Post-normal science diagramJerome Ravetz and Silvio Funtowicz, circa 1988, at Sheffield
Post-normal science (PNS) was developed in the 1990s by Silvio Funtowicz and Jerome R. Ravetz.
It is a problem-solving strategy appropriate when "facts [are]
uncertain, values in dispute, stakes high and decisions urgent",
conditions often present in policy-relevant research. In those
situations, PNS recommends suspending temporarily the traditional
scientific ideal of truth, concentrating on quality as assessed by
internal and extended peer communities.
PNS can be considered as complementing the styles of analysis
based on risk and cost-benefit analysis prevailing at that time and
integrating concepts of a new critical science developed in previous
works by the same authors.
PNS is not a new scientific method following Aristotle and Bacon,
a new paradigm in the Kuhnian sense, or an attempt to reach a new
‘normal’. It is instead, a set of insights to guide actionable and
robust knowledge production for policy decision making and action in
challenges like pandemics, ecosystems collapse, biodiversity loss and, in general, sustainability transitions.
Context
According to its proponents Silvio Funtowicz and Jerome R. Ravetz, the name "post-normal science" echoes the seminal work on modern science by Thomas Kuhn. For Carrozza
PNS can be "framed in terms of a call for the ‘democratization of
expertise’", and as a "reaction against long-term trends of
‘scientization’ of politics—the tendency towards assigning to experts a
critical role in policymaking while marginalizing laypeople". For Mike
Hulme (2007), writing on The Guardian, climate change
seems to fall into the category of issues which are best dealt with in
the context of PNS and notes that “Disputes in post-normal science focus
as often on the process of science - who gets funded, who evaluates
quality, who has the ear of policy - as on the facts of science”. Climate science as PNS was already proposed by the late Stephen Schneider, and a similar linkage was propose for the workings of the Intergovernmental Panel on Climate Change.
From the ecological perspective post-normal science can be
situated in the context of 'crisis disciplines' – a term coined by the
conservation biologist Michael E. Soulé to indicate approaches addressing fears, emerging in the seventies, that the world was on the verge of ecological collapse. In this respect Michael Egan
defines PNS as a 'survival science'. More recently PNS has been defined
as a movement of ‘informed critical resistance, reform and the making
of futures’.
Moving from PNS Ziauddin Sardar developed the concept of Postnormal Times (PNT). Sardar was the editor of FUTURES when it published the article ‘Science for the post-normal age’ presently the most cited paper of the journal. A recent review of academic literature conducted on the Web of Science and encompassing the topics of Futures studies, Foresight, Forecasting and Anticipation Practice identifies the same paper as "the all-time publication that received the highest number of citations".
Content
"At
birth Post-normal science was conceived as an inclusive set of robust
insights more than as an exclusive fully structured theory or field of
practice".
Some of the ideas underpinning PNS can already be found in a work
published in 1983 and entitled "Three types of risk assessment: a
methodological analysis" This and subsequent works show that PNS concentrates on few aspects of the complex relation
between science and policy: the communication of uncertainty, the
assessment of quality, and the justification and practice of the
extended peer communities.
Coming to the PNS diagram (figure above) the horizontal axis
represents ‘Systems Uncertainties’ and the vertical one ‘Decision
Stakes’. The three quadrants identify Applied Science, Professional
Consultancy, and Post-Normal Science. Different standards of quality and
styles of analysis are appropriate to different regions in the diagram,
i.e. post-normal science does not claim relevance and cogency on all of
science's application but only on those defined by the PNS's mantram
with a fourfold challenge: ‘facts uncertain, values in dispute, stakes
high and decisions urgent’. For applied research science's own peer
quality control system will suffice (or so was assumed at the moment PNS
was formulated in the early nineties), while professional consultancy
was considered appropriate for these settings which cannot be
‘peer-reviewed’, and where the skills and the tacit knowledge of a
practitioner are needed at the forefront, e.g. in a surgery room, or in a
house on fire. Here a surgeon or a firefighter takes a difficult
technical decision based on her or his training and appreciation of the
situation (the Greek concept of ‘Metis’ as discussed by J. C. Scott.)
Complexity
There are important linkages between PNS and complexity science, e.g. system ecology (C. S. Holling) and hierarchy theory (Arthur Koestler).
In PNS, complexity is respected through its recognition of a
multiplicity of legitimate perspectives on any issue; this is close to
the meaning espoused by Robert Rosen (theoretical biologist).
Reflexivity is realised through the extension of accepted ‘facts’
beyond the supposedly objective productions of traditional research.
Also, the new participants in the process are not treated as passive
learners at the feet of the experts, being coercively convinced through
scientific demonstration. Rather, they will form an ‘extended peer
community’, sharing the work of quality assurance of the scientific
inputs to the process, and arriving at a resolution of issues through
debate and dialogue. The necessity to embrace complexity in a post-normal perspective to understand and face zoonoses is argumented by David Waltner-Toews.
In PNS extended peer communities are spaces where perspectives,
values, styles of knowing and power differentials are expressed in a
context of inequalities and conflict. Resolutions, compromises and
knowledge co-production are contingent and not necessarily achievable.
Applications
Beside its dominating influence in the literature on 'futures',
PNS is considered to have influenced the ecological ‘conservation
versus preservation debate’, especially via its reading by American
pragmatist Bryan G. Norton. According to Jozef Keulartz
the PNS concept of "extended peer community" influenced how Norton's
developed his 'convergence hypothesis'. The hypothesis posits that
ecologists of different orientation will converge once they start
thinking 'as a mountain', or as a planet. For Norton this will be
achieved via deliberative democracy, which will pragmatically overcome
the black and white divide between conservationists and
preservationists. More recently it has been argued that conservation
science, embedded as it is in a multi-layered governance structures of
policy-makers, practitioners, and stakeholders, is itself an 'extended
peer community', and as a result conservation has always been
‘post-normal’.
Other authors attribute to PNS the role of having stimulated the
take up of transdisciplinary methodological frameworks, reliant on the
social constructivist perspective embedded in PNS.
Post-normal science is intended as applicable to most instances
where the use of evidence is contested due to different norms and
values. Typical instances are in the use of evidence based policy and in evaluation.
As summarized in a recent work "the ideas and concepts of post
normal science bring about the emergence of new problem solving
strategies in which the role of science is appreciated in its full
context of the complexity and the uncertainty of natural systems and the
relevance of human commitments and values."
For Peter Gluckman (2014), chief science advisor to the Prime
Minister of New Zealand, post-normal science approaches are today
appropriate for a host of problems including "eradication of exogenous
pests […], offshore oil prospecting, legalization of recreational
psychotropic drugs, water quality, family violence, obesity, teenage
morbidity and suicide, the ageing population, the prioritization of
early-childhood education, reduction of agricultural greenhouse gases,
and balancing economic growth and environmental sustainability".
Conservation science is also a field where PNS is suggested as to fill the space between research, policy, and implementation, as well as to ensure pluralism in analysis. Ecosystem services are a topical subject for PNS.
Reviews of the history and evolution of PNS, its definitions, conceptualizations,
and uses can be found in Turnpenny et al., 2010, and in The Routledge Handbook of Ecological Economics (Nature and Society). Articles on PNS are published in Nature and related journals.
Criticism
A criticism of post-normal science is offered by Weingart (1997)
for whom post-normal science does not introduce a new epistemology but
retraces earlier debates linked to the so-called "finalization thesis".
For Jörg Friedrichs
– comparing the issues of climate change and peak energy – an extension
of the peer community has taken place in the climate science community,
transforming climate scientists into ‘stealth advocates’,
while scientists working on energy security – without PNS, would still
maintain their credentials of neutrality and objectivity. Another
criticism is that the extended peer community's use undermines the scientific method's use of empiricism and that its goal would be better addressed by providing greater science education.
The crisis of science
It has been argued
that post-normal science scholars have been prescient in anticipating
the present crisis in science's quality control and reproducibility. A
group of scholars of post-normal science orientation has published in
2016 a volume on the topic, discussing inter alia what this community perceive as the root causes of the present science's crisis.
Quantitative approaches
Among the quantitative styles of analysis which make reference to post-normal science one can mention NUSAP for numerical information, sensitivity auditing for indicators and mathematical modelling, Quantitative storytelling for exploring multiple frames in a quantitative analysis, and MUSIASEM in the field of social metabolism. A work where these approaches are suggested for sustainability is in.
Mathematical modelling
In
relation to mathematical modelling post-normal science suggests a
participatory approach, whereby ‘models to predict and control the
future’ are replaced by ‘models to map our ignorance about the future’,
in the process exploring and revealing the metaphors embedded in the
model.
PNS is also known for its definition of garbage in, garbage out (GIGO):
in modelling GIGO occurs when the uncertainties in the inputs must be
suppressed, lest the outputs become completely indeterminate.
COVID-19
On 25 March 2020, in the midst of the COVID-19 pandemic, a group of scholars of post-normal orientation published on the blog section of the STEPS Centre (for Social, Technological and Environmental Pathways to Sustainability) at the University of Sussex. The piece
argues that the COVID-19 emergency has all the elements of a
post-normal science context, and notes that "this pandemic offers
society an occasion to open a fresh discussion on whether we now need to
learn how to do science in a different way".
Special issues
The journal FUTURES devoted several specials issues to post-normal science.
The second special issue, edited by Merryl Wyn Davies, was entitled "Post normal times" in 2011.
This was a selection of papers from the symposium "Post Normal Science –
perspectives & prospectives 26-27th June 2009, Oxford." A summary
of the abstracts can be found on the NUSAP net.
The third special issue on post-normal science was in 2017. This special issue contains a selection of papers discussed at the University of Bergen's
Centre for the Study of the Sciences and the Humanities between 2014
and 2016. The issue includes also two extended commentaries on the
present crisis in science and the post-fact/post-truth discourse, one
from Europe and one from Japan.
In psychology, the false consensus effect, also known as consensus bias, is a pervasive cognitive bias
that causes people to "see their own behavioral choices and judgments
as relatively common and appropriate to existing circumstances".
In other words, they assume that their personal qualities,
characteristics, beliefs, and actions are relatively widespread through
the general population.
This false consensus is significant because it increases self-esteem (overconfidence effect). It can be derived from a desire to conform and be liked by others in a social environment.
This bias is especially prevalent in group settings where one thinks
the collective opinion of their own group matches that of the larger
population. Since the members of a group reach a consensus and rarely
encounter those who dispute it, they tend to believe that everybody
thinks the same way. The false-consensus effect is not restricted to
cases where people believe that their values are shared by the majority,
but it still manifests as an overestimate of the extent of their
belief.
Additionally, when confronted with evidence that a consensus does
not exist, people often assume that those who do not agree with them
are defective in some way. There is no single cause for this cognitive bias; the availability heuristic, self-serving bias, and naïve realism
have been suggested as at least partial underlying factors. The bias
may also result, at least in part, from non-social stimulus-reward
associations. Maintenance of this cognitive bias may be related to the tendency to make decisions with relatively little information.
When faced with uncertainty and a limited sample from which to make
decisions, people often "project" themselves onto the situation. When
this personal knowledge is used as input to make generalizations, it
often results in the false sense of being part of the majority.
The false consensus effect has been widely observed and supported
by empirical evidence. Previous research has suggested that cognitive
and perceptional factors (motivated projection, accessibility of
information, emotion, etc.) may contribute to the consensus bias, while
recent studies have focused on its neural mechanisms. One recent study
has shown that consensus bias may improve decisions about other people's
preferences.
Ross, Green and House first defined the false consensus effect in 1977
with emphasis on the relative commonness that people perceive about
their own responses; however, similar projection phenomena had already
caught attention in psychology. Specifically, concerns with respect to
connections between individual's personal predispositions and their
estimates of peers appeared in the literature for a while. For
instances, Katz and Allport in 1931 illustrated that students’ estimates
of the amount of others on the frequency of cheating was positively
correlated to their own behavior. Later, around 1970, same phenomena
were found on political beliefs and prisoner's dilemma
situation. In 2017, researchers identified a persistent egocentric bias
when participants learned about other people's snack-food preferences.
Moreover, recent studies suggest that the false consensus effect can
also affect professional decision makers; specifically, it has been
shown that even experienced marketing managers project their personal
product preferences onto consumers.
Major theoretical approaches
The false-consensus effect can be traced back to two parallel theories of social perception, "the study of how we form impressions of and make inferences about other people". The first is the idea of social comparison. The principal claim of Leon Festinger's (1954) social comparison theory was that individuals evaluate their thoughts and attitudes based on other people.
This may be motivated by a desire for confirmation and the need to feel
good about oneself. As an extension of this theory, people may use
others as sources of information to define social reality and guide
behavior. This is called informational social influence.
The problem, though, is that people are often unable to accurately
perceive the social norm and the actual attitudes of others. In other
words, research has shown that people are surprisingly poor "intuitive
psychologists" and that our social judgments are often inaccurate.
This finding helped to lay the groundwork for an understanding of
biased processing and inaccurate social perception. The false-consensus
effect is just one example of such an inaccuracy.
The second influential theory is projection, the idea that people project their own attitudes and beliefs onto others. This idea of projection is not a new concept. In fact, it can be found in Sigmund Freud's work on the defense mechanism of projection, D.S. Holmes' work on "attributive projection" (1968), and Gustav Ichheisser's work on social perception (1970).
D.S. Holmes, for example, described social projection as the process by
which people "attempt to validate their beliefs by projecting their own
characteristics onto other individuals".
Here a connection can be made between the two stated theories of
social comparison and projection. First, as social comparison theory
explains, individuals constantly look to peers as a reference group and
are motivated to do so in order to seek confirmation for their own
attitudes and beliefs.
The false-consensus effect, as defined by Ross,
Greene, and House in 1977, came to be the culmination of the many
related theories that preceded it. In their well-known series of four
studies, Ross and associates hypothesized and then demonstrated that
people tend to overestimate the popularity of their own beliefs and
preferences.
Studies were both conducted in hypothetical situations by questionnaire
surveys and in authentic conflict situations. For questionnaire
studies, participants were presented with hypothetical events and then
were not only asked to indicate their own behavioral choices and
characteristics under the provided circumstances, but also asked to rate
the responses and traits of their peers who referred as "actors". As
for real occasion studies, participants were actually confronted with
the conflict situations in which they were asked to choose behavioral
alternatives and to judge the traits as well as decisions of two
supposedly true individuals who had attended in the study. In general, the raters made more "extreme predictions" about the
personalities of the actors that did not share the raters' own
preference. In fact, the raters may have even thought that there was
something wrong with the people expressing the alternative response.
In the ten years after the influential Ross et al. study, close
to 50 papers were published with data on the false-consensus effect.
Theoretical approaches were also expanded. The theoretical perspectives
of this era can be divided into four categories: (a) selective exposure
and cognitive availability, (b) salience and focus of attention, (c)
logical information processing, and (d) motivational processes.
In general, the researchers and designers of these theories believe
that there is not a single right answer. Instead, they admit that there
is overlap among the theories and that the false-consensus effect is
most likely due to a combination of these factors.
Selective exposure and cognitive availability
This
theory is closely tied to the availability heuristic, which suggests
that perceptions of similarity (or difference) are affected by how
easily those characteristics can be recalled from memory.
And as one might expect, similarities between oneself and others are
more easily recalled than differences. This is in part because people
usually associate with those who are similar to themselves. This
selected exposure to similar people may bias or restrict the "sample of
information about the true diversity of opinion in the larger social
environment".
As a result of the selective exposure and availability heuristic, it is
natural for the similarities to prevail in one's thoughts.
Botvin et al. (1992)
did a popular study on the effects of the false-consensus effect among a
specific adolescent community in an effort to determine whether
students show a higher level of false-consensus effect among their
direct peers as opposed to society at large.
The participants of this experiment were 203 college students ranging
in age from 18 to 25 (with an average age of 18.5). The participants
were given a questionnaire and asked to answer questions regarding a
variety of social topics. For each social topic, they were asked to
answer how they felt about the topic and to estimate the percentage of
their peers who would agree with them. The results determined that the
false-consensus effect was extremely prevalent when participants were
describing the rest of their college community; out of twenty topics
considered, sixteen of them prominently demonstrated the false-consensus
effect. The high levels of false-consensus effect seen in this study
can be attributed to the group studied; because the participants were
asked to compare themselves to a group of peers that they are constantly
around (and view as very similar to themselves), the levels of
false-consensus effect increased.
Salience and focus of attention
This
theory suggests that when an individual focuses solely on their own
preferred position, they are more likely to overestimate its popularity,
thus falling victim to the false-consensus effect.
This is because that position is the only one in their immediate
consciousness. Performing an action that promotes the position will make
it more salient and may increase the false-consensus effect. If,
however, more positions are presented to the individual, the degree of
the false-consensus effect might decrease significantly.
Logical information processing
This theory assumes that active and seemingly rational thinking underlies an individual's estimates of similarity among others.
In a study done by Fox, Yinon, and Mayraz, researchers were attempting
to determine whether or not the levels of the false-consensus effect
changed in different age groups. In order to come to a conclusion, it
was necessary for the researchers to split their participants into four
different age groups. Two hundred participants were used, and gender was
not considered to be a factor. Just as in the previous study mentioned,
this study used a questionnaire as its main source of information. The
results showed that the false-consensus effect was extremely prevalent
in all groups, but was the most prevalent in the oldest age group (the
participants who were labeled as "old-age home residents"). They showed
the false-consensus effect in all 12 areas that they were questioned
about. The increase in false-consensus effect seen in the oldest age
group can be accredited to their high level of "logical" reasoning
behind their decisions; the oldest age group has obviously lived the
longest, and therefore feels that they can project their beliefs onto
all age groups due to their (seemingly objective) past experiences and
wisdom. The younger age groups cannot logically relate to those older to
them because they have not had that experience and do not pretend to
know these objective truths. These results demonstrate a tendency for
older people to rely more heavily on situational attributions (life
experience) as opposed to internal attributions.
Motivational processes
This
theory stresses the benefits of the false-consensus effect: namely, the
perception of increased social validation, social support, and
self-esteem. It may also be useful to exaggerate similarities in social
situations in order to increase liking.
Belief in a favorable future
The concept of false consensus effect can also be extended to predictions about future others. Belief in a favorable future is the belief that future others will change their preferences and beliefs in alignment with one's own.
Rogers, Moore, and Norton (2017) find that belief in a favorable future is greater in magnitude than the false-consensus effect for two reasons:
It is based in future others whose beliefs are not directly observable, and
It is focused on future beliefs, which gives these future others time to "discover" the truth and change their beliefs.
Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and was made available in 1960 by Hoffmann–La Roche, which followed with the development of diazepam (Valium) three years later, in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.
Benzodiazepines are generally viewed as safe and effective for short-term use of two to four weeks, although cognitive impairment and paradoxical effects such as aggression or behavioral disinhibition can occur. According to the Government of Victoria's (Australia) Department of Health, long-term use can cause "impaired thinking or memory loss, anxiety and depression, irritability, paranoia, aggression, etc." A minority of people have paradoxical reactions after taking benzodiazepines such as worsened agitation or panic.
Benzodiazepines are associated with an increased risk of suicide due to aggression, impulsivity, and negative withdrawal effects. Long-term use is controversial because of concerns about decreasing effectiveness, physical dependence, benzodiazepine withdrawal syndrome, and an increased risk of dementia and cancer. The elderly are at an increased risk of both short- and long-term adverse effects, and as a result, all benzodiazepines are listed in the Beers List of inappropriate medications for older adults. There is controversy concerning the safety of benzodiazepines in pregnancy. While they are not major teratogens, uncertainty remains as to whether they cause cleft palate in a small number of babies and whether neurobehavioural effects occur as a result of prenatal exposure; they are known to cause withdrawal symptoms in the newborn.
In an overdose, benzodiazepines can cause dangerous deep unconsciousness, but are less toxic than their predecessors, the barbiturates, and death rarely results when a benzodiazepine is the only drug taken. Combined with other central nervous system (CNS) depressants such as alcohol and opioids, the potential for toxicity and fatal overdose increases significantly. Benzodiazepines are commonly used recreationally and also often taken in combination with other addictive substances, and are controlled in most countries.
Benzodiazepines possess psycholeptic, sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant, and amnesic actions, which are useful in a variety of indications such as alcohol dependence, seizures, anxiety disorders, panic, agitation, and insomnia. Most are administered orally; however, they can also be given intravenously, intramuscularly, or rectally.
In general, benzodiazepines are well tolerated and are safe and
effective drugs in the short term for a wide range of conditions. Tolerance can develop to their effects and there is also a risk of dependence,
and upon discontinuation a withdrawal syndrome may occur. These
factors, combined with other possible secondary effects after prolonged
use such as psychomotor, cognitive, or memory impairments, limit their
long-term applicability. The effects of long-term use or misuse include the tendency to cause or worsen cognitive deficits, depression, and anxiety. The College of Physicians and Surgeons of British Columbia recommends discontinuing the usage of benzodiazepines in those on opioids and those who have used them long term.
Benzodiazepines can have serious adverse health outcomes, and these
findings support clinical and regulatory efforts to reduce usage,
especially in combination with non-benzodiazepine receptor agonists.
Because of their effectiveness, tolerability, and rapid onset of anxiolytic action, benzodiazepines are frequently used for the treatment of anxiety associated with panic disorder.
However, there is disagreement among expert bodies regarding the
long-term use of benzodiazepines for panic disorder. The views range
from those holding benzodiazepines are not effective long-term and should be reserved for treatment-resistant cases to those holding they are as effective in the long term as selective serotonin reuptake inhibitors (SSRIs).
American Psychiatric Association (APA) guidelines, published in January 2009,
note that, in general, benzodiazepines are well tolerated, and their
use for the initial treatment for panic disorder is strongly supported
by numerous controlled trials. APA states that there is insufficient
evidence to recommend any of the established panic disorder treatments
over another. The choice of treatment between benzodiazepines, SSRIs, serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants,
and psychotherapy should be based on the patient's history, preference,
and other individual characteristics. Selective serotonin reuptake
inhibitors are likely to be the best choice of pharmacotherapy for many
patients with panic disorder, but benzodiazepines are also often used,
and some studies suggest that these medications are still used with
greater frequency than the SSRIs. One advantage of benzodiazepines is
that they alleviate the anxiety symptoms much faster than
antidepressants, and therefore may be preferred in patients for whom
rapid symptom control is critical. However, this advantage is offset by
the possibility of developing benzodiazepine dependence. APA does not recommend benzodiazepines for persons with depressive symptoms or a recent history of substance use disorder.
APA guidelines state that, in general, pharmacotherapy of panic
disorder should be continued for at least a year, and that clinical
experience supports continuing benzodiazepine treatment to prevent
recurrence. Although major concerns about benzodiazepine tolerance and
withdrawal have been raised, there is no evidence for significant dose
escalation in patients using benzodiazepines long-term. For many such
patients, stable doses of benzodiazepines retain their efficacy over
several years.
Guidelines issued by the UK-based National Institute for Health and Clinical Excellence
(NICE), carried out a systematic review using different methodology and
came to a different conclusion. They questioned the accuracy of studies
that were not placebo-controlled. And, based on the findings of placebo-controlled studies, they do not recommend use of benzodiazepines beyond two to four weeks, as tolerance and physical dependence develop rapidly, with withdrawal symptoms including rebound anxiety occurring after six weeks or more of use. Nevertheless, benzodiazepines are still prescribed for long-term treatment of anxiety disorders, although specific antidepressants and psychological therapies are recommended as the first-line treatment options with the anticonvulsant drug pregabalin indicated as a second- or third-line treatment and suitable for long-term use.[36] NICE stated that long-term use of benzodiazepines for panic disorder with or without agoraphobia
is an unlicensed indication, does not have long-term efficacy, and is,
therefore, not recommended by clinical guidelines. Psychological
therapies such as cognitive behavioural therapy
are recommended as a first-line therapy for panic disorder;
benzodiazepine use has been found to interfere with therapeutic gains
from these therapies.
Benzodiazepines are usually administered orally; however, very
occasionally lorazepam or diazepam may be given intravenously for the
treatment of panic attacks.
Benzodiazepines have robust efficacy in the short-term management of generalized anxiety disorder (GAD), but were not shown effective in producing long-term improvement overall. According to National Institute for Health and Clinical Excellence
(NICE), benzodiazepines can be used in the immediate management of GAD,
if necessary. However, they should not usually be given for longer than
2–4 weeks. The only medications NICE recommends for the longer term
management of GAD are antidepressants.
Likewise, Canadian Psychiatric Association (CPA) recommends benzodiazepines alprazolam, bromazepam, lorazepam, and diazepam
only as a second-line choice, if the treatment with two different
antidepressants was unsuccessful. Although they are second-line agents,
benzodiazepines can be used for a limited time to relieve severe anxiety
and agitation. CPA guidelines note that after 4–6 weeks the effect of
benzodiazepines may decrease to the level of placebo, and that
benzodiazepines are less effective than antidepressants in alleviating ruminative worry,
the core symptom of GAD. However, in some cases, a prolonged treatment
with benzodiazepines as the add-on to an antidepressant may be
justified.
Benzodiazepines are sometimes used in the treatment of acute anxiety, since they result in rapid and marked relief of symptoms in most individuals;
however, they are not recommended beyond 2–4 weeks of use due to risks
of tolerance and dependence and a lack of long-term effectiveness. As
for insomnia, they may also be used on an irregular/"as-needed" basis,
such as in cases where said anxiety is at its worst. Compared to other
pharmacological treatments, benzodiazepines are twice as likely to lead
to a relapse of the underlying condition upon discontinuation.
Psychological therapies and other pharmacological therapies are
recommended for the long-term treatment of generalized anxiety disorder.
Antidepressants have higher remission rates and are, in general, safe
and effective in the short and long term.
Benzodiazepines can be useful for short-term treatment of insomnia.
Their use beyond 2 to 4 weeks is not recommended due to the risk of
dependence. The Committee on Safety of Medicines report recommended that
where long-term use of benzodiazepines for insomnia is indicated then
treatment should be intermittent wherever possible.
It is preferred that benzodiazepines be taken intermittently and at the
lowest effective dose. They improve sleep-related problems by
shortening the time spent in bed before falling asleep, prolonging the
sleep time, and, in general, reducing wakefulness.
However, they worsen sleep quality by increasing light sleep and
decreasing deep sleep. Other drawbacks of hypnotics, including
benzodiazepines, are possible tolerance to their effects, rebound insomnia,
and reduced slow-wave sleep and a withdrawal period typified by rebound
insomnia and a prolonged period of anxiety and agitation.
The list of benzodiazepines approved for the treatment of
insomnia is fairly similar among most countries, but which
benzodiazepines are officially designated as first-line hypnotics
prescribed for the treatment of insomnia varies between countries. Longer-acting benzodiazepines such as nitrazepam and diazepam have residual effects that may persist into the next day and are, in general, not recommended.
Since the release of nonbenzodiazepines,
also known as z-drugs, in 1992 in response to safety concerns,
individuals with insomnia and other sleep disorders have increasingly
been prescribed nonbenzodiazepines (2.3% in 1993 to 13.7% of Americans
in 2010), less often prescribed benzodiazepines (23.5% in 1993 to 10.8%
in 2010). It is not clear as to whether the new non benzodiazepine
hypnotics (Z-drugs) are better than the short-acting benzodiazepines.
The efficacy of these two groups of medications is similar. According to the US Agency for Healthcare Research and Quality,
indirect comparison indicates that side-effects from benzodiazepines
may be about twice as frequent as from nonbenzodiazepines. Some experts suggest using nonbenzodiazepines preferentially as a first-line long-term treatment of insomnia. However, the UK National Institute for Health and Clinical Excellence
did not find any convincing evidence in favor of Z-drugs. NICE review
pointed out that short-acting Z-drugs were inappropriately compared in
clinical trials with long-acting benzodiazepines. There have been no
trials comparing short-acting Z-drugs with appropriate doses of
short-acting benzodiazepines. Based on this, NICE recommended choosing
the hypnotic based on cost and the patient's preference.
Older adults should not use benzodiazepines to treat insomnia unless other treatments have failed.
When benzodiazepines are used, patients, their caretakers, and their
physician should discuss the increased risk of harms, including evidence
that shows twice the incidence of traffic collisions among driving patients, and falls and hip fracture for older patients.
Prolonged convulsive epileptic seizures are a medical emergency that can usually be dealt with effectively by administering fast-acting benzodiazepines, which are potent anticonvulsants. In a hospital environment, intravenousclonazepam, lorazepam, and diazepam are first-line choices. In the community, intravenous administration is not practical and so rectal diazepam or buccalmidazolam are used, with a preference for midazolam as its administration is easier and more socially acceptable.
When benzodiazepines were first introduced, they were enthusiastically adopted for treating all forms of epilepsy. However, drowsiness and tolerance become problems with continued use and none are now considered first-line choices for long-term epilepsy therapy. Clobazam is widely used by specialist epilepsy clinics worldwide and clonazepam is popular in the Netherlands, Belgium and France.
Clobazam was approved for use in the United States in 2011. In the UK,
both clobazam and clonazepam are second-line choices for treating many
forms of epilepsy. Clobazam also has a useful role for very short-term seizure prophylaxis and in catamenial epilepsy.
Discontinuation after long-term use in epilepsy requires additional
caution because of the risks of rebound seizures. Therefore, the dose is
slowly tapered over a period of up to six months or longer.
Chlordiazepoxide is the most commonly used benzodiazepine for alcohol detoxification, but diazepam
may be used as an alternative. Both are used in the detoxification of
individuals who are motivated to stop drinking, and are prescribed for a
short period of time to reduce the risks of developing tolerance and
dependence to the benzodiazepine medication itself.
The benzodiazepines with a longer half-life make detoxification more
tolerable, and dangerous (and potentially lethal) alcohol withdrawal
effects are less likely to occur. On the other hand, short-acting
benzodiazepines may lead to breakthrough seizures, and are, therefore, not recommended for detoxification in an outpatient setting. Oxazepam and lorazepam are often used in patients at risk of drug accumulation, in particular, the elderly and those with cirrhosis, because they are metabolized differently from other benzodiazepines, through conjugation.
Benzodiazepines are the preferred choice in the management of alcohol withdrawal syndrome, in particular, for the prevention and treatment of the dangerous complication of seizures and in subduing severe delirium.
Lorazepam is the only benzodiazepine with predictable intramuscular
absorption and it is the most effective in preventing and controlling
acute seizures.
Other indications
Benzodiazepines are often prescribed for a wide range of conditions:
They can sedate patients receiving mechanical ventilation or those in extreme distress. Caution is exercised in this situation due to the risk of respiratory depression, and it is recommended that benzodiazepine overdose treatment facilities should be available. They have also been found to increase the likelihood of later PTSD after people have been removed from ventilators.
Benzodiazepines are indicated in the management of breathlessness
(shortness of breath) in advanced diseases, in particular where other
treatments have failed to adequately control symptoms.
Benzodiazepines are effective as medication given a couple of hours before surgery to relieve anxiety. They also produce amnesia, which can be useful, as patients may not remember unpleasantness from the procedure. They are also used in patients with dental phobia
as well as some ophthalmic procedures like refractive surgery; although
such use is controversial and only recommended for those who are very
anxious.
Midazolam is the most commonly prescribed for this use because of its
strong sedative actions and fast recovery time, as well as its water
solubility, which reduces pain upon injection. Diazepam and lorazepam
are sometimes used. Lorazepam has particularly marked amnesic properties
that may make it more effective when amnesia is the desired effect.
Benzodiazepines are well known for their strong muscle-relaxing properties and can be useful in the treatment of muscle spasms, although tolerance often develops to their muscle relaxant effects. Baclofen or tizanidine
are sometimes used as an alternative to benzodiazepines. Tizanidine has
been found to have superior tolerability compared to diazepam and
baclofen.
Benzodiazepines are also used to treat the acute panic caused by hallucinogen intoxication.
Benzodiazepines are also used to calm the acutely agitated individual
and can, if required, be given via an intramuscular injection. They can sometimes be effective in the short-term treatment of psychiatric emergencies such as acute psychosis as in schizophrenia or mania, bringing about rapid tranquillization and sedation until the effects of lithium or neuroleptics (antipsychotics) take effect. Lorazepam is most commonly used but clonazepam is sometimes prescribed for acute psychosis or mania; their long-term use is not recommended due to risks of dependence.
Further research investigating the use of benzodiazepines alone and in
combination with antipsychotic medications for treating acute psychosis
is warranted.
Benzodiazepines are sometimes used for obsessive–compulsive disorder
(OCD), although they are generally believed ineffective for this
indication. Effectiveness was, however, found in one small study. Benzodiazepines can be considered as a treatment option in treatment resistant cases.
Antipsychotics are generally a first-line treatment for delirium; however, when delirium is caused by alcohol or sedative hypnotic withdrawal, benzodiazepines are a first-line treatment.
There is some evidence that low doses of benzodiazepines reduce adverse effects of electroconvulsive therapy.
Contraindications
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbidpsychiatric disorders.
In the United States, the Food and Drug Administration has categorized benzodiazepines into either category D or X meaning potential for harm in the unborn has been demonstrated.
Exposure to benzodiazepines during pregnancy has been associated with a slightly increased (from 0.06 to 0.07%) risk of cleft palate
in newborns, a controversial conclusion as some studies find no
association between benzodiazepines and cleft palate. Their use by
expectant mothers shortly before the delivery may result in a floppy infant syndrome. Newborns with this condition tend to have hypotonia, hypothermia, lethargy, and breathing and feeding difficulties. Cases of neonatal withdrawal syndrome have been described in infants chronically exposed to benzodiazepines in utero.
This syndrome may be hard to recognize, as it starts several days after
delivery, for example, as late as 21 days for chlordiazepoxide. The
symptoms include tremors, hypertonia, hyperreflexia, hyperactivity, and vomiting and may last for up to three to six months.
Tapering down the dose during pregnancy may lessen its severity. If
used in pregnancy, those benzodiazepines with a better and longer safety
record, such as diazepam or chlordiazepoxide, are recommended over potentially more harmful benzodiazepines, such as temazepam or triazolam. Using the lowest effective dose for the shortest period of time minimizes the risks to the unborn child.
Elderly
The benefits of benzodiazepines are least and the risks are greatest in the elderly. They are listed as a potentially inappropriate medication for older adults by the American Geriatrics Society. The elderly are at an increased risk of dependence
and are more sensitive to the adverse effects such as memory problems,
daytime sedation, impaired motor coordination, and increased risk of
motor vehicle accidents and falls, and an increased risk of hip fractures. The long-term effects of benzodiazepines and benzodiazepine dependence in the elderly can resemble dementia, depression, or anxiety syndromes,
and progressively worsens over time. Adverse effects on cognition can
be mistaken for the effects of old age. The benefits of withdrawal
include improved cognition, alertness, mobility, reduced risk of
incontinence, and a reduced risk of falls and fractures. The success of
gradual-tapering benzodiazepines is as great in the elderly as in
younger people. Benzodiazepines should be prescribed to the elderly only
with caution and only for a short period at low doses. Short to intermediate-acting benzodiazepines are preferred in the elderly such as oxazepam and temazepam. The high potency benzodiazepines alprazolam and triazolam and long-acting benzodiazepines are not recommended in the elderly due to increased adverse effects. Nonbenzodiazepines such as zaleplon and zolpidem and low doses of sedating antidepressants are sometimes used as alternatives to benzodiazepines.
Long-term use of benzodiazepines is associated with increased
risk of cognitive impairment and dementia, and reduction in prescribing
levels is likely to reduce dementia risk.
The association of a history of benzodiazepine use and cognitive
decline is unclear, with some studies reporting a lower risk of
cognitive decline in former users, some finding no association and some
indicating an increased risk of cognitive decline.
Benzodiazepines are sometimes prescribed to treat behavioral symptoms of dementia. However, like antidepressants, they have little evidence of effectiveness, although antipsychotics have shown some benefit. Cognitive impairing effects of benzodiazepines that occur frequently in the elderly can also worsen dementia.
Adverse effects
Table
from the 2010 ISCD study ranking various drugs (legal and illegal)
based on statements by drug-harm experts. Benzodiazepines were found to
be the 10th most dangerous drug overall.
The most common side-effects of benzodiazepines are related to their sedating and muscle-relaxing action. They include drowsiness, dizziness, and decreased alertness and concentration. Lack of coordination may result in falls and injuries particularly in the elderly. Another result is impairment of driving skills and increased likelihood of road traffic accidents. Decreased libido and erection problems are a common side effect. Depression and disinhibition may emerge. Hypotension and suppressed breathing (hypoventilation) may be encountered with intravenous use. Less common side effects include nausea and changes in appetite, blurred vision, confusion, euphoria, depersonalization and nightmares. Cases of liver toxicity have been described but are very rare.
The long-term effects of benzodiazepine use can include cognitive impairment as well as affective and behavioural problems. Feelings of turmoil, difficulty in thinking constructively, loss of sex-drive, agoraphobia
and social phobia, increasing anxiety and depression, loss of interest
in leisure pursuits and interests, and an inability to experience or
express feelings can also occur. Not everyone, however, experiences
problems with long-term use. Additionally, an altered perception of self, environment and relationships may occur.
A study published in 2020 found that long-term use of prescription
benzodiazepines is associated with an increase in all-cause mortality
among those age 65 or younger, but not those older than 65. The study
also found that all-cause mortality was increased further in cases in
which benzodiazepines are co-prescribed with opioids, relative to cases
in which benzodiazepines are prescribed without opioids, but again only
in those age 65 or younger.
Compared to other sedative-hypnotics, visits to the hospital
involving benzodiazepines had a 66% greater odds of a serious adverse
health outcome. This included hospitalization, patient transfer, or
death, and visits involving a combination of benzodiazepines and
non-benzodiapine receptor agonists had almost four-times increased odds
of a serious health outcome.
In September 2020, the US Food and Drug Administration (FDA) required the boxed warning
be updated for all benzodiazepine medicines to describe the risks of
abuse, misuse, addiction, physical dependence, and withdrawal reactions
consistently across all the medicines in the class.
Cognitive effects
The
short-term use of benzodiazepines adversely affects multiple areas of
cognition, the most notable one being that it interferes with the
formation and consolidation of memories of new material and may induce
complete anterograde amnesia.
However, researchers hold contrary opinions regarding the effects of
long-term administration. One view is that many of the short-term
effects continue into the long-term and may even worsen, and are not
resolved after stopping benzodiazepine usage. Another view maintains
that cognitive deficits in chronic benzodiazepine users occur only for a
short period after the dose, or that the anxiety disorder is the cause
of these deficits.
While the definitive studies are lacking, the former view received support from a 2004 meta-analysis of 13 small studies.
This meta-analysis found that long-term use of benzodiazepines was
associated with moderate to large adverse effects on all areas of
cognition, with visuospatial
memory being the most commonly detected impairment. Some of the other
impairments reported were decreased IQ, visiomotor coordination,
information processing, verbal learning and concentration. The authors
of the meta-analysis and a later reviewer
noted that the applicability of this meta-analysis is limited because
the subjects were taken mostly from withdrawal clinics; the coexisting
drug, alcohol use, and psychiatric disorders were not defined; and
several of the included studies conducted the cognitive measurements
during the withdrawal period.
Paradoxical effects
Paradoxical reactions, such as increased seizures in epileptics, aggression, violence, impulsivity, irritability and suicidal behavior sometimes occur.
These reactions have been explained as consequences of disinhibition
and the subsequent loss of control over socially unacceptable behavior.
Paradoxical reactions are rare in the general population, with an
incidence rate below 1% and similar to placebo. However, they occur with greater frequency in recreational abusers, individuals with borderline personality disorder, children, and patients on high-dosage regimes. In these groups, impulse control
problems are perhaps the most important risk factor for disinhibition;
learning disabilities and neurological disorders are also significant
risks. Most reports of disinhibition involve high doses of high-potency
benzodiazepines. Paradoxical effects may also appear after chronic use of benzodiazepines.
Long-term worsening of psychiatric symptoms
While
benzodiazepines may have short-term benefits for anxiety, sleep and
agitation in some patients, long-term (i.e., greater than 2–4 weeks) use
can result in a worsening of the very symptoms the medications are
meant to treat. Potential explanations include exacerbating cognitive
problems that are already common in anxiety disorders, causing or
worsening depression and suicidality,disrupting sleep architecture by inhibiting deep stage sleep, withdrawal symptoms or rebound symptoms in between doses mimicking or exacerbating underlying anxiety or sleep disorders, inhibiting the benefits of psychotherapy by inhibiting memory consolidation and reducing fear extinction, and reducing coping with trauma/stress and increasing vulnerability to future stress. The latter two explanations may be why benzodiazepines are ineffective and/or potentially harmful in PTSD and phobias.
Anxiety, insomnia and irritability may be temporarily exacerbated
during withdrawal, but psychiatric symptoms after discontinuation are
usually less than even while taking benzodiazepines. Functioning significantly improves within 1 year of discontinuation.
Physical dependence, withdrawal and post-withdrawal syndromes
The main problem of the chronic use of benzodiazepines is the development of tolerance and dependence.
Tolerance manifests itself as diminished pharmacological effect and
develops relatively quickly to the sedative, hypnotic, anticonvulsant,
and muscle relaxant actions of benzodiazepines. Tolerance to
anti-anxiety effects develops more slowly with little evidence of
continued effectiveness beyond four to six months of continued use. In general, tolerance to the amnesic effects does not occur. However, controversy exists as to tolerance to the anxiolytic effects with some evidence that benzodiazepines retain efficacy and opposing evidence from a systematic review of the literature that tolerance frequently occursand some evidence that anxiety may worsen with long-term use. The question of tolerance to the amnesic effects of benzodiazepines is, likewise, unclear.
Some evidence suggests that partial tolerance does develop, and that,
"memory impairment is limited to a narrow window within 90 minutes after
each dose".
A major disadvantage of benzodiazepines is that tolerance to
therapeutic effects develops relatively quickly while many adverse
effects persist. Tolerance develops to hypnotic and myorelaxant effects
within days to weeks, and to anticonvulsant and anxiolytic effects
within weeks to months.
Therefore, benzodiazepines are unlikely to be effective long-term
treatments for sleep and anxiety. While BZD therapeutic effects
disappear with tolerance, depression and impulsivity with high suicidal
risk commonly persist. Several studies have confirmed that long-term benzodiazepines are not significantly different from placebo for sleep or anxiety.
This may explain why patients commonly increase doses over time and
many eventually take more than one type of benzodiazepine after the
first loses effectiveness.
Additionally, because tolerance to benzodiazepine sedating effects
develops more quickly than does tolerance to brainstem depressant
effects, those taking more benzodiazepines to achieve desired effects
may experience sudden respiratory depression, hypotension or death. Most patients with anxiety disorders and PTSD have symptoms that persist for at least several months,
making tolerance to therapeutic effects a distinct problem for them and
necessitating the need for more effective long-term treatment (e.g.,
psychotherapy, serotonergic antidepressants).
Discontinuation of benzodiazepines or abrupt reduction of the dose,
even after a relatively short course of treatment (two to four weeks),
may result in two groups of symptoms, rebound and withdrawal.
Rebound symptoms are the return of the symptoms for which the patient
was treated but worse than before. Withdrawal symptoms are the new
symptoms that occur when the benzodiazepine is stopped. They are the
main sign of physical dependence.
The most frequent symptoms of withdrawal from benzodiazepines are insomnia, gastric problems, tremors, agitation, fearfulness, and muscle spasms. The less frequent effects are irritability, sweating, depersonalization, derealization, hypersensitivity to stimuli, depression, suicidal behavior, psychosis, seizures, and delirium tremens. Severe symptoms usually occur as a result of abrupt or over-rapid withdrawal. Abrupt withdrawal can be dangerous and lead to excitotoxicity, causing damage and even death to nerve cells as a result of excessive levels of the excitatory neurotransmitter glutamate.
Increased glutamatergic activity is thought to be part of a
compensatory mechanism to chronic GABAergic inhibition from
benzodiazepines.Therefore, a gradual reduction regimen is recommended.
Symptoms may also occur during a gradual dosage reduction, but
are typically less severe and may persist as part of a protracted withdrawal syndrome for months after cessation of benzodiazepines.
Approximately 10% of patients experience a notable protracted
withdrawal syndrome, which can persist for many months or in some cases a
year or longer. Protracted symptoms tend to resemble those seen during
the first couple of months of withdrawal but usually are of a sub-acute
level of severity. Such symptoms do gradually lessen over time,
eventually disappearing altogether.
Benzodiazepines have a reputation with patients and doctors for
causing a severe and traumatic withdrawal; however, this is in large
part due to the withdrawal process being poorly managed. Over-rapid
withdrawal from benzodiazepines increases the severity of the withdrawal
syndrome and increases the failure rate. A slow and gradual withdrawal
customised to the individual and, if indicated, psychological support
is the most effective way of managing the withdrawal. Opinion as to the
time needed to complete withdrawal ranges from four weeks to several
years. A goal of less than six months has been suggested, but due to factors such as dosage and type of benzodiazepine, reasons for prescription, lifestyle, personality, environmental stresses, and amount of available support, a year or more may be needed to withdraw.
Withdrawal is best managed by transferring the physically
dependent patient to an equivalent dose of diazepam because it has the
longest half-life of all of the benzodiazepines, is metabolised into
long-acting active metabolites and is available in low-potency tablets,
which can be quartered for smaller doses. A further benefit is that it is available in liquid form, which allows for even smaller reductions. Chlordiazepoxide, which also has a long half-life and long-acting active metabolites, can be used as an alternative.
Nonbenzodiazepines are contraindicated during benzodiazepine withdrawal as they are cross tolerant with benzodiazepines and can induce dependence.
Alcohol is also cross tolerant with benzodiazepines and more toxic and
thus caution is needed to avoid replacing one dependence with another. During withdrawal, fluoroquinolone-based
antibiotics are best avoided if possible; they displace benzodiazepines
from their binding site and reduce GABA function and, thus, may
aggravate withdrawal symptoms. Antipsychotics are not recommended for benzodiazepine withdrawal (or other CNS depressant withdrawal states) especially clozapine, olanzapine or low potency phenothiazines, e.g., chlorpromazine as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required.
Withdrawal from long term benzodiazepines is beneficial for most individuals. Withdrawal of benzodiazepines from long-term users, in general, leads to improved physical and mental health
particularly in the elderly; although some long term users report
continued benefit from taking benzodiazepines, this may be the result of
suppression of withdrawal effects.
Controversial associations
Beyond
the well established link between benzodiazepines and psychomotor
impairment resulting in motor vehicle accidents and falls leading to
fracture; research in the 2000s and 2010s has raised the association
between benzodiazepines (and Z-drugs)
and other, as of yet unproven, adverse effects including dementia,
cancer, infections, pancreatitis and respiratory disease exacerbations.
Dementia
A
number of studies have drawn an association between long-term
benzodiazepine use and neuro-degenerative disease, particularly
Alzheimer's disease.
It has been determined that long-term use of benzodiazepines is
associated with increased dementia risk, even after controlling for protopathic bias.
Infections
Some
observational studies have detected significant associations between
benzodiazepines and respiratory infections such as pneumonia where others have not.
A large meta-analysis of pre-marketing randomized controlled trials on
the pharmacologically related Z-Drugs suggest a small increase in
infection risk as well. An immunodeficiency effect from the action of benzodiazepines on GABA-A receptors has been postulated from animal studies.
Cancer
A
meta-analysis of observational studies has determined an association
between benzodiazepine use and cancer, though the risk across different
agents and different cancers varied significantly.
In terms of experimental basic science evidence, an analysis of
carcinogenetic and genotoxicity data for various benzodiazepines has
suggested a small possibility of carcinogenesis for a small number of
benzodiazepines.
Pancreatitis
The
evidence suggesting a link between benzodiazepines (and Z-Drugs) and
pancreatic inflammation is very sparse and limited to a few
observational studies from Taiwan.
A criticism of confounding can be applied to these findings as with the
other controversial associations above. Further well-designed research
from other populations as well as a biologically plausible mechanism is
required to confirm this association.
Although benzodiazepines are much safer in overdose than their predecessors, the barbiturates, they can still cause problems in overdose. Taken alone, they rarely cause severe complications in overdose; statistics in England showed that benzodiazepines were responsible for 3.8% of all deaths by poisoning from a single drug. However, combining these drugs with alcohol, opiates or tricyclic antidepressants markedly raises the toxicity. The elderly are more sensitive to the side effects of benzodiazepines, and poisoning may even occur from their long-term use. The various benzodiazepines differ in their toxicity; temazepam appears most toxic in overdose and when used with other drugs. The symptoms of a benzodiazepine overdose may include; drowsiness, slurred speech, nystagmus, hypotension, ataxia, coma, respiratory depression, and cardiorespiratory arrest.
A reversal agent for benzodiazepines exists, flumazenil (Anexate), itself belonging to the chemical class of benzodiazepines. Its use as an antidote is not routinely recommended because of the high risk of resedation and seizures.
In a double-blind, placebo-controlled trial of 326 people, 4 people had
serious adverse events and 61% became resedated following the use of
flumazenil.
Numerous contraindications to its use exist. It is contraindicated in
people with a history of long-term use of benzodiazepines, those having
ingested a substance that lowers the seizure threshold or may cause an arrhythmia, and in those with abnormal vital signs. One study found that only 10% of the people presenting with a benzodiazepine overdose are suitable candidates for treatment with flumazenil.
Top: US yearly overdose deaths involving benzodiazepines.
Center: The top line represents the number of benzodiazepine deaths
that also involved opioids in the US. The bottom line represents
benzodiazepine deaths that did not involve opioids. Right: Chemical structure of the benzodiazepine flumazenil, whose use is controversial following benzodiazepine overdose.
Interactions
Individual benzodiazepines may have different interactions with certain drugs. Depending on their metabolism pathway, benzodiazepines can be divided roughly into two groups. The largest group consists of those that are metabolized by cytochrome P450
(CYP450) enzymes and possess significant potential for interactions
with other drugs. The other group comprises those that are metabolized
through glucuronidation, such as lorazepam, oxazepam, and temazepam, and, in general, have few drug interactions.
Many drugs, including oral contraceptives, some antibiotics, antidepressants, and antifungal
agents, inhibit cytochrome enzymes in the liver. They reduce the rate
of elimination of the benzodiazepines that are metabolized by CYP450,
leading to possibly excessive drug accumulation and increased
side-effects. In contrast, drugs that induce cytochrome P450 enzymes,
such as St John's wort, the antibiotic rifampicin, and the anticonvulsantscarbamazepine and phenytoin, accelerate elimination of many benzodiazepines and decrease their action. Taking benzodiazepines with alcohol, opioids and other central nervous system depressants
potentiates their action. This often results in increased sedation,
impaired motor coordination, suppressed breathing, and other adverse
effects that have potential to be lethal.Antacids can slow down absorption of some benzodiazepines; however, this effect is marginal and inconsistent.
Pharmacology
Pharmacodynamics
Schematic diagram of the (α1)2(β2)2(γ2) GABAA receptor complex that depicts the five-protein subunits that form the receptor, the chloride (Cl−)
ion channel pore at the center, the two GABA active binding sites at
the α1 and β2 interfaces and the benzodiazepine (BZD) allosteric binding
site at the α1 and γ2 interface.
Benzodiazepines work by increasing the effectiveness of the endogenous chemical, GABA, to decrease the excitability of neurons. This reduces the communication between neurons and, therefore, has a calming effect on many of the functions of the brain.
GABA controls the excitability of neurons by binding to the GABAA receptor. The GABAA receptor is a protein complex located in the synapses between neurons. All GABAA receptors contain an ion channel that conducts chloride ions across neuronal cell membranes and two binding sites for the neurotransmitter gamma-aminobutyric acid (GABA), while a subset of GABAA
receptor complexes also contain a single binding site for
benzodiazepines. Binding of benzodiazepines to this receptor complex
does not alter binding of GABA. Unlike other positive allosteric modulators
that increase ligand binding, benzodiazepine binding acts as a positive
allosteric modulator by increasing the total conduction of chloride
ions across the neuronal cell membrane when GABA is already bound to its
receptor. This increased chloride ion influx hyperpolarizes the
neuron's membrane potential. As a result, the difference between resting potential and threshold potential is increased and firing is less likely.
Different GABAA receptor subtypes have varying distributions within different regions of the brain and, therefore, control distinct neuronal circuits. Hence, activation of different GABAA receptor subtypes by benzodiazepines may result in distinct pharmacological actions.
In terms of the mechanism of action of benzodiazepines, their
similarities are too great to separate them into individual categories
such as anxiolytic or hypnotic. For example, a hypnotic administered in
low doses produces anxiety-relieving effects, whereas a benzodiazepine
marketed as an anti-anxiety drug at higher doses induces sleep.
The subset of GABAA receptors that also bind benzodiazepines are referred to as benzodiazepine receptors (BzR). The GABAA receptor is a heteromer composed of five subunits, the most common ones being two αs, two βs, and one γ (α2β2γ1). For each subunit, many subtypes exist (α1–6, β1–3, and γ1–3). GABAA
receptors that are made up of different combinations of subunit
subtypes have different properties, different distributions in the brain
and different activities relative to pharmacological and clinical
effects. Benzodiazepines bind at the interface of the α and γ subunits on the GABAA receptor. Binding also requires that alpha subunits contain a histidine amino acid residue, (i.e., α1, α2, α3, and α5 containing GABAA receptors). For this reason, benzodiazepines show no affinity for GABAA receptors containing α4 and α6 subunits with an arginine instead of a histidine residue. Once bound to the benzodiazepine receptor, the benzodiazepine ligand locks the benzodiazepine receptor into a conformation in which it has a greater affinity for the GABAneurotransmitter. This increases the frequency of the opening of the associated chloride ion channel and hyperpolarizes
the membrane of the associated neuron. The inhibitory effect of the
available GABA is potentiated, leading to sedative and anxiolytic
effects. For instance, those ligands with high activity at the α1 are associated with stronger hypnotic effects, whereas those with higher affinity for GABAA receptors containing α2 and/or α3 subunits have good anti-anxiety activity.
GABAA receptors participate in the regulation of synaptic pruning by prompting microglial spine engulfment.
Benzodiazepines have been shown to upregulate microglial spine
engulfment and prompt overzealous eradication of synaptic connections. This mechanism may help explain the increased risk of dementia associated with long-term benzodiazepine treatment.
The benzodiazepine class of drugs also interact with peripheral benzodiazepine receptors. Peripheral benzodiazepine receptors are present in peripheral nervous system tissues, glial cells, and to a lesser extent the central nervous system. These peripheral receptors are not structurally related or coupled to GABAA receptors. They modulate the immune system and are involved in the body response to injury. Benzodiazepines also function as weak adenosine reuptake inhibitors.
It has been suggested that some of their anticonvulsant, anxiolytic,
and muscle relaxant effects may be in part mediated by this action.
Benzodiazepines have binding sites in the periphery, however their
effects on muscle tone is not mediated through these peripheral
receptors. The peripheral binding sites for benzodiazepines are present
in immune cells and gastrointestinal tract.
A benzodiazepine can be placed into one of three groups by its elimination half-life, or time it takes for the body to eliminate half of the dose. Some benzodiazepines have long-acting active metabolites, such as diazepam and chlordiazepoxide, which are metabolised into desmethyldiazepam.
Desmethyldiazepam has a half-life of 36–200 hours, and flurazepam, with
the main active metabolite of desalkylflurazepam, with a half-life of
40–250 hours. These long-acting metabolites are partial agonists.
Short-acting compounds have a median half-life of 1–12 hours. They have few residual effects if taken before bedtime, rebound insomnia may occur upon discontinuation, and they might cause daytime withdrawal symptoms such as next day rebound anxiety with prolonged usage. Examples are brotizolam, midazolam, and triazolam.
Intermediate-acting compounds have a median half-life of 12–40
hours. They may have some residual effects in the first half of the day
if used as a hypnotic.
Rebound insomnia, however, is more common upon discontinuation of
intermediate-acting benzodiazepines than longer-acting benzodiazepines.
Examples are alprazolam, estazolam, flunitrazepam, clonazepam, lormetazepam, lorazepam, nitrazepam, and temazepam.
Long-acting compounds have a half-life of 40–250 hours. They have a
risk of accumulation in the elderly and in individuals with severely
impaired liver function, but they have a reduced severity of rebound effects and withdrawal. Examples are diazepam, clorazepate, chlordiazepoxide, and flurazepam.
Chemistry
Left: The 1,4-benzodiazepine ring system. Right: 5-phenyl-1H-benzo[e] [1,4]diazepin-2(3H)-one forms the skeleton of many of the most common benzodiazepine pharmaceuticals, such as diazepam (7-chloro-1-methyl substituted).A pharmacophore model of the benzodiazepine binding site on the GABAA receptor. White sticks represent the carbon atoms of the benzodiazepine diazepam, while green represents carbon atoms of the nonbenzodiazepine CGS-9896.
Red and blue sticks are oxygen and nitrogen atoms that are present in
both structures. The red spheres labeled H1 and H2/A3 are, respectively,
hydrogen bond donating and accepting sites in the receptor, while L1, L2, and L3 denote lipophilic binding sites.
Benzodiazepines share a similar chemical structure, and their effects in humans are mainly produced by the allosteric modification of a specific kind of neurotransmitter receptor, the GABAA receptor,
which increases the overall conductance of these inhibitory channels;
this results in the various therapeutic effects as well as adverse
effects of benzodiazepines. Other less important modes of action are also known.
Benzodiazepine drugs are substituted 1,4-benzodiazepines,
although the chemical term can refer to many other compounds that do not
have useful pharmacological properties. Different benzodiazepine drugs
have different side groups attached to this central structure. The
different side groups affect the binding of the molecule to the GABAA receptor and so modulate the pharmacological properties. Many of the pharmacologically active "classical" benzodiazepine drugs contain the 5-phenyl-1H-benzo[e] [1,4]diazepin-2(3H)-one substructure (see figure to the right).
Benzodiazepines have been found to mimic protein reverse turns
structurally, which enable them with their biological activity in many
cases.
Nonbenzodiazepines also bind to the benzodiazepine binding site on the GABAA
receptor and possess similar pharmacological properties. While the
nonbenzodiazepines are by definition structurally unrelated to the
benzodiazepines, both classes of drugs possess a common pharmacophore, which explains their binding to a common receptor site.
The molecular structure of chlordiazepoxide, the first benzodiazepine, marketed by Hoffmann–La Roche beginning in 1960 and branded as Librium
The first benzodiazepine, chlordiazepoxide (Librium), was synthesized in 1955 by Leo Sternbach while working at Hoffmann–La Roche
on the development of tranquilizers. The pharmacological properties of
the compounds prepared initially were disappointing, and Sternbach
abandoned the project. Two years later, in April 1957, co-worker Earl
Reeder noticed a "nicely crystalline" compound left over from the
discontinued project while spring-cleaning in the lab. This compound,
later named chlordiazepoxide, had not been tested in 1955 because of
Sternbach's focus on other issues. Expecting pharmacology results to be
negative, and hoping to publish the chemistry-related findings,
researchers submitted it for a standard battery of animal tests. The
compound showed very strong sedative, anticonvulsant, and muscle relaxant effects. These impressive clinical findings led to its speedy introduction throughout the world in 1960 under the brand name Librium. Following chlordiazepoxide, diazepam marketed by Hoffmann–La Roche under the brand name Valium
in 1963, and for a while the two were the most commercially successful
drugs. The introduction of benzodiazepines led to a decrease in the
prescription of barbiturates, and by the 1970s they had largely replaced the older drugs for sedative and hypnotic uses.
The new group of drugs was initially greeted with optimism by the
medical profession, but gradually concerns arose; in particular, the
risk of dependence became evident in the 1980s. Benzodiazepines have a
unique history in that they were responsible for the largest-ever class-action lawsuit against drug manufacturers in the United Kingdom, involving 14,000 patients and 1,800 law firms
that alleged the manufacturers knew of the dependence potential but
intentionally withheld this information from doctors. At the same time,
117 general practitioners and 50 health authorities were sued by
patients to recover damages for the harmful effects of dependence and withdrawal.
This led some doctors to require a signed consent form from their
patients and to recommend that all patients be adequately warned of the
risks of dependence and withdrawal before starting treatment with
benzodiazepines. The court case against the drug manufacturers never reached a verdict; legal aid
had been withdrawn and there were allegations that the consultant
psychiatrists, the expert witnesses, had a conflict of interest. The court case fell through, at a cost of £30 million, and led to more cautious funding through legal aid for future cases.
This made future class action lawsuits less likely to succeed, due to
the high cost from financing a smaller number of cases, and increasing
charges for losing the case for each person involved.
Although antidepressants with anxiolytic properties have been
introduced, and there is increasing awareness of the adverse effects of
benzodiazepines, prescriptions for short-term anxiety relief have not
significantly dropped. For treatment of insomnia, benzodiazepines are now less popular than nonbenzodiazepines, which include zolpidem, zaleplon and eszopiclone.
Nonbenzodiazepines are molecularly distinct, but nonetheless, they work
on the same benzodiazepine receptors and produce similar sedative
effects.
Benzodiazepines have been detected in plant specimens and brain
samples of animals not exposed to synthetic sources, including a human
brain from the 1940s. However, it is unclear whether these compounds are
biosynthesized by microbes or by plants and animals themselves. A
microbial biosynthetic pathway has been proposed.
In the United Kingdom, benzodiazepines are Class C controlled
drugs, carrying the maximum penalty of 7 years imprisonment, an
unlimited fine or both for possession and a maximum penalty of 14 years
imprisonment, an unlimited fine or both for supplying benzodiazepines to
others.
In the Netherlands, since October 1993, benzodiazepines,
including formulations containing less than 20 mg of temazepam, are all
placed on List 2 of the Opium Law.
A prescription is needed for possession of all benzodiazepines.
Temazepam formulations containing 20 mg or greater of the drug are
placed on List 1, thus requiring doctors to write prescriptions in the
List 1 format.
In East Asia and Southeast Asia, temazepam and nimetazepam are often heavily controlled and restricted. In certain countries, triazolam, flunitrazepam, flutoprazepam and midazolam are also restricted or controlled to certain degrees. In Hong Kong, all benzodiazepines are regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. Previously only brotizolam, flunitrazepam and triazolam were classed as dangerous drugs.
British law requires that temazepam (but not midazolam) be
stored in safe custody. Safe custody requirements ensures that
pharmacists and doctors holding stock of temazepam must store it in
securely fixed double-locked steel safety cabinets and maintain a
written register, which must be bound and contain separate entries for
temazepam and must be written in ink with no use of correction fluid
(although a written register is not required for temazepam in the United
Kingdom). Disposal of expired stock must be witnessed by a designated
inspector (either a local drug-enforcement police officer or official
from health authority).Benzodiazepine use ranges from occasional binges on large doses, to chronic and compulsive drug use of high doses.
Benzodiazepines are commonly used recreationally by poly-drug users. Mortality is higher among poly-drug users that also use benzodiazepines. Heavy alcohol use also increases mortality among poly-drug users.
Polydrug use involving benzodiazepines and alcohol can result in an
increased risk of blackouts, risk-taking behaviours, seizures, and
overdose.
Dependence and tolerance, often coupled with dosage escalation, to
benzodiazepines can develop rapidly among people who misuse drugs;
withdrawal syndrome may appear after as little as three weeks of
continuous use. Long-term use has the potential to cause both physical
and psychological dependence and severe withdrawal symptoms such as
depression, anxiety (often to the point of panic attacks), and agoraphobia. Benzodiazepines and, in particular, temazepam
are sometimes used intravenously, which, if done incorrectly or in an
unsterile manner, can lead to medical complications including abscesses, cellulitis, thrombophlebitis, arterial puncture, deep vein thrombosis, and gangrene. Sharing syringes and needles for this purpose also brings up the possibility of transmission of hepatitis, HIV, and other diseases. Benzodiazepines are also misused intranasally,
which may have additional health consequences. Once benzodiazepine
dependence has been established, a clinician usually converts the
patient to an equivalent dose of diazepam before beginning a gradual
reduction program.
A 1999–2005 Australian police survey of detainees reported
preliminary findings that self-reported users of benzodiazepines were
less likely than non-user detainees to work full-time and more likely to
receive government benefits, use methamphetamine or heroin, and be
arrested or imprisoned. Benzodiazepines are sometimes used for criminal purposes; they serve to incapacitate a victim in cases of drug assisted rape or robbery.
Overall, anecdotal evidence suggests that temazepam may be the most psychologically habit-forming (addictive)
benzodiazepine. Non-medical temazepam use reached epidemic proportions
in some parts of the world, in particular, in Europe and Australia, and
is a major addictive substance in many Southeast Asian countries. This
led authorities of various countries to place temazepam under a more
restrictive legal status. Some countries, such as Sweden, banned the
drug outright.
Temazepam also has certain pharmacokinetic properties of absorption,
distribution, elimination, and clearance that make it more apt to
non-medical use compared to many other benzodiazepines.
Veterinary use
Benzodiazepines are used in veterinary practice in the treatment of various disorders and conditions. As in humans, they are used in the first-line management of seizures, status epilepticus, and tetanus, and as maintenance therapy in epilepsy (in particular, in cats).
They are widely used in small and large animals (including horses,
swine, cattle and exotic and wild animals) for their anxiolytic and
sedative effects, as pre-medication before surgery, for induction of anesthesia and as adjuncts to anesthesia.
