Opiate of the masses

With the holiday season approaching in Western Europe, for many, it is now time to check the first-aid travel kit. Just in time for this, the FDA recently made the headlines on 7 June 2016, announcing ‘next steps’ in the seemingly bizarre case series of fatal overdoses of common over-the-counter antidotes for Montezuma’s revenge. According to the recent safety statement, ‘serious heart problems occurred in individuals who were intentionally misusing and abusing high doses of loperamide in attempts to self-treat opioid withdrawal symptoms or to achieve a feeling of euphoria’ (FDA 2016). Wow. Usually, ‘Imodium’ and ‘euphoria’ do not usually sit peacefully side by side in one sentence, or so the odd physiologist might have thought, while at the same time her colleagues on call in the emergency room are fighting for the life of an individual having taken up to 20 times the recommended daily dose at once, and while National Poison Centers in the USA. have been seeing a 71% rise in calls related to loperamide overdoses since 2011 only (Eggleston et al. 2016). On pages such as howtoquitheroin.com, high-dose loperamide is recommended for quitting heroine while working. ‘How much you take is entirely up to you’: A verbatim citation from that page regarding loperamide dosage pretty much nails down the problem of OTC opioid derivatives, which may soon be history. Substance abuse, addiction and opioid dependence are no novel phenomena. For millennia, shamans have induced trance states, while ordinary people have looked for recreational effects. In Homer’s Odyssey from the 9th century B.C.E. , Helen of Troy receives from an Egyptian queen a poppy seed potion ‘to lull all pain and anger and bring forgetfulness of every sorrow’ to the warriors (Odyssey 4, 221, cited in: Crocq 2007). Neither are these phenomena exclusive to humans: most Northern Europeans are familiar with the annual autumnal newspaper headlines of intoxicated elks (moose) which, after having feasted on fermented apples, tangle their antlers in one another’s or decide to sleep off their delirium on some unsuspecting folks’ terrace. What is new, though, is the evolving complex picture of what lies behind: our understanding of addiction and dependence has changed from seeing these as uncontrolled, antisocial forms of behaviour to a profound dysregulation of several interconnected regulatory systems and switches with differential risk profiles, in which environmental and hereditary factors interact. Dopamine, involved in processes as complex as motor control and motivation and dysregulated in Parkinson’s disease (Zheng et al. 2014), has become famous for its role in the endogenous reward systems. In contrast to the relatively low number of dopaminergic neurones and the relatively small areas covered by dopaminergic nuclei within the CNS, their complex neuromodulatory projections reach numerous brain areas (McKinley et al. 2015). Half a century ago, Annica Dahlstr€ om and Kjell Fuxe first suggested in Acta Physiologica Scand the nomenclature for all dopaminergic cell groups which is still in use today (Dahlstroem & Fuxe 1964). Clinical psychiatrists report a ‘chicken and egg’ problem when evaluating multidrug-dependent patients with, for example, schizophrenic spectrum disorders, in whom it is often not discernible whether the psychiatric symptoms would result from drug abuse or whether drugs had been taken to ‘quiet the voices’ in the patient’s head. Recent research results are unveiling the manifold interfaces of drug abuse and disorders of the psyche. Stress, stress response, sleep disorders and PTSD are linked to depression (Urrila et al. 2015) and the risk and consequences of substance abuse (Thompson et al. 2014) (Sheerin et al. 2016). So are early life events, whose underlying biological mechanisms are slowly being understood (Loria et al. 2014) (Patchev et al. 2014). The role of neuropeptides such as NPY (Farzi et al. 2015) (V€ah€atalo et al. 2015) or the orexin/hypocretin systems (Sundvik & Panula 2015) in addiction and dependence is evolving (van den Pol 2012), and may provide one neurobiological link between stress, sleep disorders, resilience and substance abuse. Recent physiological research has shed light on another imminent problem: within the fatal network of (especially i.v.) abuse, acquisitive crime, needle sharing and the risk of infection, opioids independently increase the susceptibility to infectious disease (Wan et al. 2015). Drug abuse, addiction and dependence are just a few selected aspects of a multifaceted problem, which is very real and on the rise. Physiology will continue to contribute to its understanding!