Tag: Sleep Disorder

What is Zolpidem?

Published on by Andrew Marshall13 Comments

Introduction

Zolpidem, sold under the brand name Ambien, among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioural therapy (CBT) for insomnia and behavioural changes, such as sleep hygiene, have been tried. It decreases the time to sleep onset by about fifteen minutes and at larger doses helps people stay asleep longer. It is taken by mouth and is available in conventional tablets, sublingual tablets, or oral spray.

Common side effects include daytime sleepiness, headache, nausea, and diarrhoea. Other side effects include memory problems, hallucinations, and substance abuse. The previously recommended dose was decreased in 2013, by the US Food and Drug Administration (FDA), to the immediate-release 10 mg for men, and 5 mg for women, in an attempt to reduce next-day somnolence. Newer extended-release formulations include the 6.25 mg for women, and 12.5 mg or 6.25 mg for men, which also cause next-day somnolence when used in higher doses. Additionally, driving the next morning is not recommended with either higher doses or the long-acting formulation. While flumazenil, a GABAA-receptor antagonist, can reverse zolpidem’s effects, usually supportive care is all that is recommended in overdose.

Zolpidem is a nonbenzodiazepine Z drug which acts as a sedative and hypnotic. Zolpidem is a GABAA receptor agonist of the imidazopyridine class. It works by increasing GABA effects in the central nervous system by binding to GABAA receptors at the same location as benzodiazepines. It generally has a half-life of two to three hours. This, however, is increased in those with liver problems.

Zolpidem was approved for medical use in the United States in 1992. It became available as a generic medication in 2007. Zolpidem is a Schedule IV controlled substance under the Controlled Substances Act of 1970 (CSA). More than ten million prescriptions are filled a year in the United States, making it one of the most commonly used treatments for sleeping problems. In 2018, it was the 60th most commonly prescribed medication in the United States, with more than 12 million prescriptions.

Brief History

Zolpidem was used in Europe starting in 1988, and was brought to market there by Synthelabo. Synthalabo and Searle collaborated to bring it to market in the US, and it was approved in the United States in 1992 under the brand name “Ambien”. It became available as a generic medication in 2007.

In 2015, the American Geriatrics Society said that zolpidem, eszopiclone, and zaleplon met the Beers criteria and should be avoided in individuals 65 and over “because of their association with harms balanced with their minimal efficacy in treating insomnia.” The AGS stated the strength of the recommendation that older adults avoid zolpidem is “strong” and the quality of evidence supporting it is “moderate.”

Medical Uses

Zolpidem is labelled for short-term (usually about two to six weeks) treatment of insomnia at the lowest possible dose. It may be used for both improving sleep onset, sleep onset latency, and staying asleep.

Guidelines from the UK’s National Institute for Health and Care Excellence (NICE), the European Sleep Research Society, and the American College of Physicians recommend medication for insomnia (including possibly zolpidem) only as a second line treatment after non-pharmacological treatment options have been tried (e.g. CBT for insomnia). This is based in part on a 2012 review which found that zolpidem’s effectiveness is nearly as much due to psychological effects as to the medication itself.

A lower-dose version (3.5 mg for men and 1.75 mg for women) is given as a tablet under the tongue and used for middle-of-the-night awakenings. It can be taken if there are at least 4 hours between the time of administration and when the person must be awake.

Contraindications

Zolpidem should not be taken by people with obstructive sleep apnoea, myasthenia gravis, severe liver disease, respiratory depression; or by children, or people with psychotic illnesses. It should not be taken by people who are or have been addicted to other substances.

Use of zolpidem may impair driving skills with a resultant increased risk of road traffic accidents. This adverse effect is not unique to zolpidem, but also occurs with other hypnotic drugs. Caution should be exercised by motor vehicle drivers. In 2013, the FDA recommended the dose for women be reduced and that prescribers should consider lower doses for men due to impaired function the day after taking the drug.

Zolpidem should not be prescribed to older people, who are more sensitive to the effects of hypnotics including zolpidem and are at an increased risk of falls and adverse cognitive effects, such as delirium and neurocognitive disorder.

Zolpidem has not been assigned to a pregnancy category by the FDA. Animal studies have revealed evidence of incomplete ossification and increased intrauterine foetal death at doses greater than seven times the maximum recommended human dose or higher; however, teratogenicity was not observed at any dose level. There are no controlled data in human pregnancy. In one case report, zolpidem was found in cord blood at delivery. Zolpidem is recommended for use during pregnancy only when benefits outweigh risks.

Adverse Effects

The most common adverse effects of:

  • Short-term use include headache (reported by 7% of people in clinical trials), drowsiness (2%), dizziness (1%), and diarrhoea (1%); and
  • Long-term use included drowsiness (8%), dizziness (5%), allergy (4%), sinusitis (4%), back pain (3%), diarrhoea (3%), drugged feeling (3%), dry mouth (3%), lethargy (3%), sore throat (3%), abdominal pain (2%), constipation (2%), heart palpitations (2%), lightheadedness (2%), rash (2%), abnormal dreams (1%), amnesia (1%), chest pain (1%), depression (1%), flu-like symptoms (1%), and sleep disorder (1%).

Zolpidem increases risk of depression, falls and bone fracture, poor driving, suppressed respiration, and has been associated with an increased risk of death. Upper and lower respiratory infections are also common (experienced by between 1 and 10% of people).

Residual ‘hangover’ effects, such as sleepiness and impaired psychomotor and cognitive function, may persist into the day following night-time administration. Such effects may impair the ability of users to drive safely and increase risks of falls and hip fractures. Around 3% of people taking zolpidem are likely to break a bone as a result of a fall due to impaired coordination caused by the drug.

Some users have reported unexplained sleepwalking while using zolpidem, as well as sleep driving, night eating syndrome while asleep, and performing other daily tasks while sleeping. Research by Australia’s National Prescribing Service found these events occur mostly after the first dose taken, or within a few days of starting therapy. In February 2008, the Australian Therapeutic Goods Administration attached a boxed warning concerning this adverse effect.

Tolerance, Dependence, and Withdrawal

As zolpidem is associated with drug tolerance and substance dependence, its prescription guidelines are only for severe insomnia and short periods of use at the lowest effective dose. Tolerance to the effects of zolpidem can develop in some people in just a few weeks. Abrupt withdrawal may cause delirium, seizures, or other adverse effects, especially if used for prolonged periods and at high doses. When drug tolerance and physical dependence to zolpidem develop, treatment usually entails a gradual dose reduction over a period of months to minimise withdrawal symptoms, which can resemble those seen during benzodiazepine withdrawal. Failing that, an alternative method may be necessary for some people, such as a switch to a benzodiazepine equivalent dose of a longer-acting benzodiazepine drug, as for diazepam or chlordiazepoxide, followed by a gradual reduction in dose of the long-acting benzodiazepine. In people who are difficult to treat, an inpatient flumazenil administration allows for rapid competitive binding of flumazenil to GABAA-receptor as an antagonist, thus stopping (a effectively detoxifying) zolpidem from being able to bind as an agonist on GABAA-receptor; slowly drug dependence or addiction to zolpidem will wane.

Alcohol has cross tolerance with GABAA receptor positive allosteric modulators, such as the benzodiazepines and the nonbenzodiazepine drugs. For this reason, alcoholics or recovering alcoholics may be at increased risk of physical dependency or abuse of zolpidem. It is not typically prescribed in people with a history of alcoholism, recreational drug use, physical dependency, or psychological dependency on sedative-hypnotic drugs. A 2014 review found evidence of drug-seeking behaviour, with prescriptions for zolpidem making up 20% of falsified or forged prescriptions.

Rodent studies of the tolerance-inducing properties have shown that zolpidem has less tolerance-producing potential than benzodiazepines, but in primates, the tolerance-producing potential of zolpidem was the same as seen with benzodiazepines.

Overdose

Overdose can lead to coma or death. When overdose occurs, there are often other drugs in the person’s system.

Zolpidem overdose can be treated with the GABAA receptor antagonist flumazenil, which displaces zolpidem from its binding site on the GABAA receptor to rapidly reverse the effects of the zolpidem. It is unknown if dialysis is helpful.

Detection in Body Fluids

Zolpidem may be quantitated in blood or plasma to confirm a diagnosis of poisoning in people who are hospitalized, to provide evidence in an impaired driving arrest, or to assist in a medicolegal death investigation. Blood or plasma zolpidem concentrations are usually in a range of 30-300 μg/l in persons receiving the drug therapeutically, 100-700 μg/l in those arrested for impaired driving, and 1000-7000 μg/l in victims of acute overdosage. Analytical techniques, in general, involve gas or liquid chromatography.

Pharmacology

Mechanism of Action

Zolpidem is a ligand of high-affinity positive modulator sites of GABAA receptors, which enhances GABAergic inhibition of neurotransmission in the central nervous system. It selectively binds to α1 subunits of this pentameric ion channel. Accordingly, it has strong hypnotic properties and weak anxiolytic, myorelaxant, and anticonvulsant properties. Opposed to diazepam, zolpidem is able to bind to binary αβ GABA receptors, where it was shown to bind to the α1–α1 subunit interface. Zolpidem has about 10-fold lower affinity for the α2- and α3- subunits than for α1, and no appreciable affinity for α5 subunit-containing receptors. ω1 type GABAA receptors are the α1-containing GABAA receptors and are found primarily in the brain, the ω2 receptors are those that contain the α2-, α3-, α4-, α5-, or α6 subunits, and are found primarily in the spine. Thus, zolpidem favours binding to GABAA receptors located in the brain rather the spine. Zolpidem has no affinity for γ1 and γ3 subunit-containing receptors and, like the vast majority of benzodiazepine-like drugs, it lacks affinity for receptors containing α4 and α6. Zolpidem modulates the receptor presumably by inducing a receptor conformation that enables an increased binding strength of the orthosteric agonist GABA towards its cognate receptor without affecting desensitization or peak currents.

Like zaleplon, zolpidem may increase slow wave sleep but cause no effect on stage 2 sleep. A meta-analysis that compared benzodiazepines against nonbenzodiazepines has shown few consistent differences between zolpidem and benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.

Interactions

People should not consume alcohol while taking zolpidem, and should not be prescribed opioid drugs nor take such illicit drugs recreationally. Opioids can also increase the risk of becoming psychologically dependent on zolpidem. Use of opioids with zolpidem increases the risk of respiratory depression and death. the FDA is advising that the opioid addiction medications buprenorphine and methadone should not be withheld from patients taking benzodiazepines or other drugs that depress the central nervous system (CNS).

Next day sedation can be worsened if people take zolpidem while they are also taking antipsychotics, other sedatives, anxiolytics, antidepressant agents, antiepileptic drugs, and antihistamines. Some people taking antidepressants have had visual hallucinations when they also took zolpidem.

Cytochrome P450 inhibitors, particularly CYP3A4 and CYP1A2 inhibitors, fluvoxamine and ciprofloxacin will increase the effects of a given dose of zolpidem.

Cytochrome P450 activators like St. John’s Wort may decrease the activity of zolpidem.

Chemistry

Three syntheses of zolpidem are common. 4-methylacetophenone is used as a common precursor. This is brominated and reacted with 2-amino-5-methylpyridine to give the imidazopyridine. From here the reactions use a variety of reagents to complete the synthesis, either involving thionyl chloride or sodium cyanide. These reagents are challenging to handle and require thorough safety assessments. Though such safety procedures are common in industry, they make clandestine manufacture difficult.

A number of major side-products of the sodium cyanide reaction have been characterised and include dimers and mannich products.

Society and Culture

Prescriptions in the US for all sleeping pills (including zolpidem) steadily declined from around 57 million tablets in 2013, to around 47 million in 2017, possibly in relation to concern about prescribing addictive drugs in the midst of the opioid crisis.

Military Use

The United States Air Force uses zolpidem as one of the hypnotics approved as a “no-go pill” (with a six-hour restriction on subsequent flight operation) to help aviators and special duty personnel sleep in support of mission readiness. (The other hypnotics used are temazepam and zaleplon.) “Ground tests” are required prior to authorization issued to use the medication in an operational situation.

Recreational Use

Zolpidem has potential for either medical misuse when the drug is continued long term without or against medical advice, or for recreational use when the drug is taken to achieve a “high”. The transition from medical use of zolpidem to high-dose addiction or drug dependence can occur with use, but some believe it may be more likely when used without a doctor’s recommendation to continue using it, when physiological drug tolerance leads to higher doses than the usual 5 mg or 10 mg, when consumed through inhalation or injection, or when taken for purposes other than as a sleep aid. Recreational use is more prevalent in those having been dependent on other drugs in the past, but tolerance and drug dependence can still sometimes occur in those without a history of drug dependence. Chronic users of high doses are more likely to develop physical dependence on the drug, which may cause severe withdrawal symptoms, including seizures, if abrupt withdrawal from zolpidem occurs.

Other drugs, including the benzodiazepines and zopiclone, are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range, suggesting a high degree of excessive-use potential for benzodiazepines, zolpidem and zopiclone. US Congressman Patrick J. Kennedy says that he was using zolpidem (Ambien) and promethazine (Phenergan) when caught driving erratically at 3 a.m. “I simply do not remember getting out of bed, being pulled over by the police, or being cited for three driving infractions,” Kennedy said.

Nonmedical use of zolpidem is increasingly common in the US, Canada, and the UK. Some users have reported decreased anxiety, mild euphoria, perceptual changes, visual distortions, and hallucinations. Zolpidem was used by Australian Olympic swimmers at the London Olympics in 2012, leading to controversy.

Regulation

For the stated reason of its potential for recreational use and dependence, zolpidem (along with the other benzodiazepine-like Z-drugs) is a Schedule IV substance under the Controlled Substances Act in the US. The United States patent for zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis.

Use in Crime

The Z-drugs including zolpidem have been used as date rape drugs. Zolpidem is available legally by prescription, and broadly prescribed unlike other date rape drugs: gamma-hydroxybutyrate (GHB), which is used to treat a rare form of narcolepsy, or flunitrazepam (Rohypnol), which is only prescribed as a second-line choice for insomnia. Zolpidem can typically be detected in bodily fluids for 36 hours, though it may be possible to detect it by hair testing much later, which is due to the short elimination half-life of 2.5-3 hours. This use of the drug was highlighted during proceedings against Darren Sharper, who was accused of using the tablets he was prescribed to facilitate a series of rapes.

Sleepwalking

Zolpidem received widespread media coverage in Australia after the death of a student who fell 20 metres (66 ft) from the Sydney Harbour Bridge while under the influence of zolpidem.

Brands

As of September 2018, zolpidem was marketed under many brands: Adorma, Albapax, Ambien, Atrimon, Belbien, Bikalm, Cymerion, Dactive, Dalparan, Damixan, Dormeben, Dormilam, Dormilan, Dormizol, Eanox, Edluar, Flazinil, Fulsadem, Hypnogen, Hypnonorm, Intermezzo, Inzofresh, Ivadal, Ivedal, Le Tan, Lioram, Lunata, Medploz, Mondeal, Myslee, Nasen, Niterest, Nocte, Nottem, Noxidem, Noxizol, Nuo Bin, Nytamel, Nyxe, Olpitric, Onirex, Opsycon, Patz, Polsen, Sanval, Semi-Nax, Sleepman, Somex, Somidem, Somit, Somnil, Somnipax, Somnipron, Somno, Somnogen, Somnor, Sonirem, Sove, Soza, Stilnoct, Stilnox, Stilpidem, Stimin, Sublinox, Sucedal, Sumenan, Vicknox, Viradex, Xentic, Zasan, Zaviana, Ziohex, Zipsoon, Zodem, Zodenox, Zodium, Zodorm, Zolcent, Zoldem, Zoldorm, Zoldox, Zolep, Zolfresh, Zolip, Zolman, Zolmia, Zolnox, Zolnoxs, Zolodorm, Zolnyt, Zolpeduar, Zolpel, Zolpi, Zolpi-Q, Zolpic, Zolpidem, Zolpidem tartrate, Zolpidemi tartras, Zolpidemtartraat, Zolpidemtartrat, Zolpidemum, Zolpigen, Zolpihexal, Zolpimist, Zolpineo, Zolpinox, Zolpirest, Zolpistar, Zolpitop, Zolpitrac, Zolpium, Zolprem, Zolsana, Zolta, Zoltar, Zolway, Zomnia, Zonadin, Zonoct, Zopid, Zopidem, Zopim, and Zorimin.

Research

While cases of zolpidem improving aphasia in people with stroke have been described, use for this purpose has unclear benefit. Zolpidem has also been studied in persistent vegetative states with unclear effect. A 2017 systematic review concluded that while there is preliminary evidence of benefit for treating disorders of movement and consciousness other than insomnia (including Parkinson’s disease), more research is needed. More recent research has found zolpidem treatment to be effective in the short term, but only in a small proportion of cases (estimated at around 5%) and only when the brain injury is of a specific type. Tolerance to the beneficial effects also develops rapidly, and so for these reasons while zolpidem may sometimes be used as a “last resort” treatment, it has numerous disadvantages and research continues into novel treatments that might provide the same kind of benefits in a larger proportion of patients, and with a more sustained benefit.

Animal studies in FDA files for zolpidem showed a dose dependent increase in some types of tumours, although the studies were too small to reach statistical significance. Some observational epidemiological studies have found a correlation between use of benzodiazepines and certain hypnotics including zolpidem and an increased risk of getting cancer, but others have found no correlation; a 2017 meta-analysis of such studies found a correlation, stating that use of hypnotics was associated with a 29% increased risk of cancer, and that “zolpidem use showed the strongest risk of cancer” with an estimated 34% increased risk, but noted that the results were tentative because some of the studies failed to control for confounders like cigarette smoking and alcohol use, and some of the studies analysed were case-controls, which are more prone to some forms of bias. Similarly, a meta-analysis of benzodiazepine drugs also shows their use is associated with increased risk of cancer.

What is a Nonbenzodiazepine?

Published on by Andrew Marshall17 Comments

Introduction

Nonbenzodiazepines, sometimes referred to colloquially as Z-drugs (as many of them begin with the letter “z”), are a class of psychoactive drugs that are very benzodiazepine-like in nature.

They are used in the treatment of sleep problems.

Nonbenzodiazepine pharmacodynamics are almost entirely the same as benzodiazepine drugs and therefore exhibit similar benefits, side-effects, and risks. However, nonbenzodiazepines have dissimilar or entirely different chemical structures and are therefore unrelated to benzodiazepines on a molecular level.

Brief History

Z-drugs emerged in the last years of the 1980s and early 1990s, with zopiclone (Imovane) approved by the British National Health Service (NHS) as early as 1989, quickly followed by Sanofi with zolpidem (Ambien). By 1999, King Pharmaceuticals had finalised approval with the US Food and Drug Administration (FDA) to market zaleplon (Sonata, Starnoc) across the US. In 2005, the FDA approved eszopiclone (Lunesta) the (S)-enantiomer of zopiclone. That same year, 2005, the FDA finalised approval for Ambien CR, or extended-release zolpidem. Most recently, in 2012 the FDA approved Intermezzo (zolpidem tartate sublingual), which is marketed for middle-of-the-night insomnia, available in doses only half of the strength of immediate-release zolpidem tartrate to avoid residual next-day sedation.

Classes

Currently, the major chemical classes of nonbenzodiazepines are:

  • Imidazopyridines:
    • Alpidem.
    • Necopidem.
    • Saripidem.
    • Zolpidem (Ambien, Ambien CR, Intermezzo, Zolpimist, Edluar, Ivadal, Sanval, Stilnox, etc.).
  • Pyrazolopyrimidines:
    • Divaplon.
    • Fasiplon.
    • Indiplon.
    • Lorediplon.
    • Ocinaplon.
    • Panadiplon.
    • Taniplon.
    • Zaleplon (Sonata, Starnoc, Andante).
  • Cyclopyrrolones:
    • Eszopiclone (Lunesta, Valnoc, etc.).
    • Pagoclone.
    • Pazinaclone.
    • Suproclone.
    • Suriclone.
    • Zopiclone (Imovane, Zimovane, Somnol, etc.).
  • β-Carbolines:
    • Abecarnil.
    • Gedocarnil.
    • SL-651,498.
    • ZK-93423.
  • Others:
    • CGS-20625.
    • CGS-9896.
    • CL-218,872.
    • ELB-139.
    • GBLD-345.
    • HIE-124.
    • L-838,417.
    • NS-2664.
    • NS-2710.
    • Pipequaline.
    • RWJ-51204.
    • SB-205,384.
    • SL-651,498.
    • SX-3228.
    • TP-003.
    • TP-13.
    • TPA-023.
    • Y-23684.

Pharmacology

The nonbenzodiazepines are positive allosteric modulators of the GABA-A receptor. Like the benzodiazepines, they exert their effects by binding to and activating the benzodiazepine site of the receptor complex. Many of these compounds are subtype selective providing novel anxiolytics with little to no hypnotic and amnesiac effects and novel hypnotics with little or no anxiolytic effects.

Background

Nonbenzodiazepines have demonstrated efficacy in treating sleep disorders. There is some limited evidence that suggests that tolerance to nonbenzodiazepines is slower to develop than with benzodiazepines. However, data is limited so no conclusions can be drawn. Data is also limited into the long-term effects of nonbenzodiazepines. Further research into the safety of nonbenzodiazepines and long-term effectiveness of nonbenzodiazepines has been recommended in a review of the literature. Some differences exist between the Z-drugs, for example tolerance and rebound effects may not occur with zaleplon.

Pharmaceuticals

The first three nonbenzodiazepine drugs to enter the market were the “Z-drugs”, zopiclone, zolpidem and zaleplon. These three drugs are all sedatives used exclusively for the treatment of mild insomnia. They are safer than the older barbiturates especially in overdosage and they may, when compared to the benzodiazepines, have less of a tendency to induce physical dependence and addiction, although these issues can still become a problem. This has led to the Z-drugs becoming widely prescribed for the treatment of insomnia particularly in elderly patients. A little under a third (31%) of all Americans over 65 years of age are taking Z-drugs.

Long-term use is not recommended as tolerance and addiction can occur. A survey of patients using nonbenzodiazepine Z drugs and benzodiazepine hypnotic users found that there was no difference in reports of adverse effects that were reported in over 41% of users and, in fact, Z drug users were more likely to report that they had tried to quit their hypnotic drug and were more likely to want to stop taking Z drugs than benzodiazepine users. Efficacy also did not differ between benzodiazepine and Z drug users.

Side Effects

The Z-drugs are not without disadvantages, and all three compounds are notable for producing side-effects such as pronounced amnesia and more rarely hallucinations, especially when used in large doses. On rare occasions, these drugs can produce a fugue state, wherein the patient sleepwalks and may perform relatively complex actions, including cooking meals or driving cars, while effectively unconscious and with no recollection of the events upon awakening. While this effect is rare (and has also been reported to occur with some of the older sedative drugs such as temazepam and secobarbital), it can be potentially hazardous, and so further development of this class of drugs has continued in an effort to find new compounds with further improved profiles.

Daytime withdrawal-related anxiety can also occur from chronic nightly nonbenzodiazepine hypnotic usage such as with zopiclone.

Side-effects can differ within the drug class due to differences in metabolism and pharmacology. For example, long-acting benzodiazepines have problems of drug accumulation especially in the elderly or those with liver disease, and shorter-acting benzodiazepines have a higher risk of more severe withdrawal symptoms. In the case of the nonbenzodiazepines, zaleplon may be the safest in terms of next-day sedation, and – unlike zolpidem and zopiclone – zaleplon has been found to have no association with increased motor vehicle accidents even when taken for middle-of-the-night insomnia due to its ultrashort elimination half-life.

Increased Risk of Depression

It has been claimed that insomnia causes depression and hypothesized that insomnia medications may help to treat depression. In support of this claim an analysis of data of clinical trials submitted to the US Food and Drug Administration (FDA) concerning the drugs zolpidem, zaleplon, and eszopiclone found that these sedative hypnotic drugs more than doubled the risks of developing depression compared to those taking placebo pills. Hypnotic drugs, therefore, may be contraindicated in patients suffering from or at risk of depression. Hypnotics were found to be more likely to cause depression than to help it. Studies have found that long-term users of sedative hypnotic drugs have a markedly raised suicide risk as well as an overall increased mortality risk. Cognitive-behavioural therapy (CBT) for insomnia, on the other hand, has been found to both improve sleep quality as well as general mental health.

Other Risks

Sleeping pills, including the Z-drugs, have been associated with an increased risk of death.

In older people this family of medications increases the risk of fractures and falls.

The Z-drug zaleplon may have fewer side effects compared to benzodiazepines.

Dependence and Withdrawal Management

Nonbenzodiazepines should not be discontinued abruptly if taken for more than a few weeks due to the risk of rebound withdrawal effects and acute withdrawal reactions, which may resemble those seen during benzodiazepine withdrawal. Treatment usually entails gradually reducing the dosage over a period of weeks or several months depending on the individual, dosage, and length of time the drug has been taken. If this approach fails, a crossover to a benzodiazepine equivalent dose of a long-acting benzodiazepine (such as chlordiazepoxide or more preferably diazepam) can be tried followed by a gradual reduction in dosage. In extreme cases and, in particular, where severe addiction and/or abuse is manifested, an inpatient detoxification may be required, with flumazenil as a possible detoxification tool.

Carcinogenicity

The Journal of Clinical Sleep Medicine published a paper that had carried out a systematic review of the medical literature concerning insomnia medications and raised concerns about benzodiazepine receptor agonist drugs, the benzodiazepines, and the Z-drugs that are used as hypnotics in humans. The review found that almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry. It was found that the odds ratio for finding results favourable to industry in industry-sponsored trials was 3.6 times higher than non-industry-sponsored studies and that 24% of authors did not disclose being funded by the drug companies in their published papers when they were funded by the drug companies. The paper found that there is little research into hypnotics that is independent from the drug manufacturers. Also of concern was the lack of focus in industry-sponsored trials on their own results showing that use of hypnotics is correlated with depression.

The author was concerned that there is no discussion of adverse effects of benzodiazepine agonist hypnotics discussed in the medical literature such as significant increased levels of infection, cancers, and increased mortality in trials of hypnotic drugs and an overemphasis on the positive effects. No hypnotic manufacturer has yet tried to refute the epidemiology data that shows that use of their product is correlated with excess mortality. The author stated that “major hypnotic trials is needed to more carefully study potential adverse effects of hypnotics such as daytime impairment, infection, cancer, and death and the resultant balance of benefits and risks.” The author concluded that more independent research into daytime impairment, infection, cancer, and shortening of lives of sedative hypnotic users is needed to find the true balance of benefits and risks of benzodiazepine agonist hypnotic drugs in the treatment of insomnia. Significant increases in skin cancers and tumours are found in clinical trial data of the nonbenzodiazepine hypnotics compared to trial subjects having taken placebo tablets. Other cancers of the brain, lung, bowel, breast, and bladder also occurred. An increase of infections, possibly due to decreased immune function, also occurred in the nonbenzodiazepine users. It has been hypothesised that either depressed immune function or the viral infections themselves were the cause of the increased rates of cancer.

Initially, the FDA was hesitant to approve some of the nonbenzodiazepines due to concerns regarding increases in cancers. The author reported that, due to the fact that the FDA requires reporting of both favourable and unfavourable results of clinical trials, the FDA New Drug Application data is more reliable than the peer-reviewed literature, which is subject to serious bias regarding hypnotics. In 2008, the FDA analysed their data again and confirmed an increased rate of cancers in the randomised trials compared to placebos but concluded that the rate of cancers did not warrant any regulatory action. Later studies on several common hypnotics found that receiving hypnotic prescriptions was associated with greater than threefold increased hazards of death even when prescribed <18 pills/year and that hypnotics cause mortality through the growing US overdose epidemic.

Elderly

Nonbenzodiazepine hypnotic drugs, similar to benzodiazepines, cause impairments in body balance and standing steadiness upon waking; falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial but incomplete tolerance develops to these impairments. In general, nonbenzodiazepines are not recommended for older patients due to the increased risk of falls and fractures. An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and lasting benefits of non-drug treatments for insomnia in adults of all age groups and that these interventions are underused. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics offer little if any advantages in efficacy or tolerability in elderly persons. It was found that newer agents such as the melatonin agonists may be more suitable and effective for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and is discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (e.g. anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that further research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.

Controversy

A review of the literature regarding hypnotics including the nonbenzodiazepine Z drugs concluded that these drugs cause an unjustifiable risk to the individual and to public health and lack evidence of long-term effectiveness due to tolerance. The risks include dependence, accidents, and other adverse effects. Gradual discontinuation of hypnotics leads to improved health without worsening of sleep. It is preferred that they should be prescribed for only a few days at the lowest effective dose and avoided altogether wherever possible in the elderly.

New Compounds

More recently, a range of non-sedating anxiolytic drugs derived from the same structural families as the Z-drugs have been developed, such as alpidem (Ananyxl) and pagoclone, and approved for clinical prescription. Nonbenzodiazepine drugs are much more selective than the older benzodiazepine anxiolytics, producing effective relief of anxiety/panic with little or no sedation, anterograde amnesia, or anticonvulsant effects, and are thus potentially more precise than older, anti-anxiety drugs. However, anxiolytic nonbenzodiazepines are not widely prescribed and many have collapsed after initial clinical trials and consumption halted many projects, including but not limited to alpidem, indiplon, and suriclone.

What is the REM Sleep Behaviour Disorder Screening Questionnaire?

Published on by Andrew Marshall1 Comment

Introduction

The REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ) is a specific questionnaire for rapid eye movement behaviour disorder (RBD) developed by Stiasny-Kolster and team, to assess the most prominent clinical features of RBD.

It is a 10-item, patient self-rating instrument with short questions to be answered by either ‘yes’ or ‘no’.

The validity of the questionnaire was studied by researchers and they have observed it to perform with high sensitivity and reasonable specificity in the diagnosis of RBD.

Refer to Parasomnia.

Use

RBDSQ has the potential to be useful as a screening instrument for neurodegenerative disorder, such as the α-synucleinopathies, Parkinson’s disease or multiple system atrophy which may enable early diagnosis and also recruitment of people with RBD necessary for research studies.

Format

RBDSQ contains a set of 10 items that are to be answered by either ‘yes’ or ‘no’.

  • Items 1 to 4 address the frequency and content of dreams and their relationship to nocturnal movements and behaviour.
  • Item 5 asks about self-injuries and injuries of the bed partner.
  • Item 6 consists of four subitems assessing nocturnal motor behaviour more specifically, e.g. questions about nocturnal vocalisation, sudden limb movements, complex movements, or bedding items that fell down.
  • Items 7 and 8 deal with nocturnal awakenings.
  • Item 9 focuses on disturbed sleep in general.
  • Item 10 focuses on the presence of any neurological disorder.

The maximum total score of the RBDSQ is 13 points.

What is Parasomnia?

Published on by Andrew Marshall3 Comments

Introduction

Parasomnias are a category of sleep disorders that involve abnormal movements, behaviours, emotions, perceptions, and dreams that occur while falling asleep, sleeping, between sleep stages, or during arousal from sleep.

Parasomnias are dissociated sleep states which are partial arousals during the transitions between wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep, and their combinations.

Refer to Night Eating Syndrome (NES) and Sleep-Related Eating Disorder (SRED).

Classification

The International Classification of Sleep Disorders (ICSD uses State Dissociation as the paradigm for parasomnias. Unlike before, where wakefulness, NREM sleep, and REM sleep were considered exclusive states, research has shown that combinations of these states are possible and thus, may result in unusual unstable states that could eventually manifest as parasomnias or as altered levels of awareness.

Although, the previous definition is technically correct, it contains flaws. The consideration of the State Dissociation paradigm facilitates the understanding of the sleep disorder and provides a classification of 10 core categories.

NREM-Related Parasomnias

NREM parasomnias are arousal disorders that occur during stage 3 (or 4 by the R&K standardisation) of NREM sleep – also known as slow wave sleep (SWS). They are caused by a physiological activation in which the patient’s brain exits from SWS and is caught in between a sleeping and waking state. In particular, these disorders involve activation of the autonomic nervous system, motor system, or cognitive processes during sleep or sleep-wake transitions.

Some NREM parasomnias (sleep-walking, night-terrors, and confusional arousal) are common during childhood but decrease in frequency with increasing age. They can be triggered in certain individuals, by alcohol, sleep deprivation, physical activity, emotional stress, depression, medications, or a fevered illness. These disorders of arousal can range from confusional arousals, somnambulism, to night terrors. Other specific disorders include sleepeating, sleep sex, teeth grinding, rhythmic movement disorder, restless legs syndrome, and somniloquy.

Differential Diagnosis for NREM-Related Parasomnias

  • Sleep-disordered breathing.
  • REM-related parasomnias.
  • Nocturnal seizures.
  • Psychogenic dissociative disorders

Confusional Arousals

Confusional arousal is a condition when an individual awakens from sleep and remains in a confused state. It is characterized by the individual’s partial awakening and sitting up to look around. They usually remain in bed and then return to sleep. These episodes last anywhere from seconds to minutes and may not be reactive to stimuli. Confusional arousal is more common in children than in adults. It has a lifetime prevalence of 18.5% in children and a lifetime prevalence of 2.9-4.2% in adults. Infants and toddlers usually experience confusional arousals beginning with large amounts of movement and moaning, which can later progress to occasional thrashings or inconsolable crying. In rare cases, confusional arousals can cause injuries and drowsy driving accidents, thus it can also be considered dangerous. Another sleeping disorder may be present triggering these incomplete arousals.

Sleep-Related Abnormal Sexual Behaviour

Sleep-related abnormal sexual behaviour, Sleep sex, or sexsomnia, is a form of confusional arousal that may overlap with somnambulism. Thereby, a person will engage in sexual acts while still asleep. It can include such acts as masturbation, inappropriate fondling themselves or others, having sex with another person; and in more extreme cases, sexual assault. These behaviours are unconscious, occur frequently without dreaming, and bring along clinical, social, and legal implications. It has a lifetime prevalence of 7.1% and an annual prevalence of 2.7%.

Sleepwalking (Somnambulism)

Sleepwalking has a prevalence of 1-17% in childhood, with the most frequent occurrences around the age of eleven to twelve. About 4% of adults experience somnambulism. Normal sleep cycles include states varying from drowsiness all the way to deep sleep. Every time an individual sleeps, he or she goes through various sequences of non-REM and REM sleep. Anxiety and fatigue are often connected with sleepwalking. For adults, alcohol, sedatives, medications, medical conditions and mental disorders are all associated with sleepwalking. Sleep walking may involve sitting up and looking awake when the individual is actually asleep, and getting up and walking around, moving items or undressing themselves. They will also be confused when waking up or opening their eyes during sleep. Sleep walking can be associated with sleeptalking.

Sleep Terrors (Night Terrors/Pavor Nocturnus)

Sleep terror is the most disruptive arousal disorder since it may involve loud screams and panic; in extreme cases, it may result in bodily harm or property damage by running about or hitting walls. All attempts to console the individual are futile and may prolong or intensify the victim’s confused state. Usually the victim experiences amnesia after the event but it may not be complete amnesia. Up to 3% of adults suffer from sleep terrors and exhibited behaviour of this parasomnia can range from mild to extremely violent. This is very prevalent in those who suffer violent post-traumatic stress disorder (PTSD). They typically occur in stage 3 sleep.

Sleep-Related Eating Disorder (SRED)

The Diagnostic and Statistical Manual of Mental Disorders (DSM) classifies sleep-related eating disorder (SRED) under sleepwalking, while ICSD classifies it as NREM-related parasomnia. It is conceptualised as a mixture of binge-eating behaviour and arousal disorder. Thereby, preferentially high-caloric food is consumed in an uncontrolled manner. However, SRED should not be confused with nocturnal eating syndrome, which is characterised by an excessive consumption of food before or during sleep in full consciousness. Since sleep-related eating disorders are associated with other sleep disorders, successful treatment of the latter can reduce symptoms of this parasomnia.

REM-Related Parasomnias

REM Sleep Behaviour Disorder

Unlike other parasomnias, rapid eye movement sleep behaviour disorder (RBD) in which muscle atonia is absent is most common in older adults. This allows the individual to act out their dreams and may result in repeated injury – bruises, lacerations, and fractures – to themselves or others. Patients may take self-protection measures by tethering themselves to bed, using pillow barricades, or sleeping in an empty room on a mattress. Besides ensuring the sleep environment is a safe place, pharmacologic therapy using melatonin and clonazepam is also common as a treatment for RBD, even though might not eliminate all abnormal behaviours. Before starting a treatment with clonazepam, a screening for obstructive sleep apnoea should performed. However, clonazepam needs to be manipulated carefully because of its significant side effects, i.e. morning confusion or memory impairment, mainly in patients with neurodegenerative disorders with dementia.

Demographically, 90% of RBD patients are males, and most are older than 50 years of age. However, this prevalence in males could be biased due to the fact that women tends to have a less violent type of RBD, which leads to lower reports at sleep centres and different clinical characteristics. While men might have more aggressive behaviour during dreaming, women have presented more disturbance in their sleep. RBD may be also influenced by a genetic compound, since primary relatives seem to have significantly more chance to develop RBD compared with non-relatives control group.

Typical clinical features of REM sleep behavior disorder are:

  • Male gender predilection.
  • Mean age of onset 50-65 years (range 20-80 years).
  • Vocalisation, screaming, swearing that may be associated with dreams.
  • Motor activity, simple or complex, that may result in injury to patient or bed-partner.
  • Occurrence usually in latter half of sleep period (REM sleep).
  • May be associated with neurodegenerative disease.

Acute RBD occurs mostly as a result of a side-effect in prescribed medication – usually antidepressants. Furthermore, substance abuse or withdrawal can result in RBD.

Chronic RBD is idiopathic, meaning of unknown origin, or associated with neurological disorders. There is a growing association of chronic RBD with neurodegenerative disorders – Parkinson’s disease, multiple system atrophy (MSA), or dementia – as an early indicator of these conditions by as much as 10 years. RBD associated with neurological disorders is frequently related to abnormal accumulation of alpha-synuclein, and more than 80% of patients with idiopathic RBD might develop Lewy body disease (LBD). Patients with narcolepsy are also more likely to develop RBD.

The diagnosis is based on clinical history, including partner’s account and needs to be confirmed by polysomnography (PSG), mainly for its accuracy in differentiating RBD from other sleep disorders, since there is a loss of REM atonia with excessive muscle tone. However, screening questionnaires, such as the REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ), are also very useful for diagnosing RBD.

Recurrent Isolated Sleep Paralysis

Recurrent isolated sleep paralysis is an inability to perform voluntary movements at sleep onset, or upon waking from sleep. Although the affected individual is conscious and recall is present, the person is not able to speak or move. However, respiration remains unimpaired. The episodes last seconds to minutes and diminish spontaneously. The lifetime prevalence is 7%. Sleep paralysis is associated with sleep-related hallucinations. Predisposing factors for the development of recurrent isolated sleep paralysis are sleep deprivation, an irregular sleep-wake cycle, e.g. caused by shift work, or stress. A possible cause could be the prolongation of REM sleep muscle atonia upon awakening.

Nightmare Disorder

Nightmares are like dreams primarily associated with REM sleep. Nightmare disorder is defined as recurrent nightmares associated with awakening dysphoria that impairs sleep or daytime functioning. It is rare in children, however persists until adulthood. About two thirds of the adult population report experiencing nightmares at least once in their life.

Catathrenia

Before the ICSD-3, Catathrenia was classified as a rapid-eye-movement sleep parasomnia, but is now classified as sleep-related breathing disorder. It consists of breath holding and expiratory groaning during sleep, is distinct from both somniloquy and obstructive sleep apnoea. The sound is produced during exhalation as opposed to snoring which occurs during inhalation. It is usually not noticed by the person producing the sound but can be extremely disturbing to sleep partners, although once aware of it, sufferers tend to be woken up by their own groaning as well. Bed partners generally report hearing the person take a deep breath, hold it, then slowly exhale; often with a high-pitched squeak or groaning sound.

Sleep-Related Painful Erections

Painful erections appear only during the sleep. This condition is present during the REM sleep. Sexual activity doesn’t produce any pain. There is not any lesion or physical damage but an hypertonia of the pelvic floor could be one cause. It affects men of all ages but especially from the middle-age. Some pharmacologic treatment as propranolol, clozapine, clonazepam, baclofen and various antidepressants, seems to be effective.

Other Parasomnias

Exploding head syndrome

Exploding head syndrome (EHS) is an abnormal sensory perception during sleep in which a person experiences unreal noises that are loud and of short duration when falling asleep or waking up. The noise may be frightening, typically occurs only occasionally, and is not a serious health concern. People may also experience a flash of light. Pain is typically absent.

Despite the name, the sufferer’s head does not actually explode!

Sleep-Related Hallucinations

Sleep-related hallucinations are brief episodes of dream-like imagery that can be of any sensory modality, i.e. auditory, visual, or tactile. They are differentiated between hypnagogic hallucination, that occur at sleep onset, and hypnopompic hallucinations, which occur at the transition of sleep to awakening. Although normal individuals have reported nocturnal hallucinations, they are more frequent in comorbidity with other sleep disorders, e.g. narcolepsy.

Sleep Enuresis

Nocturnal enuresis, also called bedwetting, is involuntary urination while asleep after the age at which bladder control usually begins. Bedwetting in children and adults can result in emotional stress. Complications can include urinary tract infections.

Parasomnias Due to Medical Disorder

Parasomnias Due to Medication or Substance

Parasomnia (Unspecific)

Sleep drunkenness, also known as confusional arousal, is the feeling of confusion or sudden action upon waking up from deep sleep. Severe sleep inertia, one cause of oversleeping, is considered to develop sleep drunkenness.

Isolated Symptom/Normal Variant

Sleep Talking (Somniloquy)

According to ICSD-3 it is not defined a disorder in particular. It is rather an isolated symptom or normal variant and ranges from isolated speech to full conversations without recall. With a lifetime prevalence of 69% it is considered fairly common. Sleep talking is associated with REM-related parasomnias as well as with disorders or arousal. It occurs in all sleep states. As yet, there is no specific treatment for sleeptalking available.

Diagnosis

Parasomnias are most commonly diagnosed by means of questionnaires. These questionnaires include a detailed analyses of the clinical history and contain questions to:

  • Rule out sleep deprivation.
  • Rule out effects of intoxication or withdrawal.
  • Rule out sleep disorders causing sleep instability.
  • Rule out medical disorders or treatments associated with sleep instability.
  • Confirm presence of NREM parasomnias in other family members and during the patient’s childhood.
  • Determine the timing of the events.
  • Determine the morphology of the events.

Furthermore, a sleep diary is helpful to exclude that sleep deprivation could be a precipitating factor. An additional tool could be the partner’s log of the events. The following questions should therefore be considered:

  • Do you or your bed partner believe that you move your arms, legs, or body too much, or have unusual behaviours during sleep?
  • Do you move while dreaming, as if you are simultaneously attempting to carry out the dream? l Have you ever hurt yourself or your bed partner during sleep?
  • Do you sleepwalk or have sleep terrors with loud screaming?
  • Do your legs feel restless or begin to twitch a lot or jump around when you are drowsy or sleepy, either at bedtime or during the day?
  • Do you eat food or drink fluids without full awareness during the night? Do you wake up in the morning feeling bloated and with no desire to eat breakfast?

In potentially harmful or disturbing cases a specialist in sleep disorders should be approached. Video polysomnographic documentation is necessary only in REM sleep behaviour disorder (RBD), since it is an essential diagnostic criteria in the ICSD to demonstrate the absence of muscle atonia and to exclude comorbid sleep disorders. For most of the other parasomnias, polysomnographic monitoring is a costly, but still supportive tool in the clinical diagnosis.

The use of actigraphy can be promising in the diagnostical assessment of NREM-related parasomnias, for example to rule out sleep deprivation or other sleep disorders, like circadian sleep-wake rhythm disorder which often develops among shift workers. However, there is currently no generally accepted standardised technique available of identifying and quantifying periodic limb movements in sleep (PLMS) that distinguishes movements resulting from parasomnias, nocturnal seizures, and other dyskinesias. Eventually, using actigraphy for parasomnias in general is disputed.

Treatment

Parasomnias can be considered as potentially harmful to oneself as well as to bed partners, and are associated with other disorders. Children with parasomnias do not undergo medical intervention, because they tend to recover the NREM-related disorder with the process of growth. In those cases, the parents receive education on sleep hygiene to reduce and eventually eliminate precipitating factors.

In adults psychoeducation about a proper sleep hygiene can reduce the risk to develop parasomnia. Case studies have shown that pharmacological interventions can improve symptoms of parasomnia, however mostly they are accompanied by side-effects. Behavioural treatments, i.e. relaxation therapy, biofeedback, hypnosis, and stress reduction, may also be helpful, but are not considered as universally effective.

Prognosis

NREM-related parasomnias which are common in childhood show a good prognosis, since severity decreases with age, the symptoms tend to resolve during puberty. Adults suffering from NREM-related parasomnias, however, are faced with a stronger persistence of the symptoms, therefore, full remission is quite unlikely and is also associated with violent complications, including homicide. The variant sleep-related eating disorders is chronic, without remission, but treatable.

REM sleep behaviour disorder (RBD) can mostly be handled well with the use of melatonin or clonazepam. However, there is high comorbidity with neurodegenerative disorders, that is in up to 93% of cases. The underlying psychopathology of nightmare disorder complicates a clear prognosis.

The prognosis for other parasomnias seems promising. While exploding head syndrome usually resolves spontaneously, the symptoms for sleep-related hallucinations tend to diminish over time.