Who's included? The role of the Clinical Research Nurse in enabling research participation for under-represented and under-served groups.

Background: There is a global call for more inclusive clinical research that is representative of all populations, particularly those historically under-represented or under-served. A lack of broad representation results in disproportionate health outcomes and limits the applicability and translation of research findings. Aim: Identify and describe barriers to participation across the research lifecycle and consider the role of the Clinical Research Nurse (CRN) in promoting inclusivity, including for Aboriginal and Torres Strait Islander Peoples within Australia. Discussion: Review of recent literature and best practice identified barriers to research participation across the research process; at system, participant and practitioner levels. This discussion paper explores the role of the CRN; acting as enablers, facilitators and navigators, to mitigate participation barriers. Conclusion: With their comprehensive understanding of the research process, clinical care pathways, reflective practices and participant-centred approaches, CRNs are uniquely positioned to advocate for greater equity in access to clinical research and to motivate stakeholders across the research enterprise to embed inclusive approaches in the design, conduct and dissemination of research. Implications for Practice: An in-depth understanding of the research process, self, and cultural norms of the populations they serve is essential for CRNs to effectively advocate for equity in access to research.

Science at Warp Speed: Medical Research, Publication, and Translation During the COVID-19 Pandemic.

In response to the COVID-19 pandemic, there has been a rapid growth in research focused on developing vaccines and therapies. In this context, the need for speed is taken for granted, and the scientific process has adapted to accommodate this. On the surface, attempts to speed up the research enterprise appear to be a good thing. It is, however, important to consider what, if anything, might be lost when biomedical innovation is sped up. In this article we use the case of a study recently retracted from the Lancet to illustrate the potential risks and harms associated with speeding up science. We then argue that, with appropriate governance mechanisms in place (and adequately resourced), it should be quite possible to both speed up science and remain attentive to scientific quality and integrity.

Reduced response to the thermal grill illusion in chronic pain patients.

OBJECTIVE: Sensory illusions may reveal fundamental features of the nervous system. The thermal grill illusion is such a pain illusion, where interlaced warm and cool temperature bars (thermal grill) produce a paradoxical burning sensation. Previous studies have only systematically investigated the thermal grill illusion in pain-free volunteers. The objective of this study was to investigate whether the response to the thermal grill illusion was tolerable in patients with chronic pain and whether the response differed between patients with chronic pain and pain-free volunteers. SUBJECTS: Sixteen pain-free participants and 18 chronic pain patients (seven not receiving opioids and 11 receiving opioids). METHODS: The thermal grill response was investigated using a custom-built thermal grill. Heat and cold pain thresholds were also determined. RESULTS: Chronic pain patients reported less intense pain, heat, and unpleasantness to the thermal grill compared with pain-free participants; in particular, there was an overall main effect for significantly less heat from the thermal grill compared with pain-free participants (P = 0.016). At the 22/38°C combination, although the majority of pain-free participants experienced the illusion to some degree, the majority of pain patients in both groups did not (median pain score 0). Although perceived heat from the thermal grill was significantly lower in chronic pain patients, both heat and cold pain thresholds did not differ among the three populations. CONCLUSIONS: This preliminary data suggest that the thermal grill response may provide insights into pain sensitivity that are not detected by conventional thermal quantitative sensory testing.

Low-dose endotoxin potentiates capsaicin-induced pain in man: evidence for a pain neuroimmune connection.

Despite the wealth of evidence in animals that immune activation has a key role in the development and maintenance of chronic pain, evidence to support this in humans is scant. We have sought such evidence by examining the effect of a subtle immunological stimulus, low dose intravenous endotoxin, on the allodynia, hyperalgesia, flare and pain produced by intradermal capsaicin in healthy volunteers. Here we provide evidence of immune priming of this neuropathic-like pain response in humans. Specifically, in 12 healthy volunteers, activation of Toll-Like Receptor 4 by endotoxin (0.4ng/kg IV) caused significant 5.1-fold increase in the 90-min integral of areas of capsaicin-induced allodynia (95% CI 1.3-9.1), 2.2-fold increase in flare (95% CI 1.9-2.6) and 1.8-fold increase in hyperalgesia (95% CI 1.1-2.5) following 50µg intradermal capsaicin injected into the forearm 3.5h after endotoxin. These data demonstrate clinically a significant role for the neuroimmune pain connection in modifying pain, thus providing evidence that immune priming may produce pain enhancement in humans and hence offer a novel range of pharmacological targets for anti-allodynics and/or analgesics. Additionally, the simplicity of the model makes it suitable as a test-bed for novel immune-targeted pain therapeutics.

The pharmacokinetics and pharmacodynamics of single dose (R)- and (S)-warfarin administered separately and together: relationship to VKORC1 genotype.

AIMS: 1) To determine the pharmacokinetics and pharmacodynamics of (R)- and (S)-warfarin given alone and in combination and 2) to determine whether the relative potency of (R)- and (S)-warfarin is dependent on VKORC1 genotype. METHODS: A three way crossover study was conducted in which 17 healthy male subjects stratified by VKORC1 1173 C>T genotype and all CYP2C9 1*/1* received (R)-warfarin 80 mg, (S)-warfarin 12.5 mg and rac-warfarin sodium 25 mg. Plasma (R)- and (S)-warfarin unbound and total concentrations and prothrombin time were determined at multiple time points to 168 h. RESULTS: Pharmacokinetic parameters for (R)- and (S)-warfarin were similar to the literature. (R)-warfarin 80 mg alone resulted in a mean AUC(PT) (0,168 h) of 3550 s h (95% CI 3220, 3880). Rac-warfarin sodium 25 mg containing (S)-warfarin 11.7 mg produced a greater effect on AUC(PT) (0,168 h) than (S)-warfarin 12.5 mg (mean difference 250 s.h, 95% CI 110, 380, P < 0.002) given alone. In a mixed effects model the ratio of response between (R)- and (S)-warfarin (AUC(PT((R)-warfarin)) : AUC(PT((S)-warfarin))) was 1.21 fold higher (95% CI 1.05, 1.41, P < 0.02) in subjects of VKORC1 TT genotype compared with the CC genotype. CONCLUSIONS: (R)-warfarin has a clear PD effect and contributes to the hypoprothrombinaemic effect of rac-warfarin. VKORC1 genotype is a covariate of the relative R/S potency relationship. Prediction of drug interactions with warfarin needs to consider effects on (R)-warfarin PK and VKORC1 genotype.

Increased responsiveness of peripheral blood mononuclear cells to in vitro TLR 2, 4 and 7 ligand stimulation in chronic pain patients.

Glial activation via Toll-like receptor (TLR) signaling has been shown in animals to play an important role in the initiation and establishment of chronic pain. However, our ability to assess this central immune reactivity in clinical pain populations is currently lacking. Peripheral blood mononuclear cells (PBMCs) are an accessible source of TLR expressing cells that may mirror similarities in TLR responsiveness of the central nervous system. The aim of this study was to characterize the IL-1ß response to various TLR agonists in isolated PBMCs from chronic pain sufferers (on and not on opioids) and pain-free controls. Venous blood was collected from 11 chronic pain sufferers on opioids (≥ 20 mg of morphine / day), 8 chronic pain sufferers not on opioids and 11 pain-free controls. PBMCs were isolated and stimulated in vitro with a TLR2 (Pam3CSK4), TLR4 (LPS) or TLR7 (imiquimod) agonist. IL-1ß released into the supernatant was measured with ELISA. Significantly increased IL-1ß expression was found in PBMCs from chronic pain sufferers (on and not on opioids) compared with pain-free controls for TLR2 (F((6, 277)) = 15, P<0.0001), TLR4 (F((8, 263)) = 3, P = 0.002) and TLR7 (F((2,201)) = 5, P = 0.005) agonists. These data demonstrate that PBMCs from chronic pain sufferers were more responsive to TLR agonists compared with controls, suggesting peripheral cells may have the potential to become a source of biomarkers for chronic pain.

The effects of pregabalin and the glial attenuator minocycline on the response to intradermal capsaicin in patients with unilateral sciatica.

BACKGROUND: Patients with unilateral sciatica have heightened responses to intradermal capsaicin compared to pain-free volunteers. No studies have investigated whether this pain model can screen for novel anti-neuropathic agents in patients with pre-existing neuropathic pain syndromes. AIM: This study compared the effects of pregabalin (300 mg) and the tetracycline antibiotic and glial attenuator minocycline (400 mg) on capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia in patients with unilateral sciatica on both their affected and unaffected leg. METHODS/RESULTS: Eighteen patients with unilateral sciatica completed this randomised, double-blind, placebo-controlled, three-way cross-over study. Participants received a 10 µg dose of capsaicin into the middle section of their calf on both their affected and unaffected leg, separated by an interval of 75 min. Capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia were recorded pre-injection and at 5, 20, 40, 60 and 90 min post-injection. Minocycline tended to reduce pre-capsaicin injection values of hyperalgesia in the affected leg by 28% (95% CI 0% to 56%). The area under the effect time curves for capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia were not affected by either treatment compared to placebo. Significant limb differences were observed for flare (AUC) (-38% in affected leg, 95% CI for difference -19% to -52%). Both hand dominance and sex were significant covariates of response to capsaicin. CONCLUSIONS: It cannot be concluded that minocycline is unsuitable for further evaluation as an anti-neuropathic pain drug as pregabalin, our positive control, failed to reduce capsaicin-induced neuropathic pain. However, the anti-hyperalgesic effect of minocycline observed pre-capsaicin injection is promising pilot information to support ongoing research into glial-mediated treatments for neuropathic pain. The differences in flare response between limbs may represent a useful biomarker to further investigate neuropathic pain. Inclusion of a positive control is imperative for the assessment of novel therapies for neuropathic pain.

Comparison of pain models to detect opioid-induced hyperalgesia.

OBJECTIVE: Chronic opioid therapy may be associated with hyperalgesia. Our objective was to determine if opioid-induced hyperalgesia detection sensitivity is dependent on the stimulus used to detect it. METHODS: This open design study compared the detection of hyperalgesia in opioid-dependent subjects (n = 16) and healthy control subjects (n = 16) using the following pain stimuli: cold pain, electrical stimulation, mechanical pressure, and ischemic pain. The opioid-dependent subjects were maintained on either methadone (n = 8) or buprenorphine (n = 8) for at least 3 months. None of the controls was dependent on opioids or other drugs of abuse. RESULTS: The opioid-dependent subjects were markedly more sensitive than controls to the cold pain test. Compared with the control group, the hazard ratio for ceasing the test due to intolerable pain was 7.7 (95% confidence interval [CI] 2.6-23.3) in the buprenorphine group and 4.5 (95% CI 1.7-15.6) in the methadone group, with similar data for the cold pain threshold. Of the remaining tests, there were differences only for the electrical pain threshold between treatment groups, with the geometric mean threshold in the buprenorphine group being 1.5 (95% CI 1.1-1.9)-fold higher (ie, less sensitive) than that of the controls; the geometric mean for the methadone group was 1.3 (95% CI 1.04-1.7)-fold higher than that of the controls. There were no significant differences between buprenorphine and methadone patients in test responses. Women were more sensitive to the cold pain (hazard ratio for tolerance, 3.1 [95% CI 1.4-7.3]) and ischemic tests (hazard ratio for tolerance, 2.7 [95% CI 1.2-6.1]). There were significant correlations between cold and ischemic tolerances (r = 0.50; P = 0.003) and between electrical and mechanical pain tolerances (r = 0.52; P = 0.002). CONCLUSION: These findings indicate that cold pain is the most suitable of the methods tested to detect opioid-induced hyperalgesia. This is consistent with its sensitivity to detect opioid analgesia.

Intradermal capsaicin as a neuropathic pain model in patients with unilateral sciatica.

AIM: This study compared the responses between patients with unilateral sciatica and pain-free volunteers following administration of intradermal capsaicin. METHODS Fourteen patients with unilateral sciatica and 12 pain-free volunteers received one injection per hour over 4 h of 1 µg and 10 µg capsaicin, into each calf. For each dose, spontaneous pain (10 cm VAS), area of flare (cm²) and the sum of allodynia and hyperalgesia radii across eight axes (cm) were recorded pre-injection and at 5, 15, 30, 45 and 60 min post injection. RESULTS: Sciatica subjects experienced higher spontaneous pain and hyperalgesia responses in both legs compared with pain-free volunteers. The largest mean difference in spontaneous pain was 2.8 cm (95% CI 1.6, 3.9) at 5 min in the unaffected leg following 10 µg. The largest mean difference in hyperalgesia was 19.7 cm (95% CI 12.4, 27.0) at 60 min in the unaffected leg following 10 µg. Allodynia was greater in patients than in controls with the largest mean difference of 2.9 cm (95% CI 1, 4.8) at 5 min following 10 µg in the affected leg. Allodynia was also higher in the affected leg compared with the unaffected leg in sciatica patients with the highest mean difference of 3.0 cm (95% CI 1.2, 4.7) at 5 min following 10 µg. CONCLUSIONS: The responses to intradermal capsaicin are quantitatively and qualitatively different in unilateral sciatica patients compared with pain-free controls.

Utility of saccadic eye movement analysis as an objective biomarker to detect the sedative interaction between opioids and sleep deprivation in opioid-naive and opioid-tolerant populations.

Analysis of saccadic eye movements (SEMs) has previously been used to detect drug- and sleep-deprivation-induced sedation, but never in combination. We compared the effects of sleep deprivation and opioids on 10 opioid-naive with nine opioid-tolerant participants. The naive-participant study evaluated the effects of sleep deprivation alone, morphine alone and the combination; the tolerant-participant study compared day-to-day effects of alternate-daily-dosed buprenorphine and the combination of buprenorphine on the dosing day with sleep deprivation. Psychomotor impairment was measured using SEMs, a 5-minute pupil adaptation test (PAT), pupil light reflex (PLR) and alertness visual analogue scale (AVAS). The PAT and PLR did not detect sleep deprivation, in contrast to previous studies. Whilst consistently detecting sleep deprivation, the AVAS also detected buprenorphine in the tolerant study, but not morphine in the naive study. SEMs detected morphine alone and sleep deprivation alone as well as an additive interaction in the naive study and the effect of sleep deprivation in the tolerant study. The alternate-day buprenorphine dosing did not alter SEMs. The current study revealed greater SEMs, but not AVAS impairment in tolerant versus naive participants. The current study demonstrates that objective measures provide additional information to subjective measures and thus should be used in combination.

Randomized cross-over comparison of intravenous and subcutaneous darbepoetin dosing efficiency in haemodialysis patients.

BACKGROUND: Studies have consistently shown the superior dosing efficiency of subcutaneous (s.c.) compared to intravenous (i.v.) erythropoietin (r-HuEPO). Unlike r-HuEPO, data from pivotal darbepoetin trials support s.c. and i.v. dosing equivalence, however, no blinded cross-over randomized studies of s.c. and i.v. dose efficiency or intra-patient variability in response have been published. METHODS: During this 12-month study, 53 haemodialysis patients were randomized to s.c. or i.v. darbepoetin for a 6-month period and then switched to the alternative route for a second 6-month period. Darbepoetin dose was titrated during the first 4-months of each period to achieve a stable haemoglobin during the final 2-month observation period of each arm. RESULTS: Twenty-four patients were included in analysis. No significant difference between s.c. and i.v. administration was observed for any measured parameter. Patients achieved a non-significantly higher haemoglobin (123.6 +/- 3.76 vs 120.9 +/- 4.42 g/L, P = 0.11) from a non-significantly lower darbepoetin dose (40.8 +/- 10.7 vs 42.5 +/- 11.0 mcg/week, P = 0.23) with i.v. administration. The population-based weight normalized s.c./i.v. dose ratio was 1.04 (0.97-1.11). Despite no significant overall difference, some patients experienced changes in individual dose efficiency response. Three of 24 patients recorded a greater than 30% change, four of 24 recorded between a 20 and 30% change, and five of 24 patients recorded between a 10 and 20% change relative to i.v. dose efficiency. CONCLUSIONS: This study further supports s.c. and i.v. dosing equality and that overall the more convenient i.v. route can be used with equal dosing efficiency. However, patients switching routes of administration should be monitored due to the wide range in individual response.