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by an exponential growth in people suffering from opioid use disorders in several countries, notably the USA. This opioid crisis has been described as the latest self-inflicted threat to public health in the USA where drug overdoses, predominantly caused by opioids, are the leading cause of death for people under the age of 50 (1).The USA opioid crisis rose from a perfect storm of events with three major waves (Graph 1) (6). Since the 1990s, a first wave resulted in increased deaths related to natural and semi-synthetic prescription opioids (7). Since 2010, a second wave was observed with a rapid increase in deaths caused by heroin overdoses. Since 2013, a third wave began with overdose deaths involving synthetic opioids, especially fentanyl (8). Together, this has led to an exponential increase in deaths related to opioid overdose and it has been widely debated what caused those waves.The opioid crisis has been proposed to initially stem from efforts to address the problem of under-treatment of pain, which motivated practice and policy shifts (9). In the early 1990s, the number of opioid prescriptions increased consequently, not only for the treatment of acute pain (10) but for chronic pain as well (11). Given that up to eleven percent of chronic pain patients using opioids were found to meet criteria for substance abuse disorders (12), these practice and policy shifts may readily explain the steady growth in prescription opioid abuse. This was exacerbated by other factors. Pharmaceutical companies interested in expanding their markets misused the practice and policy shifts with aggressive marketing strategies (13, 14). In 1996, an extended-release oxycodone formulation was introduced to the market that was proposed by the manufacturer to be effective for 12 h while being less addictive (15). At the same time, when patients still experienced pain, they were advised to take higher doses, rather than taking the extended-release oxycodone more frequently (16). This further nurtured so called “pill mills,” physicians who prescribe opioids regardless of medical need (17). Moreover, not all prescription opioids are taken by pain patients. Particularly acute pain patients take on average only one third of the prescription opioids (18). Each of those leftover pills can be sold with substantial financial profit, leading to an increased availability of prescription opioids for non-medical use. Due to the disappearance of manufacturing jobs, rising inequality, the economic crisis in 2008 and long-term unemployment, the temptation to sell the drugs for cash or to take them for emotional relief instead of physical pain, increased. Moreover, some of the prescription opioid users discovered that the time-release mechanism of slow-release oxycodone could be defeated by crushing the pills and injecting or snorting the now effectively short-acting and highly addictive opioid. Discussions about how to misuse the prescription opioids and their effects became public and spread quickly, especially through the growing use of the internet (16). In 2010, the government started to crack down on “pill mills” (17). Additionally, an abuse deterrent formula for slow-release oxycodone was announced as an attempt to meaningfully deter abuse by making it more difficult to crush the pills (19). As a result of those actions, some of the people addicted to prescription opioids changed to using heroin, since it is easier to use and cheaper (20). Indeed, as much as eighty percent of heroin users started with taking prescription opioids (21). Compared to heroin, synthetic opioids are relatively easy to produce and traffic in substantial quantities given their very high potency. It is therefore not surprising that from 2014 onwards, the number of fentanyl-related deaths increased by 72% (22).Pharmaceutical companies provide physicians with free drug samples, including prescription opioids, for promotion purposes. This is a common practice in the USA. While in the European Union (EU), opioids are subject to legal measures since 1992, so far, no initiative to ban the provision of free samples has been introduced in the USA. Even though the difference in drug marketing can be linked to different health care systems between the EU and the