Tag: Insomnia

What are Reversed Vegetative Symptoms?

Published on by Andrew Marshall1 Comment

Introduction

Vegetative symptoms are disturbances of a person’s functions necessary to maintain life (vegetative functions). These disturbances are most commonly seen in mood disorders, and are part of the diagnostic criteria for depression, but also appear in other conditions.

Vegetative symptoms in a patient with typical depression include:

  • Weight loss and anorexia (loss of appetite).
  • Insomnia.
  • Fatigue and low energy.
  • Inattention.

Reversed Vegetative Symptoms

Reversed vegetative symptoms include only oversleeping (hypersomnia) and overeating (hyperphagia), as compared to insomnia and loss of appetite. These features are characteristic of atypical depression (AD).

However, there have been studies claiming that these symptoms alone are sufficient to diagnose the condition of AD.

What is Eszopiclone?

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Introduction

Eszopiclone, sold under the brand-name Lunesta among others, is a medication used in the treatment of insomnia.

Evidence supports slight to moderate benefit up to six months. It is taken orally. Common side effects include headache, dry mouth, nausea, and dizziness. Severe side effects may include suicidal thoughts, unhealthy non-medical use, hallucinations, and angioedema. Greater care is recommended in those with liver problems and older people. Rapid decreasing of the dose may result in withdrawal. Eszopiclone is classified as a nonbenzodiazepine sedative hypnotic and as a cyclopyrrolone. It is the S-stereoisomer of zopiclone. It works by interacting with the GABA receptors.

Approved for medical use in the United States in 2004, eszopiclone is available as generic medication. In 2017, it was the 214th most commonly prescribed medication in the United States, with more than two million prescriptions. Eszopiclone is not sold in the European Union, as in 2009 the EMA ruled that it was too similar to zopiclone to be considered a new patentable product.

Brief History

In a controversial 2009 article in the New England Journal of Medicine, “Lost in Transmission — FDA Drug Information That Never Reaches Clinicians”, it was reported that the largest of three Lunesta trials found that compared to placebo Lunesta “was superior to placebo” while it only shortened initial time falling asleep by 15 minutes on average. “Clinicians who are interested in the drug’s efficacy cannot find efficacy information in the label: it states only that Lunesta is superior to placebo. The FDA’s medical review provides efficacy data, albeit not until page 306 of the 403-page document. In the longest, largest phase 3 trial, patients in the Lunesta group reported falling asleep an average of 15 minutes faster and sleeping an average of 37 minutes longer than those in the placebo group. However, on average, Lunesta patients still met criteria for insomnia and reported no clinically meaningful improvement in next-day alertness or functioning.”

Availability in Europe

On 11 September 2007, Sepracor signed a marketing deal with British pharmaceutical company GlaxoSmithKline for the rights to sell eszopiclone (under the name Lunivia rather than Lunesta) in Europe. Sepracor was expected to receive approximately $155 million if the deal went through. In 2008 Sepracor submitted an application to the EMA (the European Union’s equivalent to the US FDA) for authorisation to market the drug in the EU, and initially received a favourable response. However, Sepracor withdrew its authorization application in 2009 after the EMA stated it would not be granting eszopiclone ‘new active substance’ status, as it was essentially pharmacologically and therapeutically too similar to zopiclone to be considered a new patentable product. Since the patent on zopiclone has expired, this ruling would have allowed rival companies to also legally produce cheaper generic versions of eszopiclone for the European market. As of November 2012, Sepracor has not resubmitted its authorisation application and eszopiclone is not available in Europe. The deal with GSK fell through, and GSK instead launched a $3.3 billion deal to market Actelion’s almorexant sleeping tablet, which entered phase 3 medical trials before development was abandoned due to side effects.

Medical Uses

A 2018 Cochrane review found that it produced moderate improvement in sleep onset and maintenance. The authors suggest that where preferred non-pharmacological treatment strategies have been exhausted, eszopiclone provides an efficient treatment for insomnia. In 2014, the USFDA asked that the starting dose be lowered from 2 milligrams to 1 milligram after it was observed in a study that even 8 hours after taking the drug at night, some people were not able to cope with their next-day activities like driving and other activities that require full alertness.

Eszopiclone is slightly effective in the treatment of insomnia where difficulty in falling asleep is the primary complaint. Kirsch et al. found the benefit over placebo to be of questionable clinical significance. Although the drug effect and the placebo response were rather small and of questionable clinical importance, the two together produce a reasonably large clinical response. It is not recommended for chronic use in the elderly.

Elderly

Sedative hypnotic drugs including eszopiclone are more commonly prescribed to the elderly than to younger patients despite benefits of medication being generally unimpressive. Care should be taken in choosing an appropriate hypnotic drug and if drug therapy is initiated it should be initiated at the lowest possible dose to minimise side effects.

In 2015, the American Geriatrics Society reviewed the safety information about eszopiclone and similar drugs and concluded that the “nonbenzodiazepine, benzodiazepine receptor agonist hypnotics (eszopiclone, zaleplon, zolpidem) are to be avoided without consideration of duration of use because of their association with harms balanced with their minimal efficacy in treating insomnia.”

The review made this determination both because of the relatively large dangers to elderly individuals from zolpidem and other “z-drugs” together with the fact the drugs have “minimal efficacy in treating insomnia.” This was a change from the 2012 AGS recommendation, which suggested limiting use to 90 days or less. The review stated: “the 90‐day‐use caveat [was] removed from nonbenzodiazepine, benzodiazepine receptor agonist hypnotics, resulting in an unambiguous ‘avoid’ statement (without caveats) because of the increase in the evidence of harm in this area since the 2012 update.”

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 durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, including eszopiclone appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin receptor agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (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 more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.

A 2009 meta-analysis found a higher rate of infections.

Adverse Effects

Sleeping pills, including eszopiclone, have been associated with an increased risk of death.

Hypersensitivity to eszopiclone is a contra-indication to its use. Some side effects are more common than others. Recommendations around use of eszopiclone may be altered by other health conditions. These conditions or circumstances may occur in people that have lowered metabolism and other conditions. The presence of liver impairment, lactation and activities requiring mental alertness (e.g. driving) may be considered when determining frequency and dosage.

  • Unpleasant taste.
  • Headache.
  • Peripheral oedema.
  • Chest pain.
  • Abnormal thinking.
  • Behaviour changes.
  • Depression.
  • Hallucinations.
  • Sleep driving and sleepwalking.
  • Dry mouth.
  • Rash.
  • Altered sleep patterns.
  • Impaired coordination.
  • Dizziness.
  • Daytime drowsiness.
  • Itching.
  • Painful or frequent urination.
  • Back pain.
  • Aggressive behaviour.
  • Confusion.
  • Agitation.
  • Suicidal thoughts.
  • Depersonalisation.
  • Amnesia.

A 2009 meta-analysis found a 44% higher rate of mild infections, such as pharyngitis or sinusitis, in people taking eszopiclone or other hypnotic drugs compared to those taking a placebo.

Dependence

In the United States eszopiclone is a schedule IV controlled substance under the Controlled Substances Act. Use of eszopiclone may lead to physical and psychological dependence. The risk of non-medical use and dependence increases with the dose and duration of usage and concomitant use of other psychoactive substances. The risk is also greater in patients with a history of alcohol use disorder or other substance use disorder or history of psychiatric disorders. Tolerance may develop after repeated use of benzodiazepines and benzodiazepine-like drugs for a few weeks.

A study funded and carried out by Sepracor, the manufacturer of eszopiclone, found no signs of tolerance or dependence in a group of patients followed for up to six months.

Non-Medical Use

A study of non-medical use potential of eszopiclone found that in persons with a known history of non-medical benzodiazepine use, eszopiclone at doses of 6 and 12 mg produced effects similar to those of diazepam 20 mg. The study found that at these doses which are two or more times greater than the maximum recommended doses, a dose-related increase in reports of amnesia, sedation, sleepiness, and hallucinations was observed for both eszopiclone (Lunesta) as well as for diazepam (Valium).

Overdose

According to the US Prescribing Information, overdoses of eszopiclone up to 90 times the recommended dose have been reported in which the patient fully recovered. According to the May 2014 edition of the official US Prescribing Information, fatalities have been reported only in cases in which eszopiclone was combined with other drugs or alcohol.

Poison control centres reported that between 2005 and 2006 there were 525 total eszopiclone overdoses recorded in the state of Texas, the majority of which were intentional suicide attempts.

If consumed within the last hour, eszopiclone overdose can be treated with the administration of activated charcoal or via gastric lavage.

Interactions

There is an increased risk of central nervous system depression when eszopiclone is taken together with other CNS depressant agents, including antipsychotics, sedative hypnotics (like barbiturates or benzodiazepines), antihistamines, opioids, phenothiazines, and some antidepressants. There is also increased risk of central nervous system depression with other medications that inhibit the metabolic activities of the CYP3A4 enzyme system of the liver. Medications that inhibit this enzyme system include nelfinavir, ritonavir, ketoconazole, itraconazole and clarithromycin. Alcohol also has an additive effect when used concurrently with eszopiclone. Eszopiclone is most effective if it is not taken after a heavy meal with high fat content.

Pharmacology

Eszopiclone acts on benzodiazepine binding site situated on GABAA neurons as a positive allosteric modulator. Eszopiclone is rapidly absorbed after oral administration, with serum levels peaking between .45 and 1.3 hours. The elimination half-life of eszopiclone is approximately 6 hours and it is extensively metabolized by oxidation and demethylation. Approximately 52% to 59% of a dose is weakly bound to plasma protein. Cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1 are involved in the biotransformation of eszopiclone; thus, drugs that induce or inhibit these CYP isozymes may affect the metabolism of eszopiclone. Less than 10% of the orally administered dose is excreted in the urine as racemic zopiclone. In terms of benzodiazepine receptor binding and relevant potency, 3 mg of eszopiclone is equivalent to 10 mg of diazepam.

What is Flunitrazepam?

Published on by Andrew Marshall3 Comments

Introduction

Flunitrazepam, also known as Rohypnol among other names, is a benzodiazepine used to treat severe insomnia and assist with anaesthesia.

As with other hypnotics, flunitrazepam has been advised to be prescribed only for short-term use or by those with chronic insomnia on an occasional basis. It is said to be 10 times as potent as diazepam.

It was patented in 1962 and came into medical use in 1974. Flunitrazepam, nicknamed “roofies”, is widely known for its use as a date rape drug.

Brief History

Flunitrazepam was discovered at Roche as part of the benzodiazepine work led by Leo Sternbach; the patent application was filed in 1962 and it was first marketed in 1974.

Due to use of the drug for date rape and recreation, in 1998 Roche modified the formulation to give lower doses, make it less soluble, and add a blue dye for easier detection in drinks. It was never marketed in the United States, and by 2016 had been withdrawn from the markets in Spain, France, Norway, Germany, and the United Kingdom.

Use

In countries where this drug is used, it is used for treatment of severe cases of sleeping problems, and in some countries as a preanesthetic agent. These were also the uses for which it was originally studied.

It has also been administered as a concurrent dose for patients that are taking ketamine. Rohypnol lowers the side effects of the anaesthetic (ketamine), resulting in less confusion in awakening states, less negative influence on pulse rate, and fewer fluctuations in blood pressure.

It has also been shown to have therapeutic use in polysubstance use when combined with anaesthetics, opioids, ethanol, cocaine, and methamphetamine.

Adverse Effects

Adverse effects of flunitrazepam include dependency, both physical and psychological; reduced sleep quality resulting in somnolence; and overdose, resulting in excessive sedation, impairment of balance and speech, respiratory depression or coma, and possibly death. Because of the latter, flunitrazepam is commonly used in suicide. When used in late pregnancy, it might cause hypotonia of the foetus.

Dependence

Flunitrazepam, as with other benzodiazepines, can lead to drug dependence. Discontinuation may result in benzodiazepine withdrawal syndrome, characterised by seizures, psychosis, insomnia, and anxiety. Rebound insomnia, worse than baseline insomnia, typically occurs after discontinuation of flunitrazepam even from short-term single nightly dose therapy.

Paradoxical Effects

Flunitrazepam may cause a paradoxical reaction in some individuals, including anxiety, aggressiveness, agitation, confusion, disinhibition, loss of impulse control, talkativeness, violent behaviour, and even convulsions. Paradoxical adverse effects may even lead to criminal behaviour.

Hypotonia

Benzodiazepines such as flunitrazepam are lipophilic and rapidly penetrate membranes and, therefore, rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines including flunitrazepam in late pregnancy, especially high doses, may result in hypotonia, also known as floppy baby syndrome.

Other

Flunitrazepam impairs cognitive functions. This may appear as lack of concentration, confusion and anterograde amnesia – the inability to create memories while under the influence. It can be described as a hangover-like effect which can persist to the next day. It also impairs psychomotor functions similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs; falls and hip fractures were frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments.

Other adverse effects include:

  • Slurred speech.
  • Gastrointestinal disturbances, lasting 12 or more hours.
  • Vomiting.
  • Respiratory depression in higher doses.

Special Precautions

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, in alcohol- or drug-dependent individuals, and in individuals with comorbid psychiatric disorders.

Impairment of driving skills with a resultant increased risk of road traffic accidents is probably the most important adverse effect. This side-effect is not unique to flunitrazepam but also occurs with other hypnotic drugs. Flunitrazepam seems to have a particularly high risk of road traffic accidents compared to other hypnotic drugs. Extreme caution should be exercised by drivers after taking flunitrazepam.

Interactions

The use of flunitrazepam in combination with alcoholic beverages synergizes the adverse effects, and can lead to toxicity and death.

Overdose

Refer to Benzodiazepine Overdose.

Flunitrazepam is a drug that is frequently involved in drug intoxication, including overdose. Overdose of flunitrazepam may result in excessive sedation, or impairment of balance or speech. This may progress in severe overdoses to respiratory depression or coma and possibly death. The risk of overdose is increased if flunitrazepam is taken in combination with CNS depressants such as ethanol (alcohol) and opioids. Flunitrazepam overdose responds to the GABAA receptor antagonist flumazenil, which thus can be used as a treatment.

Detection

As of 2016, blood tests can identify flunitrazepam at concentrations of as low as 4 nanograms per millilitre; the elimination half life of the drug is 11-25 hours. For urine samples, metabolites can be identified for 60 hours to 28 days, depending on the dose and analytical method used. Hair and saliva can also be analysed; hair is useful when a long time has transpired since ingestion, and saliva for workplace drug tests.

Flunitrazepam can be measured in blood or plasma to confirm a diagnosis of poisoning in hospitalised patients, provide evidence in an impaired driving arrest, or assist in a medicolegal death investigation. Blood or plasma flunitrazepam concentrations are usually in a range of 5-20 μg/L in persons receiving the drug therapeutically as a nighttime hypnotic, 10-50 μg/L in those arrested for impaired driving and 100-1000 μg/L in victims of acute fatal overdosage. Urine is often the preferred specimen for routine substance use monitoring purposes. The presence of 7-aminoflunitrazepam, a pharmacologically-active metabolite and in vitro degradation product, is useful for confirmation of flunitrazepam ingestion. In postmortem specimens, the parent drug may have been entirely degraded over time to 7-aminoflunitrazepam. Other metabolites include desmethylflunitrazepam and 3-hydroxydesmethylflunitrazepam.

Pharmacology

The main pharmacological effects of flunitrazepam are the enhancement of GABA, an inhibitory neurotransmitter, at various GABA receptors.

While 80% of flunitrazepam that is taken orally is absorbed, bioavailability in suppository form is closer to 50%.

Flunitrazepam has a long half-life of 18-26 hours, which means that flunitrazepam’s effects after nighttime administration persist throughout the next day. This is due to the production of active metabolites. These metabolites further increase the duration of drug action compared to benzodiazepines that produce nonactive metabolites.

Flunitrazepam is lipophilic and is metabolised by the liver via oxidative pathways. The enzyme CYP3A4 is the main enzyme in its phase 1 metabolism in human liver microsomes.

Chemistry

Flunitrazepam is classed as a nitro-benzodiazepine. It is the fluorinated N-methyl derivative of nitrazepam. Other nitro-benzodiazepines include nitrazepam (the parent compound), nimetazepam (methylamino derivative) and clonazepam (2ʹ-chlorinated derivative).

Society and Culture

Recreational and Illegal Uses

Recreational Use

A 1989 article in the European Journal of Clinical Pharmacology reports that benzodiazepines accounted for 52% of prescription forgeries, suggesting that benzodiazepines was a major prescription drug class of abuse. Nitrazepam accounted for 13% of forged prescriptions.

Flunitrazepam and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other benzodiazepines and nonbenzodiazepines (anxiolytic or hypnotic) such as zolpidem and zopiclone (as well as cyclopyrrolones, imidazopyridines, and pyrazolopyrimidines) 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 potential for addiction for benzodiazepines and similar drugs.

Suicide

In studies in Sweden, flunitrazepam was the second most common drug used in suicides, being found in about 16% of cases. In a retrospective Swedish study of 1,587 deaths, in 159 cases benzodiazepines were found. In suicides when benzodiazepines were implicated, the benzodiazepines flunitrazepam and nitrazepam were occurring in significantly higher concentrations, compared to natural deaths. In 4 of the 159 cases, where benzodiazepines were found, benzodiazepines alone were the only cause of death. It was concluded that flunitrazepam and nitrazepam might be more toxic than other benzodiazepines.

Drug-Facilitated Sexual Assault

Flunitrazepam is known to induce anterograde amnesia in sufficient doses; individuals are unable to remember certain events that they experienced while under the influence of the drug, which complicates investigations. This effect could be particularly dangerous if flunitrazepam is used to aid in the commission of sexual assault; victims may be unable to clearly recall the assault, the assailant, or the events surrounding the assault.

While use of flunitrazepam in sexual assault has been prominent in the media, as of 2015 appears to be fairly rare, and use of alcohol and other benzodiazepine drugs in date rape appears to be a larger but underreported problem.

Drug-Facilitated Robbery

In the United Kingdom, the use of flunitrazepam and other “date rape” drugs have also been connected to stealing from sedated victims. An activist quoted by a British newspaper estimated that up to 2,000 individuals are robbed each year after being spiked with powerful sedatives, making drug-assisted robbery a more commonly reported problem than drug-assisted rape.

Regional Use

Flunitrazepam is a Schedule III drug under the international Convention on Psychotropic Substances of 1971.

  • In Australia, as of 2013 the drug was authorised for prescribing for severe cases of insomnia but was restricted as a Schedule 8 medicine.
  • In France, as of 2016 flunitrazepam was not marketed.
  • In Germany, as of 2016 flunitrazepam is an Anlage III Betäubungsmittel (controlled substance which is allowed to be marketed and prescribed by physicians under specific provisions) and is available on a special narcotic drug prescription as the Rohypnol 1 mg film-coated tablets and several generic preparations (November 2016).
  • In Ireland, flunitrazepam is a Schedule 3 controlled substance with strict restrictions.
  • In Japan, flunitrazepam is marketed by Japanese pharmaceutical company Chugai under the trade name Rohypnol and is indicated for the treatment of insomnia as well as used for preanesthetic medication.
  • In Mexico, Rohypnol is legally available and approved for medical use.
  • In Norway, on 01 January 2003, flunitrazepam was moved up one level in the schedule of controlled drugs and, on 01 August 2004, the manufacturer Roche removed Rohypnol from the market there altogether.
  • In South Africa, Rohypnol is classified as a Schedule 6 drug. It is available by prescription only, and restricted to 1 mg doses.
  • In Iceland, Flunitrazepam is a controlled substance available from Mylan. It is prescribed for severe insomnia and is sometimes used before surgery to induce a calm, relaxed state of mind for the patient.
  • In Sweden, flunitrazepam was previously available from Mylan, but has been removed from the market in January 2020. It is listed as a List II (Schedule II) under the Narcotics Control Act (1968).
  • In the United Kingdom, flunitrazepam is not licensed for medical use and is a controlled drug under Schedule 3 and Class C.
  • In the United States, the drug has not been approved by the Food and Drug Administration and is considered to be an illegal drug; as of 2016 it is Schedule IV. 21 U.S.C. § 841 and 21 U.S.C. § 952 provide for punishment for the importation and distribution of up to 20 years in prison and a fine; possession is punishable by three years and a fine. Travelers travelling into the United States are limited to a 30-day supply. The drug must be declared to US Customs upon arrival. If a valid prescription cannot be produced, the drug may be subject to Customs search and seizure, and the traveller may face criminal charges or deportation.

Names

Flunitrazepam is marketed under many brand names in the countries where it is legal. It also has many street names, including “roofie” and “ruffie”. It is also known as Circles, Forget Me Pill, La Rocha, Lunch Money Drug, Mexican Valium, Pingus, R2, and Roach 2.

What is the Rebound Effect?

Published on by Andrew Marshall1 Comment

Introduction

The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage.

In the case of re-emergence, the severity of the symptoms is often worse than pre-treatment levels.

Examples

Sedative Hypnotics

Rebound Insomnia

Rebound insomnia is insomnia that occurs following discontinuation of sedative substances taken to relieve primary insomnia. Regular use of these substances can cause a person to become dependent on its effects in order to fall asleep. Therefore, when a person has stopped taking the medication and is ‘rebounding’ from its effects, he or she may experience insomnia as a symptom of withdrawal. Occasionally, this insomnia may be worse than the insomnia the drug was intended to treat.

Common medicines known to cause this problem are eszopiclone, zolpidem, and anxiolytics such as benzodiazepines and which are prescribed to people having difficulties falling or staying asleep.

Rebound Depression

Depressive symptoms may appear to arise in patients previously free of such an illness.

Daytime Rebound

Rebound phenomena do not necessarily only occur on discontinuation of a prescribed dosage. For example, daytime rebound effects of anxiety, metallic taste, perceptual disturbances which are typical benzodiazepine withdrawal symptoms can occur the next day after a short-acting benzodiazepine hypnotic wears off. Another example is early morning rebound insomnia which may occur when a rapidly eliminated hypnotic wears off which leads to rebounding awakeness forcing the person to become wide awake before he or she has had a full night’s sleep. One drug which seems to be commonly associated with these problems is triazolam, due to its high potency and ultra short half life, but these effects can occur with other short-acting hypnotic drugs. Quazepam, due to its selectivity for type1 benzodiazepine receptors and long half-life, does not cause daytime anxiety rebound effects during treatment, showing that half-life is very important for determining whether a night-time hypnotic will cause next-day rebound withdrawal effects or not. Daytime rebound effects are not necessarily mild but can sometimes produce quite marked psychiatric and psychological disturbances.

Stimulants

Rebound effects from stimulants such as methylphenidate or dextroamphetamine include stimulant psychosis, depression and a return of ADHD symptoms but in a temporarily exaggerated form. Up to a third of ADHD children experience a rebound effect when methylphenidate is withdrawn.

Antidepressants

Many antidepressants, including SSRIs, can cause rebound depression, panic attacks, anxiety, and insomnia when discontinued.

Antipsychotics

Sudden and severe emergence or re-emergence of psychosis may appear when antipsychotics are switched or discontinued too rapidly.

Alpha-2 Adrenergic Agents

Rebound hypertension, above pre-treatment level, was observed after clonidine, and guanfacine discontinuation.

Others

Other Rebound Effects

An example is the use of highly potent corticosteroids, such as clobetasol for psoriasis. Abrupt withdrawal can cause a much more severe case of the psoriasis to develop. Therefore, withdrawal should be gradual, diluting the medication with lotion perhaps, until very little actual medication is being applied.

Another example of pharmaceutical rebound is a rebound headache from painkillers when the dose is lowered, the medication wears off, or the drug is abruptly discontinued.

Continuous usage of topical decongestants (nasal sprays) can lead to constant nasal congestion, known as rhinitis medicamentosa.

What is Ramelteon?

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Introduction

Ramelteon, sold under the brand name Rozerem among others, is a sleep agent medication that selectively binds to the MT1 and MT2 receptors in the suprachiasmatic nucleus (SCN), instead of binding to GABAA receptors, such as with drugs like zolpidem.

It appears to speed the onset of sleep and alter the total amount of sleep a person gets. It is approved by the US Food and Drug Administration (FDA) for long-term use.

Ramelteon does not show any appreciable binding to GABAA receptors, which are associated with anxiolytic, myorelaxant, and amnesic effects.

Brief History

Ramelteon was approved for use in the United States in July 2005.

Medical Uses

Ramelteon is approved in the United States for the treatment of insomnia characterised by difficulty with sleep onset.

A systematic review, published in 2014, concluded “ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo.”

Mechanism of Action

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT1 or MT2 receptors, and high selectivity for human MT1 and MT2 receptors compared to the MT3 receptor.

The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle. Ramelteon has no appreciable affinity for the GABA receptor complex or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, and opioids. Ramelteon also does not interfere with the activity of a number of selected enzymes in a standard panel.

The major metabolite of ramelteon, M-II, is active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively, and is 17-25-fold less potent than ramelteon in in vitro functional assays. Although the potency of M-II at MT1 and MT2 receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20-100-fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes.

Adverse Effects

Ramelteon has not been shown to produce dependence and has shown no potential for abuse, and the withdrawal and rebound insomnia that is typical with GABA modulators is not present in ramelteon.

Six percent of ramelteon-treated patients in clinical trials discontinued due to an adverse event, compared with two percent in the placebo arms. The most frequent adverse events leading to discontinuation were somnolence, dizziness, nausea, fatigue, headache, and insomnia. The US official Prescribing Information warns of rare cases of anaphylactic reactions, abnormal thinking, worsening of depression or suicidal thinking in patients with pre-existing depression, and decreased testosterone and increased prolactin levels. It also notes that ramelteon is not recommended for use in patients with severe sleep apnoea.

In mice treated with ramelteon for two years, increases in liver and testicular tumours were observed, but only at doses at least 20 times greater than the recommended human dose on a milligram/kilogram basis.

Drug Interactions

Ramelteon has been evaluated for potential drug interactions with the following medications and showed no significant effects: omeprazole, theophylline, dextromethorphan, and midazolam, digoxin and warfarin. There were no clinically meaningful effects when ramelteon was co-administered with any of these drugs.

A drug interaction study showed that there were no clinically meaningful effects or an increase in adverse events when ramelteon and the SSRI Prozac (fluoxetine) were co-administered. When co-administered with ramelteon, fluvoxamine (strong CYP1A2 inhibitor) increased AUC approximately 190-fold, and the Cmax increased approximately 70-fold, compared to ramelteon administered alone. Ramelteon and fluvoxamine should not be co-administered.

Ramelteon has significant drug-drug interaction with the following drugs: amiodarone, ciprofloxacin, fluvoxamine, ticlopidine.

Ramelteon should be administered with caution in patients taking other CYP1A2 inhibitors, strong CYP3A4 inhibitors such as ketoconazole, and strong CYP2C9 inhibitors such as fluconazole.

Efficacy may be reduced when ramelteon is used in combination with potent CYP enzyme inducers such as rifampin, since ramelteon concentrations may be decreased.

What is Loprazolam?

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Introduction

Loprazolam (triazulenone) marketed under many brand names is a benzodiazepine medication.

It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It is licensed and marketed for the short-term treatment of moderately-severe insomnia.

It was patented in 1975 and came into medical use in 1983.

Medical Uses

Insomnia can be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Loprazolam is a short-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or have difficulty falling asleep. Hypnotics should only be used on a short-term basis or in those with chronic insomnia on an occasional basis.

Dose

The dose of loprazolam for insomnia is usually 1 mg but can be increased to 2 mg if necessary. In the elderly a lower dose is recommended due to more pronounced effects and a significant impairment of standing up to 11 hours after dosing of 1 mg of loprazolam. The half-life is much more prolonged in the elderly than in younger patients. A half-life of 19.8 hours has been reported in elderly patients. Patients and prescribing physicians should, however, bear in mind that higher doses of loprazolam may impair long-term memory functions.

Side Effects

Side effects of loprazolam are generally the same as for other benzodiazepines such as diazepam.[5] The most significant difference in side effects of loprazolam and diazepam is it is less prone to day time sedation as the half-life of loprazolam is considered to be intermediate whereas diazepam has a very long half-life. The side effects of loprazolam are the following:

  • Drowsiness.
  • Paradoxical increase in aggression.
  • Lightheadedness.
  • Confusion.
  • Muscle weakness.
  • Ataxia (particularly in the elderly).
  • Amnesia.
  • Headache.
  • Vertigo.
  • Hypotension.
  • Salivation changes.
  • Gastro-intestinal disturbances.
  • Visual disturbances.
  • Dysarthria.
  • Tremor.
  • Changes in libido.
  • Incontinence.
  • Urinary retention.
  • Blood disorders and jaundice.
  • Skin reactions.
  • Dependence and withdrawal reactions.

Residual ‘hangover’ effects after night-time administration of loprazolam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may increase risks of falls and hip fractures.

Tolerance, Dependence and Withdrawal

Loprazolam, like all other benzodiazepines, is recommended only for the short-term management of insomnia in the UK, owing to the risk of serious adverse effects such as tolerance, dependence and withdrawal, as well as adverse effects on mood and cognition. Benzodiazepines can become less effective over time, and patients can develop increasing physical and psychological adverse effects, e.g. agoraphobia, gastrointestinal complaints, and peripheral nerve abnormalities such as burning and tingling sensations.

Loprazolam has a low risk of physical dependence and withdrawal if it is used for less than 4 weeks or very occasionally. However, one placebo-controlled study comparing 3 weeks of treatment for insomnia with either loprazolam or triazolam showed rebound anxiety and insomnia occurring 3 days after discontinuing loprazolam therapy, whereas with triazolam the rebound anxiety and insomnia was seen the next day. The differences between the two are likely due to the differing elimination half-lives of the two drugs. These results would suggest that loprazolam and possibly other benzodiazepines should be prescribed for 1-2 weeks rather than 2-4 weeks to reduce the risk of physical dependence, withdrawal, and rebound phenomenon.

Withdrawal Symptoms

Slow reduction of the dosage over a period of months at a rate that the individual can tolerate greatly minimises the severity of the withdrawal symptoms. Individuals who are benzodiazepine dependent often cross to an equivalent dose of diazepam to taper gradually, as diazepam has a longer half-life and small dose reductions can be achieved more easily.

  • Anxiety and panic attacks.
  • Sweating.
  • Nightmares.
  • Insomnia.
  • Headache.
  • Tremor.
  • Nausea and vomiting.
  • Feelings of unreality.
  • Abnormal sensation of movement.
  • Hypersensitivity to stimuli.
  • Hyperventilation.
  • Flushing.
  • Sweating.
  • Palpitations.
  • Dimensional distortions of rooms and television pictures.
  • Paranoid thoughts and feelings of persecution.
  • Depersonalisation.
  • Fears of going mad.
  • Heightened perception of taste, smell, sound, and light; photophobia.
  • Agoraphobia.
  • Clinical depression.
  • Poor memory and concentration.
  • Aggression.
  • Excitability.
  • Somatic symptoms.
  • Numbness.
  • Altered sensations of the skin.
  • Pain.
  • Stiffness.
  • Weakness in the neck, head, jaw, and limbs.
  • Muscle fasciculation, ranging from twitches to jerks, affecting the legs or shoulders.
  • Ataxia.
  • Paraesthesia.
  • Influenza-like symptoms.
  • Blurred double vision.
  • Menorrhagia.
  • Loss of or dramatic gain in appetite.
  • Thirst with polyuria.
  • Urinary incontinence.
  • Dysphagia.
  • Abdominal pain.
  • Diarrhoea.
  • Constipation.

Major complications can occur after abrupt or rapid withdrawal, especially from high doses, producing symptoms such as:

  • Psychosis.
  • Confusion.
  • Visual and auditory hallucinations.
  • Delusions.
  • Epileptic seizures (which may be fatal).
  • Suicidal thoughts or actions.
  • Abnormal, often severe, drug seeking behaviour.

It has been estimated that between 30% and 50% of long-term users of benzodiazepines will experience withdrawal symptoms. However, up to 90% of patients withdrawing from benzodiazepines experienced withdrawal symptoms in one study, but the rate of taper was very fast at 25% of dose per week. Withdrawal symptoms tend to last between 3 weeks to 3 months, although 10-15% of people may experience a protracted benzodiazepine withdrawal syndrome with symptoms persisting and gradually declining over a period of many months and occasionally several years.

Contraindications and Special Caution

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders. Loprazolam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments.

Mechanism of Action

Loprazolam is a benzodiazepine, which acts via positively modulating the GABAA receptor complex via a binding to the benzodiazepine receptor which is situated on alpha subunit containing GABAA receptors. This action enhances the effect of the neurotransmitter GABA on the GABAA receptor complex by increasing the opening frequency of the chloride ion channel. This action allows more chloride ions to enter the neuron which in turn produces such effects as; muscle relaxation, anxiolytic, hypnotic, amnesic and anticonvulsant action. These properties can be used for therapeutic benefit in clinical practice. These properties are also sometimes used for recreational purposes in the form of drug abuse of benzodiazepines where high doses are used to achieve intoxication and or sedation.

Pharmacokinetics

After oral administration of loprazolam on an empty stomach, it takes 2 hours for serum concentration levels to peak, significantly longer than other benzodiazepine hypnotics. This delay brings into question the benefit of loprazolam for the treatment of insomnia when compared to other hypnotics (particularly when the major complaint is difficulty falling asleep instead of difficulty maintaining sleep for the entire night), although some studies show that loprazolam may induce sleep within half an hour, indicating rapid penetration into the brain. The peak plasma delay of loprazolam, therefore, may not be relevant to loprazolam’s efficacy as a hypnotic. If taken after a meal it can take even longer for loprazolam plasma levels to peak and peak levels may be lower than normal. Loprazolam significantly alters electrical activity in the brain as measured by EEG, with these changes becoming more pronounced as the dose increases. Roughly half of each dose is metabolized in humans to produce an active metabolite, (a piperazine with lesser potency), the other half is excreted unchanged. The half-life of the active metabolite is about the same as the parent compound loprazolam.

What is Temazepam?

Published on by Andrew Marshall7 Comments

Introduction

Temazepam, sold under the brand names Restoril among others, is a medication used to treat insomnia.

Such use should generally be for less than ten days. It is taken by mouth. Effects generally begin within an hour and last for up to eight hours.

Common side effects include sleepiness, anxiety, confusion, and dizziness. Serious side effects may include hallucinations, abuse, anaphylaxis, and suicide. Use is generally not recommended together with opioids. If the dose is rapidly decreased withdrawal may occur. Use during pregnancy or breastfeeding is not recommended. Temazepam is an intermediate acting benzodiazepine and hypnotic. It works by affecting GABA within the brain.

Temazepam was patented in 1962 and came into medical use in 1969. It is available as a generic medication. In 2017, it was the 142nd most commonly prescribed medication in the United States, with more than four million prescriptions.

Brief History

Temazepam was synthesized in 1964, but it came into use in 1981 when its ability to counter insomnia was realised. By the late 1980s, temazepam was one of the most popular and widely prescribed hypnotics on the market and it became one of the most widely prescribed drugs.

Medical Uses

In sleep laboratory studies, temazepam significantly decreased the number of nightly awakenings, but has the drawback of distorting the normal sleep pattern. It is officially indicated for severe insomnia and other severe or disabling sleep disorders. The prescribing guidelines in the UK limit the prescribing of hypnotics to two to four weeks due to concerns of tolerance and dependence.

The United States Air Force uses temazepam as one of the hypnotics approved as a “no-go pill” to help aviators and special-duty personnel sleep in support of mission readiness. “Ground tests” are necessary prior to required authorisation being issued to use the medication in an operational situation, and a 12-hour restriction is imposed on subsequent flight operation. The other hypnotics used as “no-go pills” are zaleplon and zolpidem, which have shorter mandatory recovery periods.

Contraindications

Use of temazepam should be avoided, when possible, in individuals with these conditions:

  • Ataxia (gross lack of coordination of muscle movements).
  • Severe hypoventilation.
  • Acute narrow-angle glaucoma.
  • Severe hepatic deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of two).
  • Severe renal deficiencies (e.g. patients on dialysis).
  • Sleep apnoea.
  • Severe depression, particularly when accompanied by suicidal tendencies.
  • Acute intoxication with alcohol, narcotics, or other psychoactive substances.
  • Myasthenia gravis (autoimmune disorder causing muscle weakness).
  • Hypersensitivity or allergy to any drug in the benzodiazepine class.

Special Caution Needed

Temazepam should not be used in pregnancy, as it may cause harm to the foetus. The safety and effectiveness of temazepam has not been established in children; therefore, temazepam should generally not be given to individuals under 18 years of age, and should not be used at all in children under six months old. Benzodiazepines also require special caution if used in the elderly, alcohol- or drug-dependent individuals, and individuals with comorbid psychiatric disorders.

Temazepam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs, causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial but incomplete tolerance develops to these impairments. The smallest possible effective dose should be used in elderly or very ill patients, as a risk of apnoea and/or cardiac arrest exists. This risk is increased when temazepam is given concomitantly with other drugs that depress the central nervous system (CNS).

Misuse and Dependence

Because benzodiazepines can be abused and lead to dependence, their use should be avoided in people in certain particularly high-risk groups. These groups include people with a history of alcohol or drug dependence, people significantly struggling with their mood or people with longstanding mental health difficulties. If temazepam must be prescribed to people in these groups, they should generally be monitored very closely for signs of misuse and development of dependence.

Adverse Effects

Refer to Benzodiazepine Withdrawal Syndrome.

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Common

Side effects typical of hypnotic benzodiazepines are related to CNS depression, and include somnolence, sedation, dizziness, fatigue, ataxia, headache, lethargy, impairment of memory and learning, longer reaction time and impairment of motor functions (including coordination problems), slurred speech, decreased physical performance, numbed emotions, reduced alertness, muscle weakness, blurred vision (in higher doses), and inattention. Euphoria was rarely reported with its use. According to the FDA, temazepam had an incidence of euphoria of 1.5%, much more rarely reported than headaches and diarrhoea. Anterograde amnesia may also develop, as may respiratory depression in higher doses.

A 2009 meta-analysis found a 44% higher rate of mild infections, such as pharyngitis or sinusitis, in people taking Temazepam or other hypnotic drugs compared to those taking a placebo.

Less Common

Hyperhydrosis, hypotension, burning eyes, increased appetite, changes in libido, hallucinations, faintness, nystagmus, vomiting, pruritus, gastrointestinal disturbances, nightmares, palpitation and paradoxical reactions including restlessness, aggression, violence, overstimulation and agitation have been reported, but are rare (less than 0.5%).

Before taking temazepam, one should ensure that at least 8 hours are available to dedicate to sleep. Failing to do so can increase the side effects of the drug.

Like all benzodiazepines, the use of this drug in combination with alcohol potentiates the side effects, and can lead to toxicity and death.

Though rare, residual “hangover” effects after night-time administration of temazepam occasionally occur. These include sleepiness, impaired psychomotor and cognitive functions which may persist into the next day, impaired driving ability, and possible increased risks of falls and hip fractures, especially in the elderly.

Tolerance

Chronic or excessive use of temazepam may cause drug tolerance, which can develop rapidly, so this drug is not recommended for long-term use. In 1979, the US Institute of Medicine and the National Institute on Drug Abuse stated that most hypnotics lose their sleep-inducing properties after about three to 14 days. In use longer than one to two weeks, tolerance will rapidly develop towards the ability of temazepam to maintain sleep, resulting in a loss of effectiveness. Some studies have observed tolerance to temazepam after as little as one week’s use. Another study examined the short-term effects of the accumulation of temazepam over seven days in elderly inpatients, and found little tolerance developed during the accumulation of the drug. Other studies examined the use of temazepam over six days and saw no evidence of tolerance. A study in 11 young male subjects showed significant tolerance occurs to temazepam’s thermoregulatory effects and sleep inducing properties after one week of use of 30-mg temazepam. Body temperature is well correlated with the sleep-inducing or insomnia-promoting properties of drugs.

In one study, the drug sensitivity of people who had used temazepam for one to 20 years was no different from that of controls. An additional study, in which at least one of the authors is employed by multiple drug companies, examined the efficacy of temazepam treatment on chronic insomnia over three months, and saw no drug tolerance, with the authors even suggesting the drug might become more effective over time.

Establishing continued efficacy beyond a few weeks can be complicated by the difficulty in distinguishing between the return of the original insomnia complaint and withdrawal or rebound related insomnia. Sleep EEG studies on hypnotic benzodiazepines show tolerance tends to occur completely after one to four weeks with sleep EEG returning to pre-treatment levels. The paper concluded that due to concerns about long-term use involving toxicity, tolerance and dependence, as well as to controversy over long-term efficacy, wise prescribers should restrict benzodiazepines to a few weeks and avoid continuing prescriptions for months or years. A review of the literature found the nonpharmacological treatment options were a more effective treatment option for insomnia due to their sustained improvements in sleep quality.

Physical Dependence

Temazepam, like other benzodiazepine drugs, can cause physical dependence and addiction. Withdrawal from temazepam or other benzodiazepines after regular use often leads to benzodiazepine withdrawal syndrome, which resembles symptoms during alcohol and barbiturate withdrawal. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can also occur from standard dosages and after short-term use. Abrupt withdrawal from therapeutic doses of temazepam after long-term use may result in a severe benzodiazepine withdrawal syndrome. Gradual and careful reduction of the dosage, preferably with a long-acting benzodiazepine with long half-life active metabolites, such as chlordiazepoxide or diazepam, are recommended to prevent severe withdrawal syndromes from developing. Other hypnotic benzodiazepines are not recommended. A study in rats found temazepam is cross tolerant with barbiturates and is able to effectively substitute for barbiturates and suppress barbiturate withdrawal signs. Rare cases are reported in the medical literature of psychotic states developing after abrupt withdrawal from benzodiazepines, even from therapeutic doses. Antipsychotics increase the severity of benzodiazepine withdrawal effects with an increase in the intensity and severity of convulsions. Patients who were treated in the hospital with temazepam or nitrazepam have continued taking these after leaving the hospital. Hypnotic uses in the hospital were recommended to be limited to five nights’ use only, to avoid the development of withdrawal symptoms such as insomnia.

Interactions

As with other benzodiazepines, temazepam produces additive CNS-depressant effects when co-administered with other medications which themselves produce CNS depression, such as barbiturates, alcohol, opiates, tricyclic antidepressants, nonselective MAO inhibitors, phenothiazines and other antipsychotics, skeletal muscle relaxants, antihistamines, and anaesthetics. Administration of theophylline or aminophylline has been shown to reduce the sedative effects of temazepam and other benzodiazepines.

Unlike many benzodiazepines, pharmacokinetic interactions involving the P450 system have not been observed with temazepam. Temazepam shows no significant interaction with CYP3A4 inhibitors (e.g. itraconazole, erythromycin). Oral contraceptives may decrease the effectiveness of temazepam and speed up its elimination half-life.

Overdose

Refer to Benzodiazepine Overdose.

Overdose (or an excess dose(s)) of temazepam results in increasing CNS effects, including:

  • Somnolence (difficulty staying awake).
  • Mental confusion.
  • Respiratory depression.
  • Hypotension.
  • Impaired motor functions.
  • Impaired or absent reflexes.
  • Impaired coordination.
  • Impaired balance.
  • Dizziness, sedation.
  • Coma.
  • Death.

Temazepam had the highest rate of drug intoxication, including overdose, among common benzodiazepines in cases with and without combination with alcohol in a 1985 study. Temazepam and nitrazepam were the two benzodiazepines most commonly detected in overdose-related deaths in an Australian study of drug deaths. A 1993 British study found temazepam to have the highest number of deaths per million prescriptions among medications commonly prescribed in the 1980s (11.9, versus 5.9 for benzodiazepines overall, taken with or without alcohol).

A 1995 Australian study of patients admitted to hospital after benzodiazepine overdose corroborated these results, and found temazepam overdose much more likely to lead to coma than other benzodiazepines (odds ratio 1.86). The authors noted several factors, such as differences in potency, receptor affinity, and rate of absorption between benzodiazepines, could explain this higher toxicity. Although benzodiazepines have a high therapeutic index, temazepam is one of the more dangerous of this class of drugs. The combination of alcohol and temazepam makes death by alcohol poisoning more likely.

Pharmacology

Temazepam is a white, crystalline substance, very slightly soluble in water, and sparingly soluble in alcohol. Its main pharmacological action is to increase the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor. This causes sedation, motor impairment, ataxia, anxiolysis, an anticonvulsant effect, muscle relaxation, and a reinforcing effect. As a medication before surgery, temazepam decreased cortisol in elderly patients. In rats, it triggered the release of vasopressin into paraventricular nucleus of the hypothalamus and decreased the release of ACTH under stress.

Pharmacokinetics

Oral administration of 15 to 45 mg of temazepam in humans resulted in rapid absorption with significant blood levels achieved in fewer than 30 minutes and peak levels at two to three hours. In a single- and multiple-dose absorption, distribution, metabolism, and excretion (ADME) study, using tritium-labelled drug, temazepam was well absorbed and found to have minimal (8%) first-pass drug metabolism. No active metabolites were formed and the only significant metabolite present in blood was the O-conjugate. The unchanged drug was 96% bound to plasma proteins. The blood-level decline of the parent drug was biphasic, with the short half-life ranging from 0.4-0.6 hours and the terminal half-life from 3.5-18.4 hours (mean 8.8 hours), depending on the study population and method of determination.

Temazepam has very good bioavailability, with almost 100% being absorbed following being taken by mouth. The drug is metabolized through conjugation and demethylation prior to excretion. Most of the drug is excreted in the urine, with about 20% appearing in the faeces. The major metabolite was the O-conjugate of temazepam (90%); the O-conjugate of N-desmethyl temazepam was a minor metabolite (7%).

Society and Culture

Recreational Use

Refer to Benzodiazepine Use Disorder.

Temazepam is a drug with a moderate potential for misuse.

Benzodiazepines have been abused orally and intravenously. Different benzodiazepines have different abuse potential; the more rapid the increase in the plasma level following ingestion, the greater the intoxicating effect and the more open to abuse the drug becomes. The speed of onset of action of a particular benzodiazepine correlates well with the ‘popularity’ of that drug for abuse. The two most common reasons for preference were that a benzodiazepine was ‘strong’ and that it gave a good ‘high’.

A 1995 study found that temazepam is more rapidly absorbed and oxazepam is more slowly absorbed than most other benzodiazepines.

A 1985 study found that temazepam and triazolam maintained significantly higher rates of self-injection than a variety of other benzodiazepines. The study tested and compared the abuse liability of temazepam, triazolam, diazepam, lorazepam, oxazepam, flurazepam, alprazolam, chlordiazepoxide, clonazepam, nitrazepam, flunitrazepam, bromazepam, and clorazepate. The study tested self-injection rates on human, baboon, and rat subjects. All test subjects consistently showed a strong preference for temazepam and triazolam over all the rest of the benzodiazepines included in the study.

North America

In North America, temazepam misuse is not widespread. Other benzodiazepines are more commonly prescribed for insomnia. In the United States, temazepam is the fifth-most prescribed benzodiazepine, however there is a major drop off from the top four most prescribed (alprazolam, lorazepam, diazepam, and clonazepam in that order). Individuals abusing benzodiazepines obtain the drug by getting prescriptions from several doctors, forging prescriptions, or buying diverted pharmaceutical products on the illicit market. North America has never had a serious problem with temazepam misuse, but is becoming increasingly vulnerable to the illicit trade of temazepam.

Australia

Temazepam is a Schedule 4 drug and requires a prescription. The drug accounts for most benzodiazepine sought by forgery of prescriptions and through pharmacy burglary in Victoria. Due to rife intravenous abuse, the Australian government decided to put it under a more restrictive schedule than it had been, and since March 2004 temazepam capsules have been withdrawn from the Australian market, leaving only 10 mg tablets available. Benzodiazepines are commonly detected by Customs at different ports and airports, arriving by mail, also found occasionally in the baggage of air passengers, mostly small or medium quantities (up to 200-300 tablets) for personal use. From 2003 to 2006, customs detected about 500 illegal importations of benzodiazepines per year, most frequently diazepam. Quantities varied from single tablets to 2,000 tablets.

United Kingdom

In 1987, temazepam was the most widely abused legal prescription drug in the United Kingdom. The use of benzodiazepines by street-drug abusers was part of a polydrug abuse pattern, but many of those entering treatment facilities were declaring temazepam as their main drug of abuse. Temazepam was the most commonly used benzodiazepine in a study, published 1994, of injecting drug users in seven cities, and had been injected from preparations of capsules, tablets, and syrup. The increase in use of heroin, often mixed with other drugs, which most often included temazepam, diazepam, and alcohol, was a major factor in the increase in drug-related deaths in Glasgow and Edinburgh in 1990-1992. Temazepam use was particularly associated with violent or disorderly behaviours and contact with the police in a 1997 study of young single homeless people in Scotland. The BBC series Panorama featured an episode titled “Temazepam Wars”, dealing with the epidemic of temazepam abuse and directly related crime in Paisley, Scotland. The trend was mocked in the 1995 Black Grape song “Temazi Party” (also called “Tramazi Party”).

Medical Research Issues

The Journal of Clinical Sleep Medicine published a paper expressing concerns about benzodiazepine receptor agonist drugs, the benzodiazepines and the Z-drugs used as hypnotics in humans. The paper cites a systematic review of the medical literature concerning insomnia medications and states almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry, while this is not the case in general medicine or psychiatry. It cites another study that “found that the odds ratio for finding results favourable to industry in industry-sponsored trials was 3.6 times as high as in non–industry-sponsored studies”. Issues discussed regarding industry-sponsored studies include: comparison of a drug to a placebo, but not to an alternative treatment; unpublished studies with unfavourable outcomes; and trials organized around a placebo baseline followed by drug treatment, but not counterbalanced with parallel-placebo-controlled studies. Quoting a 1979 report that too little research into hypnotics was independent of the drug manufacturers, the authors conclude, “the public desperately needs an equipoised assessment of hypnotic benefits and risks” and the NIH and VA should provide leadership to that end.

Street Terms

Street terms for temazepam include king kong pills (formerly referred to barbiturates, now more commonly refers to temazepam), jellies, jelly, Edinburgh eccies, tams, terms, mazzies, temazies, tammies, temmies, beans, eggs, green eggs, wobbly eggs, knockouts, hardball, norries, oranges (common term in Australia and New Zealand), rugby balls, ruggers, terminators, red and blue, no-gos, num nums, blackout, green devils, drunk pills, brainwash, mind erasers, neurotrashers, tem-tem’s (combined with buprenorphine), mommy’s big helper, vitamin T, big T, TZ, The Mazepam, Resties (North America) and others.

Availability

Temazepam is available in English-speaking countries under the following brand names:

  • Euhypnos.
  • Normison.
  • Norkotral.
  • Nortem.
  • Remestan.
  • Restoril.
  • Temaze.
  • Temtabs.
  • Tenox.

In Spain, the drug is sold as ‘temzpem’. In Hungary the drug is sold as Signopam.

Legal Status

  • In Austria, temazepam is listed in UN71 Schedule III under the Psychotropic Substances Decree of 1997.
    • The drug is considered to have a high potential for abuse and addiction, but has accepted medical use for the treatment of severe insomnia.
  • In Australia, temazepam is a Schedule 4 – Prescription Only medicine.
    • It is primarily used for the treatment of insomnia, and is also seen as pre-anaesthetic medication.
  • In Canada, temazepam is a Schedule IV controlled substance requiring a registered doctor’s prescription.
  • In Denmark, temazepam is listed as a Class D substance under the Executive Order 698 of 1993 on Euphoric Substances which means it has a high potential for abuse, but is used for medical and scientific purposes.
  • In Finland, temazepam is more tightly controlled than other benzodiazepines.
    • The temazepam product Normison was pulled out of shelves and banned because the liquid inside gelatin capsules had caused a large increase in intravenous temazepam use.
    • The other temazepam product, Tenox, was not affected and remains as prescription medicine.
    • Temazepam intravenous use has not decreased to the level before Normison came to the market.
  • In France, temazepam is listed as a psychotropic substance as are other similar drugs.
    • It is prescribed with a non-renewable prescription (a new doctor visit every time), available only in 7 or 14-pill packaging for one or two weeks.
    • One brand was withdrawn from the market in 2013.
  • In Hong Kong, temazepam is regulated under Schedule 1 of Hong Kong’s Chapter 134 Dangerous Drugs Ordinance.
    • Temazepam can only be used legally by health professionals and for university research purposes.
    • The substance can be given by pharmacists under a prescription.
    • Anyone who supplies the substance without prescription can be fined HKD$10,000.
    • The penalty for trafficking or manufacturing the substance is a $5,000,000-fine and life imprisonment.
    • Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000-fine and/or seven years of jail time.
  • In Ireland, temazepam is a Schedule 3 controlled substance with strict restrictions.
  • In the Netherlands, temazepam is available for prescription as 10- or 20-mg tablets and capsules.
    • Formulations of temazepam containing less than 20 mg are included in List 2 of the Opium Law, while formulations containing 20 mg or more of the drug (along with the gel-capsules) are a List 1 substance of the Opium Law, thus subject to more stringent regulation.
    • Besides being used for insomnia, it is also occasionally used as a preanesthetic medication.
  • In Norway, temazepam is not available as a prescription drug.
    • It is regulated as a Class A substance under Norway’s Narcotics Act.
  • In Portugal, temazepam is a Schedule IV controlled drug under Decree-Law 15/93.
  • In Singapore, temazepam is a Class A controlled drug (Schedule I), making it illegal to possess and requiring a private prescription from a licensed physician to be dispensed.
  • In Slovenia, it is regulated as a Group II (Schedule 2) controlled substance under the Production and Trade in Illicit Drugs Act.
  • In South Africa, temazepam is a Schedule 5 drug, requiring a special prescription, and is restricted to 10- to 30-mg doses.
  • In Sweden, temazepam is classed as a “narcotic” drug listed as both a List II (Schedule II) which denotes it is a drug with limited medicinal use and a high risk of addiction, and is also listed as a List V (Schedule V) substance which denotes the drug is prohibited in Sweden under the Narcotics Drugs Act (1968).
    • Temazepam is banned in Sweden and possession and distribution of even small amounts is punishable by a prison sentence and a fine.
  • In Switzerland, temazepam is a Class B controlled substance, like all other benzodiazepines.
    • This means it is a prescription-only drug.
  • In Thailand, temazepam is a Schedule II controlled drug under the Psychotropic Substances Act.
    • Possession and distribution of the drug is illegal.
  • In the United Kingdom, temazepam is a Class C controlled drug under the Misuse of Drugs Act 1971 (Schedule 3 under the Misuse of Drugs Regulations 2001).
    • If prescribed privately (not on the NHS), temazepam is available only by a special controlled drug prescription form (FP10PCD) and pharmacies are obligated to follow special procedures for storage and dispensing.
    • Additionally, all manufacturers in the UK have replaced the gel-capsules with solid tablets.
    • Temazepam requires safe custody and up until June 2015 was exempt from CD prescription requirements.
  • In the United States, Temazepam is currently a Schedule IV drug under the international Convention on Psychotropic Substances of 1971 and is only available by prescription.
    • Specially coded prescriptions may be required in certain states.

What is Zaleplon?

Published on by Andrew Marshall6 Comments

Introduction

Zaleplon, sold under the brand names Sonata among others, is a sedative-hypnotic, used to treat insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class.

It is manufactured by King Pharmaceuticals and Gedeon Richter Plc. It has been discontinued in Canada but can be manufactured if a prescription is brought to a compounding pharmacy. It was prescribed rarely in the United Kingdom, with zopiclone being the preferred Z-drug by the National Health Service (NHS) and is now unavailable.

Medical Uses

Zaleplon is slightly effective in insomnia, primarily characterised by difficulty falling asleep. Zaleplon significantly reduces the time required to fall asleep by improving sleep latency and may therefore facilitate sleep induction rather than sleep maintenance. Due to its ultrashort elimination half-life, zaleplon may not be effective in reducing premature awakenings; however, it may be administered to alleviate middle-of-the-night awakenings. However, zaleplon has not been empirically shown to increase total sleep time.

It may result in an impaired ability to drive the next day, though it has proven promising when compared to other sedative/hypnotics and next-day residual sedation. It may have advantages over benzodiazepines with fewer adverse effects.

Neither zaleplon, nor any nonbenzodiazepine hypnotic class medication should be combined with alcohol, as both modulate GABAA receptor sites, and in a synergistic manner increase the chances of fatal respiratory depression and asphyxiation from vomiting.

Special Populations

Zaleplon is not recommended for chronic use in the elderly. The elderly are more sensitive to the adverse effects of zaleplon such as cognitive side effects. Zaleplon may increase the risk of injury among the elderly. It should not be used while in pregnancy or lactation, and in patients with a history of alcohol or drug abuse, psychotic illness or depression, clinicians should devote more attention.

When compared with benzodiazepines, nonbenzodiazepines (including zaleplon) offer few significant advantages in efficacy and tolerability among elderly individuals. Long-term use of sedative/hypnotics for insomnia has traditionally been discouraged for reasons that include concerns about addiction and rebound insomnia, as well to the risk of side effects associated to GABAA agonists, such as cognitive impairment, anterograde amnesia, daytime sedation, musculoskeletal impairment, and subsequently an increased risk of harm to oneself (e.g. falling) and to others (e.g. automotive accidents). Though, quite obviously as the body and brain age, these aforementioned phenomena are expected events, as they occur daily regardless of ingestion of a sedative/hypnotic. Thus, statistically significant and empirical evidence are arguably still absent as dramatic precautions and conclusions are drawn irrespective of the debilitating realities that accompany insomnia and the fact that these medicines do indeed provide assistance to millions of elderly individuals. It is important to distinguish between the extrapolation of potential side effects relative to the vast number of examples, wherein the sedative/hypnotic has proven therapeutically beneficial and appropriate.

In addition, some contend the efficacy and safety of long-term use of these agents remains to be enumerated, but nothing concrete suggests long-term use poses any direct harm to a person. Still, as of today neither benzodiazepines nor nonbenzodiazepines are recommended for the long-term treatment of insomnia.

Adverse Effects

The adverse effects of zaleplon are similar to the adverse effects of benzodiazepines, although with less next-day sedation, and in two studies zaleplon use was found not to cause an increase in traffic accidents, as compared to other hypnotics currently on the market.

Sleeping pills, including zaleplon, have been associated with an increased risk of death.

Available data cannot provide a reliable estimate of the incidence of dependence during treatment at recommended doses of zaleplon (typically 5-20 mg before bed). Other sedative/hypnotics have been associated with various signs and symptoms of a withdrawal syndrome, following abrupt discontinuation, ranging from mild dysphoria and insomnia to more serious cases that include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. Following abrupt cessation, the seizure threshold is further lowered, wherein coma and death are possible outcomes if untreated.

Some evidence suggests zaleplon is not as chemically reinforcing and exhibits far fewer rebound effects when compared with other nonbenzodiazepines, or Z-drugs.

Interactions

Cimetidine, rifampicin, and thioridazine cause interactions with zaleplon.

Cimetidine and grapefruit are known to increase blood plasma concentrations of benzodiazepines metabolized by the P450 CYP3A4 liver enzyme (e.g. alprazolam) by extending the time by which the drug leaves the body, effectively extending the half-life and enhancing effects to potentially toxic levels. Thus, given the similarities between zaleplon and benzodiazepines, particularly in effect, and not just chemical structure, it is reasonable to take precautions (e.g. inquire at a pharmacy) before one consumes cimetidine (or grapefruit) while also taking zaleplon.

Pharmacology

Mechanism of Action

Zaleplon is a high-affinity ligand of positive modulator sites of GABAA receptors, which enhances GABAergic inhibition of neurotransmission in the central nervous system. The ultrashort half-life gives zaleplon a unique advantage over other hypnotics because of its lack of next-day residual effects on driving and other performance-related skills. Unlike nonselective benzodiazepine drugs and zopiclone, which distort the sleep pattern, zaleplon appears to induce sleep without disrupting the natural sleep architecture.

A meta-analysis of randomized, controlled clinical trials which compared benzodiazepines against zaleplon or other Z-drugs such as zolpidem, zopiclone, and eszopiclone has found few clear and consistent differences between zaleplon and the benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.

Zaleplon has a pharmacological profile similar to benzodiazepines, characterized by an increase in slow wave deep sleep (SWDS) with rapid onset of hypnotic action. Zaleplon is a full agonist for the benzodiazepine α1 receptor located on the GABAA receptor complex in the body, with lower affinity for the α2 and α3 subsites. It selectively enhances the action of GABA similar to, but more selectively than benzodiazepines. Zaleplon, although not a benzodiazepine, maintains a very similar pharmacological profile nonetheless, known for inducing hypnotic effects by α1 subreceptor sites, anxiolytic and muscle relaxant effects via α2 and α3 subsites, with negligible anticonvulsant properties (via α5 subsite), as zaleplon action is modulated at benzodiazepine receptor sites. The elimination half-life of zaleplon is about 1-1.5 hours. The absorption rate of zaleplon is rapid and the onset of therapeutic effects is typically breached within 5-15 minutes following ingestion.

Zaleplon should be understood as an ultrashort-acting sedative-hypnotic drug for the treatment of insomnia. Zaleplon increases EEG power density in the δ-frequency band and a decrease in the energy of the θ-frequency band.

Pharmacokinetics

Zaleplon is primarily metabolised by aldehyde oxidase, and its half-life can be affected by substances which inhibit or induce aldehyde oxidase. Taken orally, zaleplon reaches full concentration in about one hour. It is extensively metabolised into 5-oxozaleplon and 5-oxodesethylzaleplon (the latter via desethylzaleplon), with less than 1% of it excreted intact in urine.

Chemistry

Pure zaleplon in its solid state is a white to off-white powder with very low solubility in water, as well as low solubility in ethanol and propylene glycol. It has a constant octanol-water partition coefficient of log P = 1.23 in the pH range between 1 and 7.

It is classified as a pyrazolopyrimidine.

Society and Culture

Recreational Use

Zaleplon has the potential to be a drug of recreational use, and has been found to have an addictive potential similar to benzodiazepine and benzodiazepine-like hypnotics. The mind- and judgement-altering effects of zaleplon are similar to those of many benzodiazepines, but the fast-acting nature and short half-life of the chemical mean high doses set on much more quickly and last for short periods of time (usually from 45 to 60 minutes).

Some individuals use a different delivery method than prescribed, such as insufflation, to induce effects faster.

A common effect of recreational zaleplon use is the occurrence of (typically short-lived) hallucinations. Fewer visual and auditory hallucinations/disruptions occur with the use of zaleplon than with other Z-drugs, like zolpidem.[citation needed] Anterograde amnesia can occur and can cause one to lose track of the amount of zaleplon already ingested, prompting the ingesting of more than originally planned. However, continuous ingestion is extremely unlikely precisely because of zaleplon’s quick onset of action.

The combination of alcohol and zaleplon can result in fatal respiratory depression and asphyxiation from vomiting.

Aviation Use

The US Federal Aviation Administration (FAA) allows zaleplon with a 12-hour wait period and no more than twice a week, which makes it the sleep medication with the shortest allowed waiting period after use. The substances with the 2nd shortest period, which is of 24 hours, are zolpidem and ramelteon.

Military Use

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

Is a Positive COVID-19 Infection Status Associated with Higher Risk of Depression, Insomnia, & Anxiety in Medical Workers?

Published on by Andrew Marshall1 Comment

Research Paper Title

Prevalence of psychological disorders in the COVID-19 epidemic in China: A real world cross-sectional study.

Background

This study aimed to explore the prevalence of psychological disorders and associated factors at different stages of the COVID-19 epidemic in China.

Methods

The mental health status of respondents was assessed via the Patient Health Questionnaire-9 (PHQ-9), Insomnia Severity Index (ISI) and the Generalised Anxiety Disorder 7 (GAD-7) scale.

Results

5,657 individuals participated in this study. History of chronic disease was a common risk factor for severe present depression (OR 2.2, 95% confidence interval [CI], 1.82-2.66, p < 0.001), anxiety (OR 2.41, 95% CI, 1.97-2.95, p < 0.001), and insomnia (OR 2.33, 95% CI, 1.83-2.95, p < 0.001) in the survey population. Female respondents had a higher risk of depression (OR 1.61, 95% CI, 1.39-1.87, p < 0.001) and anxiety (OR 1.35, 95% CI, 1.15-1.57, p < 0.001) than males. Among the medical workers, confirmed or suspected positive COVID-19 infection as associated with higher scores for depression (confirmed, OR 1.87; suspected, OR 4.13), anxiety (confirmed, OR 3.05; suspected, OR 3.07), and insomnia (confirmed, OR 3.46; suspected, OR 4.71).

Limitations

The cross-sectional design of present study presents inference about causality. The present psychological assessment was based on an online survey and on self-report tools, albeit using established instruments. We cannot estimate the participation rate, since we cannot know how many potential subjects received and opened the link for the survey.

Conclusions

Females, non-medical workers and those with a history of chronic diseases have had higher risks for depression, insomnia, and anxiety. Positive COVID-19 infection status was associated with higher risk of depression, insomnia, and anxiety in medical workers.

Reference

Wang, M., Zhao, Q., Hu, C., Wang, Y., Cao, J., Huang, S., Li, J., Huang, Y., Liang, Q., Guo, Z., Wang, L., Ma, L., Zhang, S., Wang, H.,m Zhu, C., Luo, W., Guo, C., Chen, C., Chen, Y., Xu, K., Yang, H., Ye., L., Wang, Q., Zhan, P., Li, G., Yang, M.J., Fang, Y., Zhu, S. & Yang, Y. (2020) Prevalence of psychological disorders in the COVID-19 epidemic in China: A real world cross-sectional study. Journal of Affective Disorders. 281, pp.312-320. doi: 10.1016/j.jad.2020.11.118. Online ahead of print.

Book: Sleep Medicine and Mental Health

Published on by Andrew MarshallLeave a comment

Book Title:

Sleep Medicine and Mental Health – A Guide for Psychiatrists and Other Healthcare Professionals.

Author(s): Karim Sedky, Racha Nazir, and David Bennett (Editors).

Year: 2020.

Edition: First (1st).

Publisher: Springer.

Type(s): Hardcover and Kindle.

Synopsis:

Advances in sleep medicine research are improving our clinical work for individuals with sleep problems. The aim of this book is to educate psychiatrists and other mental health professionals about the importance of understanding sleep disorders, including their bidirectional relationship with psychiatric conditions.

This book consists of six major sections with seventeen chapters. It is led off by an introduction on the function of sleep, its neurophysiology, and types of sleep problems. Since insomnia represents a common and significant challenge for patients with psychiatric disorders, its clinical presentation and treatments are reviewed in the second section. Cognitive behavioural therapy for insomnia (CBT-I), mindfulness-based CBT, acceptance and commitment therapy (ACT), and the medication management of insomnia are reviewed.

A third section addresses sleep related breathing disorders. The pathology of sleep apnea, its treatments, and therapeutic modalities to address non-compliance with positive pressure ventilation are reviewed. Other sleep disorders such as hypersomnia, circadian rhythm disorders, movement disorders and parasomnias are discussed in the fourth section.

Since features of sleep disorders can vary by age, gender, and trauma history, a fifth section discusses the unique sleep problems associated with children, women, older adults, and veterans. The book concludes with a final section discussing how sleep disorders and psychiatric conditions overlap.

We hope this book highlights the importance of understanding and addressing comorbid sleep disorders among individuals with psychiatric conditions. We are confident that this book will be valuable in helping clinicians improve the management of sleep disorders in their clinical practice.