Towards an understanding of the burdens of medication management affecting older people: the MEMORABLE realist synthesis.

BACKGROUND: More older people are living in the community with multiple diagnoses and medications. Managing multiple medications produces issues of unrivalled complexity for those involved. Despite increasing literature on the subject, gaps remain in understanding how, why and for whom complex medication management works, and therefore how best to improve practice and outcomes. MEMORABLE, MEdication Management in Older people: Realist Approaches Based on Literature and Evaluation, aimed to address these gaps. METHODS: MEMORABLE used realism to understand causal paths within medication management. Informed by RAMESES (Realist And Meta-narrative Evidence Synthesis: and Evolving Standards) guidelines, MEMORABLE involved three overlapping work packages: 1) Realist Review of the literature (24 articles on medication management exploring causality); 2) Realist Evaluation (50 realist-informed interviews with older people, family carers and health and care practitioners, explaining their experiences); and 3) data synthesis and theorising from 1) and 2). RESULTS: Medication management was viewed from the perspective of 'implementation' and structured into five stages: identifying a problem (Stage 1), getting a diagnosis and/or medications (Stage 2), starting, changing or stopping medications (Stage 3), continuing to take medications (Stage 4), and reviewing/reconciling medications (Stage 5). Three individual stages (1, 3 and 4) are conducted by the older person sometimes with family carer support when they balance routines, coping and risk. Stages 2 and 5 are interpersonal where the older person works with a practitioner-prescriber-reviewer, perhaps with carer involvement. Applying Normalisation Process Theory, four steps were identified within each stage: 1) sense making: information, clarification; 2) action: shared-decision-making; 3) reflection/monitoring; and 4) enduring relationships, based on collaboration and mutual trust. In a detailed analysis of Stage 5: Reviewing/reconciling medications, adopting the lens of 'burden', MEMORABLE identified five burdens amenable to mitigation: ambiguity, concealment, unfamiliarity, fragmentation and exclusion. Two initial improvement propositions were identified for further research: a risk screening tool and individualised information. CONCLUSIONS: Older people and family carers often find medication management challenging and burdensome particularly for complex regimens. Practitioners need to be aware of this potential challenge, and work with older people and their carers to minimise the burden associated with medication management. TRIAL REGISTRATION: PROSPERO 2016:CRD42016043506.

Intense isolectin-B4 binding in rat dorsal root ganglion neurons distinguishes C-fiber nociceptors with broad action potentials and high Nav1.9 expression.

Binding to isolectin-B4 (IB4) and expression of tyrosine kinase A (trkA) (the high-affinity NGF receptor) have been used to define two different subgroups of nociceptive small dorsal root ganglion (DRG) neurons. We previously showed that only nociceptors have high trkA levels. However, information about sensory and electrophysiological properties in vivo of single identified IB4-binding neurons, and about their trkA expression levels, is lacking. IB4-positive (IB4+) and small dark neurons had similar size distributions. We examined IB4-binding levels in >120 dye-injected DRG neurons with sensory and electrophysiological properties recorded in vivo. Relative immunointensities for trkA and two TTX-resistant sodium channels (Nav1.8 and Nav1.9) were also measured in these neurons. IB4+ neurons were classified as strongly or weakly IB4+. All strongly IB4+ neurons were C-nociceptor type (C-fiber nociceptive or unresponsive). Of 32 C-nociceptor-type neurons examined, approximately 50% were strongly IB4+, approximately 20% were weakly IB4+ and approximately 30% were IB4-. Adelta low-threshold mechanoreceptive (LTM) neurons were weakly IB4+ or IB4-. All 33 A-fiber nociceptors and all 44 Aalpha/beta-LTM neurons examined were IB4-. IB4+ compared with IB4- C-nociceptor-type neurons had longer somatic action potential durations and rise times, slower conduction velocities, more negative membrane potentials, and greater immunointensities for Nav1.9 but not Nav1.8. Immunointensities of IB4 binding in C-neurons were positively correlated with those of Nav1.9 but not Nav1.8. Of 23 C-neurons tested for both trkA and IB4, approximately 35% were trkA+/IB4+ but with negatively correlated immunointensities; 26% were IB4+/trkA-, and 35% were IB4-/trkA+. We conclude that strongly IB4+ DRG neurons are exclusively C-nociceptor type and that high Nav1.9 expression may contribute to their distinct membrane properties.

trkA is expressed in nociceptive neurons and influences electrophysiological properties via Nav1.8 expression in rapidly conducting nociceptors.

To test the hypothesis that trkA (the high-affinity NGF receptor) is selectively expressed in nociceptive dorsal root ganglion (DRG) neurons, we examined the intensity of trkA immunoreactivity in single dye-injected rat DRG neurons, the sensory receptor properties of which were identified in vivo with mechanical and thermal stimuli. We provide the first evidence in single identified neurons that strong trkA expression in DRGs is restricted to nociceptive neurons, probably accounting for the profound influence of NGF on these neurons. Furthermore, we demonstrate that trkA expression is as high in rapidly conducting (Aalpha/beta) as in more slowly conducting (Adelta and C) nociceptors. All Aalpha/beta low-threshold mechanoreceptors (LTMs) are trkA negative, although weak but detectable trkA is present in some C and Adelta LTMs. NGF can influence electrophysiological properties of DRG neurons, probably by binding to trkA. We found positive correlations for single identified Aalpha/beta (but not C or Adelta) nociceptors between trkA immunocytochemical intensity and electrophysiological properties typical of nociceptors, namely long action potential and afterhyperpolarization durations and large action potential amplitudes. Furthermore, for Aalpha/beta (notCorAdelta) nociceptors, trkA intensity is inversely correlated with conduction velocity. Similar relationships, again only in Aalpha/beta nociceptors, between electrophysiological properties and trkA expression exist for sodium channel Nav1.8 but not Nav1.9 immunoreactivities. These findings suggest that in Aalpha/beta nociceptors, influences of NGF on expression levels of Nav1.8 are related to, and perhaps limited by, expression levels of trkA. This view is supported by a positive correlation between immuno-intensities of trkA and Nav1.8 in A-fiber, but not C-fiber, nociceptors.