Comparing pain intensity rating scales in acute postoperative pain: boundary values and category disagreements.

Pain intensity assessment scales are important in evaluating postoperative pain and guiding management. Different scales can be used for patients to self-report their pain, but research determining cut points between mild, moderate and severe pain has been limited to studies with < 1500 patients. We examined 13,017 simultaneous acute postoperative pain ratings from 913 patients taken at rest and on activity, between 4 h and 48 h following surgery using both a verbal rating scale (no, mild, moderate or severe pain) and 0-100 mm visual analogue scale. We determined the best cut points on the visual analogue scale between mild and moderate pain as 35 mm, and moderate and severe pain as 80 mm. These remained consistent for pain at rest and on activity, and over time. We also explored the presence of category disagreements, defined as patients verbally describing no or mild pain scored above the mild/moderate cut point on the visual analogue scale, and patients verbally describing moderate or severe pain scored below the mild/moderate cut point on the visual analogue scale. Using 30 and 60 mm cut points, 1533 observations (12%) showed a category disagreement and using 35 and 80 mm cut points, 1632 (13%) showed a category disagreement. Around 1 in 8 simultaneous pain scores implausibly disagreed, possibly resulting in incorrect pain reporting. The reasons are not known but low rates of literacy and numeracy may be contributing factors. Understanding these disagreements between pain scales is important for pain research and medical practice.

Whole-genome and transcriptome analysis enhances precision cancer treatment options.

BACKGROUND: Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole-genome and transcriptome sequencing and analysis (WGTA) present an opportunity to align a much larger proportion of patients to therapies. PATIENTS AND METHODS: Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected. RESULTS: Clinically actionable targets were identified for 83% of patients, of which 37% of patients received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, poly-ADP ribose polymerase inhibitors and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%) and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies. CONCLUSIONS: Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.

Correction to: Dexketoprofen/tramadol 25 mg/75 mg: randomised double-blind trial in moderate-to-severe acute pain after abdominal hysterectomy.

CORRECTION: Following publication of the original article [1], the authors reported that additional file 10 contained a typing error in the table "Percentage of responders (≥50% max TOTPAR) over two, four, six and eight hours (single-dose phase) (ITT Population)". The table is to be read as follows.

Successful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic cancer.

BACKGROUND: NRG1 fusion-positive lung cancers have emerged as potentially actionable events in lung cancer, but clinical support is currently limited and no evidence of efficacy of this approach in cancers beyond lung has been shown. PATIENTS AND METHODS: Here, we describe two patients with advanced cancers refractory to standard therapies. Patient 1 had lung adenocarcinoma and patient 2 cholangiocarcinoma. Whole-genome and transcriptome sequencing were carried out for these cases with select findings validated by fluorescence in situ hybridization. RESULTS: Both tumors were found to be positive for NRG1 gene fusions. In patient 1, an SDC4-NRG1 gene fusion was detected, similar gene fusions having been described in lung cancers previously. In patient 2, a novel ATP1B1-NRG1 gene fusion was detected. Cholangiocarcinoma is not a disease type in which NRG1 fusions had been described previously. Integrative genome analysis was used to assess the potential functional significance of the detected genomic events including the gene fusions, prioritizing therapeutic strategies targeting the HER-family of growth factor receptors. Both patients were treated with the pan HER-family kinase inhibitor afatinib and both displayed significant and durable response to treatment. Upon progression sites of disease were sequenced. The lack of obvious genomic events to describe the disease progression indicated that broad transcriptomic or epigenetic mechanisms could be attributed to the lack of prolonged response to afatinib. CONCLUSION: These observations lend further support to the use of pan HER-tyrosine kinase inhibitors for the treatment of NRG1 fusion-positive in both cancers of lung and hepatocellular origin and indicate more broadly that cancers found to be NRG1 fusion-positive may benefit from such a clinical approach regardless of their site of origin. CLINICAL TRIAL INFORMATION: Personalized Oncogenomics (POG) Program of British Columbia: Utilization of Genomic Analysis to Better Understand Tumour Heterogeneity and Evolution (NCT02155621).

Randomized clinical trial of dexketoprofen/tramadol 25 mg/75 mg in moderate-to-severe pain after total hip arthroplasty.

BACKGROUND: The aim was to evaluate the analgesic efficacy and safety of the dexketoprofen/tramadol 25 mg/75 mg fixed-dose combination vs dexketoprofen (25 mg) and tramadol (100 mg) in moderate-to-severe acute pain after total hip arthroplasty. METHODS: This was a randomized, double-blind, parallel-group study in patients experiencing pain of at least moderate intensity on the day after surgery, compared with placebo at first administration to validate the pain model. The study drug was administered orally every 8 h throughout a 5 day period. Rescue medication, metamizole 500 mg, was available during the treatment period. The evaluation of efficacy was based on patient assessments of pain intensity and pain relief. The primary end point was the mean sum of the pain intensity difference values throughout the first 8 h (SPID8). RESULTS: Overall, 641 patients, mean age 62 (range 29-80) yr, were analysed; mean (sd) values of SPID8 were 247 (157) for dexketoprofen/tramadol, 209 (155) for dexketoprofen, 205 (146) for tramadol, and 151 (159) for placebo. The primary analysis confirmed the superiority of the combination over dexketoprofen 25 mg (P=0.019; 95% confidence interval 6.4-73) and tramadol 100 mg (P=0.012; 95% confidence interval 9.5-76). The single components were superior to placebo (P<0.05), confirming model sensitivity. Most secondary analyses supported the superiority of the combination. The incidence of adverse drug reactions was low and similar among active treatment groups. CONCLUSION: The efficacy results confirmed the superiority of dexketoprofen/tramadol over its single components, even at higher doses (tramadol), with a safety profile fully in line with that previously known for these agents in monotherapy. CLINICAL TRIAL REGISTRATION: EudraCT 2012-004548-31 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-004548-31);ClinicalTrials.gov NCT01902134 (https://www.clinicaltrials.gov/ct2/show/NCT01902134?term=NCT01902134&rank=1).

Dexketoprofen/tramadol 25 mg/75 mg: randomised double-blind trial in moderate-to-severe acute pain after abdominal hysterectomy.

BACKGROUND: Dexketoprofen trometamol plus tramadol hydrochloride is a new oral combination of two analgesics, which have different mechanisms of action for the treatment of moderate to severe acute pain. METHODS: Randomised, double-blind, parallel, placebo and active-controlled, single and multiple-dose study to evaluate the analgesic efficacy and safety of dexketoprofen/tramadol 25 mg/75 mg in comparison with the single agents (dexketoprofen 25 mg and tramadol 100 mg) in moderate to severe acute pain after abdominal hysterectomy. Patients received seven consecutive doses of study drug within a 3-day period, each dose separated by an 8-hour interval. A placebo arm was included during the single-dose phase to validate the pain model. Efficacy assessments included pain intensity, pain relief, patient global evaluation and use of rescue medication. The primary endpoint was the mean sum of pain intensity differences over the first 8 h (SPID8). RESULTS: The efficacy analysis included 606 patients, with a mean age of 48 years (range 25-73). The study results confirmed the superiority of the combination over the single agents in terms of the primary endpoint (p <0.001). Secondary endpoints were generally supportive of the superiority of the combination for both single and multiple doses. Most common adverse drug reactions (ADRs) were nausea (4.6%) and vomiting (2.3%). All other ADRs were experienced by less than 2% of patients. CONCLUSIONS: The study results provided robust evidence of the superiority of dexketoprofen/tramadol 25 mg/75 mg over the single components in the management of moderate to severe acute pain, as confirmed by the single-dose efficacy, repeated-dose sustained effect and good safety profile observed. TRIAL REGISTRATION: EU Clinical Trials Register (EudraCT number 2012-004545-32, registered 04 October 2012); Clinicaltrials.gov ( NCT01904149, registered 17 July 2013).

Speed, science and optimal pain relief.

Pain is a major global health problem. Six of the 11 most prevalent conditions worldwide are pain-related, with tension-type headache and migraine being the second and third most prevalent conditions. Pain also ranks high among the conditions that have the longest-lasting impact: five of the top 11 contributors to years lived with disability are pain-related.

Analgesic safety - myths, mysteries and misconceptions.

Acute episodes of tension-type headache (TTH) are common and affect people of all ages, races and income levels. Two recommended and commonly used drugs for the treatment of this condition are ibuprofen and paracetamol. However, despite - or perhaps because of - their widespread use, many misconceptions persist about their comparative efficacy and safety. Are concerns about the gastrointenstinal (GI) safety of ibuprofen justified in the non-prescription over-the-counter (OTC) setting? Do low doses of ibuprofen - as used for TTH - increase the risk of heart attacks? Is the efficacy of ibuprofen and paracetamol really the same?

Reversal of PSA progression on abiraterone acetate through the administration with food in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Owing to efficacy and tolerability, abiraterone acetate (AA) is a leading treatment for men with metastatic castration-resistant prostate cancer. Increased serum concentrations of AA, such as by taking AA with food, may lead to the inhibition of additional enzymes in the androgen synthesis pathway implicated in castration-resistant prostate cancer progression. METHODS: Medical records of men with metastatic castration-resistant prostate cancer (mCRPC) who received AA between 1 April 2011 and 31 December 2013 were retrospectively reviewed. The primary outcome was the percent of men with a rising PSA on AA who experienced any PSA decline within 3 months after changing the administration of AA from without food to with food. Secondary outcomes were median time on AA therapy in men who received AA therapy without food versus those that switched administration from without food to with food at PSA progression, and the percent of men who experienced any decline in serum testosterone concentration, and the rate of adverse events observed while taking AA with food. RESULTS: Nineteen men who switched AA administration from without food to with food and 41 patients who administered AA without food only were included in the study. Of those patients who took AA with food at PSA progression, a PSA decline was observed in 3 of the 19 (16%) men, including 3 of the 14 men who had an initial response to AA (21%). Testosterone declined in five out of seven patients from pre-food levels. The median time on AA therapy was increased by nearly 100 days in patients who switched AA administration from without food to with food. No increases in toxicity were observed. CONCLUSION: Some men with mCRPC may benefit from taking AA with food. Further prospective comparative studies are needed to determine if changing AA administration is beneficial.

Validating speed of onset as a key component of good analgesic response in acute pain.

BACKGROUND: Previous analysis of a single data set in acute pain following third molar extraction demonstrated a strong relationship between the speed of reduction of pain intensity and overall pain relief, as well as need for additional analgesia. METHODS: Individual patient data analysis of a single randomized, double-blind trial of placebo, paracetamol 1000 mg, ibuprofen sodium 400 mg and ibuprofen-poloxamer 400 mg following third molar extraction. Visual analogue scale pain intensity (VASPI) and other measurements were made at baseline, every 5-45 min, and at 60, 90, 120, 180, 240, 300 and 360 min. RESULTS: Most patients produced consistent VASPI results over time. For placebo and paracetamol, few patients achieved low VASPI scores and maintained them. For both ibuprofen formulations, VASPI scores fell rapidly during the first hour and were then typically maintained until later re-medication. Analysis of all patients showed that rapid VASPI reduction in the first hour was strongly correlated with good overall pain relief (high total pain relief over 0-6 h), and with lesser need for additional analgesia within 6 h. Results for this analysis were in very good agreement with a previous analysis, validating the relationship between fast initial pain intensity reduction and overall good pain relief in this setting. CONCLUSIONS: In acute pain following third molar extraction, faster acting analgesic formulations provide earlier onset of pain relief, better overall pain relief and a less frequent need for additional analgesia, indicating longer lasting pain relief.

Overview review: Comparative efficacy of oral ibuprofen and paracetamol (acetaminophen) across acute and chronic pain conditions.

BACKGROUND: Ibuprofen and paracetamol have long been used as analgesics in a range of acute, intermittent and chronic pain conditions. Paracetamol is often the first line analgesic recommended, without consensus about which is the better analgesic. METHODS: An overview review of systematic reviews and meta-analyses directly compares ibuprofen and paracetamol at standard doses in particular painful conditions, or uses indirect comparisons against placebo. Electronic searches for systematic reviews were sought published since 1995 using outcomes approximating to ≥50% pain intensity reduction. Painful conditions were acute post-operative pain, dysmenorrhoea, tension-type headache (TTH), migraine, osteoarthritis and rheumatoid arthritis, back pain, cancer and paediatric pain. There was no systematic assessment of harm. RESULTS: Sixteen systematic reviews and four individual patient data meta-analyses were included. Ibuprofen was consistently superior to paracetamol at conventional doses in a range of painful conditions. Two direct comparisons favoured ibuprofen (acute pain, osteoarthritis). Three of four indirect comparisons favoured ibuprofen (acute pain, migraine, osteoarthritis); one showed no difference (TTH), although there were methodological problems. In five pain conditions (dysmenorrhoea, paediatric pain, cancer pain, back pain and rheumatoid arthritis), there were limited data on paracetamol and ibuprofen. CONCLUSIONS: At standard doses in different painful conditions, ibuprofen was usually superior producing more patients with the degree of pain relief that patients feel worthwhile. Neither of the drugs will be effective for everyone, and both are needed. This overview questions the practice of routinely using paracetamol as a first line analgesic because there is no good evidence for efficacy of paracetamol in many pain conditions.

Duloxetine use in chronic painful conditions--individual patient data responder analysis.

BACKGROUND: Duloxetine has been studied in four distinct chronic pain conditions - osteoarthritis (OA), fibromyalgia, chronic low back pain (CLBP) and diabetic peripheral neuropathic pain (DPNP). These trials have involved large numbers of patients with at least moderate pain, and have used similar methods for recording pain intensity, over about 12 weeks. METHODS: Data from the trials were pooled according to painful condition, and reanalysed at the level of the individual patient and using increasing levels of pain intensity reduction (<15%, 15-29%, 30-49%, ≥ 50%), with different imputation methods on withdrawal. RESULTS: The proportion of patients recording at least 50% pain intensity reduction plateaued after 2-6 weeks in fibromyalgia, and 8-12 weeks in other conditions. The duloxetine-specific benefit [number needed to treat (NNT) for at least 50% pain intensity reduction] was fairly constant after about 2 weeks for DPNP and fibromyalgia and after about 4 or 5 weeks for OA and CLBP. In all conditions, responses were bimodal, with patients generally experiencing either very good or very poor pain relief. Last-observation-carried-forward imputation produced numerically and occasionally statistically better (lower) NNTs than use of baseline-observation-carried-forward (true response). CONCLUSIONS: Baseline-observation-carried-forward (true response), which combines the success of high levels of pain relief with the failure to experience pain relief on withdrawal of the drug is conservative and probably reflective of clinical practice experience. The distribution of effect was not normal; few patients had the average response and averages are not an appropriate descriptor for these data.

A survey of post-amputation pains in serving military personnel.

INTRODUCTION: Amputation is a common injury in survivors of current military conflicts. The primary aim of this study was to establish the prevalence rate of phantom limb pain (PLP) in military personnel undergoing rehabilitation at the UK's Defence Medical Rehabilitation Centre. The secondary aims were to establish treatment failure rates and prevalence rates of phantom limb sensations (PLS) and residual limb pains (RLP). METHOD: A questionnaire survey was developed from that used in a previous study of pains in veterans. Questions were asked of the intensity of PLP, RLP and PLS over the previous month and the entire time since amputation. Treatment failure was defined as greater than 'mild' pain. A literature review for similar studies was undertaken. RESULTS: There were 48 responders with 65 amputations. PLP in the previous month was reported by 49% of respondents and 20% were classed as treatment failures; 76% had PLP at some point and 56% were analgesic failures. PLS was commoner with 70% reported over the previous month and 66% at any time. 65% had RLP over the previous month, 31% were treatment failures and 80% had experienced RLP at some point and 63% of these were failures of treatment. Eight other papers were found for comparison. CONCLUSIONS: This is the first paper that describes prevalence of pains associated with amputation in a serving military population. It also describes the use of analgesic failure as a concept and provides an encouraging rate of as low as 20% in this population.

Challenges in design and interpretation of chronic pain trials.

The process of systematic review has shone a light on the methodology of randomized controlled trials. Notably, a range of potential biases hinders the interpretation of chronic pain trials. These include a consistent bias favouring active over placebo in trials that are small and of short duration. The use of the 'last observation carried forward' imputation method is known to inflate results, often generating statistically significance when adverse event withdrawals are high; in clinical practice terms, this is the wrong answer. Patients want outcomes of low pain scores, large reductions in pain and relief from associated symptoms, with improvements in ability to function and in quality of life. Some patients achieve this, but many do not. The distribution of benefit is skewed and the use of average pain scores, or change in pain, can be misleading compared with responder analysis in which withdrawal is regarded as non-response. Historically, chronic pain trials have had a simple classic or a crossover design. They have been small and short, and used inappropriate imputation and outcomes unconnected to the experiences of most patients. While these designs are useful for answering some questions, they may be insensitive for many interventions. Newer designs, like enriched enrolment randomized withdrawal (EERW) trials or clinical effectiveness trials, are potentially more interesting and informative.

Efficacy of OTC analgesics.

For many 'over-the-counter' (OTC) analgesics, there is little information available about their relative efficacy. We have examined information available in a series of Cochrane reviews of single doses of analgesic drugs in acute pain and migraine for its relevance for analgesic products commonly available without prescription, at doses generally equivalent to two tablets. Pain following third molar extraction was used as a homogeneous acute pain model; with the outcome of at least 50% maximum pain relief over 6 h. For many OTC drugs, there was no information available. For some OTC drugs, there was at least some information available either for the marketed product itself, or from studies that used the same doses of drug or drugs. For acute pain, data from third molar extraction studies showed that several OTC products were highly efficacious, principally non-steroidal anti-inflammatory drugs (ibuprofen, naproxen, diclofenac) and combination products based on ibuprofen; aspirin and paracetamol-based products were less efficacious. Fixed-dose combinations, especially those with ibuprofen, provided high levels of analgesia. For migraine headache, the outcome used was pain initially moderate or severe becoming no worse than mild pain (no pain, mild pain) at 2 h. Single-dose ibuprofen 400 mg was better than aspirin and paracetamol.

A conservative method of testing whether combination analgesics produce additive or synergistic effects using evidence from acute pain and migraine.

Fixed-dose combination analgesics are used widely, and available both on prescription and over-the-counter. Combination drugs should provide more analgesia than with any single drug in the combination, but there is no evidence in humans about whether oral combinations have just additive effects, or are synergistic or even subadditive. We suggest that the measured result for the combination would be the summation of the absolute benefit increase (effect of active drug minus effect of placebo) of each component of a combination if effects were (merely) additive, and greater than the sum of the absolute benefits if they were synergistic. We tested measured effects of combination analgesics against the sum of the absolute benefits in acute pain and migraine using meta-analysis where individual components and combinations were tested against placebo in the same trials, and verified the result with meta-analyses where individual components and combinations were tested against placebo in different trials. Results showed that expected numbers needed to treat (NNT) for additive effects were generally within the 95% confidence interval of measured NNTs. This was true for combinations of paracetamol plus ibuprofen and paracetamol plus opioids in acute pain, and naproxen plus sumatriptan in migraine, but not where efficacy was very low or very high, nor combinations of paracetamol plus dextropropoxyphene. There was no evidence of synergy, defined as supra-additive effects.

Relative efficacy of oral analgesics after third molar extraction--a 2011 update.

This article provides a summary of the efficacy, and relative efficacy, of 38 different drugs or drug combinations tested in standard postoperative pain trials. It will help clinicians and patients make informed choices about analgesia based on pain relief, duration of action, and adverse events, which can then be put into context for the individual patient, depending on local availability. This article highlights the fact that no single drug is effective in all patients--even the best drugs fail to provide good levels of pain relief in at least 30%. These patients should try a different analgesic.

End-to-end military pain management.

The last three years have seen significant changes in the Defence Medical Services approach to trauma pain management. This article seeks to outline these changes that have occurred at every level of the casualty's journey along the chain of evacuation, from the point of injury to rehabilitation and either continued employment in the Services or to medical discharge. Particular attention is paid to the evidence for the interventions used for both acute pain and chronic pain management. Also highlighted are possible differences in pain management techniques between civilian and military casualties.