tag:theconversation.com,2011:/ca/topics/diclofenac-4790/articlesDiclofenac – The Conversation2014-04-09T05:09:50Ztag:theconversation.com,2011:article/253452014-04-09T05:09:50Z2014-04-09T05:09:50ZProzac alters prawns’ behaviour, reproduction and even their colour<figure><img src="https://images.theconversation.com/files/45885/original/8gsqrqmb-1396981323.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Amphipods on anti-depressants found their lives brightened, right up until they were eaten.</span> <span class="attribution"><a class="source" href="http://commons.wikimedia.org/wiki/File:Talitrus_saltator_2c.jpg">Arnold Paul</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>The idea that tiny amounts of antidepressants present in our rivers and estuaries may be affecting aquatic life is generally met with surprise, sometimes scepticism, or even a degree of humour. </p>
<p>The public were first alerted to pharmaceuticals in the environment in the 1990s through <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1518861/">studies</a> which showed that synthetic oestrogens, such as in the contraceptive pill, could feminise male fish, even in incredibly low concentrations of nanograms per litre (ng/L). This led to concerns of a similar effect on <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1519860/">male human fertility</a>, although it’s been hard to draw any conclusions. </p>
<p>The idea that even tiny amounts of chemicals might dramatically alter the physiology of fish and other aquatic organisms isn’t that new. Back in the 1980s scientists were aware that concentrations even below 10ng/L of <a href="http://www.abc.net.au/environment/articles/2014/01/13/3916477.htm">tributyltin or TBT</a>, a compound used in anti-fouling paints for ships’ hulls, would cause female dog whelks (a sort of sea snail) to <a href="http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=4390216">grow a penis</a>. This resulted in catastrophic reproductive failure in females which wiped out snail populations along the world’s coasts, which had knock-on effects on organisms further up and down the food chain.</p>
<p>A more recent example is diclofenac, a non-steroidal anti-inflammatory drug given to lame cattle in India and Pakistan. While considered harmless to mammals, what was not predicted was that vultures preying on dead cattle would <a href="http://rspb.royalsocietypublishing.org/content/271/Suppl_6/S458">suffer catastrophic renal failure</a>, resulting in their populations <a href="http://www.nature.com/nature/journal/v427/n6975/full/nature02317.html">plunging by 90%</a>.</p>
<p>Some scientists have suggested that reduced vulture populations led to a boom in feral dog populations and an increase in rabies among the human population. <a href="http://www.theguardian.com/world/2004/apr/22/outlook.development1">Highly publicised</a>, this focused people’s attention on the toxicological impact of human and veterinary drugs on wildlife. </p>
<h2>Amphipods on anti-depressants</h2>
<p>So what’s the evidence that anti-depressants, now quite commonly prescribed medicines, are affecting aquatic wildlife? After all, studies have found that sewage effluent entering rivers can carry anti-depressants at concentrations up to around 1µg/l (one microgram, equal to 1000ng/L), although in most rivers the concentrations recorded are considerably less at around 10-20ng/L. There is growing evidence that even at these low concentrations of under 100ng/L medicines can cause changes in a wide range of biological functions and behaviours. </p>
<p>For example, many anti-depressants were designed to modulate serotonin. Serotonin is a hormone that is found throughout the animal kingdom and is known to play a role in controlling <a href="http://www.ncbi.nlm.nih.gov/pubmed/24374179">behaviour, growth, metabolism, reproduction, colour, and the immune system</a>.</p>
<p>At the <a href="http://www.port.ac.uk/school-of-biological-sciences/facilities/institute-of-marine-sciences/">Institute of Marine Sciences</a> in the University of Portsmouth we <a href="http://dx.doi.org/10.1016/j.aquatox.2010.05.019">published an article</a> in 2010 that demonstrated that serotonin in amphipods, a crustacean rather like a tiny prawn, was responsible for controlling their preference to seek light or dark areas. </p>
<p>As amphipods high in serotonin preferred light areas, would anti-depressants such as fluoxetine (Prozac) have the same effect? We found that a few weeks’ exposure to 10-100ng/L of fluoxetine – about the level found in rivers around urban areas – resulted in a five times greater preference for light.</p>
<h2>Many effects on many creatures</h2>
<p>A <a href="http://www.sciencedirect.com/science/article/pii/S0166445X14000551">special edition</a> of the journal Aquatic Toxicology has pooled together studies of antidepressants in the aquatic environment. The most striking results suggest that many species, including fish, snails, bivalves, cuttlefish and crustaceans, are affected by anti-depressants even in low concentrations. The observed effects include altered swimming and behaviour patterns, locomotion, immune function, reproduction, feeding and predator behaviour through to gene expression – even a physical change of colour. There appears to be considerable variability between the species affected.</p>
<p>Despite these findings however, there is no evidence that these particular pharmaceuticals have the same effects in the wild as all studies to date have been laboratory studies. While it’s relatively easy to determine whether a fish has had past exposure to, for example, an oestrogenic chemical, it’s currently very difficult to determine abnormal behaviour from exposure to antidepressants. Others have <a href="http://dx.doi.org/10.1016/j.aquatox.2013.11.021">expressed caution</a>, suggesting that these studies must be repeated at other laboratories and rigorous measurements must be taken on the exposure concentrations used in the laboratory experiments. </p>
<p>There are other factors to consider too: while the crustaceans exposed to serotonin showed a preference for light, some of the species studied also carry parasites which have evolved to alter their host’s serotonin precisely so that they swim in open areas. This makes them more vulnerable to being eaten – the ultimate goal of the parasite, for whom the crustacean is merely an intermediate step towards entering the predator’s body where it completes its lifecycle.</p>
<h2>Medicines, medicines, everywhere</h2>
<p>This isn’t just about anti-depressants. We consume hundreds of different types of medication every day and they all appear to some extent in sewage effluent. Even the most modern, most costly sewage treatment processes still aren’t able to filter out all chemical contaminants.</p>
<p>The question of “greener” pharmaceuticals that break down more readily into harmless chemicals has been suggested, but this may prove incredibly difficult to achieve given they are formulated specifically to work optimally in the human (or animal) body. Some countries are strongly debating the need for national <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866706/">take-back programs</a> whereby unused medication is collected and appropriately disposed.</p>
<p>I expect the next few years will strengthen the evidence that anti-depressants and other biologically active compounds are pollutants of concern, in which case they will join a long list of chemicals, including industrial pollutants such as sulphur and lead, whose effects on health were scientifically established and regulations passed to protect human and environmental health.</p><img src="https://counter.theconversation.com/content/25345/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Alex Ford receives funding from the Natural Environment Research Council (NERC) & EU Interreg program (PeReNE) to study reproductive and neuro-endocrine disruption in crustaceans.</span></em></p>The idea that tiny amounts of antidepressants present in our rivers and estuaries may be affecting aquatic life is generally met with surprise, sometimes scepticism, or even a degree of humour. The public…Alex Ford, Reader in Biology, University of PortsmouthLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/157362013-07-02T14:43:36Z2013-07-02T14:43:36ZRegulator still falling short over painkiller warnings<figure><img src="https://images.theconversation.com/files/26726/original/kncmgpzf-1372771773.jpg?ixlib=rb-1.1.0&rect=3%2C7%2C2651%2C1760&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">It's a numbers game: warning of heart attack risk is reassuring but misleading.</span> <span class="attribution"><span class="source">Flickr/ansik</span></span></figcaption></figure><p>Millions of people use diclofenac, an over-the-counter painkiller, to relieve pain and inflammation caused by arthritis, backache and other conditions. But on Friday, the UK medicines regulator, the Medicines and Healthcare products Regulatory Agency (MHRA), announced that patients with heart problems should avoid the medicine because it can <a href="http://www.guardian.co.uk/society/2013/jun/29/painkiller-diclofenac-heart-condition-patients-stroke">significantly increase the risk</a> of having a heart attack or stroke. </p>
<p>Diclofenac belongs to a family of drugs called non-steroidal anti-inflammatory drugs, or NSAIDs, which also includes a drug called naproxen and ibuprofen. They are available through prescription and over-the-counter. In 2011, there were nearly 5m prescriptions for diclofenac (<a href="http://www.guardian.co.uk/society/2013/jun/29/painkiller-diclofenac-heart-condition-patients-stroke">about a third of all NSAIDs</a> prescribed), and until 2012 it was the most prescribed NSAID in England.</p>
<p>But while reviews show naproxen isn’t associated with an increased risk of heart attacks and <a href="http://www.telegraph.co.uk/news/uknews/1547672/High-doses-of-ibuprofen-raise-heart-attack-risk.html">ibuprofen a lower risk</a>, this isn’t the case for diclofenac. </p>
<p>In 2011, a European review showed that patients using diclofenac were <a>40% more likely</a>) to have a heart attack than those who weren’t. This is the same level of risk as rofecoxib (brand name Vioxx) which was <a href="http://www.washingtonpost.com/wp-dyn/articles/A40458-2004Oct17.html">withdrawn in 2004</a> because of the dangers.</p>
<h2>Dangers evident since 2006</h2>
<p>Health officials have made the right decision but it’s been too slow coming. As long ago as 2006 there was evidence that diclofenac greatly increased the risk of heart attack.</p>
<p>In 2006 several published studies, <a href="http://www.ncbi.nlm.nih.gov/pubmed/16968831">including one by us</a>, made this link. The studies were systematic reviews of other smaller studies and included data from both randomised studies, where neither patients nor doctors know who is getting what treatment until the study is completed, and non-randomised ones, where observations are made in real-life situations. Like many decision-making bodies, the MHRA prefers data from randomised studies. </p>
<p>So despite the evidence, and the potential health threat, it was only when two reviews were published in journals this year, including <a href="http://bit.ly/1aCwym8">a Lancet review</a> of randomised studies, that the regulator acted.</p>
<p>In the meantime, how many people who have had diclofenac have needlessly suffered a heart attack? </p>
<h2>MHRA still falling short on warnings</h2>
<p>The regulator tells us that for every 1000 people who take diclofenac, it may cause three extra heart attacks (one fatal) over the number that would have occurred anyway. This doesn’t sound like a lot and it is true in so far as it goes. However, the trouble is that it’s misleadingly reassuring. </p>
<p>This “excess risk” as it is known, applies to people considered in the 2013 Lancet review. These were mostly white women with an average age of 61 and who were in pretty good health; just 9% of these had any history of heart disease and a similar percent for diabetes. So, about eight to nine per 1000 of these people would have had a heart attack a year without diclofenac. </p>
<p>If even this group of people had an excess of three heart attacks a year, what about those with higher levels of cardiac risk who take diclofenac? For them, the excess is a lot more.</p>
<p>Consider people who have already had a heart attack, still smoke a bit, have diabetes and high blood pressure with resulting kidney damage: of 1000 people like this, 50-100 will have a heart attack in the next year. Give them diclofenac – many of them also have arthritis pain - and 70-140 will have a heart attack. That’s an excess of 20-40 heart attacks that did not need to happen if they had been prescribed a safer NSAID like naproxen – and it’s an awful lot more than the three out of a 1000 excess in the MHRA warning. </p>
<p>And people walking around with these levels of cardiac risk aren’t rare. According <a>to the British Heart Foundation</a>), almost 2m people in England aged 65 and over have “serious cardiovascular disease”. If just 10% of these individuals got diclofenac, that’s 4000-8000 extra heart attacks that didn’t need to happen.</p>
<p>And it’s not as if people need to take diclofenac for weeks on end for their risk to rise. There are non-randomised studies showing the risk rises within days of commencing it. Neither does it have to be taken in high doses – the studies have found no “safe” lower dose.</p>
<p>High risk patients and their doctors might be inclined to dismiss the three in a 1000 heart attack excess as worth it for pain relief. They may not take the same view of an excess of 20 or 40 per 1000 people. So even now while the MHRA is providing the correct advice for patients at high risk of heart attacks it is publishing risk estimates that minimise the true hazard.</p>
<p>Diclofenac isn’t a risky drug being prescribed to just a handful of people. However, as concerns about its safety have increased, doctors have voted with their pens. Prescribing has slowed to around 3m prescriptions in 2012. In many cases it has now been replaced by naproxen for which there were almost 6m prescriptions in 2012, compared with under 3m in 2010. </p>
<p>But patients can thank their doctors for paying attention to the clear evidence on risk. There is little for which to thank the regulator.</p><img src="https://counter.theconversation.com/content/15736/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Patricia McGettigan does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Millions of people use diclofenac, an over-the-counter painkiller, to relieve pain and inflammation caused by arthritis, backache and other conditions. But on Friday, the UK medicines regulator, the Medicines…Patricia McGettigan, Senior Lecturer in Clinical Pharmacology, Queen Mary University of LondonLicensed as Creative Commons – attribution, no derivatives.