Relief of Neuropathic Pain Through Epidermal Growth Factor Receptor Inhibition: A Randomized Proof-of-Concept Trial.

OBJECTIVE: Case reports and a case series have described relief of neuropathic pain (NP) after treatment with epidermal growth factor receptor inhibitors (EGFR-Is). These observations are supported by preclinical findings. The aim of this trial was to explore a potential clinical signal supporting the therapeutic efficacy of EGFR-Is in NP. METHODS: In a proof-of-concept trial using a randomized, double-blind, placebo-controlled design, 14 patients with severe, chronic, therapy-resistant NP due to compressed peripheral nerves or complex regional pain syndrome were randomized to receive a single infusion of the EGFR-I cetuximab and placebo in crossover design, followed by a single open-label cetuximab infusion. RESULTS: The mean reduction in daily average pain scores three to seven days after single-blinded cetuximab infusion was 1.73 points (90% confidence interval [CI] = 0.80 to 2.66), conferring a 1.22-point greater reduction than placebo (90% CI = -0.10 to 2.54). Exploratory analyses suggested that pain reduction might be greater in the 14 days after treatment with blinded cetuximab than after placebo. The proportion of patients who reported ≥50% reduction in average pain three to seven days after cetuximab was 36% (14% after placebo), and comparison of overall pain reduction suggests a trend in favor of cetuximab. Skin rash (grade 1-2) was the most frequent side effect (12/14, 86%). CONCLUSIONS: This small proof-of-concept evaluation of an EGFR-I against NP did not provide statistical evidence of efficacy. However, substantial reductions in pain were reported, and confidence intervals do not rule out a clinically meaningful treatment effect. Evaluation of EGFR-I against NP therefore warrants further investigation.

A Targeted Mutation Disrupting Mitochondrial Complex IV Function in Primary Afferent Neurons Leads to Pain Hypersensitivity Through P2Y1 Receptor Activation.

As mitochondrial dysfunction is evident in neurodegenerative disorders that are accompanied by pain, we generated inducible mutant mice with disruption of mitochondrial respiratory chain complex IV, by COX10 deletion limited to sensory afferent neurons through the use of an Advillin Cre-reporter. COX10 deletion results in a selective energy-deficiency phenotype with minimal production of reactive oxygen species. Mutant mice showed reduced activity of mitochondrial respiratory chain complex IV in many sensory neurons, increased ADP/ATP ratios in dorsal root ganglia and dorsal spinal cord synaptoneurosomes, as well as impaired mitochondrial membrane potential, in these synaptoneurosome preparations. These changes were accompanied by marked pain hypersensitivity in mechanical and thermal (hot and cold) tests without altered motor function. To address the underlying basis, we measured Ca2+ fluorescence responses of dorsal spinal cord synaptoneurosomes to activation of the GluK1 (kainate) receptor, which we showed to be widely expressed in small but not large nociceptive afferents, and is minimally expressed elsewhere in the spinal cord. Synaptoneurosomes from mutant mice showed greatly increased responses to GluK1 agonist. To explore whether altered nucleotide levels may play a part in this hypersensitivity, we pharmacologically interrogated potential roles of AMP-kinase and ADP-sensitive purinergic receptors. The ADP-sensitive P2Y1 receptor was clearly implicated. Its expression in small nociceptive afferents was increased in mutants, whose in vivo pain hypersensitivity, in mechanical, thermal and cold tests, was reversed by a selective P2Y1 antagonist. Energy depletion and ADP elevation in sensory afferents, due to mitochondrial respiratory chain complex IV deficiency, appear sufficient to induce pain hypersensitivity, by ADP activation of P2Y1 receptors.

Validation of verbal autopsy methods using hospital medical records: a case study in Vietnam.

BACKGROUND: Information on causes of death (COD) is crucial for measuring the health outcomes of populations and progress towards the Sustainable Development Goals. In many countries such as Vietnam where the civil registration and vital statistics (CRVS) system is dysfunctional, information on vital events will continue to rely on verbal autopsy (VA) methods. This study assesses the validity of VA methods used in Vietnam, and provides recommendations on methods for implementing VA validation studies in Vietnam. METHODS: This validation study was conducted on a sample of 670 deaths from a recent VA study in Quang Ninh province. The study covered 116 cases from this sample, which met three inclusion criteria: a) the death occurred within 30 days of discharge after last hospitalisation, and b) medical records (MRs) for the deceased were available from respective hospitals, and c) the medical record mentioned that the patient was terminally ill at discharge. For each death, the underlying cause of death (UCOD) identified from MRs was compared to the UCOD from VA. The validity of VA diagnoses for major causes of death was measured using sensitivity, specificity and positive predictive value (PPV). RESULTS: The sensitivity of VA was at least 75% in identifying some leading CODs such as stroke, road traffic accidents and several site-specific cancers. However, sensitivity was less than 50% for other important causes including ischemic heart disease, chronic obstructive pulmonary diseases, and diabetes. Overall, there was 57% agreement between UCOD from VA and MR, which increased to 76% when multiple causes from VA were compared to UCOD from MR. CONCLUSIONS: Our findings suggest that VA is a valid method to ascertain UCOD in contexts such as Vietnam. Furthermore, within cultural contexts in which patients prefer to die at home instead of a healthcare facility, using the available MRs as the gold standard may be meaningful to the extent that recall bias from the interval between last hospital discharge and death can be minimized. Therefore, future studies should evaluate validity of MRs as a gold standard for VA studies in contexts similar to the Vietnamese context.

Completeness and reliability of mortality data in Viet Nam: Implications for the national routine health management information system.

BACKGROUND: Mortality statistics form a crucial component of national Health Management Information Systems (HMIS). However, there are limitations in the availability and quality of mortality data at national level in Viet Nam. This study assessed the completeness of recorded deaths and the reliability of recorded causes of death (COD) in the A6 death registers in the national routine HMIS in Viet Nam. METHODOLOGY AND FINDINGS: 1477 identified deaths in 2014 were reviewed in two provinces. A capture-recapture method was applied to assess the completeness of the A6 death registers. 1365 household verbal autopsy (VA) interviews were successfully conducted, and these were reviewed by physicians who assigned multiple and underlying cause of death (UCOD). These UCODs from VA were then compared with the CODs recorded in the A6 death registers, using kappa scores to assess the reliability of the A6 death register diagnoses. The overall completeness of the A6 death registers in the two provinces was 89.3% (95%CI: 87.8-90.8). No COD recorded in the A6 death registers demonstrated good reliability. There is very low reliability in recording of cardiovascular deaths (kappa for stroke = 0.47 and kappa for ischaemic heart diseases = 0.42) and diabetes (kappa = 0.33). The reporting of deaths due to road traffic accidents, HIV and some cancers are at a moderate level of reliability with kappa scores ranging between 0.57-0.69 (p<0.01). VA methods identify more specific COD than the A6 death registers, and also allow identification of multiple CODs. CONCLUSIONS: The study results suggest that data completeness in HMIS A6 death registers in the study sample of communes was relatively high (nearly 90%), but triangulation with death records from other sources would improve the completeness of this system. Further, there is an urgent need to enhance the reliability of COD recorded in the A6 death registers, for which VA methods could be effective. Focussed consultation among stakeholders is needed to develop a suitable mechanism and process for integrating VA methods into the national routine HMIS A6 death registers in Viet Nam.

Demographic characteristics of Australian health consumers who were early registrants for opt-in personally controlled electronic health records.

BACKGROUND: Differential uptake of, or access to, personal electronic health records (PEHRs) has the potential to impact on health disparities among certain social groups. In 2012, the Australian Government introduced the Personally Controlled Electronic Health Record (PCEHR), an opt-in system operated by the then National E-Health Transition Authority (NEHTA). In July 2016, the My Health Record (MyHR), an opt-out model, operated by the Australian Digital Health Agency replaced the PCEHR, providing additional support for consumers. OBJECTIVE: This research was carried out between 2012 and 2015, covering the opt-in PCEHR phase. The aim of the study was to explore demographic characteristics of Australian health consumers who were first to register for a PEHR, and to identify the age and gender populations less likely to register for a PEHR in the opt-in format. The study aimed to provide early data on registrants and potential methods to encourage individuals to register for a PEHR. METHOD: A cross-sectional study investigated differences in registrations for PEHRs from 2012 to 2015 by age and sex. RESULTS: Results revealed that males were less likely to register than females, and adolescents of both sexes were the least likely to register when compared with any other age group. Similarly, middle-aged males had among the lowest reported registrations, as did older females. CONCLUSION: While e-health has the potential to improve health outcomes and PEHRs the potential to empower consumers to better manage their health and improve their access health services, evidence from this study suggested that some population groups that experience health inequalities (e.g. older people) were underrepresented among registrants for PEHRs. As income, ethnicity and education are major drivers for health disparities in Australia, future research should focus on uptake and use of PEHRs (now the MyHR) from the perspective of these variables.

EP2 receptor antagonism reduces peripheral and central hyperalgesia in a preclinical mouse model of endometriosis.

Endometriosis is an incurable gynecological disorder characterized by debilitating pain and the establishment of innervated endometriosis lesions outside the uterus. In a preclinical mouse model of endometriosis we demonstrated overexpression of the PGE2-signaling pathway (including COX-2, EP2, EP4) in endometriosis lesions, dorsal root ganglia (DRG), spinal cord, thalamus and forebrain. TRPV1, a PGE2-regulated channel in nociceptive neurons was also increased in the DRG. These findings support the concept that an amplification process occurs along the pain neuroaxis in endometriosis. We then tested TRPV1, EP2, and EP4 receptor antagonists: The EP2 antagonist was the most efficient analgesic, reducing primary hyperalgesia by 80% and secondary hyperalgesia by 40%. In this study we demonstrate reversible peripheral and central hyperalgesia in mice with induced endometriosis.

A novel model of combined neuropathic and inflammatory pain displaying long-lasting allodynia and spontaneous pain-like behaviour.

Many clinical cases of chronic pain exhibit both neuropathic and inflammatory components. In contrast, most animal models of chronic pain focus on one type of injury alone. Here we present a novel combined model of both neuropathic and inflammatory pain and characterise its distinctive properties. This combined model of chronic constriction injury (CCI) and intraplantar Complete Freund's Adjuvant (CFA) injection results in enhanced mechanical allodynia, thermal hyperalgesia, a static weight bearing deficit, and notably pronounced spontaneous foot lifting (SFL) behaviour (which under our conditions was not seen in either individual model and may reflect ongoing/spontaneous pain). Dorsal root ganglion (DRG) expression of Activating Transcription Factor-3 (ATF-3), a marker of axonal injury, was no greater in the combined model than CCI alone. Initial pharmacological characterisation of the new model showed that the SFL was reversed by gabapentin or diclofenac, typical analgesics for neuropathic or inflammatory pain respectively, but not by mexiletine, a Na(+) channel blocker effective in both neuropathic and inflammatory pain models. Static weight bearing deficit was moderately reduced by gabapentin, whereas only diclofenac reversed mechanical allodynia. This novel animal model of chronic pain may prove a useful test-bed for further analysing the pharmacological susceptibility of complicated clinical pain states.