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 Chronicles of Insomnia and the Magic Bullet’s Poisoned Chalice

How to get a good night’s sleep and persuade a quarter of women in the US to take drugs.

Genotype 1.0.18 Nov 14 - June 23 Chris King

 

Contents

 

1: The Nature and Function of Sleep

2: The Dilemma of Insomnia

3: Complementary Solutions to the Problem of Sleep and Ethics of Doctor-Patient Relationships

4: Evidence for Safety of Zopiclone in Both Short and Long-term Use

5: Melatonin as a Circadian Stabilizer

6: Drug Marketing Trends and the Over-prescription of Medical Psychoactive Drugs

 

1: The Nature and Function of Sleep

 

Fig 1: Above stages of sleep from deep sleep to dreaming REM sleep proceed in cycles through the night. Below: The EEG of sleep stages.

 

Sleep is a complex process, or rather a complex collection of processes. Early in the night we descend in stages to deep slow wave delta sleep that is believed to be essential for restoring the brain’s vitality of function in the day and also for maintaining the body’s own genetic repair and immune systems, reflected in the dynamics of  histamine neurons whose oscillations closely reflect the slow delta rhythms.  

 

At the other extreme are the phases of rapid eye movement or REM sleep which is usually associated with dreaming and nightmares, where the brain’s EEG is similar to active waking, but the body is paralysed from the neck down by cholinergic pathways in the basal brain that leave only the eye movements telling the tale of our strange interminable adventures in the world of dreams.

 

The role of dreaming sleep remains paradoxical. A collection of theories of REM and non-REM sleep have attempted to associate dreaming phases with memory consolidation processes – through specific patterns of neuromodulatory activity and electric field potential oscillations, slow-wave sleep (SWS) and rapid eye movement (REM) sleep support system consolidation and synaptic consolidation, respectively. During deep sleep, slow oscillations, spindles and ripples - at minimum cholinergic activity - coordinate the re-activation and redistribution of hippocampus-dependent memories to neocortical sites, whereas during REM sleep, local increases in plasticity-related immediate-early gene activity - at high cholinergic and theta activity — may favour the subsequent synaptic consolidation of memories in the cortex (Diekelmann & Born 2010 The memory function of sleep Nat. Rev. Neurosci. 11 114-126, Stickgold R & Walker M 2007 Sleep-Dependent Memory Consolidation and Reconsolidation Sleep Med. 8(4) 331-343 doi:10.1016/j.sleep.2007.03.011). Studies show that people perform better at memorization tasks when they have had a good episode of REM sleep. Researchers studying mice have found a causal relationship between REM sleep and memory consolidation (Boyce R et al. 2016 Causal evidence for the role of REM sleep theta rhythm in contextual memory consolidation Science 352/6287 812-816. dos:10.1126/science.aad5252). The memory enhancements of sleep also appear to be specifically targeted at memories the individual perceive to have future relevance. The mere expectancy that a memory will be used in a future test determines whether or not sleep significantly benefits consolidation of this memory. (Wilhelm, I et al. 2011 Sleep Selectively Enhances Memory Expected to Be of Future Relevance Journal of Neuroscience 31(5) 1563 dos:10.1523/JNEUROSCI.3575-10.2011). However, although we often forget our dreams consistent with memory reprocessing taking place, if we are awakened immediately from REM sleep, or our sleep is disturbed, we can often remember complex dreams in their entirety, or even become aware enough to realize we are dreaming and enter a lucid dreaming state.

 

Deep non-REM sleep has also been associated with consolidation of synaptic connections. Sleep after motor learning promotes the formation of postsynaptic dendritic spines on a subset of branches of individual layer V pyramidal neurons. Neurons activated during learning of a motor task are reactivated during subsequent non–rapid eye movement sleep, and disrupting this neuronal reactivation prevents branch-specific spine formation (Yang G et al. 2014 Sleep promotes branch-specific formation of dendritic spines after learning Science 344(6188) 1173-1178 doi:10.1126/science.1249098). More generally sleep appears to consolidate motor learning at the burst levels attained immediately after training (Nettersheim A 2015 The Role of Sleep in Motor Sequence Consolidation: Stabilization Rather Than Enhancement J. Neurosci. 35/17 6696-6702 doi:10.1523/JNEUROSCI.1236-14.2015). It has also been found that sleep recalibrates homeostatic and associative synaptic plasticity, believed to be the neural basis for adaptive behaviour, in humans (Kuhn M et al. 2016 Sleep recalibrates homeostatic and associative synaptic plasticity in the human cortex Nature Communications 7:12455 dos: 10.1038/ncomms12455). It has been found that in young people sleep spindles remain in synch with large slow waves, which may enable the prefrontal cortex to encode memories being transferred from the hippocampus, leading to consolidation. In older people disruption of this synchrony appears to lead to loss of memory consolidation during sleep (Helfrich R et al. 2017 Old Brains Come Uncoupled in Sleep: Slow Wave-Spindle Synchrony, Brain Atrophy, and Forgetting Neuron doi:10.1016/j.neuron.2017.11.020).

 

The idea that deep sleep is essential is challenged by wide variations in the sleep needed between species. For example a giraffe only sleeps an average of 1.9 hours, both chimps and orangutans sleep longer than humans 9.67 and 9.11, while a tiger slumbers for 15.5 and an armadillo 20.4. This has led to the idea that animals with a high metabolic rate for their body size sleep longer to conserve energy. Sleep periods, which extend to both the vertebrates and arthropods, can also provide a protective role, keeping animals, which are either nocturnal or diurnal, out of the sight of predators during their inactive hours. However phylogenetic analysis supports an essential functional role (Lesku J et al. 2006 A Phylogenetic Analysis of Sleep Architecture in Mammals: The Integration of Anatomy, Physiology, and Ecology American Naturalist 168/4 doi:10.1086/506973). The extent of the REM phase also varies widely between mammal species. Once evolutionary relationships are factored in, the evidence shows that animals with big brains for their body size need a significantly higher percentage of REM sleep, supporting a role in intelligence and cognitive function (Lesku J et al. 2008 Phylogenetics and the correlates of mammalian sleep: A reappraisal Sleep Medicine Reviews 12 229-244 doi:10.1016/j.smrv.2007.10.003). Humans have atypically short sleep compared with closely related primates and pack an unexpectedly higher proportion of REM sleep within a shorter overall sleep duration, and do so by reducing NREM sleep, rather than increasing REM. (Nunn C & Samson D 2018 Sleep in a comparative context: Investigating how human sleep differs from sleep in other primates Am. J. Phys. Anthro. doi:10.1002/ajpa.23427).

 

The incidence of both deep slow wave sleep and rapid eye movement (REM) sleep appears to extend far back in the evolution of vertebrates prior to the emergence of mammals. Non-invasive fluorescence-based brain activity scanning of transgenic zebrafish (right), coupled with assessment of eye movement, muscle dynamics and heart rate shows that there are two major sleep signatures - slow bursting sleep and propagating wave sleep, which share commonalities with slow-wave sleep and REM sleep. (Leung et al. 2019 Leung L et al. (2019) Neural signatures of sleep in zebrafish Nature 571 198-204 doi:10.1038/s41586-019-1336-7.).

 

Likewise periods of active sleep accompanied by flushes of colour change have been reported in both the octupus and cuttlefish (S. Medeiros et al. Cyclic alternation of quiet and active sleep states in the octopus (2021) iScience. doi: 10.1016/j.isci.2021.102223, Iglesias T et al. (2019) Cyclic nature of the REM sleep-like state in the cuttlefish Sepia officinalis Journal of Experimental Biology (2019) 222, jeb174862. doi:10.1242/jeb.174862).

 

Animals can use circadian sleep cycles to protect themselves from predators and other harm. For example, insects such as migrating monarch butterflies 'hibernate' together at night, but these phases also appear to fulfil the same biological and neurological functions seen in humans and mammals.

 

Specific phases of 'torpor' similar to the atonia of REM sleep also occur in insects, which exhibit immobility and distinctly reduced responses to stimuli, though they can rouse in a matter of seconds if the stimulus is strong enough. The cuckoo bee from the genus Nomada, for example, adopts a rigid sleeping position anchored by its mandibles.

 
Panurginus and Nomada in torpor.

 

Fruit flies show patterns of inactivity remarkably similar to human sleep - they show recovery sleep, struggle with vigilance and performance after not getting enough rest, and show a steady rhythm of wake and sleep (Huber et al. 2004 Sleep Homeostasis in Drosophila Melanogaster Sleep 27/4 628-39).

 

Neuronal activity in honey bees is found to follow a circadian rhythm (Kaiser & Steiner-Kaiser J 1983). When honey bees were kept awake they were less able to effectively carry out the waggle dance and alert other bees to resources (Klein B et al. 2010 PNAS 107(52), 22705-9.) Presentation of odors during sleep in bees also resulted in enhanced memory (Zwaka et al. 2015 Current Biology 25 2689-74 doi:10.1016/j.cub.2015.09.069.), consistent with the causative memory role of REM sleep in mammals (Boyce R et al. 2016 Science, 352(6287) 812 doi:10.1126/science.aad5252).

 

The nematode Caenorhabditis elegans also has a quiescent behavioural state during a period called lethargus, which occurs before each of the four moults. Like sleep, lethargus maintains a constant temporal relationship with the expression of key genes which has the additional sleep-like properties of reversibility, reduced responsiveness and homeostasis (Raizen et al. 2008 Nature 451 doi:10.1038/nature06535, Nelson & Raizen 2013 ature 451 doi:10.1038/nature06535).

 

Cnidaria, jellyfish and sea anemones have no central nervous system and neurons form a non-centralised radially symmetric nerve net that nevertheless shares fundamental properties with the vertebrate nervous system: action potentials, synaptic transmission, neuropeptides, and neurotransmitters. Soft corals and box jellyfish exhibit periods of quiescence and the upside-down jellyfish Cassiopea shows behavioural quiescence of its pulsing behaviour at night that is rapidly reversible, as well as a delayed response to stimulation (Nath et al. 2017 Current Biology 27 2984-90 doi:10.1016/j.cub.2017.08.014).

 

Hinting at a very fundamental role for both types of sleep, on the basis that REM sleep is thought to remove unnecessary memories, and deep sleep to consolidate important ones, researchers in artificial neural nets have found that incorporating algorithms involving both these types of memory function increase learning efficiency of Hopfield nets to the theoretical optimum (Fachechi et al. 2019 arXiv:1810.12217). Without the 'sleep' algorithms operating, the maximal capacity was α=0.14, where α represents the number of stored bits per synapse. When a sleep cycle was incorporated, the ANN reached the theoretical limit for networks of this type - α=1..

 

Support is growing for a theory that sleep evolved so that  connections in the brain can be pruned down during slumber, making room for fresh memories to form the next day. A key study has established that sleep, particularly deep sleep, enables synapses to reduce their size (and hence strength) by around 18%, enabling new memories to become consolidated without over-stimulation. This required a four-year double-blind investigation dissecting mouse cortex to establish a general trend over many thousands of synapses (Wilson C 2016 Mystery of what sleep does to our brains may finally be solved New Scientist 12 July). It is consistent with the brain being less electrically excitable at the start of the day and sleep deprivation leading to epilepsy (and ultimately death in the case of rodents) and with the loss of functional capacity on sleep deprivation (Huber R et al. 2013 Human Cortical Excitability Increases with Time Awake Cerebral Cortex 23 332-338 doi:10.1093/cercor/bhs014).

 

2: The Dilemma of Insomnia

 

At the tender age of seventy, I have always considered myself blessed by the capacity to get a good night’s sleep and watch those wretched ones who claim regular sleeplessness struggle with an existence of baleful misery. Many less fortunate people spend years at a time claiming they have had little or no sleep, feeling tired and depleted all day long and suffering long nights of unremitting despair as they fail to find the off switch to give their exhausted brain release and their bodies a chance to repair their worn out metabolisms and conserve their frazzled telomeres.

 

The complete loss of deep sleep can be lethal. For the 100 or so individuals worldwide who inherit an unusual prion mutation and suffer fatal familial insomnia, the complete lack of being able to enter sleep due to the loss of critical neurons in the basal brain leads within months to death, as the brain sinks into a permanent pre-sleep catatonia and the body atrophies, deprived of its restorative cycle.

 

That said, as people grow older their amount of deep delta sleep can become briefer and briefer, so that people over 65 may actually have little evidence of the deepest levels of sleep in their EEG.

People with changing hours, such as shift workers, experience significant cognitive and health deficits as a result. Self-reported short sleep duration (defined in most studies as ≤ 6h) is associated with negative health outcomes: all-cause mortality, obesity, diabetes, cardio-vascular disease, and impaired vigilance and cognition. Biological processes affected in a 2013 sleep study included chromatin modification, gene-expression regulation, macro-molecular metabolism, and inflammatory, immune and stress responses (PNAS doi/10.1073/pnas.1217154110). It is also associated with shortened telomere length and hence ageing (PLOSOne 2012  7/10 e47292  doi: 10.1371/journal.pone.0047292). In another study, men sleeping sleep 4.5 hours or less or women 3.5 or less inherited a 15% increase in mortality risk, while those sleeping more than 8.5 hours or more also had a 15% increase in mortality (Arch. Gen. Psychiatry 59(2) 131-6. doi:10.1001/archpsyc.59.2.131). Most of the increase was discounted after controlling for co-morbid disorders and the use of sleeping pills, which also increase mortality due partly to overdoses and falls (Pharmacoepidemiology and Drug Safety 2009 18 93-103). Mice subjected to chronic sleep deprivation literally begin to eat their own brains, as microglia – the brain’s immune cells – become hyperactive explaining why chronic sleep loss in humans can lead to early dementia (doi:10.1523/JNEUROSCI.3981-16.2017).

 

Transcriptome analysis has revealed that 711 genes were up- or down-regulated by insufficient sleep. Insufficient sleep also reduced the number of genes with a circadian expression profile from 1,855 to 1,481, reduced the circadian amplitude of these genes, and led to an increase in the number of genes that responded to subsequent total sleep deprivation from 122 to 856. Genes affected by insufficient sleep were associated with circadian rhythms, sleep homeostasis, oxidative stress, and metabolism. Biological processes affected included chromatin modification, gene-expression regulation, macro-molecular metabolism, and inflammatory, immune and stress responses. Thus, insufficient sleep affects the human blood transcriptome, disrupts its circadian regulation, and intensifies the effects of acute total sleep deprivation (Moller-Levet C et al. 2012 Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome PNAS doi:10.1073/pnas.1217154110).

 

Insomnia is a plague of modern society. People have to struggle with it to maintain stressful careers, or to commute long distances, cope with changing shift work hours, and suffer jet lag on intercontinental flights. Among the many tribulations of pain and anxiety, few are more devastating and maddening than the accumulated fatigue and despondency of several nights of sleep deprivation. People suffer a variety of forms of insomnia from a variety of causes, both psychological and organic from anxiety and depression to hypothyroidism. Some cannot get to sleep. Others wake repeatedly or become wide awake at 4 am and cannot get further rest.

 

My current encounter with insomnia came like a bolt from the blue amidst an untroubled habit of sleep from around 12.30 to 8.30 or 9 in the morning. I am a pretty speedy alert person and a bit of a night owl as many people are, with a circadian rhythm of slightly more than 24 hours. A few times in the midst of this because of worry about a family member, I woke up at 4 am and couldn’t get back to sleep. Generally the next night I would crash into compensatory sleep, but this time I remained wide awake feeling more awake the more I tried to relax and go to sleep. The third night was even worse. By now I was seriously sleep deprived and caught in one of those cycles where I am so tired I can’t get to sleep for the buzz in my head.

 

This began to become a pernicious pattern. If I managed to get one good night’s sleep, I could be pretty sure that the next night or two I would lie awake. The more I tried to relax the more I would descend into a maddening deep meditation in which I was fully relaxed but the one-pointed concentration on relaxing was the exact opposite of sleep, leaving my tired brain caught permanently on overdrive. The sheer vigilance required to cope through a long day of brain fatigue even though one’s body has been rested leads to a kind of poisoning so that when you try to sleep your vigilance circuits are over activated and nothing seems to do any good. I tried going for long walks up the nearby mountain in the middle of the night to try to wear my body down into a restful state. For nights on end I could swear I had had no sleep at all. Finally in desperation I negotiated a three or four hour sleep by cadging a sleeping tablet off a family member and at least got a from dawn and felt somewhat revived.

 

The same day I went to my GP who prescribed melatonin which is often used for jet lag to try to reset by circadian clock and gave me on request a minimal seven doses of temazepam when I deferred the suggestion of the Z-drug zopiclone because it is carcinogenic and causes metal taste.

 

For the next two weeks I continued to sleep atrociously, occasionally getting a normal sleep if I could actually get off to sleep, but the rest of the time, despite noting the transient dreaminess of melatonin, lying awake most of the night punctuated by short periods of perhaps fours hours sleep towards morning if I took half, or a whole sleeping tablet. 

 

Fig 2: (a) Plot of receptor binding in pKi of major classes of psychoactive drugs, from antipsychotics through antidepressants and antihistamines to entactogens and entheogens (King C 2014 Entheogens, the Conscious Brain and Existential Reality http://dhushara.com/psyconcs/), generated using the PDSP database (http://pdsp.med.unc.edu/dataMining/pdspConfigGraph.php and PLoS ONE 5/2 e9019 1-17). Binding may vary from inverse agonist through neutral (silent) antagonist to super-agonist, either by binding to the neurotransmitter cleft or by allosteric modulation at other sites on the receptor. For example antipsychotics such as chlorpromazine are antagonists inhibiting signalling in a broad spectrum of receptors spanning serotonin, dopamine, adrenergic, histamine and muscarinic acetyl-choline subtypes leading to quenching of subjective affect. By contrast psychedelics act as super-agonists in specific serotonin 5HT2a and 5HT2c receptor types leading in turn to coupled glutamate activation. Antidepressants and entactogens operate on serotonin and nor-epinephrine transporters reducing uptake or acting as releasing agents. Notably the antidepressant doxepin, which is also used as a sleep aid, is believed to act as an inverse agonist of the histamine H1 receptor (https://www.silenor.com/why-silenor). In (b) doxepin’s quantitative binding profile scaled by dosage is compared with the antihistamine diphenhydramine showing similar sedative and anti-cholinergic activity while doxepin is also altering the activity of serotonin and nor-epinephrine transporters causing additional potential side effects,, which would be useful only if the person is depressed. (c) Longer half-life of doxepin vs doxylamine. (d) The molecules used in the comparison with doxylamine an OTC antihistamine used specifically as a sleep aid. Fig 4 also contains some of the molecules in the chart. H1 neurones have a direct role in promoting continued sleep but H1 inhibitors don’t aid the initial stage of falling asleep. Although neither of these molecules are habituating, both the antidepressant tradozone (http://www.medscape.org/viewarticle/508820) and the antihistamine diphenhydramine (http://en.wikipedia.org/wiki/Diphenylhydramine) appear to show rapid diminution of effect over even a few days of continuous use, leading to questions of their continued efficacy. It is thus likely that the lack of addictive potential and rapid tolerance are a characteristic of the H1 receptor type.

 

I have a constitutional loathing of stoppers and tranquillizers generally and know they are both habit forming, and have withdrawal symptoms from rebound insomnia to seizures. Although they do give something resembling sleep, it is more a kind of glass box hibernation than actual sleep and can leave one hung over, feeling shaky next day if they are taken too late. That said, sleep deprivation is a serious condition leading to reduced cognitive function, lowered resistance to infection and the onset of diabetes and heart problems. 

 

Zopiclone seems to be better tolerated, making me feel if anything a little too wide awake next morning, but both drug types have similar dependence and withdrawal profiles, acting in similar ways on GABA receptors and both Z-drugs and benzodiazepines reduce immunity and increase cancer risks around threefold (doi:10.1136/bmjopen-2012-000850, doi:10.1007/s40268-017-0207-7), possibly due to CNS depression during sleep raising lung and throat infection rates.

 

One also needs to take into account risk of falls and fractures due to falling over in the night. A recent cohort study showed that risk of falls were increased significantly for both classes of sedative and also, somewhat surprisingly for melatonin, although it is a natural circadian hormone.  After adjustment for 26 covariates, the hazard ratios over controls were 1.44 for melatonin, 1.26 for hypnotic benzodiazepines and 1.52 for Z-drugs (Age and Ageing 2016 45 801-806 doi:10.1093/ageing/afw123). However this is merely a retrospective study of fracture statistics linked to past prescription records. The fact that the benzodiazepene rates lowest and all three are very close suggests the falls are due to patients suffering falls due to chronic insomnia rather than because of the medication, certainly anyway in the case of melatonin. A previous study comparing zolpidem and melatoin and checking for postuarl instability found that only zolpidem had a tendency to cause instability (Hum. Psychopharmacol Clin Exp 2012 27 270-276 doi: 10.1002/hup.2219). Melatonin is one of the four most used natural products in a survey by the Centers for Disease Control with 1.3% of the US population or around 3.1 million regularly using it as an unregulated natural supplement without any evidence of negative side effects such as fractures (Clarke TC et al. 2015 Trends in the use of complementary health approaches among adults: United States, 2002–2012. National health statistics reports 79 National Center for Health Statistics).

 

At the end of two weeks of this, having judiciously only consumed half of the sleeping tablets I had been given, I returned to my GP to say the melatonin had done little or nothing, but I was getting some help from the temazepam. I was both still sleep deprived and feeling shaky for the half temazepam I had taken at 4 am the night before and my demeanour seemed to make her think I was somewhat unhinged. At this point she pre-emptively asserted that I wasn’t getting any more sleeping tablets and that if I didn’t like it I could find another doctor. This wasn’t just any GP, but our family doctor over 35 years, who knew I had never abused sedatives and indeed had sailed through to the age of seventy with almost no medical consultations of any kind. I was aghast and said so. After a near stand up confrontation when she told me that, if seven sleeping tablets didn’t fix it, it would be standard for their practice to put me on low dose tricyclic antidepressants, she reluctantly agreed to give me a further 20 temazepam, provided I set up a monitoring regime with my partner to use them only sparingly.

 

This is a far cry from the medical profession’s profilagate use of benzodiazepines when they were first marketed as a magic bullet for tension and sleeplessness in the 1970s and 1980s. Just as the 1990s saw the Prozac age of antidepressive fashion, as if for the first time in world history, large sections of the population were finding the trials of life too melancholy to bear, so the 1970s saw drug companies and the medical profession advancing the idea that benzodiazepines were the panacea for all the stresses of modern life, used both by executives cooping with the high life and as ‘mother’s little helpers’ targeted specifically at vulnerable women coping with the stresses of being stuck at home with screeching babies and mountains of laundry to do. For ten years billions of benzodiazepines were freely prescribed as an innocuous alternative to the blunt weapon of habituating barbiturates which were far less selective for the GABAa receptors in the brain promoting relaxation and somnolence, before concerns about addiction and withdrawal began to surface. Now the pendulum has shifted so far the other way that agents which do have a legitimate purpose in promoting sleep are avoided by medical professionals like a curse, for fear of patient addiction drug abuse.

 

To most of us, “tricyclic” is even more of a dirty word, associated with both the worst antipsychotic drugs, which shut down virtually all neurotransmitter systems, turning one onto a zombie on meds and, along with the older heavier antidepressants which turn too many systems on the other way, overall having a spectrum of quite hideous side effects, from tardive dyskinesia, through Parkinsonism to Neuroleptic malignant syndrome. But that isn’t the only concern. If we are sane and not actually depressive, is it right for the medical profession to arbitrarily ascribe insomnia precipitated by genuine life concerns to a psychiatric condition? Do we seriously want to find during an acute bout of insomnia that we are being consigned to long term 24-hours a day medication, which will inevitably alter our innate drug-free consciousness and decision-making?

 

3: Complementary Solutions to the Problem of Sleep and Ethics of Doctor-Patient Relationships

 

I will come back to this later but it turns out that the certain tricyclics do have a role in treatment of insomnia because their strongest receptor action is as antihistamines and the low doses used mean that they are predominantly targeting the brain’s histamine H1 receptor, whose activity and inhibition has been discovered to be pivotal in maintaining sleep once it has been initiated.

 

The history of tricyclics doesn’t just revolve around psychoactive drugs but antihistamines, which those of us who have been around long enough know, were prone to make you drowsy.  The original aim of antihistamines was not to act on the brain but to reduce the allergic reactions which are promoted by histamine receptors in the tissues leading to the dilation of blood vessels and filling the tissues with inflammatory interstitial fluid lead to swelling and itching. As time has gone by, newer generations of antihistamines have been devised which don’t cross the blood-brain barrier and hence avoid this drowsiness, but first generation antihistamines such as diphenhydramine (Benadryl) are antagonists for the brain’s H1 receptor just as are antidepressants such as doxepin. Unlike the benzodiazepines and more recent Z-drugs, both of which have problems of habituation and withdrawal, neither doxepin nor doxylamine appear to have significant withdrawal, although their effect may wane in as few as 3 days of repeated use to placebo levels, due to the rapid adaption of the histamine system.

 

In fig 2 evidence is presented which shows that the use of low dosage antidepressants such as doxepin to treat insomnia, which works principally for sleep maintenance, has a similar effect and no clear advantage over the use of common over the counter antihistamines, such as diphenhydramine and closely related doxylamine succinate, which is in common over the counter medications such as dozile sleep aid in Australasia and with other drugs in Tylenol, Unisom Sleep Tabs, and zzzQuil.

 

The second point is that the antihistamine agents work in a complementary way to the benzodiazepines and related Z-drugs such as zopiclone, which are GABAa agonists, which promote the onset of sleep by shutting down the arousal system. In fig 3 the basal brain systems supporting alert arousal and sleep onset are illustrated. These form a kind of flip-flop in which the basal GABA system turns off arousal, silencing ascending serotonin, nor-epinephrine and histamine pathways. In turn changes in the firing of the H1 receptor histamine pathway are pivotal in sleep maintenance and in the slow-wave oscillations of deep sleep. The fact that the H1 and GABA systems are independent and complementary means that both drug avenues are valid for addressing insomnia, rather than one replacing the other as prescribing fashion and fear of drug abuse suggest.

 

Fig 3: Cortical arousal circuits involve a variety of ascending pathways involving histamine, serotonin and nor-epinephrine, Histamine H1 receptors are activated by neurons in the tuberomammillary nucleus of the hypothalamus, which become active during the 'wake' cycle, firing at approximately 2 Hz. During slow wave sleep, this firing rate drops to approximately 0.5 Hz. Finally, during REM sleep, histaminergic neurons stop firing altogether. It has been reported that histaminergic neurons have the most wake-selective firing pattern of all known neuronal types. The locus coeruleus is the principal site for nor-epinephrine ascending pathways which maintain vigilance and are almost completely silent in REM sleep. The raphe nuclei send serotonergic projections to wide areas of the cerebral cortex releasing serotonin to the rest of the brain. They also fall silent during REM sleep and are less active during non-Rem sleep. They also feedback to the suprachiasmatic nuclei (SCN), providing a responsive basis for circadian rhythms. The SCN transmits to the raphe nuclei via the dorsomedial hypothalamus nucleus altering serotonin levels for sleep/wake states. The raphe nuclei will then transmit feedback to the SCN about the animal's vigilance and levels of alertness. The onset of REM and PGO spikes is driven by cholinergic neurons in the pons. Complementing these are GABA projections from the venterolateral preoptic nucleus VLPO, which inhibit wakefulness and lead to the onset of sleep (CNS Spectrum 2008;13(12) 1047-55).  The system is believed to form a flip-flop (right) in which the VLPO shuts down arousal in one phase while orexin ORX neurons promote arousal in the other. Orexin (hypocretin) is produced by the neuronal cluster in the posterior portion of the lateral hypothalamus. Orexin-1 receptors are found in the locus coeruleus, orexin-2 receptors in the TMN, and both types in the median raphe nuclei and mesopontine reticular formation. (Current Neuropharmacology 2008 6 367-78). However note that opiate addicts are found to have 54% more active orexin neurons than the general public, recruited from a dormant condition. Morphine administered to mice also increased their orexin neurons and reduced narcolepsy. .People with narcolepsy have about 90 percent fewer hypocretin-producing neurons than normal, They have been treated with addictive stimulant drugs, such as methamphetamine, and haven't shown the same desire to keep upping the dose that's seen in addicts. The findings fit with a growing body of research that suggests that hypocretin, in addition to regulating wakefulness and arousal, may also be supporting motivated behavior in general and hence be involved in addiction (T.C. Thannickal et al 2018. doi:10.1126/scitranslmed.aao4953).

 

Reservations about the pendulum swing from sedative drugs to the widespread use of antidepressants for insomnia is notable in the medical literature.

 

In Medscape, Thomas Roth notes: Despite the availability of BZRAs and the development of safer compounds within the category [Z-drugs], low-dose sedating antidepressants represent an increasingly used modality for the management of insomnia. Specifically trazodone, and secondarily doxepin, mirtazapine, and amitriptyline, are being used for the treatment of insomnia even in the absence of a depressive disorder. There has been much speculation as to the increased use of these medications for the management of insomnia given that their use for their primary indication, treatment of depression, is declining due to safety-toxicity concerns. Although the BZRAs produce their sleep-promoting effects via the GABAa receptor, the mechanism of action of the low-dose sedating antidepressants is not fully understood. For the tricyclic antidepressants, their antihistaminic (H1) activity is critical. The role of their anticholinergic activity in the modulation of sleep has not been made clear. Trazodone is a mild inhibitor of serotonin reuptake, and also has antagonistic action at the a1 and a2 adrenoreceptors. There have been several hypotheses proposed for the use of low-dose sedating antidepressants: Insomnia patients typically also have depression; perceived safety at "lower" doses; availability of cheaper generics; nonschedule status; and the absence of quantity limits. A review of the literature suggests that some of these hypotheses are valid while others are not, but mostly there are inadequate data to judge the relative safety and efficacy of these "low-dose" antidepressants for the management of insomnia. In fact, when prescriptions for low-dose sedating antidepressants are written, they are written for more pills and for more refills compared with drugs indicated for insomnia (http://www.medscape.org/viewarticle/508820).

 

The NIH State-of-the-Science Conference Statement on manifestations and management of chronic insomnia in adults 2005 noted the lack of evidence to support the use of antidepressants in long-term insomnia: Chronic insomnia is a major public health problem affecting millions of individuals, along with their families and communities. Little is known about the mechanisms, causes, clinical course, comorbidities, and consequences of chronic insomnia. Evidence supports the efficacy of cognitive-behavioral therapy and benzodiazepine receptor agonists in the treatment of this disorder, at least in the short term. Very little evidence supports the efficacy of other treatments, despite their widespread use. Moreover, even for those treatments that have been systematically evaluated, the panel is concerned about the mismatch between the potential lifelong nature of this illness and the longest clinical trials, which have lasted 1 year or less. A substantial public and private research effort is warranted, including developing research tools and conducting longitudinal studies of randomized clinical trials. Finally, there is a major need for educational programs directed at physicians, health care providers, and the public (NIH Consens State Sci Statements. 2005 Jun 13-15;22(2):1-30).

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Fig 4: The tricyclics were first developed in the 1940s with the antihistamine promethazine. Chlorpromazine, derived from promethazine originally as a sedative, was found to have neuroleptic properties in the early 1950s, and was the first typical antipsychotic. Fluphenazine is a high-potency typical antipsychotic. It is less prone to causing sedation, low blood pressure or anticholinergic effects but is associated with a higher frequency of movement disorders. Imipramine, (fig 2) originally investigated as an antipsychotic, was discovered in the early 1950s, and was the first tricyclic antidepressant, along with amityrptyline the most widely used TCA. Carbamazepine was discovered in 1953, and was subsequently introduced as an anticonvulsant in 1965. Antidepressants with a tetracyclic structure such as mianserin were first developed in the 1970s. Clozapine was introduced as the first atypical antipsychotic in the 1990s, followed by others including Olanzapine and Quetiapine.

 

When my insomnia began I had a comprehensive series of blood tests to make sure there was no obvious organic cause, such as hypothyroidism. A week later I had a letter from my GP who thanked me for having myself checked out showing a clean slate - heart, blood, thyroid and prostate PSA normal and no diabetes.

 

Having been plagued by my last medical consultation, not liking the sleep quality and hangover effects of temazepam, I decided to explore whether there were any more natural ways of promoting a good night’s sleep than benzodiazapenes. After a search through various herbs from Passiflora incarnata, through red ginseng, which is also a stimulant, to Zisiphus and Papaver I settled on Valeriana officinalis as a prospective candidate with some actual scientific evidence for its activity on GABAa receptors.

 

Valerian, like many herbs, contains a diverse and bewildering array of phytochemicals, but among them are valeropotriates and valerenic acid, which has been demonstrated in scientific studies to bind to the β2 and β3 components of the GABAa receptor. Although its effects are mild to placebo by comparison with the hammer blow of a good dose of benzos, anecdotal evidence from users suggests they do form a natural sedative to aid the onset of sleep. In fig 5 is shown the GABAa ionotropic receptor, which is a pentamer of individual proteins, combining various α, β, and γ versions to make the active receptor. Binding sites for benzodiazepines, Z-drugs and the common binding site of valerenic acid and the synthetic sedative loreclezole are liiustrated centre.

 

My insomnia arose from three converging factors: (a) unresolved anxiety about a family member, the precipitating cause, (b) becoming older and needing slightly less sleep and beginning to have intermittent nights when I couldn’t sleep, and (c) my partner also becoming older and disrupting my sleep more with her snuffling and snoring, disrupting sleep onset. With sleep onset insomnia I would literally lie awake all night getting no sleep at all. The ongoing insomnia and the difficulties of seeking appropriate medication then caused months of anxiety and complete uncertainty whether I would be able to get to sleep for nights in a row, so that I would get severely sleep deprived, exacerbating the initial problem.

 

Recent research into changes in sleep time with age has produced the following trends, which show that, contrary to the notion that older people don't need much sleep, healthy older people sleep nearly as long as young people:

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Age 20-30: 433.5 minutes (7.23 hours)

Age 40-55: 409.9 minutes (6.83 hours)

Age 66-83: 390.4 minutes (6.51 hours)

..

Effective Strategies: Eight months into this situation I have arrived at the following spectrum of responses:

 

1: Non-pharmaceutical Measures: This is the main thrust of my therapy, consistent with cognitive behavioral therapy for insomnia (CBTI).

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Fig 5: (a) The GABAa ionotropic receptor is a pentamer of five sub-component proteins facilitating Cl^- flow. (b) Benzodiazepines such as temazepam bind to the same allosteric modulation site between α1 and γ2 components, enhancing the binding of GABA and thus chloride flow. Z-drugs such as zopiclone bind to the α subunit (J. Pharmacol. Exp. Ther. 317 (1): 369–77. doi:10.1124/jpet.105.096701) with short-acting zaleplon binding selectively to α1. Valerenic acid, in the herbal sleep remedy valerian and the synthetic sedative loreclezole, which again are structurally unrelated, bind to a site on the β2 protein (Neuropharmacology 53 (2007) 178-187, PNAS 91 (1994) 4569-73). This explains why benzodiazepines and Z-drugs show cross-tolerance, although differences between the binding sites appear to make for reduced tolerance in -drugs andsignificantly reduced withdrawal symptioms (see section 4). It is thus possible that valerian may also have a similar tolerance profile with continued use. Valerian extract is also found to be a 5HT5a agonist whose receptors are found in the suprachiasmatic nuclei involved in sleep. Suvorexant is an orexin-1 and -2 antagonist in late phase development for pharmaceutical marketing. The older barbiturates exemplified by Phenobarbital bind to multiple GABA receptor sites but also inhibit excitatory glutamate AMPA receptors adding to their sedative effects. The binding site for benzodiazepines is distinct from the binding site for barbiturates and GABA on the GABAA receptor, and also produces different effects on binding, with the benzodiazepines increasing the frequency of the chloride channel opening, while barbiturates increase the duration of chloride channel opening when GABA is bound. Since these are separate modulatory effects, they can both take place at the same time, and so the combination of benzodiazepines with barbiturates is strongly synergistic, and can be dangerous if dosage is not strictly controlled.

 

GABA-ergic Agents vs H1 Inhibitors:

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One needs to be cautious about all the sleep medications. All the H1 antagonists also have anticholinergic side effects, including dry mouth, urinary retention, glaucoma and hangover drowsiness. Both benzodiazepines (and presumably Z-drugs) and the anticholinergics like doxepin and diphenhydamine have been associated with increases in dementia in people over 65 (BMJ 2014 doi: 10.1136/bmj.g5205 , JAMA Intern Med. doi:10.1001/jamainternmed.2014.7663) with over 180 daily doses contributing to an approximately 50% increase, in both classes of sleep medication. Neither of these studies are causally conclusive, but the linkage in at least the anticholinergics has tried to avoid pre-existing dementia being a cause of sleep aid medication. GABA-ergic sedatives are also associated with an increase in mortality due to elderly people suffering fractures resulting from falls in the night, because they impair coordination. The anxiety-reducing and sedative effects of various benzodiazepines depnds on their relative affinity to two distinct sub-types of the GABAa receptor (Engin et al. 2018 doi:10.1016/j.tips.2018.04.003).

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One also needs to understand the differing efficacies and side-effects of the two types of agent.  GABAergic benzodiazepines and Z-drugs are the drug of choice, and really the only medication effective at sleep induction because the GABA circuit is key in tipping the see-saw to precipitate sleep onset (see fig 3). H1 antagonists, including doxepin and the antihistamines such as diphenhydramine and doxylamine, aid sleep maintenance but not sleep induction, so they don’t work for people with hypervigilant insomnia. All the GABAergic agents have a tendency towards tolerance, dependence and rebound insomnia, as does alcohol, which in some people can emerge within a week or two, but others appear to be able to use these drugs for years without manifest ill effects, particularly if they space their use so they are taken only one night in three to seven. Tolerance varies both with the specific drug used, and probably with the person’s genetic makeup, but it is also characteristic of GABA receptors themselves. Nevertheless withdrawal can have severe consequences due to cerebral over-excitation, including seizures.

 

benzodiazepines: You can find a definitive manual on benzodiazepines and their dependence by Prof. Heather Ashton at (http://www.benzo.org.uk/manual/bzcha01.htm) and responsible use of benzodiazepines by the same expert at (http://www.benzo.org.uk/asgr.htm). Ideally one should not use them for more than a week or two, use the lowest effective dose and to use them no more than every third day intermediate term, to avoid build up of tolerance. You will also find that they rank highly in statistics of drug abuse because some people find them pleasurable, and nearly as many people die from overdoses as do from opiate drugs, as sleeping tablets are favoured choices for suicide attempts.

 

 

Temazepam patient reviews:

 

Temazepam works fantastic for insomnia. If you don't mind using a prescription medicine, it's the best for insomnia. No side effects to report, and no next-day drowsiness. I use the lowest dose- 7.5mg, with melatonin, because melatonin is a powerful antioxidant, and I sleep great, feeling refreshed in the morning. I thank God for both temazepam and melatonin.

 

Worked for the first couple weeks. Now I am up to 60mg just to get to sleep. Its been two hrs and no sleep. Its slowly not working anymore. Been on it for a month.

 

I have been taking 10 mg per night for 29 years. It relaxes me so I can sleep for 4-5 hrs tops.

 

By 3rd night of use, it became ineffective. My system built up tolerance quickly. Fourth night I took 40 mgs and only 4 hours of sleep. Dr. just prescribed a months worth. Now I must find an alternative while I ween myself off temazepam. Not easy since I wasn't getting any sleep at all before I started.

 

False awakening dreams, nightmares, vivid dreams, reduced effectiveness over time.

 

This is the best sleeping pill I've ever tried. 30 years now, and still no tolerance issues. I wake up refreshed, no hangover, unlike all the other sleeping pills, as temazepam is very mild, yet it keeps you asleep. I take 15 or 30 mg, depending how I feel. I have tried Halcion and Dalmane, which weren't very effective. I also tried Ambien in the mid 90s and had horrible sleepwalking episodes. This has never happened with Restoril.

 

I have been taking Temazapam for approximately 20 years with great results. The key is to take it sparingly, and no more than one time per week. I usually take it approximately one time every 10-14 days, and it works wonderfully. I normally go to sleep within 10 minutes and sleep 6-8 hours uninterrupted and wake totally clear headed and no grogginess.

 

Tricyclics: Doxepin and Amitryptyline are antidepressants altering serotonin and adrenergic metabolism, which have a variety of potentially serious side effects. These include very rapid weight gain, sexual impotence, and movement disorders (hypokinesis), which are notorious with tricyclics, and can lead to potentially irreversible Parkinsons and Tourette’s syndromes. These tend to be ignored by doctors, who prefer them to GABAergic agents because they have little risk to the doctors’ reputations for allowing patient dependence to occur, so some will refuse GABAergic drugs even when they are the indicated drug of choice and try to dish out doxepin long-term. One of the most concerning aspects of this is to be told to take a mood altering drug long-term, which compromises one’s emotional autonomy and psychological decision-making, so you really aren’t quite the same person any more. This is fine if you are depressed and in need of support for one’s mental condition, but is a fundamental invasion of your personal identity otherwise. While doctors originally pushed benzodiazepines as mother’s little helper, later it has come to be antidepressants that are dished out like lollies, because doctors have little fear of comeback, even if the patient’s life is significantly compromised. Doxepin is another example of medical marketing taking an existing early-generation drug normally prescribed only for more severe cases of depression and pushing it for another condition - insomnia - because it is also a strong antihistamine that crosses the blood brain barrier. The H1-antagonist antidepressants like doxepin are liable to be prescribed long-term as antidepressants usually are, because doctors don’t fear short term dependency or drug abuse, despite the fact that their H1 potency can last as little as three nights, leading to manifest over-prescription. Although doxepin is not addicting, withdrawal symptoms after abrupt discontinuation may occur and include hypertension, tachycardia, restlessness, abdominal distress and emesis. Withdrawal mania has also been reported. (See patient experience later). The 10% rule holds for doxepin: Reduce progressively by 10% per month, calculated on the last dosage - i.e to 90% compounding down monthly.

 

Doxepin for insomnia patient reviews

 

Doxepin is great at keeping me asleep. The only major problem is the rapid weight gain. I went from 155lbs to 185lbs in only 2 weeks.

 

Helped me a lot with my insomnia. But gained over 50 pounds in the last 4 months. I have also noticed my hair getting thinner. I will not take this anymore. Going back to the dr.

 

This medicine was just like taking Benadryl, only more expensive. An hour to two hours after taking Silenor, I still couldn't fall asleep...not even the slightest bit tired. Once I had fallen asleep, I would wake up 2-4 hours later and be wide awake for the rest of the night.

 

Like most medicines, the first few days it worked like a charm. … The bad thing about this medicine is that you feel very sedated throughout the day. You know you slept because of the vivid dreams and you don't wake up the whole night. Nevertheless, you feel extremely tired the whole day.

I tried this for two weeks and yet I never got to sleep on it. I had to try it for two weeks because otherwise my doctor wouldn't give me anything else.

 

I was given doxepin 50mg after a very bad experience using Xanax for insomnia. It works fine for my depression, I have a good energy level during the day, but it doesn't do a thing for my insomnia. I feel that if I can solve my insomnia it would go a long way to helping my depression.

 

Silenor was a nightmare for me. I stuck with it for about 3 weeks and thought I was going out of my mind. I did not sleep at all for the first 4 days and then the hallucinations began. If I did sleep it was in for about 30 minutes at a time and then the terrible nightmares kept me awake for the rest of the night.

 

First night on 10mg didn't fall asleep until 5:15 am after 4 am popcorn binge. Woke up about 7:30 am. Same on next 3 nights with middle-of-the night coffee-cake, chocolates and even a couple of frozen dinners. Dr. upped to 20mg. Same result. Hardly any sleep, night snacking, and started eating more during the day. People have commented about rapid weight gain. They're right. I gained 8 lbs. the first week! My weight has been pretty consistent by 2-3 lbs. for years. Going back to Ambien!

 

I question the use of doxepin, except for people who may have an underlying depressive cause of insomnia where the two effects may work synergistically and where early awakening can be a symptom. For a woman to try to cure insomnia and find she has blown up like an obese balloon in front of her husband, or a man in later mid-life who finds that his sexual relationship with his partner is reduced to a fumbling shadow if his former prowess this is extremely hard to justify because one’s bodily attractiveness and sexual fulfilment are key to feeling one’s full vitality and health and for a doctor to compromise these merely to protect their own reputations of avoiding potential drugs of abuse is a violation of medical ethics. To me it is an absolute crime of the medical profession to foist tricyclics, which needlessly compromise an over 65 year old’s capacity to enjoy a sexually active life conducive to health and wellbeing of both themselves and their partner and experience of intimacy together and the fullness of life in mid-age, simply because they can’t trust well-informed patients to take sleep medication intermittently enough to avoid dependency.

 

The Unseemly Politics of Insomnia Medication

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To my absolute dismay, when I initially wrote to my GP to let them know I had handled their reluctant medication so responsibly that I had used only one from the second prescription in two and a half months, but was still having intermittent trouble for which I considered temazepan to be the appropriate choice, she declined to even consider further medication and tried to palm me off to an expensive private clinic for cognitive behavioural therapy, washing her hands of my medical care in so many words. This to me is a compete violation of medical ethics and shows how far doctors are prepared to go in treating their own imaginary and unjustified concerns, reducing the patient to a mere cipher – a public health drug abuse statistic, failing to treat on the basis of informed consent and reneging on treating the actual condition entirely. Once we reach this point, the whole agenda of medical care has become an unhinged travesty.

 

I was not depressed and did not have an anxiety neurosis, so being told I would get nothing but tricyclic antidepressants after a week in which I used only 3 sleeping tablets was an absolute anathema. I found my GP’s attitude to be completely counterproductive, causing further anxiety and lack of confidence to beat the problem. It is also a failure of medical ethics. A GP visit should be a consultation with a patient to avail them of the possible treatments and their risks and benefits on the basis of informed choice, just as informed consent is required for an operation, not a dictatorial “take it or go somewhere else” edict stipulating a treatment inappropriate for the onset type of insomnia. General caution about potential drugs of abuse should not reduce the doctor-patient relationship to a cipher of public health protocols and potential abuse statistics. Neither should the doctor be treating their own anxieties about drug abuse and their professional reputations, rather than the patient.

 

In the process I researched all my friends and acquaintances and found many were semi-permanently using Z-drugs. I compiled a short list of other GPs who were prepared to take a more pragmatic view and prescribe sleep medications when the patient felt they needed them. At the same time I set out to use sleeping tablets so occasionally that I was eventually able to return to my GPs medical practice consult the head practitioner and gain agreement, albeit reluctantly, for another round of temazepam on the basis of six months of extremely impeccable minimal use of only 2 to 3 tablets a month.

 

The whole basis of modern medicine is patient-specific treatment. Each patient is different genetically and mentally. Some have little knowledge of medicine and need firm guidance, but others need informed choice and the knowledge of being in control of their treatment to conquer the condition, particularly one like acute insomnia, which can be very debilitating to one’s confidence. This is a major ongoing conflict area with psychotropic drugs and pain medications, which we will examine in detail in section 4.

 

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4:

Evidence for Safety of Zopiclone in Both Short and Intermediate-term Use

Chris King

 

A: Insomnia Toll: Dementia and Comorbidities: Short sleepers (<6h) have advanced rates of dementia despite good exercise (Bloomberg et al. 2023) compared with optimal (6-8h) over 10 years. After adjusting for select co-morbidities, primary insomnia remained a significant factor for developing dementia, associated with a 2.14-fold increase in dementia risk (Hung et al.  2018). Estimates of insomnia prevalence in the elderly range from 25 to >50%. The medical and socioeconomic implications of insomnia are considerable, and include increased mortality, development of psychiatric or general comorbidities (Noble et all 1988, Patel et al. 2018).

 

B: Zopiclone Sleep Profile Improves Long-wave Sleep: Unlike benzodiazepines, Stages 3 and 4 were increased with Zopiclone 3.75 mg. REM sleep was reduced (but only as a percentage of total sleep) . The quality of sleep was improved and nocturnal awakenings reduced (Billiard et al. 1989).

 

C: Lack of Evidence of Tolerance: Subchronic treatment of mice with high doses of zopiclone does not produce the changes in sensitivity of the GABAA receptor that are observed with hypnotic benzodiazepines (Piot et al. 1990, Doble et al. 1995).  In a 12 month study of daily use, there was no evidence of tolerance on any measure (Roth et al. 2005).

 

D: Long Term Efficacy: Zopiclone increased sleep efficiency by decreasing sleep latency, wakefulness after sleep onset and increasing total sleep time. Sleep architecture was minimally affected by zopiclone treatment; no significant changes in delta or REM sleep were observed (Fleming et al. 1988). A 12 month study of nightly use of zopiclone reported: (1) decreased sleep latency, wake time after sleep onset, and number of awakenings; (2) increased total sleep time and sleep quality; and (3) improved ratings of daytime ability to function, alertness and sense of physical well-being compared to baseline (Roth et al. 2005, Krystal et al. 2003, Walsh et al. 2007). These effects did not diminish with use.

 

E: Low Abuse Potential: There is now over 15 years of clinical evidence supporting the efficacy and superior safety profile of zopiclone in insomnia (Hajak 1999). Clinical trials found no evidence for significant rebound insomnia and indicated that the risk of withdrawal reactions with therapeutic doses of zopiclone is very low. In addition, to date, dependency appears very low (Hajak 2003).

 

F: Negative Evidence for Cognitive Impairment: By contrast with benzodiazepines (de Gage et al. 2014) and anti-cholinergics (Gray et al. 2015), Guo et al. (2021) found no correlation between Z drug use and cognitive impairment. Moreover, their study showed that Z drug use might protect attention compared with non-Z drug use. Their study found no association between Z drugs and cognitive impairment, which could partly be explained by its affinity for α1GABAA subunit rather than α5GABAA. Another reason for this association might be related to the increase of slow-wave sleep with zopiclone.

 

G: Inconsistency of Recommendations, BPAC and Medsafe: Prescription use in NZ for zopiclone, as the most prescribed sedative, show a strong U-shaped profile, contradicting BPAC and Medsafe recommendations. Medsafe admits it does not have evidence on the long term risks or safety of zopiclone and neither does BPAC provide it.

H: Mortality and Cancer: Zopiclone is neither mutagenic nor clastogenic (chromosome damaging) nor are its metabolism products in urine. There was no evidence of a teratogenic potential (lactancia.org, hpra.ie).

 

Nevertheless population studies claim to show a significant increase, particularly in breast cancer and throat and liver cancer constituting an increase of 17-24% for benzodiazepines and zopiclone (Peng et al. 2020), advanced particularly by Kripke et al. (2012, 2016) in a highly politicised unsuccessful petition to the FDA. However Fang et al. (2019) note: Although both zopiclone and zaleplon usage were included in the non-BZDs group in our study, there was no significant increase in the risk of having subsequent cancers in subjects either with insomnia or without insomnia.

 

There is also claimed evidence for a significant increase in all cause mortality for benzodiazepines e.g. due to falls and infections in elderly people, however Hössjer et al. (2020)  note there was no association between hypnotic use and long-term mortality. The association between hypnotic use and increased mortality was thus restricted to a relatively short period after treatment initiation, and may be explained in terms of confounding by indication.

 

References:

 

Hirshkowitz M et al. (2015) National Sleep Foundation's sleep time duration recommendations: methodology and results summary Sleep Health 1 40–43. A: Insomnia Toll: Dementia and Co-morbidities

 

Bloomberg  M et al. (2023) Joint associations of physical activity and sleep duration with cognitive ageing: longitudinal analysis of an English cohort study Lancet Healthy Longevity 2023; 4: e345–53.

Falck R (2023) Editorial Is physical activity without good sleep enough to prevent cognitive decline?

 

Interpretation: The baseline cognitive benefit associated with more frequent, higher intensity physical activity was insufficient to ameliorate the more rapid cognitive decline associated with short sleep.

 

Findings We included 8958 respondents aged 50–95 years at baseline (median follow-up 10 years [IQR 2–10]). Lower physical activity and suboptimal sleep were independently associated with worse cognitive performance; short sleep was also associated with faster cognitive decline. At baseline, participants with higher physical activity and optimal sleep had higher cognitive scores than all combinations of lower physical activity and sleep categories (eg, difference between those with higher physical activity and optimal sleep vs those with lower physical activity and short sleep at baseline age 50 years was 0·14 SDs [95% CI 0·05–0·24]). We found no difference in baseline cognitive performance between sleep categories within the higher physical activity category. Those with higher physical activity and short sleep had faster rates of cognitive decline than those with higher physical activity and optimal sleep, such that their scores at 10 years were commensurate with those who reported low physical activity, regardless of sleep duration (eg, difference in cognitive performance after 10 years of follow-up between those with higher physical and optimal sleep and those with lower physical activity and short sleep was 0·20 SDs [0·08–0·33]; difference between those with higher physical activity and optimal sleep and those with lower physical activity and short sleep was 0·22 SDs [0·11–0·34]).

 

Noble S et al. (1998) Zopiclone An Update of its Pharmacology, Clinical Efficacy and Tolerability in the Treatment of Insomnia Drugs Feb; 55 (2): 277-302. Patel D et al. (2018) Insomnia in the elderly J Clin Sleep Med. 14(6): 1017–1024.

 

Insomnia, the inability to initiate and/or maintain sleep, is estimated to affect about one-third of the general population, with up to about one-quarter of those affected experiencing severe sleep deficit. Estimates of insomnia prevalence in the elderly range from 25 to >50%. The medical and socioeconomic implications of insomnia are considerable, and include increased mortality, development of psychiatric or general comorbidities, reduced productivity and/or work attendance and increased probability of involvement in accidents. … In conclusion, zopiclone is now well established as an effective and well tolerated hypnotic agent.

 

Hung C et al. (2018) Risk of dementia in patients with primary insomnia: a nationwide population-based case-control study BMC Psychiatry doi:10.1186/s12888-018-1623-0

 

The primary insomnia cohort had a higher prevalence of diabetes, dyslipidemia, hypertension, coronary heart disease, chronic liver disease, and chronic kidney disease at baseline. After adjusting for select co-morbidities, primary insomnia remained a significant predisposing factor for developing dementia, and was associated with a 2.14-fold (95% confidence interval, 2.01–2.29) increase in dementia risk. We also found a higher risk of dementia in younger patients.

 

Beydoun H et al. (2021) Insomnia as a predictor of diagnosed memory problems: 2006-2016 Health and Retirement Study Sleep Medicine 80 158-166.

 

In fully adjusted models, severe insomnia symptoms were associated with increased risk of physician-diagnosed memory problems. Individuals reporting any change (increase or decrease) in insomnia symptoms during the 2006-2010 period were more likely to be diagnosed with dementia based on HRS criteria. Finally, those who experienced an increase in the severity of insomnia symptoms over time exhibited 41-72% increased risks of physician-diagnosed memory problems and 45-58% increased risks of dementia diagnosis based on HRS criteria.

B: Zopiclone Sleep Profile Improves Long-wave Sleep

 

Billiard M et al. (1989) Effects of zopiclone on sleep, daytime sleepiness, and nighttime and daytime performance in healthy volunteers  Neurophysiol. clin., 19 (1989) 131-143

 

Continuity and architecture of sleep were assessed during night 1, degree of daytime sleepiness during day 1, and residual effects on night 2 and day 2. Continuity of sleep was not modified except for a reduction in the number of nocturnal awakenings. Slow air sleep stage 1 decreased and stage 2 increased, in duration and not in percentage, with Zopiclone 3.75 and 7.5 mg. Stages 3 and 4 were increased with Zopiclone 3.75 mg. REM sleep was reduced (only as a percentage of total sleep) with Zopiclone 3.75 and 7.5 mg. The degree of daytime sleepiness varied with time but not with product. A performance test, the reaction time test of choice, was affected at 00:00 and only with Zopiclone 7.5 mg. From a subjective point of view, the quality of sleep was improved and nocturnal awakenings reduced with Zopiclone 7.5 mg.

 

Improved sleep profile could partly be explained by its affinity for α1GABAA subunit rather than α5GABAA (Guo F et al. (2021) below).

 

Ruiz A et al. (2015) Bioavailability Comparison of Two Zopiclone Formulations in Healthy Colombian Volunteers J Bioequiv Availab 7: 233-238. doi:10.4172/jbb.1000246

 

A shorter half life lowers or eliminates the risk of tolerance, as the average dose in a 24-hour period is only 0.3 of the peak dose and is only at 0.04 of the peak by the time of the next dose. The green curve shows effective diminution of tolerance of twice the area.

 

C: Lack of Evidence of Tolerance

 

Doble A et al. (1995) The mechanism of action of zopiclone   Eur Psychiatry 10, Suppl3, Il7s-128s

Doble A (1999) New insights into the mechanism of action of hypnotics J. Psychopharm. 13(4) Supp. 1 Sl1-S20

 

Subchronic treatment of mice with high doses of zopiclone does not produce the changes in sensitivity of the GABAA receptor that are observed with hypnotic benzodiazepines.

 

Chronic treatment with hypnotic drugs that may have less dependence potential, such as zopiclone and zolpidem, appears to produce more limited change in GABAA receptor subunit expression.

 

Piot O et al. (1990)  Cyclopyrrolones, unlike some benzodiazepines, do not induce physical dependence in mice. Neurosci Lett 1990;117: 140-3

 

Left: No evidence for physical dependence (Piot et al.) Right: Consistent efficacy in rats in deep and REM sleep (Doble et al.)

 

D: Long Term Efficacy

 

Fleming J et al. (1988) A Sleep Laboratory Evaluation of the Long-Term Efficacy of Zopiclone Canadian J. Psychiatry 33/2

 

Six patients between the ages of 25 and 59, with chronic, primary insomnia received the new, non-benzodiazepine, hypnotic zopiclone continuously for 17 weeks after a drug free interval of 12 nights.  Patients evaluated their sleep by questionnaire and had sleep studies completed throughout active treatment. Zopiclone (7.5 mg) increased sleep efficiency by decreasing sleep latency, wakefulness after sleep onset and increasing total sleep time. Sleep architecture was minimally affected by zopiclone treatment; no significant changes in delta or REM sleep were observed.

 

Krystal A et al. (2003) Sustained Efficacy of Eszopiclone Over 6 Months of Nightly Treatment: Results of a Randomized,

Double-Blind, Placebo-Controlled Study in Adults with Chronic Insomnia SLEEP, Vol. 26, No. 7.

 

The results of this study demonstrate that nightly use of eszopiclone 3 mg, resulted in statistically significant differences in patient-reported measures of sleep onset, sleep maintenance, sleep quality, and next-day function compared with placebo in patients with chronic insomnia. These differences were apparent during the first week of treatment and were maintained throughout 6 months of double-blind treatment, with no evidence of tolerance. This study provides compelling evidence of effective long-term pharmacologic treatment of primary insomnia. The findings increase the period of sustained efficacy that has been demonstrated in large, randomized, double-blind placebo-controlled studies from approximately 1 month to 6 months. This has important clinical implications in light of growing evidence of the significant morbidity of untreated chronic insomnia, the unremitting nature of insomnia, and the common practice of long-term pharmacologic management that has been carried out without empirical support for the sustained benefit of the treatment.

 

Roth T et al. (2005) An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia Sleep Medicine 6 (2005) 487–495.

 

Results: Patients who were initially randomized to double-blind placebo and then switched to open-label eszopiclone (nZ111) significantly reported the following: (1) decreased sleep latency, wake time after sleep onset, and number of awakenings; (2) increased total sleep time and sleep quality; and (3) improved ratings of daytime ability to function, alertness and sense of physical well-being compared to baseline (P%0.0001 all monthly endpoints). There was no evidence of tolerance on any measure in either group. These subjects (nZ360) sustained the double-blind treatment gains for all sleep and daytime parameters, with further significant improvement in a number of measures. Eszopiclone was well tolerated in both groups; unpleasant taste was the only undesirable effect reported by O5% of patients.

 

Conclusions: The significant improvements in sleep and daytime function were evident in those switched from double-blind placebo to 6 months of open-label eszopiclone therapy and were sustained during the 6 months of open-label treatment for those receiving prior double- blind eszopiclone. During 12 months of nightly treatment, eszopiclone 3 mg was well tolerated; tolerance was not observed.

 

Walsh et al. (2007) Nightly Treatment of Primary Insomnia

With Eszopiclone for Six Months: Effect on Sleep, Quality of Life, and Work Limitations SLEEP 30(8):959-968.

 

Throughout 6 months, eszopiclone improved all of the components of insomnia as defined by DSM-IV, including patient ratings of daytime function. This placebo-controlled study of eszopiclone pro- vides compelling evidence that long-term pharmacologic treatment of insomnia is efficacious.

 

E: Low Abuse Potential

 

Lader M (1997) Zopiclone: Is there any dependence and abuse potential?  J Neurol 244 [Suppl 1] : S18-S22

 

Tolerance to zopiclone does not occur regularly. … Dependence on long-term use, as shown by either a characteristic withdrawal syndrome or by psychological craving, is rare considering the world-wide extent of usage. Abuse (addictive non-medical use) is documented but is also rare, in comparison with the widely abused benzodiazepines. It is concluded that zopiclone has substantial advantages over the benzodiazepines in terms of dependence and abuse potential.

 

Hajak G (1999) A Comparative Assessment of the Risks and Benefits of Zopiclone A Review of 15 Years’ Clinical Experience Drug Safety 1999 Dec; 21 (6): 457-469.

 

There is now over 15 years of clinical evidence supporting the efficacy and superior safety profile of zopiclone in insomnia. During this period, over 2.5 billion zopiclone units have been dispensed in over 30 countries. Evaluation of the accumulated evidence consistently indicates that overall zopiclone is a clinically superior alternative to the majority of benzodiazepines for the short term pharmacological treatment of insomnia.

 

Hajak G et al. (2003) Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data Addiction 98 1371–78

 

Clinical trials found no evidence for significant rebound insomnia and indicated that the risk of withdrawal reactions with therapeutic doses of zopiclone is very low. In addition, to date, dependency appears very low, although abuse potential should be considered following a history of addiction or psychiatric illness. Evaluation of the accumulated evidence from over 2.5 billion units dispensed in more than 30 countries indicates that zopiclone is effective, well tolerated and an excellent alternative to benzodiazepines in the short term treatment of insomnia.

 

F: Negative Evidence for Cognitive Impairment, by contrast with Benzodiazepines and Anti-cholinergics

 

Guo F et al. (2021) Association Between Z Drugs Use and Risk of Cognitive Impairment in Middle-Aged and Older Patients With Chronic Insomnia. Front. Hum. Neurosci. 15:775144. doi: 10.3389/fnhum.2021.775144

The Z-drug study Investigations were performed on patients with chronic insomnia who visited the outpatient Department of Neurology, Beijing Friendship Hospital, and were assessed for the global cognitive function (MoCA) and memory (AVLT), executive function (TMT- B), visuospatial ability (CDT), verbal function (BNT-30), and attention (DST). Multiple regression analysis was conducted to determine the independent factors of cognition and evaluated the effect of Z drug use (zolpidem and zopiclone) on cognition.

 

A total of 120 subjects were identified. In our analysis, BZD exposure density (P = 0.025, OR = 1.43, 95% CI, 1.25–1.86) was an independent risk factor of cognitive impairment in middle-aged and older patients with chronic insomnia. Neither Z drug use (P = 0.103) nor Z drug exposure density (P = 0.765) correlated with global cognitive function. Moreover, there was a positive association between Z drug use and attention [(P = 0.002, OR = 0.42, 95% CI, 0.24–0.73)]. Additionally, income level (P = 0.001, OR = 0.23, 95% CI, 0.10–0.53), severity of insomnia (P = 0.019, OR = 1.20, 95% CI, 1.03–1.40) and age (P = 0.044, OR = 1.07, 95% CI, 1.00–1.14) were also independent factors of global cognitive function.

 

We found that BZD exposure density was an independent risk factor of cognitive impairment in middle-aged and older patients with chronic insomnia, but no correlation was found between Z drug use and cognitive impairment. Moreover, our study showed that Z drug use might protect attention compared with non-Z drug use.

 

Discussion: Because BZDs and Z drugs are positive regulators of the GABAA receptor, they will reduce brain activation, decrease synaptic plasticity, and affect the ability of patients to create new memories (Stern, 2012). Secondly, the binding of BZDs to α5GABAA subunit, which is mainly expressed in the hippocampus, impairs context memory information in monkey models. However, zolpidem does not impair the performance of visual cue-based tasks due to the affinity for α1GABAA rather than α5GABAA (Mohamad and Has, 2019). These results suggest that α5GABAA receptor plays a special role in BZD-related cognitive impairment. It is thus speculated that BZD can increase the risk of cognitive impairment through α5GABAA in the hippocampus, while Z drugs, which bind to α1GABAA have a lower risk. However, another study has shown that the activation of α1GABAA receptor can influence the spatial learning ability of rodents (Joksimovic et al., 2013).

 

Our current study found no association between Z drugs and cognitive impairment, which could partly be explained by its affinity for α1GABAA subunit rather than α5GABAA.

 

Another reason for this association might be related to the increase of slow-wave sleep. Insomnia increases neuronal activity, decreases the clearance of β-amyloid protein (A β) and tau, and increases the accumulation of Aβ plaque and tau protein by reducing slow-wave sleep, which leads to neurodegeneration and AD. Slow-wave sleep plays an important role in sleep-dependent declarative memory consolidation (Xie et al., 2013; Rasmussen et al., 2018). Insomnia patients with less slow-wave sleep show a decrease in declarative memory consolidation the next day (Lu and Goder, 2012). The Z drugs used in this study were zolpidem and zopiclone, which could maintain sleep stages and promote slow-wave sleep, which might be part of the reason why Z drugs did not lead to cognitive decline in this study. This might also be part of the reason why BZDs, which reduced slow- wave sleep impaired cognition. The molecular mechanisms of cognitive impairment caused by BZD and Z drug need a further prospective study to confirm.

 

de Gage S et al. (2014) Benzodiazepine use and risk of Alzheimer’s disease: case-control study BMJ 2014;349:g5205 doi: 10.1136/bmj.g5205.

 

The benzodiazepine study. A team of researchers from France and Canada linked benzodiazepine use to an increased risk of being diagnosed with Alzheimer's disease. In the study, the greater people's cumulative dose of benzodiazepines, the higher their risk. The researchers relied on a database maintained by the Quebec health insurance program. From it, they identified nearly 2,000 men and women over age 66 who had been diagnosed with Alzheimer's disease. They randomly selected more than 7,000 others without Alzheimer's who were matched for age and sex to those with the disease. Once the groups were set, the researchers looked at the drug prescriptions during the five to six years preceding the Alzheimer's diagnosis. People who had taken a benzodiazepine for three consecutive months or less had about the same dementia risk as those who had never taken one. But those who had taken a benzodiazepine for three to six months had a 32% greater risk of developing Alzheimer's, and those taking one for more than six months had an 84% greater risk than those who hadn't taken one.

 

The type of drug taken also mattered. People who were on a long-acting benzodiazepine like diazepam (Valium) or flurazepam (Dalmane) were at greater risk than those on a short-acting one like triazolam (Halcion), lorazepam (Ativan), alprazolam (Xanax), or temazepam (Restoril).

 

Coupland C et al. (2019) Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study JAMA Intern Med. 179(8) 1084-1093 doi:10.1001/jamainternmed.2019.0677.

 

This confirms the previous study below.

 

Gray S et al. (2015) Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study JAMA Intern Med. 175(3) 401-407 doi:10.1001/jamainternmed.2014.7663.

 

The anticholinergic study. Researchers tracked nearly 3,500 men and women ages 65 or older who took part in Adult Changes in Thought (ACT), a long-term study conducted by the University of Washington and Group Health, a Seattle health care system. They used Group Health's pharmacy records to determine all the drugs, both prescription and over-the-counter, that each participant took in the 10 years before starting the study. Participants' health was tracked for an average of seven years. During that time, 800 of them developed dementia. When the researchers examined medication use, they found that people who used anticholinergic drugs were more likely to have developed dementia than those who didn't use them. Moreover, dementia risk increased along with the cumulative dose. Taking an anticholinergic for the equivalent of three years or more was associated with a 54% higher dementia risk than taking the same dose for three months or less. The University of Washington study is the first to include nonprescription drugs. It is also the first to eliminate the possibility that people were taking the drugs to alleviate early symptoms of undiagnosed dementia. For people who took anticholinergic bladder medications, the increased risk was just as high as for those taking tricyclic antidepressants, which are also anticholinergics.

 

G: Inconsistency of Recommendations BPAC

 

BPAC survey data in 2021 shows NZ doctors opinions on the safety of zopiclone and the Medsafe recommendations  to restrict zopiclone use to short-term only, reflect the lack of real medical evidence for harmful effects, such as loss of efficacy due to tolerance, or significant rebound effects in longer term use.

 

 

 

Dependence with Zopiclone Medsafe Prescriber Update 16: 20–22 July 1998

 

Dependence and withdrawal effects with zopiclone do occur, although rarely. These effects can occur in people without prior substance dependence and who are taking the recommended dose.

 

Zopiclone (Imovane) is indicated for the short-term treatment of insomnia and appears to be associated with a very low risk of dependence, rebound insomnia, and withdrawal problems.

Nevertheless some individuals do become dependent on zopiclone, and many of these have not experienced substance dependence or abuse previously. The approved data sheet for Imovane advises no more than 4 weeks continuous treatment, and a maximum dose of 7.5mg (1 tablet) a day.

 

A study comparing 4 weeks’ treatment with zopiclone 7.5mg, triazolam 0.5mg and placebo in patients with generalised anxiety disorder found significantly (p < 0.05) lower mean scores for anxiety, on the Hamilton Anxiety Rating Scale, for patients taking zopiclone (n=30) than for those given triazolam (n=30). The scores were 18.2 with zopiclone and 22.4 with triazolam ^{3, 4}. In the withdrawal phase of the study, zopiclone was associated with a lower frequency and lesser intensity of rebound insomnia following abrupt discontinuation than triazolam.

 

At June 1997, the WHO database held 46 reports of dependence and 42 of withdrawal syndrome with zopiclone. These figures suggest a very low rate of occurrence of these problems.   …  This is confirmed by Hajak (2003) [16].

However, during a 2.5 year period, Tranx Services, Auckland saw 24 clients seeking help for dependence who were taking zopiclone (personal communication only). … given over 200,000 patients taking zopiclone in the above BPAC chart, and some 44,000 taking over 180 tabs in a year, this confirms the actual rarity of withdrawal symptoms in NZ.

 

3. Fontaine R et al. (1990) Zopiclone and triazolam in insomnia associated with generalized anxiety disorder: a placebo-controlled evaluation of efficacy and daytime anxiety. Internat Clin Psychopharm 5:173-83.

4. Fontaine R et al. (1988) Efficacy and rebound insomnia of zopiclone and triazolam Psychopharmacology 96 S219.(inaccessible)

 

Zopiclone – Indicated for short-term use only  Medsafe Prescriber Update 40(2): 32 June 2019

 

Zopiclone is indicated for the short-term treatment of insomnia in adults¹. The approved adult dose is 7.5 mg taken shortly before bedtime for up to a maximum of 4 weeks. Medsafe has not assessed the safety and efficacy of longer-term use. Use of zopiclone for longer than 4 weeks should be considered ‘off-label’.

 

Long term use of zopiclone may cause tolerance and dependence, leading to withdrawal and rebound insomnia if the medicine is stopped abruptly. A gradual reduction in dose and/or frequency of use can reduce the likelihood of withdrawal effects after long-term use^1–3.

 

1. Imovane fact sheet Medsafe

2. I Dream of Sleep 1 BPAC

3. I Dream of Sleep 2 BPAC

 

These BPAC references do not contain a single citation on zopiclone in particular to support their claims.

 

Additional references on Specific zopiclone withdrawal studies found:

 

Bianchi M, Musch B (1990) Zopiclone discontinuation: review of 25 studies assessing withdrawal and rebound phenomena. Int Clin Pharmacol 5 [Suppl 2] : 137–145   (inaccessible)

 

21a: Hajak  J et al. (1998) Rebound insomnia after hypnotic withdrawal in insomniac outpatients Eur Arch Psychiatry Clin Neurosci 248 148–156.

 

At the end of the 4-week treatment, total response, including improved sleep quality and daytime well-being, was significantly higher with zopiclone (37.4%) than with placebo (26.8%; p ≤ 0.0017) and showed a tendency to be higher than that with triazolam (32.2%) or flunitrazepam (30.0%). This response was mainly due to response in daytime well-being, since parameters of sleep quality were markedly improved in all treatment groups including placebo (zopiclone 94.0%, flunitrazepam 95.5%, triazolam 93.8%, and placebo 85.9%; for details see Hajak et al. 1994).

 

Rebound criteria were met by patients from all treatment groups, including the placebo group. Two-factor ANOVA with repeated measures for overall rebound including all items of sleep quality and daytime well-being (treatment groups, days of withdrawal) revealed significant differences between treatment groups (F = 4.345; df = 3; p ≤ 0.01) and days of withdrawal (F = 4.88; df = 13; p ≤ 0.05). Post hoc Scheffés’ test shows that the number of patients with rebound (rebound rate) was significantly higher in the placebo group than in the groups treated with active drugs (p ≤ 0.01 for comparison of each drug to placebo), whereas there were no differences between active drugs (Table 2). The rebound rates were lower on the first day of drug discontinuation (day 29) than on day 31 (p ≤ 0.05).

 

Rebound rates for one, two, and three rebound items for both, rebound in sleep quality and daytime well-being, are shown for each day of the study in Figs. 1 and 2. A deterioration in sleep quality concerning one rebound item for at least 1 day of the post-treatment period was experienced by 12.4–21.5% of the patients, whereas 15.6–25.5% of patients experienced a deterioration in daytime well-being. Rebound rates decreased with increasing number of rebound items. With the maximum of three rebound items, rebound rates ranged between 1.0 and 4.6% (sleep quality; Fig. 1c), and 5.4% and 10.1% (daytime well-being). Figures 1 and 2 show that the rebound rates for sleep quality were highest during the first days of withdrawal, but only slightly higher than the range of variation in the rebound rate which was measured during the post-treatment period.

 

This study shows that not only a remarkable number of patients treated with active drugs, but also patients treated with placebo, experience a deterioration in subjective sleep parameters after drug discontinuation in comparison with pretreatment levels. The number of patients with rebound in the placebo group was even higher than in those patients treated with either zopiclone, triazolam, or flunitrazepam.

 

21b: Lader M (1992) Rebound insomnia and newer hypnotics  Psychopharmacology(1992) 108:248 255

 

Lader reviews a number of rebound studies presented here as evidence.

 

Studies in normal patients

In an early study, six healthy male medical students were given placebo for 4 nights, then zopiclone 7.5 mg for 5  nights, followed by a further 3 nights of placebo (Godtlibsen and Dreyfus 1980). Sleep recordings were taken every night and subjective questionnaires completed. Hypnotic effects were only mild with some minimal rebound effect on stage 2 and REM sleep.

 

A longer study involved giving nine male subjects zopiclone 7.5 mg for 21 nights or placebo 21 nights, each followed by 7 nights of placebo (Dorian et al. 1982). Sleep questionnaires were completed on days 1, 2, 4 and 6 of each withdrawal (placebo) week. On the second and fourth days of withdrawal, subjects reported significantly fewer hours of sleep, of lesser quality and with a longer sleep latency, compared to all the other withdrawal days. Inspection of the graphs suggests some rebound on the second night after withdrawal of zopiclone as compared with withdrawal of placebo, but no direct statistical comparison is included.

 

A comparative sleep-laboratory study assessed the effects of zopiclone 7.5 mg and triazolam 0.5 mg over 6 nights, each given in a cross-over design in 12 healthy male volunteers (Tiberge et al. 1988). No significant rebound was detected at the end of either period of drug administration, but the data from 3 successive nights were pooled.

 

Lader and Frcka (1987) investigated possible rebound effects in ten normal volunteers given either: placebo over 4 weeks; zopiclone 7.5 mg nightly for 2 weeks followed by placebo for 2 weeks; zopiclone 7.5 mg for 2 weeks, then 3.75 mg for 1 week and placebo 1 week; temazepam 20 mg for 2 weeks, placebo 2 weeks; and finally temazepam 20 mg 2 weeks, 10 mg 1 week, placebo 1 week. Daily ratings detected some subjective rebound after stopping temazepam which was somewhat reduced by first halving the dosage. Rebound effects were minimal with zopiclone so that tapering the dose seemed unnecessary.

 

Studies in insomniac patients'

A small-scale study involved six patients with chronic insomnia, confirmed by sleep recordings (Mamelak et al. 1982). After 4 nights of placebo, zopiclone 7.5 mg was given for 21 nights followed by placebo again for 4 withdrawal nights. Sleep recordings were obtained on the first 7 and last 8 nights of the study. No rebound beyond baseline levels was detected but several variables worsened significantly as compared with values on the first few nights of treatment. Another small-scale sleep laboratory study compared zopiclone 7.5 mg and nitrazepam 5 mg, each given for 14 nights to three and two insomniacs, respectively (Jovanovic and Dreyfus 1982). No sign of rebound insomnia was detected after discontinuing zopiclone.

 

A longer study involved giving zopiclone 7.5 mg for 54 nights to 11 chronic insomniacs followed by placebo for 14 consecutive nights (Pecknold et al. 1990). Sleep recordings were obtained before treatment, the first drug night, after 4 and 8 weeks of treatment, and on nights 1, 7, 8, 13 and 14 of the final phase. Unfortunately, rebound after the first night might well be missed. Sleep onset latency increased non-significanlty on the first night of withdrawal compared with baseline. Other changes were noted but significant and consistent rebound was not apparent; subjective questionnaire data gave parallel results.

 

Twelve insomniac women, aged 50-59, were studied in a crossover comparison of zopiclone 7.5 mg and flurazepam 30 mg using sleep laboratory recordings (Quadens et al. 1982). The authors report "an unpleasant rebound beyond baseline levels with flurazepam which is not the case with zopiclone". However, recordings were carried out on nights 11-13 after withdrawal which is too belated to detect rebound from shorter-acting compounds.

 

One sleep laboratory study involved ten insomniac patients aged over 60, given either triazolam 0.25 mg or zopiclone, 7.5 mg for 14 nights, preceded and followed by placebo (Mouret et al. 1990). The first 3 nights after active drug withdrawal were monitored polysomnographically. The authors state that no statistically significant rebound was found but inspection of the figure for total sleep time suggests a trend towards rebound for both drugs, lasting 1 night for zopiclone and 2 for triazolam.

 

Subjective questionnaires were used to compare zopiclone 7.5 mg and triazolam 0.25 mg in 48 chronic insomniacs (Fleming et al. 1990). After a 3-day wash-out period, the drug was given for 21 nights followed by 4 placebo nights of withdrawal monitoring. Both drugs proved effective although zopiclone sustained its effect better than did triazolam. On withdrawal, insomnia was complained of by three-quarters of patients on both drugs. On the first withdrawal night, sleep induction, duration and soundness of sleep scores in the triazolamtreated group were significantly worse than those recorded at baseline. For zopiclone-treated patients, quality and soundness of sleep were significantly reduced on the first, second and fourth withdrawal nights. On the fourth night, sleep soundness was significantly poorer in those withdrawn from zopiclone than those who had stopped taking triazolam. The authors interpret this as a recovery of sleep loss following the first withdrawal night's rebound insomnia in the triazolam group.

 

A general-practice study in 99 insomniac patients compared zopiclone 7.5 mg, nitrazepam 5 mg and placebo administered for two weeks and followed by placebo (Anderson 1987). Subjective assessments failed to uncover any rebound relative to baseline, pretreatment values. However, analysis of the daily ratings showed some deterioration of sleep, maximal the first night after discontinuation of zopiclone with sleep patterns normalizing within 2-3 nights. For nitrazepam, the effect was less marked but tended to occur 3 or 4 days after stopping. In another general-practice study of insomniacs (without placebo control), rebound was not apparent after discontinuing either zopiclone 7.5 mg or flunitrazepam 2 mg (Wickstrom et al. 1983). However, questionnaire responses were averaged over 3 days of withdrawal.

 

Individual nights were assessed clinically in a comparison of zopiclone (5 or 7.5 mg), triazolam (0.125 or 0.25 mg) and placebo (Elie et al. 1990a). A total of 48 patients was treated double-blind for 3 weeks and then single-blind for 4 days with placebo. The main therapeutic effects were improved sleep latency with zopiclone and triazolam and in sleep soundness with zopiclone, compared to placebo. On withdrawal, the triazolam group reported a significant increase in sleep latency and decreases in sleep soundness and quality in comparison to the placebo group. No significant changes occurred in the zopiclone group. Analysis of daily differences confirmed definite rebound compared with baseline for the triazolam-treated group`.

 

 

H: Increased risk of mortality and death.

 

Peng T et al. (2020) Hypnotics and Risk of Cancer: A Meta-Analysis of Observational Studies Medicina, 56, 513; doi:10.3390/medicina56100513.

 

Hypnotics (benzodiazepines and Z-drugs) use was significantly associated with an increased risk of cancer (odds ratio [OR] or relative risk [RR] 1.17; 95% confidence interval 1.09–1.26) in a random-effects meta-analysis of all studies. Subgroup meta-analysis by anxiolytics/sedatives effect (anxiolytics benzodiazepines vs. sedatives group (include sedatives benzodiazepines and Z-drugs)) revealed that a significant association in sedatives group (pooled OR/RR 1.26, 95% CI, 1.10–1.45), whereas no significant relationship was observed in anxiolytics benzodiazepines (pooled OR/RR 1.09, 95% CI, 0.95–1.26). Moreover, a significant dose–response relationship was observed between the use of hypnotics and the risk of cancer.

 

We found that sedatives benzodiazepines and Z-drugs have higher cancer risk (pooled OR/RR 1.26, 95% CI, 1.10–1.45). Moreover, Z-drugs (zolpidem and zopiclone) have higher cancer risk than benzodiazepines (24% vs. 19%).

 

Conclusions: This meta-analysis revealed association between use of hypnotics drugs and risk of cancer. However, the use of lower dose hypnotics and shorter duration exposed to hypnotics seemed to be not associated with an increased risk of cancer.

 

Fang H et al. (2019) Association between Sedative-hypnotics and Subsequent Cancer in Patients with and without Insomnia: A 14-year Follow-up Study  Taiwan Journal of Cancer 10(10): 2288-2298. doi: 10.7150/jca.30680

 

It has been recently suggested that sedative-hypnotics are clastogens that can transform normal cells into cancer through disruption or breakages of chromosomes. The author pointed out that non-BZDs such as zopiclone, zaleplon and ramelteon, based on the findings from the Center for Drug Evaluation and Research, are clastogenic in cell models. Although both zopiclone and zaleplon usage were included in the non-BZDs group in our study, there was no significant increase in the risk of having subsequent cancers in subjects either with insomnia or without insomnia.

 

Results: Patients with insomnia who used sedative-hypnotics had an adjusted hazard ratio of 1.49 compared with patients with insomnia who did not use any sedative-hypnotics, and patients without insomnia who used sedative-hypnotics had an adjusted hazard ratio of 1.68 compared with patients without insomnia who did not use any sedative-hypnotics. Regarding site-specific risk, patients with insomnia who used sedative-hypnotics had an increased risk of oral and breast cancers, and patients without insomnia who received sedative-hypnotics prescriptions had an increased risk of liver and breast cancers.

 

lactancia.org: In a wide battery of tests, it was shown that zopiclone has no mutagenic or clastogenic (chromosome-damaging) properties; urine extracts from zopiclone treated mice, rats and humans were similarly not mutagenic.

 

hpra.ie: Zopiclone is not mutagenic in either in-vitro or in vivo tests.

 

Increased incidence of mammary carcinomas in female rats at high multiples of the maximum plasma concentration from therapeutic doses in humans has been attributed to increased 17-beta-estradiol serum levels. Increased incidence of thyroid tumours in rats has been associated with increased TSH serum levels. In humans zopiclone has no effects on thyroid hormones.

 

Foetal developmental retardations and foetotoxic effects in rats and rabbits were observed only at doses well above the maximum human dosage. There was no evidence of a teratogenic potential.

 

Kripke Det al. (2012) Hypnotics’ association with mortality or cancer: a matched cohort study. BMJ Open 2012;2: e000850. doi:10.1136/bmjopen-2012-000850

 

Results: As predicted, patients prescribed any hypnotic had substantially elevated hazards of dying compared to those prescribed no hypnotics. For groups prescribed 0.4e18, 18e132 and >132 doses/ year, HRs (95% CIs) were 3.60 (2.92 to 4.44), 4.43 (3.67 to 5.36) and 5.32 (4.50 to 6.30), respectively, demonstrating a doseeresponse association. HRs were elevated in separate analyses for several common hypnotics, including zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates and sedative antihistamines. Hypnotic use in the upper third was associated with a significant elevation of incident cancer; HR1⁄41.35 (95% CI 1.18 to 1.55). Results were robust within groups suffering each comorbidity, indicating that the death and cancer hazards associated with hypnotic drugs were not attributable to pre-existing disease.

 

Conclusions: Receiving hypnotic prescriptions was associated with greater than threefold increased hazards of death even when prescribed <18 pills/year. This association held in separate analyses for several commonly used hypnotics and for newer shorter- acting drugs. Control of selective prescription of hypnotics for patients in poor health did not explain the observed excess mortality.

 

Hössjer O et al. (2020) Short- and long-term mortality following hypnotic use J Sleep Res. 2020;29:e13061. doi:0.1111/jsr.13061

 

Abstract Potential long-term consequences of hypnotics remain controversial. We used the prospective Swedish National March Cohort, a study based on 41,695 participants with a mean follow-up duration of 18.9 years. Logistic regression models and Cox proportional hazards models with attained age as timescale were used to assess associations of hypnotic use with short- and long-term mortality. The proportion of subjects who initiated or discontinued hypnotic use during follow-up was substantial. All groups of hypnotics were associated with increased mortality within 2 years after a first prescription, with an overall OR of 2.38 (95% CI, 2.13–2.66). The association was more pronounced among subjects younger than 60 years (OR, 6.16; 95% CI, 3.98–9.52). There was no association between hypnotic use and long-term mortality. The association between hypnotic use and increased mortality was thus restricted to a relatively short period after treatment initiation, and may be explained in terms of confounding by indication.

 

Salas M et al. (1999) Confounding by Indication: An Example of Variation in the Use of Epidemiologic Terminology American Journal of Epidemiology 149 11. doi:10.1093/oxfordjournals.aje.a009758.

 

Confounding by indication is a term used when a variable is a rise factor for a disease among nonexposed persons and is associated with the exposure of interest in the population form which the cases derive, without being an intermediate step in the causal pathway between the exposure and the disease.

 

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5: Melatonin as a Circadian Stabilizer

 

The Biology of Melatonin

 

Melatonin, N-acetyl-5-methoxy tryptamine, is a highly conserved molecule present throughout the domains of life, whose presence can be traced back to ancient photosynthetic prokaryotes. It is an ambiphilic antioxidant that can easily cross cell membranes, and in animals, the blood-brain barrier. It is a direct scavenger of radical oxygen and nitrogen species. In many less-complex life forms, this is its central function.

 

Melatonin is also produced in plants where it functions as a first line of defense against oxidative stress (Tan et al. 2012). Until its identification in plants in 1987, melatonin was for decades thought to be primarily an animal neurohormone. Melatonin has subsequently been found in all plants that have been investigated. It is present in all the different parts of plants, including leaves, stems, roots, fruits, and seeds in varying proportions.

 

Melatonin is widely present across animal phyla, being present in insects (Richter et al. 2000). The physiological effects of melatonin on various periodic processes such as rhythmic contractions in coelenterates, fissioning of asexual planarians and reproductive events in flies have been reported in the literature.

 

In vertebrates, melatonin is a neuro-transmitter/hormone produced by the pineal gland that regulates sleep and wakefulness, being involved in the entrainment (synchronization) of the circadian rhythms including sleep-wake timing, blood pressure regulation, seasonal reproduction, and many other functions. Many of its biological effects in animals are produced through activation of melatonin receptors, while others are due to its role as an antioxidant, with a particular role in the protection of nuclear and mitochondrial DNA.

 

 

The melatonin receptor (left) is a membrane bound hepta-helical G-protein linked receptor like that of the beta-2-adrenergic receptor illustrated and every metabotropic neuro-receptor, but the androgen receptor (right) is a cytoplasmic transcription factor that binds directly to DNA in the nucleus.

 

Melatonin as a ‘Hormone’

 

Although the literature describes melatonin as a ‘hormone’, this is fundamentally incorrect in terms of the molecular physiology. The classical steroid hormones such as testosterone act directly on cells by traversing the cell membrane (cholesterol is a membrane component) and binding to receptors in the cytoplasm that interact directly with DNA as transcription factors in the nucleus (e.g. the androgen receptor). Melatonin is basically an ambiphilic neurotransmitter, which binds to a membrane-bound G-protein linked receptor.

 

In mammals, melatonin binds to two receptors with complementary functions:

 

MT1 (or Mel1A) is a G protein-coupled, 7-transmembrane receptor that is responsible for melatonin effects on mammalian circadian rhythm and reproductive alterations affected by day length. The receptor is an integral membrane protein that is readily detectable and localized to two specific regions of the brain. The hypothalamic suprachiasmatic nucleus appears to be involved in circadian rhythm while the hypophysial pars tuberalis may be responsible for the reproductive effects of melatonin.

 

MT2 (or Mel1B) is found primarily in the retina and brain. It is thought to participate in light-dependent functions in the retina and may be involved in the neurobiological effects of melatonin. Besides the brain and retina this receptor is expressed on bone forming cells where it regulates their function in depositing bone.

 

The trick is that melatonin is ambiphilic enough to be released by the pineal and both have effects through the blood stream and cross the blood-brain barrier back to the receptors in the suprachiasmatic nucleus. Melatonin is not a hormone in the sense that it is a metabolic driver e.g. of sexual metabolism, but simply a circadian primer in response to light with a day-length priming effect on sexual functions in some animals. It is not habit forming, does not cause ‘droid rage’ like steroids, or addiction, like opiates, and manifests additional health benefits to cellular metabolism, in contrast, for example with the tendency for testosterone to significantly lower immunity, leading to buck deer sporting antlers becoming infested with parasites. Thus using the term “hormone” is qualitatively inaccurate and an unjustified rationalization for declaring melatonin a prescription drug.

 

General Health Benefits of Melatonin

 

Both animal and human studies have shown melatonin to protect against radiation-induced cellular damage. Melatonin and its metabolites protect organisms from oxidative stress by scavenging reactive oxygen species, which are generated during exposure. It is a broadly protective, readily available, orally self-administered antioxidant that is without major known side effects. An important characteristic of melatonin that distinguishes it from other classic radical scavengers is that its metabolites are also scavengers in what is referred to as the cascade reaction. Preliminary evidence suggests that it may help strengthen the immune system.

 

Naturally-occurring melatonin has been reported in foods including tart cherries, bananas and grapes, rice and cereals, herbs, plums, olive oil, wine and beer. When humans consume foods rich in melatonin such as banana, pineapple and orange, the blood levels of melatonin increase significantly (Sae-Teaw et al. 2012). In New Zealand both tart cherries (Howatson et al. 2012) and powder generated from night-milked cows has been marketed specifically as a natural source of melatonin in quantities claimed to help induce sleep in subject trials with exports to Korea (http://www.nzherald.co.nz/the-country/news/article.cfm?c_id=16&objectid=11440476 ). In fact there appears to be an international race with Brazil in this respect (Milagres et al. 2014). This provides clear evidence that melatonin is rightly regarded as a food supplement in the US and that the NZ classification as a prescription medicine is incorrect and inappropriate. How can it be reasonable that an Otago research firm can be encouraged to produce high-melatonin export milk for sleep while “chocolate sleep bites” legitimately purchased by mail-order in the US by NZers are being summarily seized by Medsafe in Auckland?

 

Cited health benefits from the Universities of Maryland and Michigan include: Supplementing with melatonin may reduce nighttime systolic blood pressure. It has been shown to help regulate gastrointestinal function and sensation. In one trial, people with irritable bowel syndrome who took melatonin experienced significantly less severe abdominal pain. In one trial, melatonin improved eye abnormalities in the majority of cases. It appears to work by regulating eye pigmentation and by functioning as an antioxidant. Supplementing with melatonin lowered intraocular pressure of healthy people in one study. Pineal gland function and melatonin secretion may be disturbed in people with migraine headaches. Taking melatonin may correct this problem and reduce symptoms. It may also reduce the frequency of cluster headaches. Melatonin has also been used to treat infertility. Melatonin also helps control the timing and release of female reproductive hormones. It helps determine when a woman starts to menstruate, the frequency and duration of menstrual cycles, and menopause. The AAAS also reported in 2015 that melatonin helps in the treatment of multiple sclerosis (Armitage 2015). Lowered melatonin levels have also been cited as an underlying basis for chronic insomnia in elderly people.  Melatonin has been cited as being cardio-protective and neuro-protective, encouraging hippocampal neuronal regeneration, protecting against neurodegenerative diseases, and protective in perinatal hypoxia/ischemia and stroke (Srinivasan et al. 2014). Bubenik et al. (2010) have even gone so far as to suggest on the basis of a research review that melatonin supplementation at bedtime may constitute an alternative route to to increase human lifespan, avoiding the need for caloric restriction to achieve a similar effect.

 

But by far the most clear and obvious direct health benefit of melatonin is enabling people who have any issues with circadian rhythms to get a good, refreshing night’s sleep and maintain a healthy active life style under the stresses of modern civilization. These take many forms. Light pollution, particularly of blue light in the evening from monitors and cool white light sources inhibit production of melatonin. The world is entering a phase of rapid transport across time zones where many people suffer from fatigue caused by “jet-lag”. Shift workers also suffer repeated time zone changes which are known to be broadly harmful to health. Sedative sleeping tablets is not an appropriate remedy for these impacts of modern society on human physiology, but melatonin is.

 

General Safety of Melatonin

 

Two attached systematic reviews found no adverse effects of exogenous melatonin in several clinical trials and comparative trials found the adverse effects – headaches, dizziness, nausea, and drowsiness were reported about equally for both melatonin and placebo (Buscemi et al. 2005, 2006). Prolonged-release melatonin is safe with long-term use of up to 12 months. The National Institutes of Health in the US state that here have been no reports of significant side effects of melatonin in children (https://nccih.nih.gov/health/melatonin#hed4 ). Its use has been suggested as beneficial for ADHD and for a rare child seizure condition. Melatonin may increase REM sleep, or lead to nightmares or dizziness, in larger doses then the 3 mg proposed, and to lowered body temperature in the elderly. One study has reported a reduction in sperm quality in 2 of 8 subject in a melatonin trial, possibly due to effects of FSH levels. But there is no verified evidence of withdrawal symptoms, postural instability, or of side effects continuing after cessation of use.

 

The fact that melatonin MT2 receptors also reside in bone-forming cells raises the question of the effects of melatonin on bone growth and remodeling. A significant number of research studies have found that bone remodeling is modulated in positive ways by melatonin. Bones are dynamically remodeled by the opposing actions of osteoblasts, which generate bone by weaving dense collagen mats in coordinated groups and depositing hydroxyapatite. Osteoclasts are the iconoclasts of bone, breaking down bone tissue, disassembling and digesting the composite of hydrated protein and mineral at a molecular level by secreting acid and a collagenase.  Melatonin promotes osteoblast differentiation and bone formation. One UK study found that chronic melatonin users had a higher rate of fractures than the control group,although moderate users had no such risk, but another study has confirmed that melatonin does not cause postural instabilities on waking contrdicting the previous implications, so the increased fractures in the first study are likely to be a feature of the cohort studied rather than melatonin itself.

 

Insomnia as an Epidemic of Civilized Life

 

According to US statistics, insomnia affects 20% of the population. Insomnia also presents itself in varied forms, which require differing strategies to treat effectively. Many people, including some with anxiety symptoms, find they wake early from a troubled sleep, resulting in a form of chronic insomnia where they are getting between 4 and 5 hours sleep and feel tired and seek medical help. Others, with an acute spell of sleep-onset insomnia, often due to a real life family, relationship, or financial crisis, find they cannot get to sleep at all, perhaps even on two or three nights in a row, resulting in an acute syndrome seriously affecting their brain and bodily functions and rendering them unable to carry out normal tasks, resulting in a serious medical episode unless they receive some immediate respite from sedatives to give them a chance for recuperation. At an extreme we have fatal familial insomnia, a genetic prion-related condition in which people are reduced to a catatonic coma of several months duration before death sets in.

 

Thus, from all points of view, the medical treatment of insomnia needs to be taken seriously as a debilitating condition which is a primary threat to good health. Insomnia and sleep arrhythmias are also a feature of the demands of modern civilization. While gatherer-hunter societies lived by the light of the sun and moon and many biological processes, from the circadian rhythm to the menstrual period were readily primed by the natural cycles, those living in urban societies face massive conflicting demands on their evolutionary physiology. Many people have to do shift work on sliding time scales that give them no consistent sleep biorhythm. Urban lighting, particularly of the blue light that photoreceptors in the retina independent of the visual system register, leads to suppression of melatonin production. Developed societies have also entered an era of transnational activity in which many people have to regularly traverse times zones on long flights and recover from jet lag. These are not medical conditions as such, but occupational hazards of otherwise healthy individuals, so it is fundamentally wrong for the medical profession to treat them as such. Critically, many of these social imperatives indicate a direct relationship with disruption of circadian cycles.

 

Loss of sleep has a diverse array of negative effects, both on the brain and bodily functions. Recent studies have shown that sleep enables the brain to reset synapses, which during daily activity gradually become over-excitable, back to physiological baseline levels, so that effective cognition can take place with much less expenditure of energy. This kind of problem is subjectively manifest in the fatigue and irritation over-tired people feel. Regular lack of sleep also predisposes to a significant risk of cancer (Fang et al. 2015), hypertension (Vgontzas, et al. 2009), metabolic disorders, including both diabetes mellitus (Gottleib et al. 2005) and acute gestational diabetes (Reutrakul et al. 2017).  Persistent insomnia is associated with increased risk of death, as well as increased inflammation (Parthasarathy et al. 2014). Men with insomnia have a fourfold higher death rate than normal sleepers who get at least 6 hours sleep a night (Vgontzas, et al. 2010). In a large cohort of older, mostly male veterans, investigators found that any sleep disturbance was associated with a 30% increased risk for dementia and that this risk increased to 80% if individuals also had posttraumatic stress disorder (PTSD).

 

Given these costs to individual welfare and public health, it is imperative that the medical profession takes insomnia seriously and provides all the means at our disposal to facilitate treatment of conditions rising from lack of sleep without prejudice or paying more attention to protecting medical interests that public health. However, in both the current New Zealand context, and in trends in medical treatment over time, what we find is a very confused picture. GP dependence on GABA modulators has given way to trying to purvey antidepressants, and particularly old style tricyclics such as doxepin and amitriptyline that have been discontinued for depression. This has raised serious concerns in several quarters internationally and underscores the unsatisfactory state of medical treatment of insomnia in New Zealand of which the financial and legislative restrictions on melatonin use are a significant symptom.

 

Melatonin as a Circadian Stabilizer

 

There is clear evidence that cyclic melatonin production declines with age and that chronic insomnia of one sort or another is universally accepted as concomitant with the life of the elderly. While it is not clear that the decline in melatonin levels is a primary cause of elderly insomnia, the case for circadian arrhythmias being an important factor in the plight of elderly insomniacs is compelling. It is also known that the human circadian rhythm drifts towards 25 hours in experiments underground lacking light priming, so many people who are night owls are tending towards arrhythmia unless their cycle is well-primed. Melatonin thus has a potential key role in social welfare as a natural substance.

 

Evidence of the decline in melatonin production with age from two experimental studies.

 

A study by Richard Wurtman, who first patented melatonin as a sleep supplement (Zhdanova et al. 2001 Journal of Clinical Endocrinology & Metabolism 86(10): 4727–4730) has shown that doses of melatonin in the range from 0.3 – 3 mg do improve sleep quality in elderly people with insomnia characterized by early waking, with the lower dose being at least as effective as the higher one and involving less hypothermia and residual plasma melatonin into the waking hours. This suggests that a dose in the range of 0.3 – 1 mg is effective for maintaining the circadian rhythm.  A further meta-analysis by Wurtman, and colleagues (Brzezinski et al. 2005 Sleep Medicine Reviews 9, 41–50) confirms that melatonin is an effective sleep aid. The scientists analyzed 17 peer-reviewed scientific papers. To be included the experiments reported in each paper had to be placebo-controlled and include objective measurements on at least six adult subjects. The melatonin meta-analysis delivered a definitive confirmation. Melatonin treatment in doses ranging from 0.3 mg to 10 mg significantly reduced sleep onset latency by 4.0 min; increased sleep efficiency by 2.2%, and increased total sleep duration by 12.8 min.

 

A the same time this paper gave rise to a special issue of Sleep Medicine Reviews in which the issue of melatonin as a hypnotic (Zhdanova 2005 Sleep Medicine Reviews 9, 51–65 vs van den Heuvel 2005Sleep Medicine Reviews 9, 71–80) as a chronobiotic (Arendt & Skene 2005 Sleep Medicine Reviews 9, 25–39) and its physiology and pathophysiology (Claustrat, Brun, & Chazot 2005 Sleep Medicine Reviews 9, 11–24.) and its circadian rhythms (Scheer et al. (eds) 2005 Sleep Medicine Reviews 9, 5–9) were widely discussed and debated. A & S noted that chronobiological shifts induced by melatonin treatment are sufficient to synchronise to 24 h most blind subjects suffering from non-24 h sleep–wake disorder, with consequent benefits for sleep and that successful use of melatonin’s chronobiotic properties has been reported in other sleep disorders associated with abnormal timing of the circadian system: jetlag, shiftwork, delayed sleep phase syndrome, some sleep problems of the elderly. C, B & C noted that, since the regulating system of melatonin secretion is complex, following central and autonomic pathways, there are many pathophysiological situations where the melatonin secretion can be disturbed. The resulting alteration could increase predisposition to disease, add to the severity of symptoms or modify the course and outcome of the disorder.

 

6: Drug Marketing Trends and the Over-prescription of Medical Psychoactive Drugs

 

The 2013 New York Times article “A Glut of Antidepressants” notes a level of antidepressant use in the US particularly in middle aged women echoing the profligate use of “soma” to pacify society in Aldous Huxley’s “Brave New World”: One in 10 Americans now takes an antidepressant medication; among women in their 40s and 50s, the figure is one in four (http://well.blogs.nytimes.com/2013/08/12/a-glut-of-antidepressants/).

 

'It feels like we've been lobotomised': the possible sexual consequences of SSRIs Long-term sexual dysfunction is a recognised side-effect for some patients who take these widely prescribed antidepressants, and can leave sufferers devastated. .

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Targeting of women for psychoactive medication has a long history. The benzodiazepine tranquillizer Valium was marketed as a “mother’s little helper” for women with children experiencing problems of handling their situations. 2.3 billion pills were sold by Roche at Valium’s 1978 peak. They were freely prescribed for 10 years, before their dependency potential became a concern.

Fig 6: Advertisements for antidepressants targeted at women.

Prozac (fluotexine) made Eli Lilly into a $66 billion dollar company from a $6 billion one.

The nature of gender targeted advertising is exemplified by the three passages aimed at prescribing doctors giving vulnerable women benzodiazepines:

Her mother’s obvious reference for her older sister has always rankled this patient. The deaths of her father and husband accentuated her alienation and hostility. Hypochondriasis is the way she disowns her conflicts. While you gradually turn her away from somatic concerns and guide her through old hidden problem areas, you can ease her undue psychic tension with valium (diazepam).

You can’t set her free but you can help her feel less anxious. You know this woman she is anxious, tense, irritable. She has felt this way for months. Beset by seemingly insurmountable problems of raising a young family and confined to the home most of the time, her symptoms reflect a sense of inadequacy and isolation. Your reassurance and guidance have helped some but not enough. Serax (oxazepam) cannot change her environment of course, but it can relieve anxiety tension, agitation and irritability, thus strengthening her ability to cope with day to day problems.

Fig 7: Oxazepam advertisement targeting a vulnerable female social context.

M.A. (Fine Arts) … PTA (President-elect) …representations of a life currently centered around home and children, with too little time to pursue a vocation for which she has spent many years in training … a situation that may bespeak continuous frustration and stress a perfect framework for her to translate the functional symptoms of psychic tension into major problems. For this kind of patient – with no demonstrable pathology yet with repeated complaints – consider the distinctive properties of valium (diazepam). Valium possesses a pronounced calming action that usually relieves psychic tension promptly, helping to attenuate the somatic signs and symptoms. Valium is well tolerated. ON proper maintenance dosage, valium seldom dulls the senses or interferes with functioning.

The nature of this advertising raises significant social issues. Both tranquillizers and antidepressants are aimed at vulnerable individuals who suffer stress or depression for a variety of reasons. Drug companies advertise because this is expected to increase their sales and profits. There is thus an incentive to seek out vulnerable social targets and advertise in proportion to the potential gains. If the market share for say antidepressants is skewed towards a large number of women in mid life, so the advertising will seek to exploit this market ad create a positive feedback encouraging more people in the identified categories to take up the medication. It is particularly noticeable in this advertising that categories particularly of women are chosen not because of organic physiological problems but real life constraints, such as sacrificing one’s career to raise a young family which are now turned into semi-psychiatric conditions to be treated by drug regimes, putting a clear pressure on the medical profession to misidentify problems requiring family counseling as anxiety neurosis or clinical depression.

Between 2000 and 2011, antidepressant use in Australia increased by 95.3%. In 2011, antidepressants accounted for 66.9% of total psychotropic drug prescription totals, far greater than anxiolytics (11.4%), antipsychotics (7.3%), mood stabilisers (5.8%), sedatives (5.5%), or ADHD medications (3.0%) (Aust N Z J Psychiatry. 2013 Jan;47(1) 74-87. doi: 10.1177/0004867412466595).

 

A US study, published in April 2013, found that nearly two-thirds of a sample of more than 5,000 patients who had been given a diagnosis of depression within the previous 12 months did not meet the criteria for major depressive episode - the level of depression which is known to be amenable to medication, by contrast with minor or situation caused depression, which is better treated by personal counseling and addressing the actual causative problems. Six out of seven patients, age 65 and older, who had been given a diagnosis of depression did not fit the criteria. The vast majority of individuals diagnosed with depression, rightly or wrongly, were given medication. Most people stay on the drugs, which can have a variety of side effects, for at least two years. Some for a decade or more (Psychotherapy Psychosomatics 2013;82:161-9 Doi:10.1159/000345968).

The OECD report “Health at a glance 2013” notes concerns about appropriateness of antidepressant prescribing: The consumption of antidepressants has also increased significantly in most OECD countries since 2000. Guidelines for the pharmaceutical treatment of depression vary across countries, and there is also great variation in prescribing behaviors among general practitioners and psychiatrists in each country. Iceland reported the highest level of consumption of antidepressants in 2011, followed by Australia, Canada, Denmark and Sweden. In 2008, almost 30% of women aged 65 and over had an antidepressant prescription in Iceland, compared with less than 15% in Norway. Greater intensity and duration of treatments are some of the factors explaining the general increase in antidepressant consumption across countries. In Germany there was a rise of 46% between 2007 and 2011, which was less affected by the economic crisis and experienced a more rapid economic recovery.   In England, the increase in antidepressant consumption has been associated with a longer duration of drug treatment. In addition, rising consumption levels can also be explained by the extension of the set of indications of some antidepressants to milder forms of depression, generalised anxiety disorders or social phobia. These extensions have raised concerns about appropriateness (http://www.oecd.org/els/health-systems/Health-at-a-Glance-2013.pdf).

 

Fig 8: Valium (diazepam) advertisement targeting a vulnerable female social context.

While antidepressants have little or none of the recreational abuse potential of GABA antagonists such as benzodiazepines, largely because they are not that nice to take, Des Spence notes in the British Medial Journal that they still have profound habituation problems because people fear that discontinuation will result in recurrence of depression: A policy of ever lengthening courses of antidepressants is a product largely of “expert” opinion, not evidence. Before we continue with this policy the psychiatric community must produce evidence of benefit. The internet is awash with harrowing patient stories of side effects such as gastrointestinal disturbances, hypersensitivity, anxiety, insomnia, tremor, hallucinations, drowsiness, sexual dysfunction, hypomania, and suicidal behaviour.  Research also suggests that half of patients experience a withdrawal syndrome. Patients are reluctant to stop antidepressants, assuming these symptoms mark a return of their depression. Some even believe they will never feel “happy” without medication (BMJ 2013 346 f191 doi:10.1136/bmj.f191).

 

There are also notable cases of people finding that they suffer significant withdrawal symptoms from even missing a singe day's dose of some antidepressants such as effexor (venlafaxine fig 2) which seems particularly difficult to taper off from. "In August of 2012, I had 2 days of very scary vertigo type symptoms - that's what I thought it was. Dizziness, headaches, severe lightheadedness, nausea. When I finally realized (weeks or maybe months later) what it was, it scared me. I had missed ONE day of my Effexor meds." There is a known strategy to begin taking prozac (fluoxetine) and at the same time taper off effexor over two weeks. As a measure of their habit-forming potential, patients also resort to hacking their medications to try to get off antidepressant us by tapering their dosage slowly, just as with benzodiazepines, splitting their doses or even counting out microgranules (Wilson C 2017 People are hacking antidepressant doses to avoid withdrawal New Scientist 7 July).

Common withdrawal symptoms for paroxetine, one of the more side-effect ridden anthdepressants, include nausea, dizziness, lightheadedness and vertigo; insomnia, nightmares and vivid dreams; feelings of electricity in the body, as well as crying and anxiety. "I started to take Seroxat in the Autumn of 1997. My dose was 30mg daily. In May 2004 my Doctor suggested that I reduce that to 20mg daily. Unfortunately I had problems with the reduction to 20mgs and things were so terrible I went back up to 30mgs within a week. I felt better as soon as I did this. This was a real shock to me and I started to do a little research on the internet. This was another shock to me - to find a huge community out there who had similar stories to tell - looks like I'll have to stop it rather than reduce it I decided. Once I took that decision - to stop Seroxat altogether - I thought it would be easy for me - after all, I stopped smoking with little or no fuss It took me 22 long months to wean off Seroxat and I suffered many mental and physical terrors and traumas. As I write I'm 10 months off Seroxat and my brain and body are STILL trying to adjust to life without it (https://seroxatsecrets.wordpress.com/about/)".

Doxepin and related tricyclics can also cause profound withdrawal effects if used long-term. "I have been taking a tricyclic (Doxepin or Amitriptyline) for 13 years for migraine headaches [not for depression]. Now the headaches are gone - but I cannot get off these evil drugs and it is very clear the medical professionals don’t want me to either. I started at 50mg and had gone down to 30mg over time no problem. I hovered at 30 for years because each time I went to 20mg the headaches would come back. Motivated by the risk of long term side effects, I stayed at the 20mg through the headache which lasted 10 days then went away - but I had a new symptom - surges of dizziness. For 2 weeks I was great - the dizziness was there but I felt my mind start to clear. Then with no warning I went down - I thought I was passing out, but then it turned into a seizure, but I was totally coherent just out of control of my jerking body. Then all hell broke lose in the next few days. I had all the flu like, dizziness, electric shock waves from the back of my scull to front, couldn't eat and if I did it just came right out with the intermittent seizures and now we add anxiety - the kind that grips your very being - makes you grit your teeth and doubt every fiber of your being. In my case I had to go back on the drug and get well and sane again and do it right this time. It has been 4 months since I am back on the 30mgs and I am still not 100% (http://icfda.drugawareness.org/Archives/Survivors/2004/record0040.html)."

A Guardian article noting the OECD warning about antidepressants comes with a video with a series of interviews with antidepressant users illustrating that antidepressant use is beneficial only for people with a serious clinical depression episode and leaves many people with minor depression in a permanently drugged state which compromises their mental autonomy and life judgment as well as for many, their enjoyment of life. Also notable is the preparedness of medical practitioners to diagnose serious conditions such as bipolar disorder on assumptions gained from a superficial 10 minute consultation (http://www.theguardian.com/society/2013/nov/20/antidepressant-use-rise-world-oecd).

 

If one in four women in the US in their 40s and 50s are on semi-permanent psychotherapeutic medication this means that major processes of decision making by women in stressful managerial positions are being affected by a pervasive soma mentality. This presents risks to society at least as significant as misuse of recreational drugs.

Fig 9: Shire a “Global Innovator in Specialty Biopharmaceuticals” whose flagship mission statement reads “To be as Brave as the People we help” offers mixed amphetamine salts for ADHD in the form of adderall-XR. The advert targets girls although ADHD is three times more common in boys.

While concerns may be raised about habituating drugs of potential abuse which also have serious withdrawal symptoms, similar concern has to be raised about institutional use of long-term psychiatric medications on large sections of the population, whose side effects are equally apparent and psychological long-term dependence is manifest in the ever-extending prescription periods of 2 - 10 years and increasing dosages.

In "The Emperor's New Drugs: An Analysis of Antidepressant Medication Data Submitted to the U.S. Food and Drug Administration" (Prevention & Treatment, 5/23 http://alphachoices.com/repository/assets/pdf/EmperorsNewDrugs.pdf), Irving Kirsch, and co-authors make a case that antidepressants have little more than a placebo effect except in the case of severely depressed patients, where the placebo effect is negligible. The case has also been published as a paperback with the same name.

 

While analyzing antidepressant trials as part of his research into the placebo effect, Kirsch concluded that drug companies do not publish most of their disappointing drug trial results and do publish most favorable results, and that most decisions about the efficacy of a drug are based only on published results. Using the Freedom of Information Act, he and his colleagues acquired from the US Food and Drug Administration the unpublished trial results for six antidepressants. When the results from both published and unpublished studies were averaged, the researchers concluded that the drugs produced a small but clinically meaningless improvement in mood compared with an inert placebo (sugar pill).

 

To determine whether their averaging of results was hiding a meaningful benefit to more-severely depressed patients by combining their results with those of moderately and mildly depressed patients, he and his colleagues undertook another study, this time of the four new-generation antidepressants for which all trial data were available, and concluded that the difference between drug and placebo effect was greater for more-severely depressed patients, and that this difference was clinically meaningful (but still relatively small) only at the upper end of the very severely depressed category.

 

Non-abusing recreational drug users operating in a paradigm of autonomous decision-making choose to take psychoactive drugs only on an intermittent basis to be high when they are celebrating, while the rest of the time choosing to remain drug free, so that they can make constructive life enhancing decisions in a clear mental state. While one understands that there are situations where a depressed person will seek antidepressant medication, or a manic person may be required to undertake antipsychotic medication, the dependence of the medical profession on regimes of medication taken constantly over months and years represents a significant compromise of patient autonomy and freedom of outlook - a basic human right - in favor of treatment regimes which give the practitioner security of control over the patient’s behavior to minimize risks to the practitioner and their practice. This is a conflict of interest with the patient’s best interests and welfare.

 

Fig 10: Thorazine (chlorpromazine fig 2) is a typical tricyclic antipsychotic used for schizophrenia and bipolar disorder, which shuts down all the neurotransmitter pathways from serotonin, through nor-epinephrine and dopamine to histamine and acetyl-choline. Here the man on the left is clearly portrayed as in a manic and violent state lashing out at imaginary enemies - a classic portrait of paranoid ideation: “Thorazine is especially effective when the psychotic episode is triggered by delusions or hallucinations. At the outset of treatment, Thorazine’s combination of anti-psychotic and sedative effects provides both emotional and physical calming. Assaultive or destructive behavior is rapidly controlled”. But the woman on the right is simply emotionally upset about menopause, a perfectly reasonable non-psychotic concern. Nevertheless we use an antipsychotic on her: “Thorazine can facilitate the overall management of your menopausal patient. Its unique, non-hypnotic tranquillizing effect relieves anxiety, tension, agitated depression and helps you to restore to the patient a feeling of well-being and a sense of belonging.” The same drug that renders the schizophrenic docile cannot restore to the menopausal woman well-being and a sense of belonging. It is clearly a use of marketing to identify vulnerable new targets.

 

Nowhere is this contrast more stark and striking than in the context of antipsychotic drugs which are prescribed long-term often against a person’s will either in mental institutions or as a condition of release into the wider world to ensure they will remain pacified and non-threatening to others.

 

As can bee seen in figs 2(a), the antipsychotics act as antagonists on almost the whole spectrum of ascending modulatory transmitters that give emotional mood, motivation and decision making their personal characteristics, including the dopamine, serotonin, no-epinephrine, histamine and acetyl-choline pathways, illustrated in fig 11, with a particular emphasis on the dopamine D2 receptor involved in motivation and decision-making. They also have a variety of long-term side effects, including serious movement disorders tardive dyskinesa and Parkinsonism, heart problems, obesity, hypotension, confusion and sedation. By contrast psychedelics act as super-agonists on serotonin receptors, particularly 5HT2a, precipitating a change in the glutamate dynamics through associated metabotropic glutamate receptors.

 

The non-tricyclic antipsychotic Haloperidol (Haldol, Serenace) has a particularly severe list of side effects, illustrating how very damaging drugs can end up being developed and sold to doctors with powers to prescribe medication for committed patients in their care, who have little or no say over the quality control of the substances they are institutionally prescribed. Haloperidol is on the World Health Organization's List of Essential Medicines. It is used for a wide spectrum of conditions, including schizophrenia, acute psychosis, mania, delirium, tics in Tourette syndrome, choreas, nausea and vomiting in palliative care, intractable hiccups, agitation and severe anxiety. A long-acting decanoate ester of haloperidol is used as an injection given every four weeks to people with schizophrenia or related illnesses who have poor adherence to medication regimens. It is the most prone of the antipsychotics to causing Extrapyramidal side effects, Dystonia, Muscle rigidity, Akathisia and Parkinsonism. As a result of its inverse agonist activity on the dopamine D2 receptor, haloperidol has been shown to dramatically increase dopamine activity, up to 98%, in test subjects after two weeks on a "moderate to high" dose compared to chronic schizophrenics. In another study, a live survey of a patient showed the person has 90% more dopamine receptors, of the D2 subtype, than before treatment with haloperidol. The long-term effect of this is unknown, but the first study concludes this upregulation is positively associated with severe dyskinesias. Haloperidol has also been shown to metabolize in the liver into toxic metabolites HPP+ and RHPP+. HPP+ is a structural analog of the more widely known Parkinson’s producing neurotoxin MPP+ and its precursor MPTP. Unlike MPP+, HPP+ is not dependent on monamine oxidase MAO-B for metabolism to toxic species and does not require functional dopamine transporter protein for intracellular uptake. It is toxic to both dopamine and serotonin neurons. A long-term retrospective study found a significant positive correlation between levels of HPP+ and severity of tardive dyskinesia. The receptors 5HT7 and sigma1 are both irreversibly inactivated by haloperidol. Studies showed shrinkage of whole brain by 10% focused on glial cell loss with a 5% drop in neuronal mass.

 

Fig 11: Ongoing fast excitatory electrical activity of the brain is mediated through the excitatory neurotransmitter glutamate in feedback with the inhibitory neurotransmitter GABA, or gamma-amino-butyric acid neurons, both driven by ionopore receptors which change the electrical current through ion flow. Five ascending pathways common to mammals arise from the basal brain moderating slow changes in consciousness from sleep to waking and mood and drive, through metabotropic receptors which change activity through protein interactions in the neuron. The five are dopamine (providing drive and decision-making) ,nor-epinephrine (monitoring vigilance), serotonin (expressing aspects of mood), histamine and acetyl-choline, both acting in complementary ways to maintain alertness. Antipsychotics generally act as antagonists, which dampen the activity in these circuits, leaving the person more docile and less prone to delusion.

 

In a 2013 article in the Telegraph "Why are women still considered more insane than men?" Will Nicoll notes that the new issue of theDiagnostic and Statistical Manual of Mental Disorders (DSM-V), which the British Psychological Society fears that the book might medicalise behaviour which is, actually, fairly normal looks set to generate a whole new raft of medical advertisements based on the updated categories of psychiatric illness. Dr Reg Peart, a critic of tranquilizers, noted, that “the level of science in psychiatry lies between astrology and witchcraft”.

 

Will quotes a study which found that 29 per cent of women, compared to 17 per cent of men are likely to have been treated for a mental-health problem. When depression, alone, is considered, the difference is even more pronounced. NICE the National Institute for Health and Care Excellence found that one in four women will require treatment during their lifetime – compared with only 1 in 10 men despite the fact that there are relatively few reasons to explain the actual scale of the disparity.

 

Professor Malcolm Lader, Emeritus Professor of Clinical Psychopharmacology at King’s College, London doubts this disparity is justified: “There are special influences operating in women which are absent or less important in men, citing the disorders associated with childbirth, such as puerperal depression and psychosis. But those are, obviously, extreme examples. With respect to conditions such phobias and anxiety disorders the ratios are probably about equal, With the willingness to admit or deny symptoms distorting the figures.” However this distinction is important because many of the drugs used often – namely the SSRI antidepressants – are not only licensed to treat depression, but also a variety of anxiety disorders, which make female patients key consumers.

 

In an article in MS magazine “Selling Sanity through Gender” (MS Fall 2003 40-45) Jonathan Metzel illustrates how a change of emphasis to slick patient marketing has resulted in patients demanding antidepressant brand names they have seen advertised in the media:

 

Sarah was a 33-year-old publicist and mother of two with what she described as “motherhood problems” “Some days I feel so irritable that it’s hard for me to get out of bed. I know there are things that I should be doing, but I just don’t have the energy” She had stopped making breakfast for her children, a job now performed by her husband and had fallen behind in what she perceived to be her household duties. She felt her productivity had suffered at work though no one had yet noticed. “I don’t think I’m depressed – in fact my mood has been okay. I just feel overwhelmed by my life”.  Rejecting suggestions of psychotherapy or couples counseling she said “You’ve got it all wrong! I don’t have time for therapy. I came to ask for Paxil”.

 

Fig 12: Effexor: Does it take a drug to 'get mommy back?'

 

He points out that some doctors, pharmaceutical industry and patients rights advocates argue such advertising has a positive effect because it better informs prospective patients of remedies and builds bridges between doctors and patients. However critics argue that the pharmaceutical industry is inventing diseases and hyping public concerns to increase sales of brand name medications, from propecia for baldness (despite its side effects of potentially permanent loss of libido) to botox for wrinkles. Ray Moynihan describes this in the BMJ as the corporate sponsored creation of disease – in which a cohort of researchers with close ties to drug companies, work with colleagues in the pharmaceutical industry to develop and define new categories of illness.

 

However Metzel points out the most outstanding features of this process not highlighted by Moynihan is that pharmaceutical ads overwhelmingly focus on women. Sarafem another  brand name for fluoxetine (Prozac) has for instance been marketed to “treat” “Premenstrual Dysphoric Disorder” – psychologizing and the treating with drugs seemingly normal women’s life events such as menstruation, menopause, sexuality and motherhood. Both these and the earlier ads targeting doctors cast womens’ mental health in the light of expectations for their role in society, positing psychotropic medications as agents for restoring “normal” womanhood. Metzel documents how changing trends in the depiction of women from domineering “momism” through to the perceived hostility of womens lib became reflected in ads for antipsychotics like mellaril depicting domineering women whose hostility threatened to upend their husband’s  mastery of the family situation and those for valium depicting the socially frustrated women we have seen in the above passages whose relationships have failed with men. A valium ad used the words of equal rights to genderize anxiety - “separate but not equal” to describe women’s anxieties and tensions. Some studies found that valium was 70% overprescribed to women by comparison with men.

 

Instead of being images dreamt up by marketing executives, Metzel says drugs adverts show how an entire system regarded its female patients, because they “illustrate the ways in which these new scientific treatments could not function free of the culture in which they were given meaning”. They are, he argues, representative of the same “gendered assumptions” at play in medicine and society.

 

With the changing political climate of feminism becoming mainstream and more women entering the medical profession, the thrust of advertising has moved out of medical journals into the mainstream of Newsweek and Time, appealing strategically to the female patient as well as her doctor. Metzel comments that this extends the role of medication helping women suffering anxiety and depression into a territory where it is claiming that women’s ambitions and social concerns can be treated or normalized with psychotropic medications becoming a form of social engineering for profit by pharmaceutical companies.

 

Fig 13: Seroquel (quetiapine) advertisement

 

In a 2010 Money Watch article “AstraZeneca's New Seroquel Ad Has 5 Pages of Legal Disclaimers”, Jim Edwards of CNN notes that the ad campaign run in major news magazines had no less than five pages of legal disclaimers concerning possible side effects including high blood sugar and diabetes, weight gain, "potentially fatal" neuroleptic malignant syndrome (fever, rigid muscles, confusion), "tardive dyskinesia (TD) - uncontrollable movement of the face, tongue, or other parts of the body", Cataracts, Suicidal thoughts, "Priapism" (an erection that won't go away), in the wake of their successful winning of six legal victories over collective action suits by 10,000 plaintiffs who claim Seroquel, the $1.2 billion-per-quarter selling drug, causes weight gain and diabetes.

 

Fig 14: In 2000 an AstraZeneca executive had warned in an internal email that the company's data did not show its antipsychotic drug Seroquel was superior to an older drug, Haldol, but the company promoted that notion anyway, according to documents in a lawsuit filed against the company. In 2009 the National Alliance on Mental Illness still maintained a web page about Seroquel suggesting that the AZ drug has fewer side effects than Haldol. BNET subsequently revealed that a NAMI board member was a paid consultant for AZ.

 

In 2009 AstraZeneca (AZN) agreed to pay $520 million in a settlement with the U.S. District Attorney in Pennsylvania to end a probe of its marketing practices on the atypical antipsychotic, which allegedly resulted in off-label use of the drug in children and the elderly. According to AZ's own disclosures, the cost of its alleged malfeasance on Seroquel will top $1.1 billion. According to Attorney General Eric Holder AstraZeneca was charged with fraudulently marketing Seroquel and promoting the drug to patients and physicians for uses that the Food and Drug Administration never approved. "These were not victimless crimes," said Holder. "Illegal acts by pharmaceutical companies and false claims against Medicare and Medicaid can put the public health at risk, corrupt medical decisions by health care providers, and take billions of dollars directly out of taxpayers' pockets." On top of the $520 million fine, AstraZeneca said it would enter into a five-year compliance agreement with the Department of Justice.

 

The Justice Department alleged that, between 2001 and 2006, AstraZeneca promoted Seroquel for certain uses not approved by the FDA as safe and effective, including for dementia in the elderly. The government alleged the company paid doctors to speak at events to other doctors about unapproved uses of Seroquel, among other allegations. The pharmaceutical giant has also been accused of violating anti-kickback laws, by paying doctors to refer the drug to patients, while at the same time bringing in money from government health care programs. The DOJ says AstraZeneca targeted "doctors who do not typically treat schizophrenia or bipolar disorder, such as physicians who treat the elderly, primary care physicians, pediatric and adolescent physicians" and used ploys to get doctors to write off-label prescriptions for its psychotropic drug, including paying them fees for articles and studies ghostwritten by company reps on research the doctors hadn't seen.

 

Conflicts of interest abound in the marketing of seroquel. In 2009, the Chicago Tribune and ProPublica reported that Chicago psychiatrist Michael Reinstein, who wrote 41,000 prescriptions for Seroquel, received $500,000 from AstraZenenca. Until a Philadelphia Inquirer expose in the same year, Florida child psychiatrist Jorge Armenteros, a paid AstraZeneca speaker, was chairman of the FDA Psychopharmacologic Drugs Advisory Committee responsible for recommending Seroquel approvals.

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A further demonstration of the widespread miss-prescription of antipsychotics comes from a 2015 BMJ article (doi: 10.1136/bmj.h4326) widely reported in Science and New Scientist, that shows the drugs are routinely used to pacify people with mental disabilities who have no symptoms of psychosis, rendering them even more disadvantaged than they need to be..

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