patient, or the timeliness of critical care outreach referral does not appear to affect 30-day mortality. CONCLUSION The LR model was able to predict 30-day outcome of 71% of the patients, demonstrating a reasonably high predictability in this cancer patient population. Critical care outreach initiated discussions on limiting treatment which had an effect on mortality.