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Int. J. Environ. Res. Public Health 2021, 18, 341. https://doi.org/10.3390/ijerph18010341 www.mdpi.com/journal/ijerph
Health(care) in the Crisis: Reflections in Science and
Society on Opioid Addiction
, Mita Banerjee
, David Y. W. Lee
, Norbert W. Paul
and Thomas Efferth
Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences,
Johannes Gutenberg University, 55128 Mainz, Germany; firstname.lastname@example.org
Department of English and Linguistics, Obama Institute for Transnational American Studies,
Johannes Gutenberg University, 55128 Mainz, Germany; email@example.com
McLean Hospital, Harvard Medical School, Boston, MA 02478, USA; firstname.lastname@example.org
Institute for History, Philosophy and Ethics of Medicine, Johannes Gutenberg University Medical Center,
55128 Mainz, Germany; email@example.com
* Correspondence: firstname.lastname@example.org; Tel.: +49-6131-3925751
Abstract: Opioid abuse and misuse have led to an epidemic which is currently spreading world-
wide. Since the number of opioid overdoses is still increasing, it is becoming obvious that current
rather unsystematic approaches to tackle this health problem are not effective. This review suggests
that fighting the opioid epidemic requires a structured public health approach. Therefore, it is im-
portant to consider not only scientific and biomedical perspectives, but societal implications and the
lived experience of groups at risk as well. Hence, this review evaluates the risk factors associated
with opioid overdoses and investigates the rates of chronic opioid misuse, particularly in the context
of chronic pain as well as post-surgery treatments, as the entrance of opioids in people’s lives. Link-
ing pharmaceutical biology to narrative analysis is essential to understand the modulations of the
usual themes of addiction and abuse present in the opioid crisis. This paper shows that patient nar-
ratives can be an important resource in understanding the complexity of opioid abuse and addic-
tion. In particular, the relationship between chronic pain and social inequality must be considered.
The main goal of this review is to demonstrate how a deeper transdisciplinary-enriched under-
standing can lead to more precise strategies of prevention or treatment of opioid abuse.
Keywords: OxyContin; opioid abuse; chronic pain; patient narratives
The current coronavirus crisis has brought into sharp relief that while no one is im-
mune to the virus, an epidemic may affect groups to different degrees. Thus, the COVID-
19 pandemic has shown that socially and economically disenfranchised groups are par-
ticularly at risk in an epidemic. Dramatically, the U.S. currently seems to be in the grip
not only of the COVID-19 epidemic, but also of another major crisis: the so-called opioid
epidemic, which is now also spilling into many areas of the world. This paper demon-
strates that in order to develop effective solutions to this crisis, a multidisciplinary ap-
proach is necessary, which links the life sciences and the humanities. For an in-depth un-
derstanding of the trends in opioid use and abuse, it is essential to understand a complex
network of not only doctors, pharmaceutical companies, patients and institutions, but also
society and social factors at large. This becomes even more evident, if studies indicate that
on a therapeutic level, management of pain could or should effectively be combined with
cognitive behavioral therapy [1,2]. For such therapeutic strategies, in turn, it may be cru-
cial to understand not only the individual factors, but also cultural and societal factors
which may lead to opioid addiction. As the American Psychological Association (APA)
suggests, cognitive behavioral therapy (CBT) might contribute to strategies for coping
Citation: Damiescu, R.; Banerjee, M.;
Lee, D.Y.W.; Paul, N.W.; Efferth, T.
Health(care) in the Crisis:
Reflections in Science and Society on
Opioid Addiction. Int. J. Environ.
Res. Public Health 2021, 18, 341.
Received: 2 December 2020
Accepted: 30 December 2020
Published: 5 January 2021
Publisher’s Note: MDPI stays neu-
tral with regard to jurisdictional
claims in published maps and insti-
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and con-
ditions of the Creative Commons At-
tribution (CC BY) license (http://cre-
Int. J. Environ. Res. Public Health 2021, 18, 341 2 of 18
with addiction, which are better embedded in a reconceptualization of the affected indi-
viduals . While it is not surprising that the APA walks down the paved roads of dealing
with addiction (like in alcohol or heroin abuse), the strategy sheds some light on the lack
of preventive strategies. First, this paper combines approaches from pharmaceutical biol-
ogy and the humanities in order to foster a multidisciplinary approach to combatting the
opioid crisis by a more preventive approach. Second, we would like to recommend routes
for further research where this multidisciplinary approach could be applied to comple-
ment the health impact assessment of opioid addiction with health needs assessment. We
argue that an assessment of institutional and local measures to tackle the opioid crisis is
urgently needed, in order to investigate which preventive measures might be effective
and thus become a venture point for the policy making which is urgently needed to effec-
tuate a public health approach to the opioid crisis locally, nationally and globally.
This review will first provide an overview of the opioid crisis and its inception, fo-
cusing specifically on OxyContin™ as a key example. Secondly, it will explore factors of-
ten associated with opioid overdose and analyze the necessity of opioid chronic pain man-
agement, also looking at post-surgery pain management as an entry point for opioids in
the lives of patients. It will then examine the mechanisms behind an opioid addiction from
the perspective of pharmaceutical biology. The discussion will subsequently lead to a pa-
tient perspective, exploring the role of patient compliance and the cultural framing of opi-
oid addiction. In the final part of this paper, current avenues for treatment will be exam-
ined. In the conclusion, we explore the potential advantages and challenges of an inter-
disciplinary approach, which combines the life sciences and the humanities  and we
suggest that without such interdisciplinarity, we may fail to grasp the current opioid crisis
in all its complexity. Finally, while this article discusses the opioid crisis in the U.S. spe-
cifically, it also has worldwide implications for the use of opioid-based pain medication.
What are the factors which might lead to such a global opioid epidemic? Crucially,
through its interdisciplinary approach, this review thus seeks to contribute to preventing
a further spread of the epidemic, both on the level of the U.S. and on the global level. A
recent published report has argued that it is important to tackle the opioid crisis by “going
back to its roots” . Through understanding the mechanisms which led to the U.S. opioid
epidemic, we may be able to stop it from flooding Europe as well. At the same time, it
demonstrates that most discussions so far have failed to take cultural and social perspec-
tives sufficiently into account. This paper, however, argues that the “root” of the problem
of the opioid crisis may not only be medical, but it may also be a cultural and a social
problem. For this reason, the following discussion links the methodologies of the life sci-
ences and the humanities in explaining the opioid epidemic in its current form. All this,
however, needs to be rooted in a sound understanding of the role of pain and pain man-
agement as it is practiced legis arte today.
The World Health Organization (WHO), together with the International Association
for the Study of Pain, have recognized proper pain management as a fundamental human
right . Nonetheless, adequate pain management, particularly if it comes to chronic pain,
has been a challenge both for doctors and for patients, who have been facing the problem
of insufficient pain management for years (as the goal is to reduce pain with minimum
side effects) and the ubiquitous presence of opioids with little thought on adoption, ad-
diction and abuse in the last decade. Even after decades of research in pain management,
opioids still remain the most prescribed drugs for treating postoperative pain [7–9]. His-
torically, the isolation of morphine from the opium poppy in 1805 by Friedrich W. A. Ser-
turner was a turning point for pain management in medicine. After more than 200 years,
morphine is still one of the most prescribed opioids and is used as a standard to compare
the potency of other opioids . However, because of its pharmacokinetic profile, scien-
tists have tried to synthesize stronger and more effective compounds. If administered
orally, morphine undergoes a significant first-pass effect, as it metabolizes through the
liver to morphine-6-glucuronide, a more potent analgesic; it has a half-life of 2–3 h, requir-
ing a new administration approximately every 4 h . Following repeated use, it leads
Int. J. Environ. Res. Public Health 2021, 18, 341 3 of 18
to tolerance and physical dependence . Therefore, scientists have searched for more
potent opioids with a better bioavailability and as such the release of OxyContin™ in 1996
by Purdue Pharma in USA seemed like a promising alternative. However, even then mul-
tiple studies concluded that there is no comparable advantage in comparison to other ox-
ycodone preparations, besides a reduced dose frequency . In this light, one key ques-
tions needs to be answered: how did opioids become America’s most used and misused
2. How Did Opioids Become America’s Most Used and Misused Drugs?
The Food and Drug Administration (FDA) is responsible under the Food, Drug and
Cosmetics Act to regulate the advertising and promotion of prescription and noncon-
trolled drugs in order to assure their truthfulness and have a positive impact on public
health. The U.S., together with New Zeeland, remain the only two countries in the world
which allow direct-to-consumer advertising of prescription drugs. Back in 1996, shortly
after introducing OxyContin™ on the market, Purdue Pharma started a highly aggressive
marketing and promotion campaign without submitting promotional videos to the FDA
to be reviewed . Purdue Pharma conducted multiple conferences on pain manage-
ment, which were attended by over 5000 physicians, pharmacists and nurses, who were
then recruited as Purdue’s speakers . Not only did Purdue Pharma target primary care
physicians, but they also offered branded promotional items to healthcare professionals
and various coupons for OxyContin™ for new patients . During the same time pain
was described as “the fifth vital sign” and the problem of more than seldom undertreated
pain attracted the attention of healthcare providers, who then decided to improve the
treatment guidelines of pain management [14,15]. This led to a more liberal use of opioids
in the treatment of pain. Purdue promoted the use of Oxycontin™ in non-cancer-related
pain and assured that the risk of addiction was low due to its formulation as a controlled-
release tablet . With the intent to improve pain management and patient outcomes,
doctors started overprescribing strong opioids, creating a slippery slope. By 2005, through
the liberalization of prescription opioids, nationwide there was an increase in opioid pre-
scriptions and drug abuse [16,17]. Oxycodone became the most abused prescribed opioid
in the USA and led to more deaths than heroin . In 2010, Purdue Pharma released an
abuse-deterrent formulation (ADF) for oxycodone, making it harder to crush or dissolve,
and in 2013 the FDA decided the prior formulation should be removed from the market
for safety reasons. Several studies have examined the efficacy of the abuse-deterrent for-
mulation and have concluded that it is associated with a decline in the abuse of oxycodone
[19–22]. However, one study, which also included patients misusing prescription opioids
or heroin, highlighted the limited effectiveness of the abuse-deterrent formulation, as the
level of residual abuse has remained stable despite the new formulation . Although
the ADF has reduced the abuse of oxycodone, the active compounds in these formulations
preserve their euphoric effects and strong side effects, including overdose potential. As
such, the search for new analgesics continued and a new approach targeted the peripheral
opioid receptors using hydrophilic substances and polyglycerol-based nanocarriers; this
strategy has shown promising results . Other strategies include increasing endoge-
nous opioid mechanisms, use of allosteric modulators, bivalent ligands and bivalent sig-
Even though great advancements have been made in the practice of surgery, as tech-
niques have become more precise and less invasive  in order to improve the outcomes,
opioids are still the first choice for postoperative pain management [25,26]. In the attempt
to improve recovery and quality of life, as well as reduce hospital stays, physicians started
prescribing more opioids, so that up to 80% of patients in the USA receive strong opioids
after a surgical procedure .
Due to increased morbidity associated with opioid overdose, various studies have
started analyzing the factors influencing the opioid prescribing patterns in opioid-naive
Int. J. Environ. Res. Public Health 2021, 18, 341 4 of 18
patients. Opioid-naive patients are defined as patients with no prescription for any opi-
oids in the last 6 to 12 months prior to their first opioid prescription and with no history
of substance abuse [9,27,28]. The trends in opioid prescriptions in opioid-naive patients
after low-risk surgical procedures (e.g., carpal tunnel release) have been analyzed for a
time period from 2004 to 2012. The study evaluated the proportion of patients filling an
opioid prescription (especially oxycodone/acetaminophen or hydrocodone/acetamino-
phen) within 7 days after a procedure. Seventy percent of them filled an opioid prescrip-
tion within a week. Additionally, there was an increase in opioid dose of 18% for all pro-
cedures . A more complex investigation associated the characteristics of the initial opi-
oid use with pain etiology. The most common indications for opioid prescription are
chronic non-cancer pain, surgery, trauma and burns. The authors concluded that patients
initiated with tramadol, long-acting opioids or doses over 90 morphine milligram equiv-
alents were more likely to continue opioid use  Additionally, multiple studies have
characterized the duration of the prescription and high opioid dose as strong predictors
of the likelihood of long-term use [27–30]. Other risk factors are continued use of other
medicines (benzodiazepines, muscle relaxants), history of alcohol, tobacco or drug abuse,
lower socioeconomic status and psychiatric disorders [28,31,32] which will, unfortunately,
most likely increase as a consequence of the ongoing COVID-19 pandemic and the related
anxiety and social deprivation. As numbers of opioid overdose deaths continue to grow
in the U.S., Centers for Disease Control and Prevention (CDC) discovered that in 63% of
cases there is also another drug involved. Both alcohol and CNS depressants are known
to cause respiratory depression, therefore mixing them can have fatal effects. A recent
study gathered data from the last 20 years and confirmed that co-involvement of alcohol
or benzodiazepines in opioid overdose deaths (OOD) is common and the prevalence rate
is increasing for alcohol from 12.4% (1999) to 14.7% (2017) and for benzodiazepines from
8.7% (1999) to 21.0% (2017), more and more replacing the former culturally accepted (but
now increasingly unacceptable drug), alcohol, with a “medication”. Alcohol is still more
commonly used by men , while benzodiazepines are more frequently used by women
. The proportions of co-involved alcohol and benzodiazepines vary depending on the
opioid subtype (prescription opioid vs. illicitly manufactured), as illicitly manufactured
fentanyl has been responsible for almost half of the opioid overdose deaths since 2015 .
These results should be considered by physicians when prescribing both opioids and ben-
zodiazepines and should be integrated in public health communication since many pa-
tients, at first, seem to not be fully informed of potential risks. The prescription rates of
benzodiazepines have also increased substantially in the last decades, as they have be-
come the most prescribed sedatives . In 2016, the CDC published a guideline with
recommendations for prescribing opioids for chronic pain with the intent to improve the
effectiveness of treatment and reduce adverse events and risks. In the guidelines, CDC
recommends starting an opioid therapy for chronic pain only if the benefits outweigh the
risks and the therapy should be combined with nonopioid (NSAIDs, anticonvulsants and
antidepressants) and nonpharmacologic therapy (CBT, exercise therapy). Clinicians
should determine realistic goals, discuss the risks with the patients and only continue
therapy if significant improvement appears. Additionally, opioid therapy for chronic pain
should start with the lowest effective dose and immediate-release opioids are preferred to
extended-release. Thus, an evaluation of the therapy benefits should be done within the
first 4 weeks after starting the treatment and then every three months, which is in many
Western countries the threshold for developing chronic pain. Generally, the CDC recom-
mends avoiding the concurrent prescription of opioids and benzodiazepines, as the risks
are higher than the benefits. Last but not least, a patient’s medical history should be re-
viewed, and urine drug tests should be done annually, in the case of long-term treatment.
If there are any risk factors involved, clinicians must establish strategies to minimize the
risks . To improve the knowledge of healthcare providers, avoid overprescribing opi-
oids and help them apply these guidelines, the CDC now offers different interactive online
training programs targeting professional groups.
Int. J. Environ. Res. Public Health 2021, 18, 341 5 of 18
Since opioids are frequently prescribed after both minor and major surgeries, scien-
tists have wanted to determine how often after a surgical procedure patients become
chronic opioid users and which associated risk factors (alcohol, tobacco, depression) can
influence the outcome [36,37]. Although chronic opioid use is common after surgery, the
rates were low [36–38]. A report from 2016 analyzed the risk of chronic opioid use in opi-
oid-naive patients after having 1 of the 11 most common surgical procedures, compared
to nonsurgical patients. Excluding the first 90 days post-surgery, surgical patients were
considered chronic opioid users if during the first-year post-surgery, they had a supply of
opioids for over 120 days or filled over 10 prescriptions. In the case of the nonsurgical
patients, a “surgery date” was assigned randomly, and chronic users were defined by us-
ing the same criteria. Even though two of the surgical procedures are often associated with
pain (total knee arthroplasty, total hip arthroplasty), the authors suggest different pre-
and postoperative techniques for pain management. The study confirmed the risk of
chronic opioid use during the postoperative period and also highlighted the potential of
different risk factors (history of drug or alcohol abuse, use of antidepressants and benzo-
diazepines) in the patient outcomes . These findings were also confirmed by other au-
thors, who observed that the risk of chronic opioid use in opioid-naive patients following
a minor or major surgical procedure is increased, and it is especially associated with other
risk factors (alcohol and drug abuse, use of benzodiazepines, antidepressants) and pre-
operative pain disorders (arthritis, back pain) . These data describe the influence of
psychiatric conditions in chronic opioid use. To increase awareness regarding the risk of
chronic opioid use, a new analysis focused on both opioid-naïve and opioid non-naïve
patients receiving opioids in the perioperative period. For both group of patients, it was
confirmed that, if patients received over 450 Morphine Milligram Equivalent (MME)and
a high amount of opioid medication, they were more likely to become chronic opioid users
. Additionally, various guidelines were proposed with the purpose of reducing opioid
prescriptions following surgical procedures. The first study describes that from 85% of
patients who received an opioid prescription at discharge on postoperative day 1, only
38% of the prescribed opioids were taken. The number of opioid pills taken the day before
discharge were correlated with the number of opioid pills taken afterwards. As such, the
guideline proposes the following: no opioid prescription if the patient does not need any
opioids the day prior discharge; if the patient takes 1–3 opioid pills, then they receive an
opioid prescription for 15 pills and if the patients require more than 4 opioid pills, they
obtain a prescription for 30 opioid pills . Additionally, the same group prepared an-
other guideline for surgeons to decrease postoperative opioid prescriptions. Surgeons
were recommended to prescribe NSAIDs or acetaminophen as first choice therapy. As
such, the number of opioid pills decreased by over 50% and 85% of patients received ac-
etaminophen or a NSAID and did not require opioids afterwards . These studies
demonstrate that although appropriate postoperative pain management remains a com-
plex matter, surgeons often overprescribe opioids.
In the last decades opioid therapy has been frequently prescribed for chronic pain
and as an undesired outcome the number of opioid overdoses has increased. A random-
ized clinical trial supported the efficacy of short-term (12 weeks) opioid therapy in treating
chronic pain . However, their efficiency was not higher compared to nonopioid ther-
apy . Regarding benefits of long-term opioid therapy, evidence still remain insuffi-
cient. Thus, various studies have concluded that higher doses of opioids are often associ-
ated with an increased risk of harm, opioid abuse and overdose [41–44]. Although the
risks are well known, reducing the dose was easier said than done for patients, who had
already taken high doses of opioids for a longer period. A study from 2014 evaluated,
using high-dose chronic opioid users, if the recognized benefits and harms can be used as
predictors of high-dose use after one year. A majority of patients (74%) reported at least
one side effect and many of them reported concerns and problems associated with opioid
use. Even though almost half of the patients expressed the wish to reduce or stop opioid
Int. J. Environ. Res. Public Health 2021, 18, 341 6 of 18
therapy, 80% of them continued to use high doses after one year . Other studies con-
firmed that despite the fact that chronic patients report multiple side effects and problems
related to high doses of opioids, the rates of opioid reduction were still low [41,44,46].
These results reinforce how difficult it is for chronic opioid users to reduce doses even
though it could improve their quality of life. Although a decrease in opioid prescribing
already started in 2012 after the CDC guidelines were published , opioid prescriptions
decreased at a higher rate . On the other hand, this was also associated with increased
illicit opioid use (heroin and illicitly manufactured fentanyl) and overdose deaths , as
people already dependent on the opioid therapy suddenly stopped receiving their medi-
cation. A retrospective cohort study determined that patients, who had treatment discon-
tinued and those whose doses were increased were more likely to use heroin and illicit
fentanyl . All in all, the available data confirm the complexity of the opioid problem
and that the abrupt reduction in opioid prescriptions can produce more harm than good.
Hence, it is an ethical postulate that clinicians should carefully evaluate and discuss with
the patients the best measures that should be taken to reduce or cease opioid therapy
without negatively affecting the quality of life. To help safely reduce opioid doses in
chronic patients, various risk mitigation initiatives have been started. These initiatives
have proven to be very efficient, as both high-risk patients (those with history of mental
or substance use disorder) as well as low-risk patients managed to reduce their daily doses
of opioids . Beyond clinical practice and behavioral factors, opioid addiction is also
deeply rooted in pharmacological and neurobiological mechanisms.
Although the opioid crisis has mainly affected the U.S. and Canada, a report showed
that opioid prescription rates have nearly doubled in Europe during the past two decades
and there are approximately 1.3 million high-risk opioid users, and the countries with the
highest consumption of opioids are Germany, the UK, France, Spain, Italy and the Neth-
erlands . In comparison to the U.S., the number of opioid-related overdose deaths and
hospitalizations is still low, and while in the U.S. most overdose deaths are caused by
fentanyl and other synthetic opioids, in Europe heroin is attributed to most fatal overdoses
. Additionally, in Europe the Access To Opioid Medication in Europe (ATOME) pro-
ject has provided information about opioid medication in legal, societal and policy con-
texts in order to help to implement various European policies .
A recent review has analyzed the trends in opioid prescription practices in Germany,
as the country is the second largest opioid consumer in Europe, and although opioids are
mostly being prescribed to treat chronic, non-cancer pain, the study concluded that cur-
rently there are no signs of an opioid epidemic . New studies provide information on
a national level regarding the impact of opioid misuse in different European countries
such as France, the Netherlands and the UK.
As the number of opioid prescriptions has drastically increased during the past two
decades, an investigation from the Netherlands reported that proxies for opioid misuse
augmented, the number of opioid prescriptions, substitution therapies and opioid-related
deaths doubled and opioid-related hospital admissions tripled . An analysis from
France from 2004 to 2017 described a significant increase in oxycodone use (+1950%), opi-
oid-related hospitalization (+167%, 2000–2017) and opioid overdose deaths (+146%, 2000–
2015) . Furthermore, in the UK, the number of opioid prescriptions quadrupled, and
from 1993 to 2017 opioid overdose deaths rose drastically . All three studies highlight
the importance of safe opioid prescribing guidelines and adequate monitoring of opioid
use in the respective countries.
3. What Are the Mechanisms Behind Opioid Addiction?
In order to better understand how the use of opioids affects the brain, leading to tol-
erance and dependence in chronic users, it is best to first take a look at their mechanism
of action. The opioid receptor family includes μ—(mu), δ—(delta) and κ—(kappa) recep-
tors and the more recently discovered nociception/orphanin FQ receptor, all belonging to
Int. J. Environ. Res. Public Health 2021, 18, 341 7 of 18
the G-protein-coupled receptor class . Plus, depending on the produced response, opi-
oids can classically be categorized as full agonists (morphine, oxycodone, methadone),
partial agonists (buprenorphine, tramadol, nalbuphine) or antagonists (naloxone, naltrex-
one) . However, recent developments have identified new classes: mixed MOR/DOR
agonists, MOR/NOR agonists (cebranopadol), as well as biased agonists (oliceridine,
PZM21, mitragynine pseudoindoxyl, SR-17018) . The concept of biased signaling
seemed to be a promising therapeutic strategy, as the arrestin pathway promotes side ef-
fects, while G-protein signaling induces analgesic effects. However, preclinical and clini-
cal trials have demonstrated that biased agonists cause the same side effects as opioids
. On a cellular level, an opioid agonist binds to the G-protein-coupled receptor causing
the α subunit to replace guanosine diphosphate (GDP) (inactive form) with intracellular
guanosine triphosphate (GTP) (active form) and, hence, inhibits the adenylyl cyclase. This
leads to a reduced production of cyclic adenosine monophosphate (cAMP) production.
Plus, the α-GTP complex also interacts with the ion channels, producing hyperpolariza-
tion of the cells by activating the K
channels and decreasing neurotransmitter release by
Different kinases phosphorylate the opioid receptors and promote arrestin recruit-
ment leading to receptor desensitization and internalization. Arrestin, as a scaffolding
protein, can be involved in both recycling and recovery of dephosphorylated opioid re-
ceptors or degradation by lysosomes .
Additionally, the activation of the opioid receptors can cause different effects, besides
analgesia, depending on the location of the receptor. Activation of μ-opioid receptors pro-
duces analgesia, respiratory depression, sedation, reduced gastric motility, nausea, vom-
iting and miosis. The binding of agonists to δ-opioid receptors leads to spinal and su-
praspinal analgesia and reduced gastric motility, and the activation of κ-opioid receptors
causes spinal analgesia, dysphoria and diuresis . Due to their lipophilicity, opioids can
pass through the blood–brain barrier and enter the central nervous system (CNS). In the
brain, opioids attach to the μ-opioid receptors and cause the analgesic effect. In this man-
ner, opioids also activate other brain processes like the mesolimbic reward system which
signals the ventral tegmental area (VTA) to release dopamine and stimulate dopamine 1
) receptors in the nucleus accumbens (NAc). The fast release of dopamine activates the
reward processes, causing feelings of pleasure. Opioids are not the only drugs that in-
crease dopamine levels in the NAc. Other substances of abuse achieve similar effects
through various mechanisms. Cocaine blocks dopamine transporters and inhibits the re-
moval of dopamine from the synaptic space, leading to enhanced dopamine levels. Alco-
hol increases the levels of γ-aminobutyric acid (GABA) neurotransmitter in the brain,
which leads to accumulation of dopamine in the VTA . Additionally, another study
has associated a maximum drug reward with quickly increased dopamine levels and the
binding of dopamine to both D
receptors. Through brain imaging of humans, it
was observed that the brain reward mechanism is activated by drugs, if dopamine in-
creases over a short period of time (<10 min), while the slow release of dopamine over a
longer period of time (1 h) did not . A continued consumption of these substances of
abuse (opioids, cocaine) triggers the constant release of dopamine in the NAc, which leads
to the craving of the drug. Nevertheless, the mesolimbic rewards system is also regulated
by endogenous opioids. The endogenous opioid system influences hedonic responses and
the modifications occurring with repeated drug abuse and activates κ-receptors, blocking
dopamine release in NAc. Chronic drug abuse alters the physiological functions of the
brain and triggers systems to restore the natural balance in the brain. As such, repeated
and excessive release of dopamine in the NAc eventually leads to the activation of auto-
receptors to inhibit dopamine release, causing dysphoria and drug withdrawal symptoms
. Through these adaptive mechanisms, chronic opioid users develop tolerance, so that
in order to obtain the same effect they need to increase the dose. Tolerance develops dif-
ferently for the various effects of opioids, faster for the analgesic and euphoric effect and
slower for the gastrointestinal effect. The pharmacological mechanisms involved in opioid
Int. J. Environ. Res. Public Health 2021, 18, 341 8 of 18
tolerance are complex and yet to be entirely explained, but desensitization and internali-
zation of the μ-opioid receptor seems to be one of the primary causes . Long-term
opioid treatment leads to dependence, as such if people stop taking the drug they experi-
ence symptoms of withdrawal and hyperalgesia (increased pain sensation); however
some people also develop an opioid addiction, characterized by a compulsive urge to take
the drug, even though there is no medical requirement . As a consequence, opioid
addiction can often lead to drug overdose.
4. Prescription Policy, Adherence and Abuse
As pointed out above, to develop more effective strategies to prevent opioid addic-
tion and abuse we have to look beyond biochemical mechanisms and analyze cultural and
social settings and mechanisms as well. While the pharmaceutical industry and medical
practices certainly fueled the opioid crisis, it needs to be stressed that the key to prevention
lies in the patient perspective. The opioid crisis is part of a larger development in the US,
in which a number of drugs, including amphetamines, have been both overprescribed 
and abused . This suggests that the “stimulants” crisis and the opioid crisis can be seen
as part of a continuum. Moreover, to understand the patient perspective, we have to look
at the cultural underpinnings of prescription policy. Prescription policies and patient ad-
herence to therapeutic regimens do not originate in a void. Rather, there is a cultural back-
ground, which shapes them in a multifactorial manner. Some factors are globally present,
while others may be locally and culturally specific. It is important here to specify that
cultural ramifications of the opioid crisis are in spite of a potentially huge spectrum that
is not arbitrary, but that hinges on context-specific factors such as urbanity, levels of in-
dustrialization and income structure.
Pharmaceutical biology and biomedicine necessarily look at the patient as a general-
izable category which is closely tied to the ideal of medicine as a “colorblind” practice: the
physician has to treat the patient with complete disregard of the patient’s ethnicity, gender
or social circumstances. This does not mean, however, that specific risk factors related to
one of the latter categories can justifiably be neglected. From a humanities perspective,
the reference to the “patient” is broken up, in order to explore the cultural, social and
economic contexts into which this patient is embedded if not “created”. For the U.S., this
cultural embeddedness means that the patient finds himself in a society which is deeply
meritocratic, much more so than in, for example, Europe. This means that an individual’s
identity is defined by what they can achieve, on a personal, but much more importantly,
on an economic scale. The so-called American Dream, where an individual can climb from
rags to riches overnight, has been partly shattered, but is still deeply embedded in the self-
image of the U.S. The meritocratic ideal implies, however, that all responsibility to create
a desirable fate lies with the individual. This is one of the reasons why social welfare has
not been very pronounced in the U.S. [65,66].
Interestingly, this has profound consequences for the individual’s attitude to medi-
cation. To succeed in this merit-based and highly competitive society, an individual has
to constantly perform at their best. This means that they must strive to eliminate all per-
formative insufficiencies and as a consequence, this means one has to get rid of any forms
of pain as soon as possible.
The documentary film Take Your Pills  points to the intersection between eco-
nomic, cultural and pharmaceutical aspects of the current prescription crisis in the U.S.
Even if the film is mostly concerned with the stimulants crisis outlined above, it can also
illuminate many of the cultural aspects which underlie the opioid crisis as well. The film
sees the pressure of a neoliberal economy as one of the reasons why individuals abuse
This can be related to general data about the relationship between health, life expec-
tancy and socio-economic status. The concept of “deaths of despair” was introduced by
an analysis from 2017, which highlighted the life expectancy difference between the rich-
est and the poorest counties in the U.S. The increased mortality rates among non-Hispanic
Int. J. Environ. Res. Public Health 2021, 18, 341 9 of 18
white Americans is correlated with different socioeconomic factors, including healthcare
access and education background, but it is also exacerbated by opioid over-prescription
Moreover, in a neoliberal economy, individuals are required to work in a highly com-
petitive environment, with long working hours and often with little sleep. Moreover, after
the global financial crisis from 2008, neoliberal policies and austerity measures accentu-
ated the existing socioeconomic inequalities . There is a psychological dimension to
the neoliberal economy. It is implied that the human body is the capital that an individual
possesses; the individual has to maintain it at all cost and the responsibility for maintain-
ing this capital lies solely with the individual [70,71]. It can easily be imagined what would
happen to a patient after surgery. Because of the pressures of both the economy and the
healthcare system, they will tend to go back to work as soon as possible. In order to do so,
they may turn to stronger analgesics which promise to work fast, even if this may include
severe side effects. According to the documentary Take Your Pills, this is true for both pro-
fessionals and people working in lower-paid positions.
Multiple investigations, including a report from the National Academy of Science,
have described the correlation between the social and economic factors and misuse of opi-
oids. On one hand, poverty, hopelessness, despair, poor working conditions and trauma
can be associated with increased opioid use. On the other hand, the workplace can be the
cause of opioid use . It can be suggested that to counter the misuse of drugs such as
OxyContin™, individuals have to be aware of the cultural and economic pressures which
may drive them to resort to these drugs. On an economic level, the opioid crisis may in
fact be one of the results of a neoliberal economy, with the increasing pressures of the
workplace. On a cultural level, it may mean that individuals have internalized the idea
that their bodies are their capital, whose performance must be maintained or even en-
hanced at all cost. Studies have shown that different risk factors (low socioeconomic sta-
tus, manual labor, geographic regions) can be associated with augmented opioid use, mis-
use and overdose deaths [72–74]. This implies that public discourse and thus the public
health discourse about the use of OxyContin™ must also be changed. The widespread use
of opioids must hence be seen not as an isolated incident, but as being part of a larger
continuum, which is cultural as much as it is biomedical and pharmaceutical. Moreover,
this opens up significant new directions for future research, which can compare the situ-
ation of the U.S. and Europe. In Europe, social welfare systems are more pronounced than
in the US . They could serve as protective factors. This may be one of the reasons, why
the opioid crisis has affected the U.S. more strongly than, for instance, Germany and other
European countries. One question, which future research will have to consider, is whether
with the dismantling of social welfare systems in Europe, economic pressure on individ-
uals will increase, rendering them increasingly vulnerable to addiction. Significantly, re-
searchers from Frankfurt are currently conducting an European Research Council ERC-
project, which compares opioid addiction in the U.S. and in Germany . The purpose
of the project is to gain a better understanding of the current trends in opioid use and
improve the response of the healthcare systems within the European Union to achieve a
faster response and better preparedness. Scientists have found that guidelines for long-
term use of opioids in chronic non-tumor pain published in 2009 and updated in 2015 in
Germany by Deutsche Schmerzgesellschaft have served as a protective factor . In the
updated version from 2015, contraindications and indications of opioids were established
and clear rules for stopping the therapy were determined. A second update of the German
guidelines, which has not been published yet, narrows the indication of opioids and con-
tains an additional chapter regarding the diagnosis and treatment of pharmaceutical opi-
oid misuses. Plus in contrast to the U.S., German Patients and Doctors can access a multi-
modal pain therapy, for which the costs are covered by the public or private health insur-
ances . So far, researchers agree that while the opioid crisis is threatening Germany,
specific factors may prevent addiction from becoming as widespread as in the U.S. . It
is hence important to consider both the roots of the opioid crisis and the nationally and
Int. J. Environ. Res. Public Health 2021, 18, 341 10 of 18
culturally specific situation in Europe . Since the opioid crisis has made many victims
in the U.S., scientists in Europe, especially in the countries with a high prescription rate,
are gathering data regarding prescription of opioids and related overdoses [53–55]. Eu-
rope is trying to prevent a situation similar to the U.S. and Canada, by improving both
information about opioid medication (through ATOME) , but also the response of
healthcare systems . While the majority of studies have focused on the treatment of
opioid addiction [78,79], it is also important to examine social, cultural and economic fac-
tors contributing to opioid addiction.
The film Take Your Pills shows that the prescription crisis may connect the wide-
spread abuse of stimulants to the opioid crisis. The narratives found in the film can be
linked to qualitative analyses which similarly stress the relevance of patient narratives in
understanding factors contributing to the opioid crisis . Generally, recent develop-
ments in healthcare have emphasized the benefits of including patient narratives. While
patient narratives have been present in medical discourse in the form of case studies, the
patient narrative adds multiple perspectives that case reports may not contain. This is
especially relevant with regard to the cultural, social and economic aspects included in
patient narratives . The narratives contained in the film Take Your Pills can hence be
seen in continuity with qualitative studies investigating narratives of patients with opioid
addiction. Recent data show increased trends in amphetamine prescriptions in children
and adolescents but also in nonmedical use and emergency department visits [63,64]. This
shows that addiction and over-prescription does not only start in adulthood. Addition-
ally, while in 2003 55 countries approved the medication for ADHD, the U.S. is responsible
for >92% of the global spending . A large percentage of American children and teen-
agers are on ADHD medication . One of the doctors interviewed in the film, Dr. Law-
rence Diller, goes so far as to speak of the “medicalizing of everyday life.” Public health
discourses have to acknowledge that the use of prescription drugs is no longer an excep-
tion, a temporary practice, but has become a constant and “normal” aspect of everyday
life. This has also been emphasized in an article that discusses how the medicalization of
human lives has become normal, in order to correspond to a neoliberal society . An
earlier study described how students perceive the illegal use of stimulants. Accordingly,
students justify their use for the right reasons and consider them to be without harmful
side effects and not different from other aids against fatigue . In the film, several moth-
ers are asked about, why they chose to put their children on ADHD medication. All of
them say that they wanted their children to succeed in school, in order to be able to choose
a career later on. Social pressure on the individual thus starts incredibly early on. The
patterns to which children and adults are subjected in a neoliberal economy today may
thus be highly similar; this is also confirmed by the increased trends (344%) in women
with private insurance, who filled an ADHD prescription .
The film refers to political scientist Wendy Brown. Brown emphasizes that the opioid
crisis is located at the intersection between self-enhancement, pain management and cul-
tural and economic pressure. She argues that one way out of the current dilemma, for both
the patient and the medical and pharmaceutical industry, is to look at the different factors
which contribute to the crisis. Brown states that a starting point would be an individual’s
awareness of the pressures, which drive them to take certain medications. Awareness of
cultural and economic pressures and the requirements of a neoliberal economy are essen-
tial here. At the same time, Brown urges us to look at the “human factor” in this debate.
A neoliberal economy, she notes, wants individuals to be perfect, to be infallible. This,
however, may run counter to human nature.
What does this mean for pain management? It means, first and foremost, that a per-
son must be able to afford a longer recovery period in order not to have to resort to opioid
analgesics on such a large scale. The healthcare system, an individual’s personal
healthcare plan and the pressures of a neoliberal economy may work against such an op-
tion. In order to counter the current opioid crisis, however, we need to be aware that this
Int. J. Environ. Res. Public Health 2021, 18, 341 11 of 18
crisis is multifactorial: it is made up of medical, pharmaceutical, economic, social and cul-
tural factors together. An in-depth knowledge of the social and cultural factors, which
may contribute to the opioid epidemic in turn, may also be important for cognitive behav-
As mentioned above, OUD (opioid use disorder) is often associated with alcohol or
benzodiazepine use as well as psychiatric disorders (depression). As we can see, there is
no easy solution to this problem. As such, medication-assisted treatment (MAT) has been
developed to prevent relapse and improve patient survival. MAT combines FDA-ap-
proved medicine to treat OUD (methadone, naloxone and buprenorphine) with counsel-
ing and behavioral therapies. Methadone is a long-acting opioid agonist, which sup-
presses withdrawal and craving symptoms and reduces the effects of illicit opioids (her-
oin). Methadone is used as both detoxification and maintenance medication in the treat-
ment of OUD [1,84]. Buprenorphine is a partial μ-opioid receptor agonist, which similar
to methadone reduces withdrawal symptoms and opioid craving. Buprenorphine formu-
lations are available either in monotherapy or in combination with naloxone [1,84]. Nal-
trexone is a competitive antagonist of opioid receptors which blocks the effects of opioids
(oxycodone). Because it produces severe withdrawal symptoms, it is not indicated during
the detoxification phase, but rather for a maintenance medication . Multiple studies
proved the efficiency of methadone maintenance therapy and psychosocial treatment
(CBT, supportive counseling), as patients showed better improvement and overall out-
come at a 12-month follow up. Additionally, similar results were obtained for patients
receiving naltrexone or buprenorphine maintenance therapy in combination with psycho-
social treatment. These patients demonstrated increased treatment attendance and ther-
apy compliance . The ongoing COVID-19 crisis, however, demonstrates how fragile
these structures are. Social deprivation, the shut-down of institutions and methadone pro-
grams, the aggravation of precarious life situations and poverty shed a blinding light on
the underpinnings of the opioid crisis.
5. Why It Is Important to Understand the Patient’s Perspective
In the context of public health and public understanding of the opioid crisis, it is
especially interesting that the CDC website hosts an entire collection of personal narra-
tives about opioid addiction . These narratives are written either by former patients or
by their relatives. For an understanding of the ongoing threat caused by opioid use and
abuse to human health, this collection of first-person narratives is informative both from
an ethical and a methodological perspective. From an ethical perspective, personal ac-
counts of addiction may serve the purpose of providing access to an authentic re-evalua-
tion, weighing individual behavior in the form of first-order wish-like instant satisfaction
(removing pain, being shielded from life, feeling better) against higher-order wishes based
on the reflection of more fundamental values (managing pain, leading a life, being well).
As the national Centers for Disease Control, the CDC not only gathers statistics and re-
ports on problematic developments in population health but should also help to counter-
act such developments. The fact that the CDC should include on its website not only sta-
tistics, but also patient narratives, supports the argument that approaches to combating
the opioid epidemic should be multidisciplinary and may stress patient narratives as one
resource for understanding individual, social and cultural factors. At the same time, it can
be argued that the patient narratives provided on the CDC website may be showcases of
ideal, desirable developments, rather than in-depth accounts of the complexities which
make up opioid addiction. This is why the documentary Take Your Pills is an important
example of how patient narratives are embedded into a much more complex account of
social, environmental, rural or urban settings, and socioeconomic disenfranchisement.
The rich content of such narratives can and should be used to reframe preventive strate-
gies as knowledge-based, evidence-driven and socially and culturally embedded in an
authentic way at the same time. Turning groups at risk into communities that need to be
addressed in ways specific and relevant to their settings is one of the major challenges for
Int. J. Environ. Res. Public Health 2021, 18, 341 12 of 18
healthcare in the ongoing opioid crisis. This corresponds to qualitative studies, which
stress the need for including narratives in research about the opioid crisis. Such studies
have addressed the relevance of narrative understanding for doctor–patient relationships.
For instance, an analysis suggested that the doctor and patient are equally in pain: for the
patient, the situation is about pain management; but for the physician, “pain” may involve
understanding the complexity of the patient’s somatic, social, cultural and economic con-
dition and the impetus to help the patient while precluding addition .
On a methodological level, for both humanities research and research at the intersec-
tion between pharmaceutical biology and the humanities, this raises important questions.
From a humanities perspective, personal narratives can themselves be seen as a form of
knowledge about human life; they provide what Ottmar Ette has called a form of Lebens-
wissen (life knowledge) [87,88]. From a humanities perspective, analyzing patient narra-
tives may hence be key in contributing to the knowledge base which is needed to under-
stand the opioid epidemic. Studies have shown that these narratives can increasingly be
found on social media . They are also contained on health-related websites such as the
Colorado Office of Behavioral Health .
These life narratives, in turn, can help awareness of a given development (here, the
perils of opioid addiction) for the wider public. It is essential here that these are not fic-
tional stories; they can be seen as patient narratives. As such patient narratives, they make
people aware of the concrete danger of becoming addicted to opioids. Moreover, because
people can relate to the stories of the people on the website, they may become aware that
this could easily happen to them as well. It is important to note here that the people whose
stories are being told on the website are referred to by their first names. This has the effect
that readers will relate to them on a personal level and will become aware that this could
easily become their own story. Recent studies have investigated the role of narratives both
for treating addiction  and for increasing social awareness about the risk factors lead-
ing to addiction. These studies stress that patient narratives contain turning points in in-
dividual narratives: by telling their stories, patients become aware at what point they were
becoming more susceptible to addiction . Conversely, readers of patient narratives
such as the ones hosted by the CDC may be enabled to assess, whether they are prone to
addiction. To the extent that they recognize parallels between their own lives and the life
course described in patient narratives, they may realize that they, too, may be at risk.
As seen on the CDC page, patients who narrate the story of their addiction with opi-
oids come from all walks of life: they are college or high school students or financial ad-
visers; they are white, African American, or Hispanic . Through this cross section of
society, it becomes clear that the opioid crisis can affect anyone, despite their social status
or professional background. Through their selection of stories, the CDC thus targets com-
mon misconceptions about the people that become addicted to opioids.
The patient narratives contained on the CDC website and in the film Take Your Pills
are in line with recent studies that stress the role of “storytelling” in addiction prevention
. These studies stress that addiction can be seen not only as a health problem, but also
as a social problem . This view can be applied to the use of narratives in the opioid
epidemic and the use of narratives by the CDC and the documentary. Patient narratives
reveal underlying patterns about consumption patterns  and social conditions, which
may lead to such patterns. As these studies show, a biological perspective on opioid ad-
diction and a narrative approach can be mutually complementary .
Patient narratives can then be related to prescription policies, both in the U.S. and in
other parts of the globe. If pain management is recognized by the WHO as a fundamental
human right, it may nevertheless be important for physicians to debate for what condi-
tions certain opioids are prescribed. It could thus be argued that the narratives provided
on the CDC website shy away from addressing a much more fundamental problem: the
relationship between social inequality, physical labor, chronic pain and opioid addiction.
At this juncture, the usual narratives of coping can be misleading. Opioid addiction does
not happen to people regardless of specific personal, social or economic circumstances.
Int. J. Environ. Res. Public Health 2021, 18, 341 13 of 18
We suggest here, on the other hand, that in order to adequately target the opioid crisis
and the factors leading up to it, it is important to take social inequality into account par-
ticularly on the levels of assessment, assurance, and policy making. This has far-reaching
implications for methodology. Research on patient narratives must fruitfully intersect not
only with a detailed understanding of the scientific mechanisms leading to an opioid ad-
diction, but they must also be fed into higher-order discussions of the general parameters
of the healthcare system. In particular, one of the most central problems of the healthcare
system must be to take into account social inequality and unjust access to health . For
an understanding and tackling of the opioid epidemic, this implies that socially and eco-
nomically disenfranchised groups may be seen as particularly vulnerable to opioid addic-
tion. Thus, an integrative analysis of opioid addiction must take into account the pressures
of the workplace and the economic system as much as it must consider individual factors
in the framework of adequate medical treatment and care.
The above-mentioned shortcomings notwithstanding, however, these personal nar-
ratives point to a number of factors which can be informative for combating the opioid
crisis. The narratives link medical and pharmaceutical practice to a cultural discussion
about opioids. The biggest threat that these personal narratives describe is this one: The
prescription of opioid-based analgesics has been “normalized” in US culture. Physicians
may easily prescribe them, even in instances when this may not be absolutely necessary
or even when there is a contraindication if anamnestic knowledge is sufficiently gener-
ated. Patients, on the other hand, may conceive of these medications as “harmless”, and
may not be aware of the danger of addiction. In countering the current opioid crisis, life
sciences and humanities can inform public health about the multiple factors which have
led to this crisis. In view of these considerations, it is important to consider opioid addic-
tion in a global context. Knowledge of different languages apart from English is needed
in order to analyze patient narratives not only from the U.S. and the UK, but also from
many European countries. Patient narratives may contain important information concern-
ing patient attitudes . Socio-economic factors, culture-specific attitudes and different
prescription policies must be viewed from a comparative perspective.
This paper has suggested that, in order to understand the current opioid crisis, a mul-
tifactorial approach is necessary which links approaches from pharmaceutical biology to
a cultural and social perspective. To counteract the present crisis, it is important to con-
sider the different perspectives of physicians, pharmaceutical companies, patients and
their relatives, and also society at large. Established countermeasures turned out to be
quick fixes rather than game changers. This holds particularly true in the light of the col-
lision of the COVID-19 and the opioid epidemics . The opioid epidemic has evolved
rapidly during the last decades. According to the data gathered by Substance Abuse and
Mental Health Services Administration (SAMHSA), in 2016 over 63,000 people died of
drug overdose in the U.S., most of them involving a synthetic opioid or heroin, and 2.1
million people suffered from an opioid use disorder (OUD) . The consequences of
OUD include contracting hepatitis B and C virus, human immunodeficiency virus (HIV)
or overdose, and on a psychosocial level financial and legal problems and unemployment
For a widespread misuse of a given substance to occur, society had to normalize the
use of this substance and hence make it culturally acceptable. As the opioid crisis shows,
this normalization can have disastrous consequences . This paper has considered the
role of the CDC on a number of levels. As the national health protection agency, the aim
of the CDC is to “increase health security” . Regarding the growing number of people
with an opioid addiction, the CDC has attempted to raise awareness about the cultural,
social and personal mechanisms which can cause the addiction. By providing an overview
of general policies and by including patient narratives, the CDC website could be consid-
Int. J. Environ. Res. Public Health 2021, 18, 341 14 of 18
ered a tool for the wider public and for practitioners. This suggests that public health in-
stitutions have an important, if not essential, role in fighting the opioid epidemic and need
to adjust their strategies according to the fact that dealing with social inequalities, precar-
ious lives and unjust access to health is critical for dealing with the opioid crisis.
This paper has suggested that this crisis is a pharmaceutical and medical crisis as well
as a cultural one. Individuals may be prone to misuse opioids to keep up with the pressure
of the workplace in a neoliberal economy and in a highly competitive education system.
As patient narratives show, opioid addiction can start early on in an individual’s life. At
the same time, physicians may have been too quick to prescribe opioids or may have failed
to alert their patients to the dangers of addiction. The pharmaceutical industry, too, may
have stressed only the advantages of opioid medication. In this paper, we have argued
that a multidisciplinary approach which combines pharmaceutical biology with a cultural
and special perspective can alert all the actors involved in the opioid crisis to the different
factors involved in bringing about addiction. With such a multifactorial approach, public
health strategies can be reshaped to battle the opioid crisis more efficiently. On both a
therapeutic and a preventive level, one solution to the opioid crisis may thus lie in raising
awareness. Education and awareness-raising may be one of the most effective ways of
combating the ubiquitous use of opioids.
Author Contributions: Conceptualization, R.D., M.B. and T.E.; methodology, T.E.; investigation
and data curation, R.D., M.B., N.W.P., D.Y.W.L. and T.E.; writing—original draft preparation,
R.D., M.B., N.W.P., D.Y.W.L. and T.E.; writing—review and editing, R.D., M.B. and T.E.; supervi-
sion, T.E.; project administration, T.E. All authors have read and agreed to the published version
of the manuscript.
Funding: This research was funded by Deutsche Forschungsgemeinschaft (DFG GRK2015/2).
Acknowledgments: The authors are grateful to a PhD stipend of the Deutsche Forschungsgemein-
schaft (DFG GRK2015/2) to Roxana Damiescu.
Conflicts of Interest: The authors declare no conflict of interest.
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