Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

<p>Abstract</p> <p>Background</p> <p>Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics.</p> <p>Discussion</p> <p>In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.</p> <p>As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy.</p> <p>Summary</p> <p>Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies.</p

Diluted equilibrium sterile neutrino dark matter

We present a model where sterile neutrinos with rest masses in the range ∼keV to ∼MeV can be the dark matter and be consistent with all laboratory, cosmological, and large-scale structure, as well as x-ray constraints. These sterile neutrinos are assumed to freeze out of thermal and chemical equilibrium with matter and radiation in the very early Universe, prior to an epoch of prodigious entropy generation ("dilution") from out-of-equilibrium decay of heavy particles. In this work, we consider heavy, entropy-producing particles in the ∼TeV to ∼EeV rest-mass range, possibly associated with new physics at high-energy scales. The process of dilution can give the sterile neutrinos the appropriate relic densities, but it also alters their energy spectra so that they could act like cold dark matter, despite relatively low rest masses as compared to conventional dark matter candidates. Moreover, since the model does not rely on active-sterile mixing for producing the relic density, the mixing angles can be small enough to evade current x-ray or lifetime constraints. Nevertheless, we discuss how future x-ray observations, future lepton number constraints, and future observations and sophisticated simulations of large-scale structure could, in conjunction, provide evidence for this model and/or constrain and probe its parameters