Cancer related pain: a review of patient education to challenge a dominant biomedical view

Background: Cancer related pain is a significant & growing problem for those living with & surviving cancer, requiring biopsychosocial (BPS) management independent to treatment of underlying disease. Best practice pain management has been established in the field of chronic non cancer pain (CNCP), starting with education that is grounded in pain science. Consideration of this approach for cancer related pain management is scarce, yet there is strong rationale for its use. The aim of this study was to explore the use of pain science in explaining cancer related pain to patients through education, facilitating communication of a BPS phenomenon. Methods: An exploratory narrative review was used to unveil a practice in its inception & deepen understanding of the field (Greenhalgh et al. 2018). All relevant literature was identified using 7 target concepts of pain education (search completed June ’21). A descriptive synthesis of findings was interpreted & critiqued. Methodological quality was included to assess the impact on findings, not as criteria for exclusion. Results: Pain science education is poorly established in the cancer pain management literature. 8 studies (4 RCTs, 2 pilot, 2 feasibility) met the inclusion criteria. Study sample sizes of 9-127, 238 unique participants, 112 received targeted pain education. Conclusive findings from a small evidence base of variable design & quality were limited, but positive individual outcomes provide rich detail for clinical application & a plausible basis for further research. Conclusions: To the author’s knowledge, this is the first review to explore the use of pain science in explaining cancer related pain to patients through education. It provides a basis to illuminate this field & focus & develop the evidence base for clinical practice. A biomedical model continues to dominate the management of cancer related pain when an evidence base exists for reconceptualising & communicating a BPS phenomenon through high quality education. The evidence base represents some progress, but is in its inception. The future potential could be significant. Acknowledgements and Disclosures of Interest(s): The authors report no competing interests to declare, nor funding associated with this work

Performance on a probabilistic inference task in healthy subjects receiving ketamine compared with patients with schizophrenia

Evidence suggests that some aspects of schizophrenia can be induced in healthy volunteers through acute administration of the non-competitive NMDA-receptor antagonist, ketamine. In probabilistic inference tasks, patients with schizophrenia have been shown to 'jump to conclusions' (JTC) when asked to make a decision. We aimed to test whether healthy participants receiving ketamine would adopt a JTC response pattern resembling that of patients. The paradigmatic task used to investigate JTC has been the 'urn' task, where participants are shown a sequence of beads drawn from one of two 'urns', each containing coloured beads in different proportions. Participants make a decision when they think they know the urn from which beads are being drawn. We compared performance on the urn task between controls receiving acute ketamine or placebo with that of patients with schizophrenia and another group of controls matched to the patient group. Patients were shown to exhibit a JTC response pattern relative to their matched controls, whereas JTC was not evident in controls receiving ketamine relative to placebo. Ketamine does not appear to promote JTC in healthy controls, suggesting that ketamine does not affect probabilistic inferences

GaPP2, a multicentre randomised controlled trial of the efficacy of gabapentin for the management of chronic pelvic pain in women:study protocol

Introduction: Chronic pelvic pain (CPP) affects more than 1 million UK women with associated healthcare costs of £158 million annually. Current evidence supporting interventions when no underlying pathology is identified is very limited and treatment is frequently inadequate. Gabapentin (a GABA analogue) is efficacious and often well tolerated in other chronic pain conditions. We have completed a successful pilot randomised controlled trial (GaPP1) and here describe the protocol for the definitive multicentre trial to assess the efficacy of gabapentin in the management of CPP in women (GaPP2).Methods and analysis: We plan to perform a double blind placebo controlled randomised multi-centre clinical trial, recruiting 300 women with CPP from more than 8 NHS hospitals within the UK. After randomisation, women will titrate their medication (gabapentin or placebo) over a 4-week period to a maximum of 2700mg or placebo equivalent and will then maintain a stable dose for a 12 week period. Response to treatment will be monitored with validated questionnaires and co-primary outcome measures of average and worst pain scores will be employed. The primary objective is to test the hypothesis that treatment with gabapentin has the potential to provide an effective oral treatment to alleviate pain in women with CPP in the absence of any obvious pelvic pathology.Ethics and dissemination: Ethical approval has been obtained from the Coventry and Warwick Research Ethics Committee (REC 15/WM/0036). Data will be presented at international conferences and published in peer-reviewed journals. We will make the information obtained from the study available to the public through national bodies and charities.Trial registration number: ISRCTN7745176

Gabapentin for chronic pelvic pain in women (GaPP2):a multicentre, randomised, double-blind, placebo-controlled trial

BackgroundChronic pelvic pain affects 2–24% of women worldwide and evidence for medical treatments is scarce. Gabapentin is effective in treating some chronic pain conditions. We aimed to measure the efficacy and safety of gabapentin in women with chronic pelvic pain and no obvious pelvic pathology.MethodsWe performed a multicentre, randomised, double-blind, placebo-controlled randomised trial in 39 UK hospital centres. Eligible participants were women with chronic pelvic pain (with or without dysmenorrhoea or dyspareunia) of at least 3 months duration. Inclusion criteria were 18–50 years of age, use or willingness to use contraception to avoid pregnancy, and no obvious pelvic pathology at laparoscopy, which must have taken place at least 2 weeks before consent but less than 36 months previously. Participants were randomly assigned in a 1:1 ratio to receive gabapentin (titrated to a maximum dose of 2700 mg daily) or matching placebo for 16 weeks. The online randomisation system minimised allocations by presence or absence of dysmenorrhoea, psychological distress, current use of hormonal contraceptives, and hospital centre. The appearance, route, and administration of the assigned intervention were identical in both groups. Patients, clinicians, and research staff were unaware of the trial group assignments throughout the trial. Participants were unmasked once they had provided all outcome data at week 16–17, or sooner if a serious adverse event requiring knowledge of the study drug occurred. The dual primary outcome measures were worst and average pain scores assessed separately on a numerical rating scale in weeks 13–16 after randomisation, in the intention-to-treat population. Self-reported adverse events were assessed according to intention-to-treat principles. This trial is registered with the ISRCTN registry, ISCRTN77451762.FindingsParticipants were screened between Nov 30, 2015, and March 6, 2019, and 306 were randomly assigned (153 to gabapentin and 153 to placebo). There were no significant between-group differences in both worst and average numerical rating scale (NRS) pain scores at 13–16 weeks after randomisation. The mean worst NRS pain score was 7·1 (standard deviation [SD] 2·6) in the gabapentin group and 7·4 (SD 2·2) in the placebo group. Mean change from baseline was −1·4 (SD 2·3) in the gabapentin group and −1·2 (SD 2·1) in the placebo group (adjusted mean difference −0·20 [97·5% CI −0·81 to 0·42]; p=0·47). The mean average NRS pain score was 4·3 (SD 2·3) in the gabapentin group and 4·5 (SD 2·2) in the placebo group. Mean change from baseline was −1·1 (SD 2·0) in the gabapentin group and −0·9 (SD 1·8) in the placebo group (adjusted mean difference −0·18 [97·5% CI −0·71 to 0·35]; p=0·45). More women had a serious adverse event in the gabapentin group than in the placebo group (10 [7%] of 153 in the gabapentin group compared with 3 [2%] of 153 in the placebo group; p=0·04). Dizziness, drowsiness, and visual disturbances were more common in the gabapentin group.InterpretationThis study was adequately powered, but treatment with gabapentin did not result in significantly lower pain scores in women with chronic pelvic pain, and was associated with higher rates of side-effects than placebo. Given the increasing reports of abuse and evidence of potential harms associated with gabapentin use, it is important that clinicians consider alternative treatment options to off-label gabapentin for the management of chronic pelvic pain and no obvious pelvic pathology.FundingNational Institute for Health Research

Acute and chronic effects of ketamine on semantic priming modeling schizophrenia?

Acute administration of the N-methyl-D-aspartate receptor antagonist ketamine induces schizophrenia-like symptoms in healthy volunteers; furthermore, a window on ketamine's chronic effects is provided by regular recreational users. The current study utilized both acute ketamine administration in healthy volunteers and chronic ketamine abusers to investigate semantic processing, one of the key cognitive deficits in schizophrenia. Semantic processing was examined using a semantic priming paradigm. In experiment 1, acute effects of low (75 ng/mL) and high (150 ng/mL) ketamine doses were compared in a placebo-controlled double-blind independent group design with 48 participants. In experiment 2, 19 regular recreational ketamine users were compared with 19 ketamine-naive polydrug controls and 26 non-drug-using controls. In both experiments, semantic priming parameters were manipulated to distinguish between ketamine's effects on (1) automatic and strategic processing and (2) the facilitation and inhibition components of semantic priming for strongly (directly) related primes and targets. Acute effects of ketamine on semantic priming for weakly (indirectly) related primes and targets were also assessed in experiment 1. Acutely, ketamine impaired the employment of strategic mechanisms but not automatic processing within both the direct and indirect semantic priming tasks. Acute ketamine administration also induced clear schizophrenia-like symptoms. Schizotypy traits in the cognitive and perceptual domains tended to correlate with increased semantic priming in long-term ketamine users. In summary, acute and chronic ketamine-induced changes partially mirrored the findings on semantic priming in schizophrenia

Production of functionalized single-chain Fv antibody fragments binding to the ED-B domain of the B-isoform of fibronectin in Pichia pastoris

The Pichia pastoris expression system was used to produce functionalized single-chain antibody fragments (scFv) directed against the ED-B domain of the B-fibronectin (B-Fn) isoform which was found to be present only in newly formed blood vessels during tumor angiogenesis. Therefore, scFv antibody fragments recognizing the ED-B domain are potential markers for angiogenesis. We constructed four functionalized scFv antibody fragments for direct labeling with radioactive molecules or toxins or for attachment to liposomes serving as carriers for cytotoxic or antiangiogenic compounds. The C-termini of the scFv antibody fragments contain 1-3 cysteine residues that are separated by a hydrophilic linker (GGSSGGSSGS) from the binding domain and are accessible for site-specific functionalization with thiol-reactive reagents. Plasmid expression, culture conditions, and purification were optimized in 1-L cultures. The scFv antibody fragments were purified by anion exchange chromatography. The yields were 5-20 mg/L culture medium. The large-scale production of one scFv antibody fragment in a 3.7-L fermenter gave a yield of 60 mg. The reactivity of the cyteines was demonstrated by labeling with the thiol-reactive fluorescent dye ABD-F. The four scFv antibody fragments bound specifically to ED-B-modified Sepharose and binding was further confirmed by immunofluorescence on cell cultures using ED-B-positive human Caco-2 tumor cells. Furthermore, we could demonstrate specific binding of scFv-modified liposomes to ED-B-positive tumor cells. Our results indicate that the P. pastoris expression system is useful for the large-scale production of cysteine-functionalized alpha-ED-B scFv antibody fragments