Category: Mental Health Treatment

What are the Adverse Effects of Venlafaxine?

Published on by Andrew Marshall1 Comment

Introduction

The following list shows the rates of adverse symptoms seen in people taking venlafaxine.

Very Common (>>10% Incidence)

  • Headache:
    • An often transient side effect that is common to most serotonin reuptake inhibitors and that most often occurs at the beginning of therapy or after a dose escalation.
  • Nausea:
    • An adverse effect that is more common with venlafaxine than with the SSRIs.
    • Usually transient and less severe in those receiving the extended release formulations.
  • Insomnia.
  • Asthenia (weakness).
  • Dizziness.
  • Ejaculation disorder:
    • Sexual side effects can be seen with virtually any antidepressant, especially those that inhibit the reuptake of serotonin (including venlafaxine).
  • Somnolence.
  • Dry mouth.
  • Sweating.
  • Withdrawal.

Common (1-10% incidence)

  • Constipation.
  • Nervousness.
  • Abnormal vision.
  • Anorgasmia.
  • Hypertension.
  • Impotence.
  • Paraesthesia.
  • Tremor.
  • Vasodilation.
  • Vomiting.
  • Weight loss.
  • Chills.
  • Palpitations.
  • Confusion.
  • Depersonalisation.
  • Night sweats.
  • Menstrual disorders associated with increased bleeding or increased irregular bleeding (e.g. menorrhagia, metrorrhagia).
  • Urinary frequency increased.
  • Abnormal dreams.
  • Decreased libido.
  • Increased muscle tonus.
  • Yawning.
  • Sweating.
  • Abnormality of accommodation.
  • Abnormal ejaculation/orgasm (males).
  • Urinary hesitancy.
  • Serum cholesterol increased (especially when treatment is prolonged and it may be dose-dependent).

Uncommon (0.1-1% incidence)

  • Face oedema.
  • Intentional injury (self-injury).
  • Malaise.
  • Moniliasis.
  • Neck rigidity.
  • Pelvic pain.
  • Photosensitivity reaction.
  • Suicide attempt.
  • Withdrawal syndrome (Antidepressant Discontinuation Syndrome).
  • Hypotension.
  • Postural hypotension.
  • Syncope.
  • Tachycardia.
  • Bruxism.
  • Ecchymosis.
  • Mucous membrane bleeding.
  • Gastrointestinal bleeding.
  • Abnormal liver function tests.
  • Hyponatraemia.
  • Weight gain.
  • Apathy.
  • Hallucinations.
  • Myoclonus.
  • Rash.
  • Abnormal orgasm (females).
  • Urinary retention (the inability to pass urine).
  • Angioedema.
  • Agitation.
  • Impaired coordination & balance.
  • Alopecia (hair loss).
  • Tinnitus (hearing bells).
  • Proteinuria (protein in urine).

Rare (0.01-0.1% incidence)

  • Syndrome of inappropriate antidiuretic hormone secretion (SIADH).
  • Thrombocytopenia.
  • Prolonged bleeding time.
  • Seizures.
  • Mania.
  • Neuroleptic malignant syndrome (NMS).
  • Serotonin syndrome.
  • Akathisia/psychomotor restlessness.
  • Urinary incontinence.

Very Rare (<0.01% incidence)

  • Anaphylaxis.
  • QT prolongation.
  • Ventricular fibrillation.
  • Ventricular tachycardia (including torsades de pointes).
  • Pancreatitis.
  • Blood dyscrasias (including agranulocytosis, aplastic anaemia, neutropenia and pancytopenia).
  • Elevated serum prolactin.
  • Delirium.
  • Extrapyramidal reactions (including dystonia and dyskinesia).
  • Tardive dyskinesia.
  • Pulmonary eosinophilia.
  • Erythema multiforme.
  • Stevens-Johnson syndrome.
  • Pruritus.
  • Urticaria.
  • Toxic epidermal necrolysis.
  • Angle closure glaucoma.

What is Valproate?

Published on by Andrew Marshall18 Comments

Introduction

Valproate and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalised seizures. They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.

Common side effects of valproate include nausea, vomiting, sleepiness, and dry mouth. Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended. Other serious risks include pancreatitis and an increased suicide risk. Valproate is known to cause serious abnormalities in babies if taken during pregnancy, and as such it is not typically recommended for women of childbearing age who have migraines.

Valproate’s precise mechanism of action is unclear. Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, and inhibiting histone deacetylases. Valproic acid is a branched short-chain fatty acid (SCFA) made from valeric acid.

Valproate was first made in 1881 and came into medical use in 1962. It is on the World Health Organisation’s (WHO’s) List of Essential Medicines and is available as a generic medication. It is marketed under the brand names Depakote, among others. In 2018, it was the 131st most commonly prescribed medication in the United States, with more than 5 million prescriptions.

Brief History

Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian. Valproic acid is a carboxylic acid, a clear liquid at room temperature. For many decades, its only use was in laboratories as a “metabolically inert” solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for anti-seizure activity. He found it prevented pentylenetetrazol-induced convulsions in laboratory rats. It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide. Valproic acid has also been used for migraine prophylaxis and bipolar disorder.

Terminology

Valproic acid (VPA) is an organic weak acid. The conjugate base is valproate. The sodium salt of the acid is sodium valproate and a coordination complex of the two is known as valproate semisodium.

Medical Uses

It is used primarily to treat epilepsy and bipolar disorder. It is also used to prevent migraine headaches.

Epilepsy

Valproate has a broad spectrum of anticonvulsant activity, although it is primarily used as a first-line treatment for tonic-clonic seizures, absence seizures and myoclonic seizures and as a second-line treatment for partial seizures and infantile spasms. It has also been successfully given intravenously to treat status epilepticus.

Mental Illness

Bipolar Disorder

Valproate products are also used to treat manic or mixed episodes of bipolar disorder.

Schizophrenia

A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia.

There is limited evidence that adding valproate to antipsychotics may be effective for overall response and also for specific symptoms, especially in terms of excitement and aggression. Valproate was associated with a number of adverse events among which sedation and dizziness appeared more frequently than in the control groups.

Dopamine Dysregulation Syndrome

Based upon five case reports, valproic acid may have efficacy in controlling the symptoms of the dopamine dysregulation syndrome that arise from the treatment of Parkinson’s disease with levodopa.

Migraines

Valproate is also used to prevent migraine headaches. Because this medication can be potentially harmful to the fetus, valproate should be considered for those able to become pregnant only after the risks have been discussed.

Other

The medication has been tested in the treatment of AIDS and cancer, owing to its histone-deacetylase-inhibiting effects.

Adverse Effects

Most common adverse effects include:

  • Nausea (22%).
  • Drowsiness (19%).
  • Dizziness (12%).
  • Vomiting (12%).
  • Weakness (10%).

Serious adverse effects include:

  • Bleeding.
  • Low blood platelets.
  • Encephalopathy.
  • Suicidal behaviour and thoughts.
  • Low body temperature.

Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and foetal abnormalities.

There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height. Valproic acid can also cause mydriasis, a dilation of the pupils. There is evidence that shows valproic acid may increase the chance of polycystic ovary syndrome (PCOS) in women with epilepsy or bipolar disorder. Studies have shown this risk of PCOS is higher in women with epilepsy compared to those with bipolar disorder. Weight gain is also possible.

Pregnancy

Valproate causes birth defects; exposure during pregnancy is associated with about three times as many major abnormalities as usual, mainly spina bifida with the risks being related to the strength of medication used and use of more than one drug. More rarely, with several other defects, including a “valproate syndrome”. Characteristics of this valproate syndrome include facial features that tend to evolve with age, including a triangle-shaped forehead, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth. While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.

Children of mothers taking valproate during pregnancy are at risk for lower IQs. Maternal valproate use during pregnancy increased the probability of autism in the offspring compared to mothers not taking valproate from 1.5% to 4.4%. A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%. The normal incidence for autism in the general population is estimated at less than one percent. A 2009 study found that the 3-year-old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.

Sodium valproate has been associated with paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or foetal exposure. This condition resolved after discontinuing valproate therapy.

Women who intend to become pregnant should switch to a different medication if possible, or decrease their dose of valproate. Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although valproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have worse outcomes for the foetus than exposure to valproate). Studies have shown that taking folic acid supplements can reduce the risk of congenital neural tube defects. The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in the European Union, and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available.

Elderly

Valproate in elderly people with dementia caused increased sleepiness. More people stopped the medication for this reason. Additional side effects of weight loss and decreased food intake was also associated in one half of people who become sleepy.

Contraindications

Contraindications include:

  • Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related.
  • Known hypersensitivity to valproate or any of the ingredients used in the preparation.
  • Urea cycle disorders.
  • Hepatic porphyria.
  • Hepatotoxicity.
  • Mitochondrial disease.
  • Pancreatitis.
  • Porphyria.

Interactions

Valproate inhibits CYP2C9, glucuronyl transferase, and epoxide hydrolase and is highly protein bound and hence may interact with drugs that are substrates for any of these enzymes or are highly protein bound themselves. It may also potentiate the CNS depressant effects of alcohol. It should not be given in conjunction with other antiepileptics due to the potential for reduced clearance of other antiepileptics (including carbamazepine, lamotrigine, phenytoin and phenobarbitone) and itself. It may also interact with:

  • Aspirin: may increase valproate concentrations. May also interfere with valproate’s metabolism.
  • Benzodiazepines: may cause CNS depression and there are possible pharmacokinetic interactions.
  • Carbapenem antibiotics: reduces valproate levels, potentially leading to seizures.
  • Cimetidine: inhibits valproate’s metabolism in the liver, leading to increased valproate concentrations.
  • Erythromycin: inhibits valproate’s metabolism in the liver, leading to increased valproate concentrations.
  • Ethosuximide: may increase ethosuximide concentrations and lead to toxicity.
  • Felbamate: may increase plasma concentrations of valproate.
  • Mefloquine: may increase valproate metabolism combined with the direct epileptogenic effects of mefloquine.
  • Oral contraceptives: may reduce plasma concentrations of valproate.
  • Primidone: may accelerate metabolism of valproate, leading to a decline of serum levels and potential breakthrough seizure.
  • Rifampin: increases the clearance of valproate, leading to decreased valproate concentrations
  • Warfarin: may increase warfarin concentration and prolong bleeding time.
  • Zidovudine: may increase zidovudine serum concentration and lead to toxicity.

Overdose and Toxicity

Excessive amounts of valproic acid can result in sleepiness, tremor, stupor, respiratory depression, coma, metabolic acidosis, and death. In general, serum or plasma valproic acid concentrations are in a range of 20-100 mg/l during controlled therapy, but may reach 150-1500 mg/l following acute poisoning. Monitoring of the serum level is often accomplished using commercial immunoassay techniques, although some laboratories employ gas or liquid chromatography. In contrast to other antiepileptic drugs, at present there is little favourable evidence for salivary therapeutic drug monitoring. Salivary levels of valproic acid correlate poorly with serum levels, partly due to valproate’s weak acid property (pKa of 4.9).

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body. Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored. Supplemental L-carnitine is indicated in patients having an acute overdose and also prophylactically in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly than L-carnitine.

Pharmacology

Pharmacodynamics

Although the mechanism of action of valproate is not fully understood, traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA). The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate. In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic neurotransmitter, GABA, possibly by inhibiting GABA degradative enzymes, such as GABA transaminase, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells.

Prevention of neurotransmitter-induced hyperexcitability of nerve cells, via Kv7.2 channel and AKAP5, may also contribute to its mechanism. Also, it has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.

It also has histone-deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid. Intermediate molecules mediating these effects include VEGF, BDNF, and GDNF.

Endocrine Actions

Valproic acid has been found to be an antagonist of the androgen and progesterone receptors, and hence as a nonsteroidal antiandrogen and antiprogestogen, at concentrations much lower than therapeutic serum levels. In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses oestrogen concentrations. These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.

Valproic acid has been found to directly stimulate androgen biosynthesis in the gonads via inhibition of histone deacetylases and has been associated with hyperandrogenism in women and increased 4-androstenedione levels in men. High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.

Metabolism

The vast majority of valproate metabolism occurs in the liver. In adult patients taking valproate alone, 30-50% of an administered dose is excreted in urine as a glucuronide conjugate. The other major pathway in the metabolism of valproate is mitochondrial beta-oxidation, which typically accounts for over 40% of an administered dose. Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose of valproate is excreted unchanged (i.e. as valproate) in urine.

Valproate is known to be metabolized by the Cytochrome P450 enzymes: CYP2A6, CYP2B6, CYP2C9, and CYP3A5. It is also known to be metabolised by the UDP-glucuronosyltransferase enzymes: UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15.[70] Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include: 2-ene-valproic acid, 3Z-ene-valproic acid, 3E-ene-valproic acid, 4-ene-valproic acid, valproic acid β-O-glucuronide, 3-oxovalproic acid, 3-hydroxyvalproic acid, 4-hydroxyvalproic acid, 5-hydroxyvalproic acid, and valproyl-CoA, among others.

Chemistry

Valproic acid is a branched short-chain fatty acid and the 2-n-propyl derivative of valeric acid.

Society and Culture

Valproate is available as a generic medication.

Off-Label Uses

In 2012, pharmaceutical company Abbott paid $1.6 billion in fines to US federal and state governments for illegal promotion of off-label uses for Depakote, including the sedation of elderly nursing home residents.

Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.

Formulations

Valproate exists in two main molecular variants: sodium valproate and valproic acid without sodium (often implied by simply valproate). A mixture between these two is termed semisodium valproate. It is unclear whether there is any difference in efficacy between these variants, except from the fact that about 10% more mass of sodium valproate is needed than valproic acid without sodium to compensate for the sodium itself.

Brand Names of Valproic Acid

Branded products include:

  • Absenor (Orion Corporation Finland).
  • Convulex (G.L. Pharma GmbH Austria).
  • Depakene (Abbott Laboratories in US and Canada).
  • Depakine (Sanofi Aventis France).
  • Depakine (Sanofi Synthelabo Romania).
  • Depalept (Sanofi Aventis Israel).
  • Deprakine (Sanofi Aventis Finland).
  • Encorate (Sun Pharmaceuticals India).
  • Epival (Abbott Laboratories US and Canada).
  • Epilim (Sanofi Synthelabo Australia and South Africa).
  • Stavzor (Noven Pharmaceuticals Inc.).
  • Valcote (Abbott Laboratories Argentina).
  • Valpakine (Sanofi Aventis Brazil).
  • Orfiril (Desitin Arzneimittel GmbH Norway).

Brand names of sodium valproate

  • Portugal:
    • Tablets – Diplexil-R by Bial.
  • United States:
    • Intravenous injection – Depacon by Abbott Laboratories.
    • Syrup – Depakene by Abbott Laboratories. (Note Depakene capsules are valproic acid).
    • Depakote tablets are a mixture of sodium valproate and valproic acid.
    • Tablets – Eliaxim by Bial.
  • Australia:
    • Epilim Crushable Tablets Sanofi.
    • Epilim Sugar Free Liquid Sanofi.
    • Epilim Syrup Sanofi.
    • Epilim Tablets Sanofi.
    • Sodium Valproate Sandoz Tablets Sanofi.
    • Valpro Tablets Alphapharm.
    • Valproate Winthrop Tablets Sanofi.
    • Valprease tablets Sigma.
  • New Zealand:
    • Epilim by Sanofi-Aventis.
  • UK:
    • Depakote Tablets (as in USA).
    • Tablets – Orlept by Wockhardt and Epilim by Sanofi.
    • Oral solution – Orlept Sugar Free by Wockhardt and Epilim by Sanofi.
    • Syrup – Epilim by Sanofi-Aventis.
    • Intravenous injection – Epilim Intravenous by Sanofi.
    • Extended release tablets – Epilim Chrono by Sanofi is a combination of sodium valproate and valproic acid in a 2.3:1 ratio.
    • Enteric-coated tablets – Epilim EC200 by Sanofi is a 200-mg sodium valproate enteric-coated tablet.
  • UK Only:
    • Capsules – Episenta prolonged release by Beacon.
    • Sachets – Episenta prolonged release by Beacon.
    • Intravenous solution for injection – Episenta solution for injection by Beacon.
  • Germany, Switzerland, Norway, Finland, Sweden:
    • Tablets – Orfiril by Desitin Pharmaceuticals.
    • Intravenous injection – Orfiril IV by Desitin Pharmaceuticals.
  • South Africa:
    • Syrup – Convulex by Byk Madaus.
    • Tablets – Epilim by Sanofi-synthelabo.
  • Malaysia:
    • Tablets – Epilim by Sanofi-Aventis..
  • Romania:
    • Companies are SANOFI-AVENTIS FRANCE, GEROT PHARMAZEUTIKA GMBH and DESITIN ARZNEIMITTEL GMBH.
    • Types are Syrup, Extended release mini tablets, Gastric resistant coated tablets, Gastric resistant soft capsules, Extended release capsules, Extended release tablets and Extended release coated tablets.
  • Canada:
    • Intravenous injection – Epival or Epiject by Abbott Laboratories.
    • Syrup – Depakene by Abbott Laboratories its generic formulations include Apo-Valproic and ratio-Valproic.
  • Japan:
    • Tablets – Depakene by Kyowa Hakko Kirin.
    • Extended release tablets – Depakene-R by Kyowa Hakko Kogyo and Selenica-R by Kowa.
    • Syrup – Depakene by Kyowa Hakko Kogyo.
  • Europe:
    • In much of Europe, Dépakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.
  • Taiwan:
    • Tablets (white round tablet) – Depakine (Chinese: 帝拔癲; pinyin: di-ba-dian) by Sanofi Winthrop Industrie (France)>
  • Iran:
    • Tablets – Epival 200 (enteric coated tablet) and Epival 500 (extended release tablet) by Iran Najo.
    • Slow release tablets – Depakine Chrono by Sanofi Winthrop Industrie (France).
  • Israel:
    • Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above. Manufactured and distributed by Sanofi-Aventis.
  • India, Russia and CIS countries:
    • Valparin Chrono by Torrent Pharmaceuticals India.
    • Valprol CR by Intas Pharmaceutical (India).
    • Encorate Chrono by Sun Pharmaceutical (India).
    • Serven Chrono by Leeven APL Biotech (India).

Brand Names of Valproate Semisodium

  • Brazil – Depakote by Abbott Laboratories and Torval CR by Torrent do Brasil.
  • Canada – Epival by Abbott Laboratories.
  • Mexico – Epival and Epival ER (extended release) by Abbott Laboratories.
  • United Kingdom – Depakote (for psychiatric conditions) and Epilim (for epilepsy) by Sanofi-Aventis and generics.
  • United States – Depakote and Depakote ER (extended release) by Abbott Laboratories and generics.
  • India – Valance and Valance OD by Abbott Healthcare Pvt Ltd, Divalid ER by Linux laboratories Pvt Ltd, Valex ER by Sigmund Promedica, Dicorate by Sun Pharma.
  • Germany – Ergenyl Chrono by Sanofi-Aventis and generics.
  • Chile – Valcote and Valcote ER by Abbott Laboratories.
  • France and other European countries — Depakote.
  • Peru – Divalprax by AC Farma Laboratories.
  • China – Diprate OD.

What is Zuclopenthixol?

Published on by Andrew Marshall3 Comments

Introduction

Zuclopenthixol (brand names Cisordinol, Clopixol and others), also known as zuclopentixol, is a medication used to treat schizophrenia and other psychoses.

It is classed, pharmacologically, as a typical antipsychotic. Chemically it is a thioxanthene. It is the cis-isomer of clopenthixol (Sordinol, Ciatyl). Clopenthixol was introduced in 1961, while zuclopenthixol was introduced in 1978.

Zuclopenthixol is a D1 and D2 antagonist, α1-adrenergic and 5-HT2 antagonist. While it is approved for use in Australia, Canada, Ireland, India, New Zealand, Singapore, South Africa and the UK it is not approved for use in the United States.

Brief History

Zuclopenthixol was introduced by Lundbeck in 1978.

Medical Uses

Available Forms

Zuclopenthixol is available in three major preparations:

  1. As zuclopenthixol decanoate (Clopixol Depot, Cisordinol Depot), it is a long-acting intramuscular (IM) injection.
    1. Its main use is as a long-acting injection given every two or three weeks to people with schizophrenia who have a poor compliance with medication and suffer frequent relapses of illness.
    2. There is some evidence it may be more helpful in managing aggressive behaviour.
  2. As zuclopenthixol acetate (Clopixol-Acuphase, Cisordinol-Acutard), it is a shorter-acting intramuscular injection used in the acute sedation of psychotic inpatients.
    1. The effect peaks at 48-72 hours providing 2-3 days of sedation.
  3. As zuclopenthixol dihydrochloride (Clopixol, Cisordinol), it is a tablet used in the treatment of schizophrenia in those who are compliant with oral medication.

It is also used in the treatment of acute bipolar mania.

Dosing

As a long-acting injection, zuclopenthixol decanoate comes in a 200 mg and 500 mg ampoule. Doses can vary from 50 mg weekly to the maximum licensed dose of 600 mg weekly. In general, the lowest effective dose to prevent relapse is preferred. The interval may be shorter as a patient starts on the medication before extending to 3 weekly intervals subsequently. The dose should be reviewed and reduced if side effects occur, though in the short-term an anticholinergic medication benztropine may be helpful for tremor and stiffness, while diazepam may be helpful for akathisia. 100 mg of zuclopenthixol decanoate is roughly equivalent to 20 mg of flupentixol decanoate or 12.5 mg of fluphenazine decanoate.

In acutely psychotic and agitated inpatients, 50-200 mg of zuclopenthixol acetate may be given for a calming effect over the subsequent three days, with a maximum dose of 400 mg in total to be given. As it is a long-acting medication, care must be taken not to give an excessive dose.

In oral form zuclopenthixol is available in 10, 25 and 40 mg tablets, with a dose range of 20-60 mg daily.

Side Effects

Chronic administration of zuclopenthixol (30 mg/kg/day for two years) in rats resulted in small, but significant, increases in the incidence of thyroid parafollicular carcinomas and, in females, of mammary adenocarcinomas and of pancreatic islet cell adenomas and carcinomas. An increase in the incidence of mammary adenocarcinomas is a common finding for D2 antagonists which increase prolactin secretion when administered to rats. An increase in the incidence of pancreatic islet cell tumours has been observed for some other D2 antagonists. The physiological differences between rats and humans with regard to prolactin make the clinical significance of these findings unclear.

Withdrawal syndrome: Abrupt cessation of therapy may cause acute withdrawal symptoms (eg, nausea, vomiting, or insomnia). Symptoms usually begin in 1 to 4 days of withdrawal and subside within 1 to 2 weeks.

Other permanent side effects are similar to many other typical antipsychotics, namely extrapyramidal symptoms as a result of dopamine blockade in subcortical areas of the brain. This may result in symptoms similar to those seen in Parkinson’s disease and include a restlessness and inability to sit still known as akathisia, a slow tremor and stiffness of the limbs. Zuclopenthixol is thought to be more sedating than the related flupentixol, though possibly less likely to induce extrapyramidal symptoms than other typical depots. As with other dopamine antagonists, zuclopenthixol may sometimes elevate prolactin levels; this may occasionally result in amenorrhoea or galactorrhoea in severe cases. Neuroleptic malignant syndrome is a rare but potentially fatal side effect. Any unexpected deterioration in mental state with confusion and muscle stiffness should be seen by a physician.

Zuclopenthixol decanoate induces a transient dose-dependent sedation. However, if the patient is switched to maintenance treatment with zuclopenthixol decanoate from oral zuclopenthixol or from IM zuclopenthixol acetate the sedation will be no problem. Tolerance to the unspecific sedative effect develops rapidly.

  • Very common Adverse Effects (≥10% incidence):
    • Dry Mouth.
    • Somnolence.
    • Akathisia.
    • Hyperkinesia.
    • Hypokinesia.
  • Common (1%≤incidence≤10%):
    • Tachycardia.
    • Palpitations.
    • Vertigo.
    • Accommodation disorder.
    • Vision abnormal.
    • Salivary hypersecretion.
    • Constipation.
    • Vomiting.
    • Dyspepsia.
    • Diarrhoea.
    • Asthenia.
    • Fatigue.
    • Malaise.
    • Pain (at the injection site).
    • Increased appetite.
    • Weight gain.
    • Myalgia.
    • Tremor.
    • Dystonia.
    • Hypertonia.
    • Dizziness.
    • Headache.
    • Paraesthesia.
    • Disturbance in attention.
    • Amnesia.
    • Gait abnormal.
    • Insomnia.
    • Depression.
    • Anxiety.
    • Nervousness.
    • Abnormal dreams.
    • Agitation.
    • Libido decreased.
    • Nasal congestion.
    • Dyspnoea.
    • Hyperhidrosis.
    • Pruritus.
  • Uncommon (0.1%≤incidence≤1%):
    • Hyperacusis.
    • Tinnitus.
    • Oculogyration.
    • Mydriasis.
    • Abdominal pain.
    • Nausea.
    • Flatulence.
    • Thirst.
    • Injection site reaction.
    • Hypothermia.
    • Pyrexia.
    • Liver function test abnormal.
    • Decreased appetite.
    • Weight loss.
    • Muscle rigidity.
    • Trismus.
    • Torticollis.
    • Tardive dyskinesia.
    • Hyperreflexia.
    • Dyskinesia.
    • Parkinsonism.
    • Syncope.
    • Ataxia.
    • Speech disorder.
    • Hypotonia.
    • Convulsion.
    • Migraine.
    • Apathy.
    • Nightmare.
    • Libido increased.
    • Confusional state.
    • Ejaculation failure.
    • Erectile dysfunction.
    • Female orgasmic disorder.
    • Vulvovaginal.
    • Dryness.
    • Rash.
    • Photosensitivity reaction.
    • Pigmentation disorder.
    • Seborrhoea.
    • Dermatitis.
    • Purpura.
    • Hypotension.
    • Hot flush.
  • Rare (0.01%≤incidence≤0.1%):
    • Thrombocytopenia.
    • Neutropenia.
    • Leukopenia.
    • Agranulocytosis.
    • Electrocardiogram QT prolonged.
    • Hyperprolactinaemia.
    • Hypersensitivity.
    • Anaphylactic reaction.
    • Hyperglycaemia.
    • Glucose tolerance impaired.
    • Hyperlipidaemia.
    • Gynaecomastia.
    • Galactorrhoea.
    • Amenorrhoea.
    • Priapism.
    • Withdrawal symptoms.
  • Very rare (incidence<0.01%):
    • Cholestatic hepatitis.
    • Jaundice.
    • Neuroleptic malignant syndrome.
    • Venous thromboembolism.

Pharmacology

Pharmacodynamics

Zuclopenthixol antagonises both dopamine D1 and D2 receptors, α1-adrenoceptors and 5-HT2 receptors with a high affinity, but has no affinity for cholinergic muscarine receptors. It weakly antagonises the histamine (H1) receptor but has no α2-adrenoceptor blocking activity.

Evidence from in vitro work and clinical sources (i.e. therapeutic drug monitoring databases) suggests that both CYP2D6 and CYP3A4 play important roles in zuclopenthixol metabolism.

What is Ziprasidone?

Published on by Andrew Marshall12 Comments

Introduction

Ziprasidone, sold under the brand name Geodon among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder.

It may be used by mouth and by injection into a muscle (IM). The IM form may be used for acute agitation in people with schizophrenia.

Common side effects include dizziness, drowsiness, dry mouth, and twitches. Although it can also cause weight gain, the risk is much lower than for other atypical antipsychotics. How it works is not entirely clear but is believed to involve effects on serotonin and dopamine in the brain.

Ziprasidone was approved for medical use in the United States in 2001. The pills are made up of the hydrochloride salt, ziprasidone hydrochloride. The intramuscular form is the mesylate, ziprasidone mesylate trihydrate, and is provided as a lyophilised powder. In 2017, it was the 261st most commonly prescribed medication in the United States, with more than one million prescriptions.

Brief History

Ziprasidone is chemically similar to risperidone, of which it is a structural analogue. It was first synthesized in 1987 at the Pfizer central research campus in Groton, Connecticut.

Phase I trials started in 1995. In 1998 ziprasidone was approved in Sweden. After the FDA raised concerns about long QT syndrome, more clinical trials were conducted and submitted to the FDA, which approved the drug on 05 February 2001.

Medical Uses

Ziprasidone is approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia as well as acute mania and mixed states associated with bipolar disorder. Its intramuscular injection form is approved for acute agitation in schizophrenic patients for whom treatment with just ziprasidone is appropriate.

In a 2013 study in a comparison of 15 antipsychotic drugs in effectiveness in treating schizophrenic symptoms, ziprasidone demonstrated mild-standard effectiveness. 15% more effective than lurasidone and iloperidone, approximately as effective as chlorpromazine and asenapine, and 9-13% less effective than haloperidol, quetiapine, and aripiprazole. Ziprasidone is effective in the treatment of schizophrenia, though evidence from the CATIE trials suggests it is less effective than olanzapine, and equally as effective compared to quetiapine. There are higher discontinuation rates for lower doses of ziprasidone, which are also less effective than higher doses.

Adverse Effects

Ziprasidone (and all other second generation antipsychotics (SGAs)) received a black box warning due to increased mortality in elderly patients with dementia-related psychosis.

Sleepiness and headache are very common adverse effects (>10%).

Common adverse effects (1-10%), include producing too much saliva or having dry mouth, runny nose, respiratory disorders or coughing, nausea and vomiting, stomach aches, constipation or diarrhoea, loss of appetite, weight gain (but the smallest risk for weight gain compared to other antipsychotics), rashes, fast heart beats, blood pressure falling when standing up quickly, muscle pain, weakness, twitches, dizziness, and anxiety. Extrapyramidal symptoms are also common and include tremor, dystonia (sustained or repetitive muscle contractions), akathisia (the feeling of a need to be in motion), parkinsonism, and muscle rigidity; in a 2013 meta-analysis of 15 antipsychotic drugs, ziprasidone ranked 8th for such side effects.

Ziprasidone is known to cause activation into mania in some bipolar patients.

This medication can cause birth defects, according to animal studies, although this side effect has not been confirmed in humans.

Recently, the FDA required the manufacturers of some atypical antipsychotics to include a warning about the risk of hyperglycaemia and Type II diabetes with atypical antipsychotics. Some evidence suggests that ziprasidone does not cause insulin resistance to the degree of other atypical antipsychotics, such as olanzapine. Weight gain is also less of a concern with ziprasidone compared to other atypical antipsychotics. In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI > 27) actually had a mean weight loss overall. According to the manufacturer insert, ziprasidone caused an average weight gain of 2.2 kg (4.8 lbs), which is significantly lower than other atypical antipsychotics, making this medication better for patients that are concerned about their weight. In December 2014, the FDA warned that ziprasidone could cause a potentially fatal skin reaction, Drug Reaction with Eosinophilia and Systemic Symptoms, although this was believed to occur only rarely.

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Pharmacology

Pharmacodynamics

Correspondence to Clinical Effects

Ziprasidone mostly affects the receptors of dopamine (D2), serotonin (5-HT2A, partially 5-HT1A, 5-HT2C, and 5-HT1D) and epinephrine/norepinephrine (α1) to a high degree, while of histamine (H1) – moderately. It also somewhat inhibits reuptake of serotonin and norepinephrine, though not dopamine.

Ziprasidone’s efficacy in treating the positive symptoms of schizophrenia is believed to be mediated primarily via antagonism of the dopamine receptors, specifically D2. Blockade of the 5-HT2A receptor may also play a role in its effectiveness against positive symptoms, though the significance of this property in antipsychotic drugs is still debated among researchers. Blockade of 5-HT2A and 5-HT2C and activation of 5-HT1A as well as inhibition of the reuptake of serotonin and norepinephrine may all contribute to its ability to alleviate negative symptoms. The relatively weak antagonistic actions of ziprasidone on the α1-adrenergic receptor likely in part explains some of its side effects, such as orthostatic hypotension. Unlike many other antipsychotics, ziprasidone has no significant affinity for the mACh receptors, and as such lacks any anticholinergic side effects. Like most other antipsychotics, ziprasidone is sedating due primarily to serotonin and dopamine blockade.

Pharmacokinetics

The systemic bioavailability of ziprasidone is 100% when administered intramuscularly and 60% when administered orally without food.

After a single dose intramuscular administration, the peak serum concentration typically occurs at about 60 minutes after the dose is administered, or earlier. Steady state plasma concentrations are achieved within one to three days. Exposure increases in a dose-related manner and following three days of intramuscular dosing, little accumulation is observed.

The bioavailability of the drug is reduced by approximately 50% if a meal is not eaten before Ziprasidone ingestion.

Ziprasidone is hepatically metabolized by aldehyde oxidase; minor metabolism occurs via cytochrome P450 3A4 (CYP3A4). Medications that induce (e.g. carbamazepine) or inhibit (e.g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.

Its biological half-life time is 10 hours at doses of 80-120 milligrams.

Society and Culture

Lawsuit

In September 2009, the US Justice Department announced that Pfizer had been ordered to pay a historic fine of $2.3 billion as a penalty for fraudulent marketing of several drugs, including Geodon. Pfizer had illegally promoted Geodon and submitted false claims to government health care programs for uses that were not medically accepted indications. The civil settlement also resolves allegations that Pfizer paid kickbacks to health care providers to induce them to prescribe Geodon, as well as other drugs. This was the largest civil fraud settlement in history against a pharmaceutical company.

What is an Atypical Antipsychotic?

Published on by Andrew Marshall40 Comments

Introduction

The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin-dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as major tranquilisers and neuroleptics, although the latter is usually reserved for the typical antipsychotics) largely introduced after the 1970s and used to treat psychiatric conditions.

Some atypical antipsychotics have received regulatory approval (e.g. by the Food and Drug Administration (FDA) of the US, the Therapeutic Goods Administration (TGA) of Australia, the Medical and Healthcare Products Regulatory Agency (MHRA) of the UK) for schizophrenia, bipolar disorder, autism, and as an adjunct in major depressive disorder.

Both generations of medication tend to block receptors in the brain’s dopamine pathways. Atypicals are less likely than haloperidol – the most widely used typical antipsychotic – to cause extrapyramidal motor control disabilities in patients such as unsteady Parkinson’s disease-type movements, body rigidity, and involuntary tremors. However, only a few of the atypicals have been demonstrated to be superior to lesser-used, low-potency first-generation antipsychotics in this regard.

As experience with these agents has grown, several studies have questioned the utility of broadly characterising antipsychotic drugs as “atypical/second generation” as opposed to “first generation,” noting that each agent has its own efficacy and side-effect profile. It has been argued that a more nuanced view in which the needs of individual patients are matched to the properties of individual drugs is more appropriate. Although atypical antipsychotics are thought to be safer than typical antipsychotics, they still have severe side effects, including tardive dyskinesia (a serious movement disorder), neuroleptic malignant syndrome, and increased risk of stroke, sudden cardiac death, blood clots, and diabetes. Significant weight gain may occur. Critics have argued that “the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction.”

Brief History

The first major tranquiliser or antipsychotic medication, chlorpromazine (Thorazine), a typical antipsychotic, was discovered in 1951 and introduced into clinical practice shortly thereafter. Clozapine (Clozaril), an atypical antipsychotic, fell out of favour due to concerns over drug-induced agranulocytosis. Following research indicating its effectiveness in treatment-resistant schizophrenia and the development of an adverse event monitoring system, clozapine re-emerged as a viable antipsychotic. According to Barker (2003), the three most-accepted atypical drugs are clozapine, risperidone, and olanzapine. However, he goes on to explain that clozapine is usually the last resort when other drugs fail. Clozapine can cause agranulocytosis (a decreased number of white blood cells), requiring blood monitoring for the patient. Despite the effectiveness of clozapine for treatment-resistant schizophrenia, agents with a more favourable side-effect profile were sought-after for widespread use. During the 1990s, olanzapine, risperidone, and quetiapine were introduced, with ziprasidone and aripiprazole following in the early 2000s. The atypical anti-psychotic paliperidone was approved by the FDA in late 2006.

The atypical antipsychotics have found favour among clinicians and are now considered to be first-line treatments for schizophrenia and are gradually replacing the typical antipsychotics. In the past, most researchers have agreed that the defining characteristics of atypical antipsychotics are the decreased incidence of extrapyramidal side effects (EPS) and an absence of sustained prolactin elevation.

The terminology can still be imprecise. The definition of “atypicality” was based upon the absence of extrapyramidal side effects, but there is now a clear understanding that atypical antipsychotics can still induce these effects (though to a lesser degree than typical antipsychotics). Recent literature focuses more upon specific pharmacological actions and less upon categorization of an agent as “typical” or “atypical”. There is no clear dividing line between the typical and atypical antipsychotics therefore categorisation based on the action is difficult.

More recent research is questioning the notion that second-generation antipsychotics are superior to first generation typical anti-psychotics. Using a number of parameters to assess quality of life, Manchester University researchers found that typical antipsychotics were no worse than atypical antipsychotics. The research was funded by the National Health Service (NHS) of the UK. Because each medication (whether first or second generation) has its own profile of desirable and adverse effects, a neuropsychopharmacologist may recommend one of the older (“typical” or first generation) or newer (“atypical” or second generation) antipsychotics alone or in combination with other medications, based on the symptom profile, response pattern, and adverse effects history of the individual patient.

Medical Uses

Atypical antipsychotics are typically used to treat schizophrenia or bipolar disorder. They are also frequently used to treat agitation associated with dementia, anxiety disorder, autism spectrum disorder, and obsessive-compulsive disorder (an off-label use). In dementia, they should only be considered after other treatments have failed and if the patient is a risk to themselves and/or others.

Schizophrenia

The first-line psychiatric treatment for schizophrenia is antipsychotic medication, which can reduce the positive symptoms of schizophrenia in about 8-15 days. Antipsychotics only appear to improve secondary negative symptoms of schizophrenia in the short term and may worsen negative symptoms overall. Overall there is no good evidence that atypical antipsychotics have any therapeutic benefit for treating the negative symptoms of schizophrenia.

There is very little evidence on which to base a risk and benefit assessment of using antipsychotics for long-term treatment.

The choice of which antipsychotic to use for a specific patient is based on benefits, risks, and costs. It is debatable whether, as a class, typical or atypical antipsychotics are better. Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages. There is a good response in 40-50% of patients, a partial response in 30-40%, and treatment resistance (failure of symptoms to respond satisfactorily after six weeks to two of three different antipsychotics) in the remaining 20%. Clozapine is considered a first choice treatment for treatment resistant schizophrenia, especially in the short term; in the longer-terms the risks of adverse effects complicate the choice. In turn, olanzapine, risperidone, and aripiprazole have been recommended for the treatment of first-episode psychosis.

Efficacy in the Treatment of Schizophrenia

The utility of broadly grouping the antipsychotics into first generation and atypical categories has been challenged. It has been argued that a more nuanced view, matching the properties of individual drugs to the needs of specific patients is preferable. While the atypical (second-generation) antipsychotics were marketed as offering greater efficacy in reducing psychotic symptoms while reducing side effects (and extrapyramidal symptoms in particular) than typical medications, the results showing these effects often lacked robustness, and the assumption was increasingly challenged even as atypical prescriptions were soaring. In 2005 the US government body NIMH (National Institute for Mental Health) published the results of a major independent (not funded by the pharmaceutical companies) multi-site, double-blind study (the CATIE project). This study compared several atypical antipsychotics to an older, mid-potency typical antipsychotic, perphenazine, among 1,493 persons with schizophrenia. The study found that only olanzapine outperformed perphenazine in discontinuation rate (the rate at which people stopped taking it due to its effects). The authors noted an apparent superior efficacy of olanzapine to the other drugs in terms of reduction in psychopathology and rate of hospitalizations, but olanzapine was associated with relatively severe metabolic effects such as a major weight gain problem (averaging 9.4 lbs over 18 months) and increases in glucose, cholesterol, and triglycerides. No other atypical studied (risperidone, quetiapine, and ziprasidone) did better than the typical perphenazine on the measures used, nor did they produce fewer adverse effects than the typical antipsychotic perphenazine (a result supported by a meta-analysis by Leucht et al. published in The Lancet), although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%, P=0.002). A phase 2 part of this CATIE study roughly replicated these findings. Compliance has not been shown to be different between the two types. Overall evaluations of the CATIE and other studies have led many researchers to question the first-line prescribing of atypicals over typicals, or even to question the distinction between the two classes.

It has been suggested that there is no validity to the term “second-generation antipsychotic drugs” and that the drugs that currently occupy this category are not identical to each other in mechanism, efficacy, and side-effect profiles.

Bipolar Disorder

In bipolar disorder, SGAs are most commonly used to rapidly control acute mania and mixed episodes, often in conjunction with mood stabilizers (which tend to have a delayed onset of action in such cases) such as lithium and valproate. In milder cases of mania or mixed episodes, mood stabiliser monotherapy may be attempted first. SGAs are also used to treat other aspects of the disorder (such as acute bipolar depression or as a prophylactic treatment) as adjuncts or as a monotherapy, depending on the drug. Both quetiapine and olanzapine have demonstrated significant efficacy in all three treatment phases of bipolar disorder. Lurasidone (trade name Latuda) has demonstrated some efficacy in the acute depressive phase of bipolar disorder.

Major Depressive Disorder

In non-psychotic major depressive disorder (MDD), some SGAs have demonstrated significant efficacy as adjunctive agents; and, such agents include:

  • Aripiprazole.
  • Brexpiprazole.
  • Olanzapine.
  • Quetiapine.
  • Ziprasidone.

Whereas only quetiapine has demonstrated efficacy as a monotherapy in non-psychotic MDD. Olanzapine/fluoxetine is an efficacious treatment in both psychotic and non-psychotic MDD.

Aripiprazole, brexpiprazole, olanzapine, and quetiapine have been approved as adjunct treatment for MDD by the FDA in the United States. Quetiapine and lurasidone have been approved, as monotherapies, for bipolar depression, but as of present, lurasidone has not been approved for MDD.

Autism

Both risperidone and aripiprazole have received FDA labelling for autism.

Dementia and Alzheimer’s Disease

Between May 2007 and April 2008, Dementia and Alzheimer’s together accounted for 28% of atypical antipsychotic use in patients aged 65 or older. The FDA requires that all atypical antipsychotics carry a black box warning that the medication has been associated with an increased risk of mortality in elderly patients. In 2005, the FDA issued an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia. In the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%.

Adverse Effects

The side effects reportedly associated with the various atypical antipsychotics vary and are medication-specific. Generally speaking, atypical antipsychotics are widely believed to have a lower likelihood for the development of tardive dyskinesia than the typical antipsychotics. However, tardive dyskinesia typically develops after long-term (possibly decades) use of antipsychotics. It is not clear if atypical antipsychotics, having been in use for a relatively short time, produce a lower incidence of tardive dyskinesia.

Some of the other side effects that have been suggested is that atypical antipsychotics increase the risk of cardiovascular disease. The research that Kabinoff et al. found that the increase in cardiovascular disease is seen regardless of the treatment they receive, instead it is caused by many different factors such as lifestyle or diet.

Sexual side effects have also been reported when taking atypical antipsychotics. In males antipsychotics reduce sexual interest, impair sexual performance with the main difficulties being failure to ejaculate. In females there may be abnormal menstrual cycles and infertility. In both males and females the breasts may become enlarged and a fluid will sometimes ooze from the nipples. Sexual adverse effects caused by some anti-psychotics are a result of an increase of prolactin. Sulpiride and Amisulpiride, as well as Risperdone and paliperidone (to a lesser extent) cause a high increase of prolactin.

In April 2005, the FDA issued an advisory and subsequent black box warning regarding the risks of atypical anti psychotic use among elderly patients with dementia. The FDA advisory was associated with decreases in the use of atypical antipsychotics, especially among elderly patients with dementia. Subsequent research reports confirmed the mortality risks associated with the use of both conventional and atypical antipsychotics to treat patients with dementia. Consequently, in 2008 the FDA issued although a black box warning for classical neuroleptics. Data on treatment efficacies are strongest for atypical antipsychotics. Adverse effects in patients with dementia include an increased risk of mortality and cerebrovascular events, as well as metabolic effects, extrapyramidal symptoms, falls, cognitive worsening, cardiac arrhythmia, and pneumonia. Conventional antipsychotics may pose an even greater safety risk. No clear efficacy evidence exists to support the use of alternative psychotropic classes (e.g. antidepressants, anticonvulsants).

Atypical antipsychotics may also cause anhedonia.

Drug-Induced OCD

Many different types of medication can create/induce pure OCD in patients that have never had symptoms before. A new chapter about OCD in the DSM-5 (2013) now specifically includes drug-induced OCD.

Atypical antipsychotics (second generation antipsychotics), such as olanzapine (Zyprexa), have been proven to induce de-novo OCD in patients.

Tardive Dyskinesia

All of the atypical antipsychotics warn about the possibility of tardive dyskinesia in their package inserts and in the PDR. It is not possible to truly know the risks of tardive dyskinesia when taking atypicals, because tardive dyskinesia can take many decades to develop and the atypical antipsychotics are not old enough to have been tested over a long enough period of time to determine all of the long-term risks. One hypothesis as to why atypicals have a lower risk of tardive dyskinesia is because they are much less fat-soluble than the typical antipsychotics and because they are readily released from D2 receptor and brain tissue. The typical antipsychotics remain attached to the D2 receptors and accumulate in the brain tissue which may lead to TD.

Both typical and atypical antipsychotics can cause tardive dyskinesia. According to one study, rates are lower with the atypicals at 3.9% per year as opposed to the typicals at 5.5% per year.

Metabolism

Recently, metabolic concerns have been of grave concern to clinicians, patients and the FDA. In 2003, the FDA required all manufacturers of atypical antipsychotics to change their labelling to include a warning about the risks of hyperglycaemia and diabetes with atypical antipsychotics. It must also be pointed out that although all atypicals must carry the warning on their labelling, some evidence shows that atypicals are not equal in their effects on weight and insulin sensitivity. The general consensus is that clozapine and olanzapine are associated with the greatest effects on weight gain and decreased insulin sensitivity, followed by risperidone and quetiapine. Ziprasidone and aripiprazole are thought to have the smallest effects on weight and insulin resistance, but clinical experience with these newer agents is not as developed as that with the older agents. The mechanism of these adverse effects is not completely understood but it is believed to result from a complex interaction between a number of pharmacologic actions of these drugs. Their effects on weight are believed to mostly derive from their actions on the H1 and 5-HT2C receptors, while their effects on insulin sensitivity are believed to be the result of a combination of their effects on body weight (as increased body mass is known to be a risk factor for insulin resistance) and their antagonistic effects on the M3receptor. Some of the newer agents, however, such as risperidone and its metabolite paliperidone, ziprasidone, lurasidone, aripiprazole, asenapine and iloperidone have clinically-insignificant effects on the M3 receptor and appear to carry a lower risk of insulin resistance. Whereas clozapine, olanzapine and quetiapine (indirectly via its active metabolite, norquetiapine) all antagonise the M3 receptor at therapeutic-relevant concentrations.

Recent evidence suggests a role of the α1 adrenoceptor and 5-HT2A receptor in the metabolic effects of atypical antipsychotics. The 5-HT2A receptor, however, is also believed to play a crucial role in the therapeutic advantages of atypical antipsychotics over their predecessors, the typical antipsychotics.

A study by Sernyak and colleagues found that the prevalence of diabetes in atypical antipsychotic treatments was statistically significantly higher than that of conventional treatment. The authors of this study suggest that it is a causal relationship the Kabinoff et al. suggest the findings only suggest a temporal association. Kabinoff et al. suggest that there is insufficient data from large studies to demonstrate a consistent or significant difference in the risk of insulin resistance during treatment with various atypical antipsychotics.

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Pharmacology

Pharmacodynamics

The atypical antipsychotics integrate with the serotonin (5-HT), norepinephrine (α, β), and dopamine (D) receptors in order to effectively treat schizophrenia.

D2 Receptor: Hyperactive dopaminergic activity on D2 receptors in the mesolimbic pathway is responsible for the positive symptoms of schizophrenia (hallucinations, delusions, paranoia). After taking an antipsychotic, antagonism of D2 receptors occurs throughout the entire brain, leading to a number of deleterious side effects from D2 receptor antagonism throughout the entire dopamine pathway system. Unfortunately, it’s not possible to affect D2 receptors only in the mesolimbic pathway. Fortunately, 5-HT2A receptor antagonism reverses these side effects to some extent. Reducing D2 dopaminergic activity in the mesolimbic pathway also results in an anhedonic effect, reducing pleasure, motivation, and the salience of one’s life experience. In the mesocortical pathway to the DLPFC and VMPFC, endogenous D2 receptor dopamine activity is sometimes low in schizophrenia, resulting in cognitive, affective, and, broadly, the negative symptoms of schizophrenia. D2 receptor antagonism here further compounds these problems. In the nigrostriatal pathway, D2 receptor antagonism results in extrapyramidal symptoms. If this antagonism occurs long enough, symptoms of EPS may become permanent, even if antipsychotic use is discontinued. In the tuberoinfundibular pathway, D2 receptor antagonism results in elevated prolactin. If prolactin levels become high enough, hyperprolactinaemia may occur, resulting in sexual dysfunction, weight gain, more rapid demineralisation of bones, and possibly galactorrhea and amenorrhea.

5-HT2A Receptor: When serotonin is released on to postsynaptic 5-HT2A receptors, the dopamine neuron is inhibited, thus acting as a brake on dopamine release. This brake is disrupted through action of a 5-HT2A antagonist, which disinhibits the dopamine neuron, stimulating dopamine release. The result of this is that dopamine competes with antipsychotic D2 antagonistic action at D2 receptors, thereby reducing antagonistic binding there and eliminating or lowering D2 antagonistic effects in several pathways of the dopamine system. In the nigrostratial pathway, it reduces EPS. In the tuberoinfundibular pathway, it reduces or eliminates prolactin elevation. Dopamine release in the mesolimbic pathway from 5-HT2A antagonism does not appear to be as robust as in the other pathways of the dopamine system, thereby accounting for why atypical antipsychotics still retain part of their efficacy against the positive symptoms of schizophrenia through their D2 antagonism. When 5-HT2A antagonistic agent particles occupy 5-HT2A receptors in the mesocortical pathway and in the prefrontal cortex, the negative symptoms of schizophrenia, affective symptoms, and cognitive deficits and abnormalities are treated and reduced. Furthermore, 5-HT2A receptor antagonism blocks the serotonergic excitation of cortical pyramidal cells, reducing glutamate release, which in turn lowers hyperactive dopaminergic D2 receptor activity in the mesolimbic pathway, reducing or eliminating the positive symptoms of schizophrenia.

Some effects of 5-HT1A receptor activation include decreased aggressive behaviour/ideation, increased sociability, and decreased anxiety and depression. 5-HT2C activation blocks dopamine and inhibits norepinephrine release. Blockade of the 5-HT2C receptor increases serotonin, releasing norepinephrine and dopamine within the brain. But neuronal reuptake of norepinephrine is limited sharply by some antipsychotics, for example ziprasidone. Increased norepinephrine can cause increased glucose levels, which is to say blood sugar levels. Increased blood sugar levels by increased norepinephrine causes hunger in many humans, which is why weight gain occurs with some antipsychotics if the norepinephrine is not inhibited. Inhibition of norepinephrine stabilises mood in humans. 5-HT6 receptor antagonists improve cognition, learning, and memory. The 5-HT7 receptor is very potent for the mitigation of bipolar conditions and also yields an antidepressant effect. The antipsychotics asenapine, lurasidone, risperidone, and aripiprazole are very potent at the 5-HT7 receptor. Antagonistic affinity for the H1 receptor also has an antidepressant effect. H1 antagonism blocks serotonin and norepinephrine reuptake. Patients with increased histamine levels have been observed to have lower serotonin levels. However, the H1 receptor is linked to weight gain. To have partial agonism at the 5-HT1A receptor can yield absence of weight gain in an antipsychotic. This is very relevant for ziprasidone, but it creates a risk for a prolonged QTc interval. On the other hand, blockade of the 5-HT3 receptor removes the risk for a prolonged QTc interval, but then creates a larger risk for weight gain. Relation to the 5-HT3 receptor increases caloric uptake and glucose, which is seen in clozapine and olanzapine. Other ways for dopamine to resolve is to have agonism at both the D2 receptor and 5-HT1A receptor, which normalises the dopamine level in the brain. This occurs with haloperidol and aripiprazole.

Whether the anhedonic, loss of pleasure and motivation effect resulting from dopamine insufficiency or blockade at D2 receptors in the mesolimbic pathway, which is mediated in some part by antipsychotics (and despite dopamine release in the mesocortical pathway from 5-HT2A antagonism, which is seen in atypical antipsychotics), or the positive mood, mood stabilisation, and cognitive improvement effect resulting from atypical antipsychotic serotonergic activity is greater for the overall quality of life effect of an atypical antipsychotic is a question that is variable between individual experience and the atypical antipsychotic(s) being used.

Terms

Inhibition. Disinhibition: The opposite process of inhibition, the turning on of a biological function. Release: Causes the appropriate neurotransmitters to be discharged in vesicles into the synapse where they attempt to bind to and activate a receptor. Downregulation and Upregulation.

Pharmacokinetics

Atypical antipsychotics are most commonly administered orally. Antipsychotics can also be injected, but this method is not as common. They are lipid-soluble, are readily absorbed from the digestive tract, and can easily pass the blood-brain barrier and placental barriers. Once in the brain, the antipsychotics work at the synapse by binding to the receptor. Antipsychotics are completely metabolised in the body and the metabolites are excreted in urine. These drugs have relatively long half-lives. Each drug has a different half-life, but the occupancy of the D2 receptor falls off within 24 hours with atypical antipsychotics, while lasting over 24 hours for the typical antipsychotics. This may explain why relapse into psychosis happens quicker with atypical antipsychotics than with typical antipsychotics, as the drug is excreted faster and is no longer working in the brain. Physical dependence with these drugs is very rare. However, if the drug is abruptly discontinued, psychotic symptoms, movement disorders, and sleep difficulty may be observed. It is possible that withdrawal is rarely seen because the AAP are stored in body fat tissues and slowly released.

Society and Culture

Between May 2007 and April 2008, 5.5 million Americans filled at least one prescription for an atypical antipsychotic. In patients under the age of 65, 71% of patients were prescribed an atypical antipsychotic to treat Schizophrenia or Bipolar Disorder where this dropped to 38% in patients aged 65 or above.

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 Zopiclone?

Published on by Andrew Marshall7 Comments

Introduction

Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine used to treat difficulty sleeping.

Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases the normal transmission of the neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system, via modulating benzodiazepine receptors in the same way that benzodiazepine drugs do.

Zopiclone is a sedative. It works by causing a depression or tranquilisation of the central nervous system. After prolonged use, the body can become accustomed to the effects of zopiclone. When the dose is then reduced or the drug is abruptly stopped, withdrawal symptoms may result. These can include a range of symptoms similar to those of benzodiazepine withdrawal. Although withdrawal symptoms from therapeutic doses of zopiclone and its isomers (i.e. eszopiclone) do not typically present with convulsions and are therefore not considered life-threatening, patients may experience such significant agitation or anxiety that they seek emergency medical attention.

In the United States, zopiclone is not commercially available, although its active stereoisomer, eszopiclone is. Zopiclone is a controlled substance in the United States, Japan, Brazil, and some European countries, and may be illegal to possess without a prescription. However, it is readily available in other countries and is not a controlled substance.

Zopiclone is known colloquially as a “Z-drug”. Other Z-drugs include zaleplon and zolpidem and were initially thought to be less addictive than benzodiazepines. However, this appraisal has shifted somewhat in the last few years as cases of addiction and habituation have been presented. Zopiclone is recommended to be taken on a short-term basis, usually no more than a week or two. Daily or continuous use of the drug is not usually advised, and caution must be taken when the compound is used in conjunction with antidepressants, sedatives or other drugs affecting the central nervous system.

Brief History

Zopiclone was developed and first introduced in 1986 by Rhône-Poulenc S.A., now part of Sanofi-Aventis, the main worldwide manufacturer. Initially, it was promoted as an improvement on benzodiazepines, but a recent meta-analysis found it was no better than benzodiazepines in any of the aspects assessed. On 04 April 2005, the US Food and Drug Administration (FDA) listed zopiclone under schedule IV, due to evidence that the drug has addictive properties similar to benzodiazepines.

Zopiclone, as traditionally sold worldwide, is a racemic mixture of two stereoisomers, only one of which is active. In 2005, the pharmaceutical company Sepracor of Marlborough, Massachusetts began marketing the active stereoisomer eszopiclone under the name Lunesta in the United States. This had the consequence of placing what is a generic drug in most of the world under patent control in the United States. Generic forms of Lunesta have since become available in the United States. Zopiclone is currently available off-patent in a number of European countries, as well as Brazil, Canada, and Hong Kong. The eszopiclone/zopiclone difference is in the dosage – the strongest eszopiclone dosage contains 3 mg of the therapeutic stereoisomer, whereas the highest zopiclone dosage (10 mg) contains 5 mg of the active stereoisomer. The two agents have not yet been studied in head-to-head clinical trials to determine the existence of any potential clinical differences (efficacy, side effects, developing dependence on the drug, safety, etc.).

Medical Uses

Zopiclone is used for the short-term treatment of insomnia where sleep initiation or sleep maintenance are prominent symptoms. Long-term use is not recommended, as tolerance, dependence, and addiction can occur. One low-quality study found that zopiclone is ineffective in improving sleep quality or increasing sleep time in shift workers – more research in this area has been recommended.

Specific Populations

Elderly

Zopiclone, 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 consumption increases these impairments. Partial, but incomplete tolerance develops to these impairments. Zopiclone increases postural sway and increases the number of falls in older people, as well as cognitive side effects. Falls are a significant cause of death in older people.

An extensive review of the medical literature regarding the management of insomnia and the elderly found that considerable evidence of the effectiveness and lasting benefits of nondrug treatments for insomnia exist. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, such as zopiclone, offer few if any advantages in efficacy or tolerability in elderly persons. Newer agents such as the melatonin receptor 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 (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 nonbenzodiazepine hypnotic drugs remains to be determined.

Liver Disease

Patients with liver disease eliminate zopiclone much more slowly than normal patients and in addition experience exaggerated pharmacological effects of the drug.

Adverse Reactions

Sleeping pills, including zopiclone, have been associated with an increased risk of death. The British National Formulary states adverse reactions as follows: “taste disturbance (some report a metallic like taste); less commonly nausea, vomiting, dizziness, drowsiness, dry mouth, headache; rarely amnesia, confusion, depression, hallucinations, nightmares; very rarely light headedness, incoordination, paradoxical effects […] and sleep-walking also reported”.

Contraindications

Zopiclone causes impaired driving skills similar to those of benzodiazepines. Long-term users of hypnotic drugs for sleep disorders develop only partial tolerance to adverse effects on driving with users of hypnotic drugs even after 1 year of use still showing an increased motor vehicle accident rate. Patients who drive motor vehicles should not take zopiclone unless they stop driving due to a significant increased risk of accidents in zopiclone users. Zopiclone induces impairment of psychomotor function. Driving or operating machinery should be avoided after taking zopiclone as effects can carry over to the next day, including impaired hand eye coordination.

EEG and Sleep

It causes similar alterations on EEG readings and sleep architecture as benzodiazepines and causes disturbances in sleep architecture on withdrawal as part of its rebound effect. Zopiclone reduces both delta waves and the number of high-amplitude delta waves whilst increasing low-amplitude waves. Zopiclone reduces the total amount of time spent in REM sleep as well as delaying its onset. Cognitive behavioural therapy has been found to be superior to zopiclone in the treatment of insomnia and has been found to have lasting effects on sleep quality for at least a year after therapy.

Overdose

Zopiclone is sometimes used as a method of suicide. It has a similar fatality index to that of benzodiazepine drugs, apart from temazepam, which is particularly toxic in overdose. Deaths have occurred from zopiclone overdose, alone or in combination with other drugs. Overdose of zopiclone may present with excessive sedation and depressed respiratory function that may progress to coma and possibly death. Zopiclone combined with alcohol, opiates, or other central nervous system depressants may be even more likely to lead to fatal overdoses. Zopiclone overdosage can be treated with the benzodiazepine receptor antagonist flumazenil, which displaces zopiclone from its binding site on the benzodiazepine receptor, thereby rapidly reversing its effects. Serious effects on the heart may also occur from a zopiclone overdose when combined with piperazine.

Death certificates show the number of zopiclone-related deaths is on the rise. When taken alone, it usually is not fatal, but when mixed with alcohol or other drugs such as opioids, or in patients with respiratory, or hepatic disorders, the risk of a serious and fatal overdose increases.

Interactions

Zopiclone also interacts with trimipramine and caffeine.

Alcohol has an additive effect when combined with zopiclone, enhancing the adverse effects including the overdose potential of zopiclone significantly. Due to these risks and the increased risk for dependence, alcohol should be avoided when using zopiclone.

Erythromycin appears to increase the absorption rate of zopiclone and prolong its elimination half-life, leading to increased plasma levels and more pronounced effects. Itraconazole has a similar effect on zopiclone pharmacokinetics as erythromycin. The elderly may be particularly sensitive to the erythromycin and itraconazole drug interaction with zopiclone. Temporary dosage reduction during combined therapy may be required, especially in the elderly. Rifampicin causes a very notable reduction in half-life of zopiclone and peak plasma levels, which results in a large reduction in the hypnotic effect of zopiclone. Phenytoin and carbamazepine may also provoke similar interactions. Ketoconazole and sulfaphenazole interfere with the metabolism of zopiclone. Nefazodone impairs the metabolism of zopiclone leading to increased zopiclone levels and marked next-day sedation.

Pharmacology

The therapeutic pharmacological properties of zopiclone include hypnotic, anxiolytic, anticonvulsant, and myorelaxant properties. Zopiclone and benzodiazepines bind to the same sites on GABAA-containing receptors, causing an enhancement of the actions of GABA to produce the therapeutic and adverse effects of zopiclone. The metabolite of zopiclone called desmethylzopiclone is also pharmacologically active, although it has predominately anxiolytic properties. One study found some slight selectivity for zopiclone on α1 and α5 subunits, although it is regarded as being unselective in its binding to α1, α2, α3, and α5 GABAA benzodiazepine receptor complexes. Desmethylzopiclone has been found to have partial agonist properties, unlike the parent drug zopiclone, which is a full agonist. The mechanism of action of zopiclone is similar to benzodiazepines, with similar effects on locomotor activity and on dopamine and serotonin turnover. A meta-analysis of randomised controlled clinical trials that compared benzodiazepines to zopiclone or other Z drugs such as zolpidem and zaleplon has found few clear and consistent differences between zopiclone and the benzodiazepines in sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness. Zopiclone is in the cyclopyrrolone family of drugs. Other cyclopyrrolone drugs include suriclone. Zopiclone, although molecularly different from benzodiazepines, shares an almost identical pharmacological profile as benzodiazepines, including anxiolytic properties. Its mechanism of action is by binding to the benzodiazepine site and acting as a full agonist, which in turn positively modulates benzodiazepine-sensitive GABAA receptors and enhances GABA binding at the GABAA receptors to produce zopiclone’s pharmacological properties. In addition to zopiclone’s benzodiazepine pharmacological properties, it also has some barbiturate-like properties.

In EEG studies, zopiclone significantly increases the energy of the beta frequency band and shows characteristics of high-voltage slow waves, desynchronisation of hippocampal theta waves, and an increase in the energy of the delta frequency band. Zopiclone increases both stage 2 and slow-wave sleep (SWS), while zolpidem, an α1-selective compound, increases only SWS and causes no effect on stage 2 sleep. Zopiclone is less selective to the α1 site and has higher affinity to the α2 site than zaleplon. Zopiclone is therefore very similar pharmacologically to benzodiazepines.

Pharmacokinetics

After oral administration, zopiclone is rapidly absorbed, with a bioavailability around 75-80%. Time to peak plasma concentration is 1-2 hours. A high-fat meal preceding zopiclone administration does not change absorption (as measured by AUC), but reduces peak plasma levels and delays its occurrence, thus may delay the onset of therapeutic effects.

The plasma protein-binding of zopiclone has been reported to be weak, between 45 and 80% (mean 52-59%). It is rapidly and widely distributed to body tissues, including the brain, and is excreted in urine, saliva, and breast milk. Zopiclone is partly extensively metabolised in the liver to form an active N-demethylated derivative (N-desmethylzopiclone) and an inactive zopiclone-N-oxide. Hepatic enzymes playing the most significant role in zopiclone metabolism are CYP3A4 and CYP2E1. In addition, about 50% of the administered dose is decarboxylated and excreted via the lungs. In urine, the N-demethyl and N-oxide metabolites account for 30% of the initial dose. Between 7 and 10% of zopiclone is recovered from the urine, indicating extensive metabolism of the drug before excretion. The terminal elimination half-life of zopiclone ranges from 3.5 to 6.5 hours (5 hours on average).

The pharmacokinetics of zopiclone in humans are stereoselective. After oral administration of the racemic mixture, Cmax (time to maximum plasma concentration), area under the plasma time-concentration curve (AUC) and terminal elimination half-life values are higher for the dextrorotatory enantiomers, owing to the slower total clearance and smaller volume of distribution (corrected by the bioavailability), compared with the levorotatory enantiomer. In urine, the concentrations of the dextrorotatory enantiomers of the N-demethyl and N-oxide metabolites are higher than those of the respective antipodes.

The pharmacokinetics of zopiclone are altered by aging and are influenced by renal and hepatic functions. In severe chronic kidney failure, the area under the curve value for zopiclone was larger and the half-life associated with the elimination rate constant longer, but these changes were not considered to be clinically significant. Sex and race have not been found to interact with pharmacokinetics of zopiclone.

Chemistry

The melting point of zopiclone is 178 °C. Zopiclone’s solubility in water, at room temperature (25 °C) are 0.151 mg/mL. The logP value of zopiclone is 0.8.

Detection in Biological Fluids

Zopiclone may be measured in blood, plasma, or urine by chromatographic methods. Plasma concentrations are typically less than 100 μg/l during therapeutic use, but frequently exceed 100 μg/l in automotive vehicle operators arrested for impaired driving ability and may exceed 1000 μg/l in acutely poisoned patients. Post mortem blood concentrations are usually in a range of 0.4-3.9 mg/l in victims of fatal acute overdose.

Society and Culture

Recreational Use

Zopiclone has the potential for non-medical use, dosage escalation, and drug dependence. It is taken orally and sometimes intravenously when used non-medically, and often combined with alcohol to achieve a combined sedative hypnotic – alcohol euphoria. Patients abusing the drug are also at risk of dependence. Withdrawal symptoms can be seen after long-term use of normal doses even after a gradual reduction regimen. The Compendium of Pharmaceuticals and Specialties recommends zopiclone prescriptions not exceed 7 to 10 days, owing to concerns of addiction, tolerance, and physical dependence. Two types of drug misuse can occur: either recreational misuse, wherein the drug is taken to achieve a high, or when the drug is continued long-term against medical advice. Zopiclone may be more addictive than benzodiazepines. Those with a history of substance misuse or mental health disorders may be at an increased risk of high-dose zopiclone misuse. High dose misuse of zopiclone and increasing popularity amongst people who use substances who have been prescribed with zopiclone. The symptoms of zopiclone addiction can include depression, dysphoria, hopelessness, slow thoughts, social isolation, worrying, sexual anhedonia, and nervousness.

Zopiclone and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other drugs, including the benzodiazepines and zolpidem, are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range and often in combination with other alcohol, illegal, or addictive prescription drugs, suggesting a high degree of potential for non-medical use of benzodiazepines, zolpidem, and zopiclone. Zopiclone, which at prescribed doses causes moderate impairment the next day, has been estimated to increase the risk of vehicle accidents by 50%, causing an increase of 503 excess accidents per 100,000 persons. Zaleplon or other non-impairing sleep aids were recommended be used instead of zopiclone to reduce traffic accidents. Zopiclone, as with other hypnotic drugs, is sometimes used to carry out criminal acts such as sexual assaults.

Zopiclone has cross-tolerance with barbiturates and is able to suppress barbiturate withdrawal signs. It is frequently self-administered intravenously in studies on monkeys, suggesting a high risk of addictive potential.

Zopiclone is in the top ten medications obtained using a false prescription in France.

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.

What is a Nonbenzodiazepine?

Published on by Andrew Marshall19 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 are the Long-Term Effects of Benzodiazepine Use?

Published on by Andrew Marshall4 Comments

Introduction

The effects of long-term benzodiazepine use include drug dependence and neurotoxicity as well as the possibility of adverse effects on cognitive function, physical health, and mental health.

Refer to Benzodiazepine Use Disorder, Benzodiazepine Dependence, Benzodiazepine Overdose, and Benzodiazepine Withdrawal Syndrome.

Long term use is sometimes described as use not shorter than three months. Benzodiazepines are generally effective when used therapeutically in the short term, but even then the risk of dependency can be significantly high. There are significant physical, mental and social risks associated with the long-term use of benzodiazepines. Although anxiety can temporarily increase as a withdrawal symptom, there is evidence that a reduction or withdrawal from benzodiazepines can lead in the long run to a reduction of anxiety symptoms. Due to these increasing physical and mental symptoms from long-term use of benzodiazepines, slow withdrawal is recommended for long-term users. Not everyone, however, experiences problems with long-term use.

Some of the symptoms that could possibly occur as a result of a withdrawal from benzodiazepines after long-term use include emotional clouding, flu-like symptoms, suicide, nausea, headaches, dizziness, irritability, lethargy, sleep problems, memory impairment, personality changes, aggression, depression, social deterioration as well as employment difficulties, while others never have any side effects from long-term benzodiazepine use. Abruptly or rapidly stopping benzodiazepines can be dangerous; when withdrawing a gradual reduction in dosage is recommended, under professional supervision.

While benzodiazepines are highly effective in the short term, adverse effects associated with long-term use, including impaired cognitive abilities, memory problems, mood swings, and overdoses when combined with other drugs, may make the risk-benefit ratio unfavourable. In addition, benzodiazepines have reinforcing properties in some individuals and thus are considered to be addictive drugs, especially in individuals that have a “drug-seeking” behaviour; further, a physical dependence can develop after a few weeks or months of use. Many of these adverse effects associated with long-term use of benzodiazepines begin to show improvements three to six months after withdrawal.

Other concerns about the effects associated with long-term benzodiazepine use, in some, include dose escalation, benzodiazepine use disorder, tolerance and benzodiazepine dependence and benzodiazepine withdrawal problems. Both physiological tolerance and dependence can be associated with worsening the adverse effects associated with benzodiazepines. Increased risk of death has been associated with long-term use of benzodiazepines in several studies; however, other studies have not found increased mortality. Due to conflicting findings in studies regarding benzodiazepines and increased risks of death including from cancer, further research in long-term use of benzodiazepines and mortality risk has been recommended; most of the available research has been conducted in prescribed users, even less is known about illicit misusers. The long-term use of benzodiazepines is controversial and has generated significant debate within the medical profession. Views on the nature and severity of problems with long-term use of benzodiazepines differ from expert to expert and even from country to country; some experts even question whether there is any problem with the long-term use of benzodiazepines.

Brief History

Benzodiazepines when introduced in 1961 were widely believed to be safe drugs but as the decades went by increased awareness of adverse effects connected to their long-term use became known. Recommendations for more restrictive medical guidelines followed. Concerns regarding the long-term effects of benzodiazepines have been raised since 1980. These concerns are still not fully answered. A review in 2006 of the literature on use of benzodiazepine and nonbenzodiazepine hypnotics concluded that more research is needed to evaluate the long-term effects of hypnotic drugs. The majority of the problems of benzodiazepines are related to their long-term use rather than their short-term use. There is growing evidence of the harm of long-term use of benzodiazepines, especially at higher doses. In 2007, the Department of Health recommended that individuals on long-term benzodiazepines be monitored at least every 3 months and also recommended against long-term substitution therapy in benzodiazepine drug misusers due to a lack of evidence base for effectiveness and due to the risks of long-term use. The long-term effects of benzodiazepines are very similar to the long-term effects of alcohol consumption (apart from organ toxicity) and other sedative-hypnotics. Withdrawal effects and dependence are almost identical. A report in 1987 by the Royal College of Psychiatrists in Great Britain reported that any benefits of long-term use of benzodiazepines are likely to be far outweighed by the risks of long-term use. Despite this benzodiazepines are still widely prescribed. The socioeconomic costs of the continued widespread prescribing of benzodiazepines is high.

Political Controversy

In 1980, the Medical Research Council (United Kingdom) recommended that research be conducted into the effects of long-term use of benzodiazepines A 2009 British Government parliamentary inquiry recommended that research into the long-term effects of benzodiazepines must be carried out. The view of the Department of Health is that they have made every effort to make doctors aware of the problems associated with the long-term use of benzodiazepines, as well as the dangers of benzodiazepine drug addiction.

In 1980, the Medicines and Healthcare products Regulatory Agency’s Committee on the Safety of Medicines issued guidance restricting the use of benzodiazepines to short-term use and updated and strengthened these warnings in 1988. When asked by Phil Woolas in 1999 whether the Department of Health had any plans to conduct research into the long-term effects of benzodiazepines, the Department replied, saying they have no plans to do so, as benzodiazepines are already restricted to short-term use and monitored by regulatory bodies. In a House of Commons debate, Phil Woolas claimed that there had been a cover-up of problems associated with benzodiazepines because they are of too large of a scale for governments, regulatory bodies, and the pharmaceutical industry to deal with. John Hutton stated in response that the Department of Health took the problems of benzodiazepines extremely seriously and was not sweeping the issue under the carpet. In 2010, the All-Party Parliamentary Group on Involuntary Tranquilliser Addiction filed a complaint with the Equality and Human Rights Commission under the Disability Discrimination Act 1995 against the Department of Health and the Department for Work and Pensions alleging discrimination against people with a benzodiazepine prescription drug dependence as a result of denial of specialised treatment services, exclusion from medical treatment, non-recognition of the protracted benzodiazepine withdrawal syndrome, as well as denial of rehabilitation and back-to-work schemes. Additionally the APPGITA complaint alleged that there is a “virtual prohibition” on the collection of statistical information on benzodiazepines across government departments, whereas with other controlled drugs there are enormous volumes of statistical data. The complaint alleged that the discrimination is deliberate, large scale and that government departments are aware of what they are doing.

Declassified Medical Research Council Meeting

The Medical Research Council (UK) held a closed meeting among top UK medical doctors and representatives from the pharmaceutical industry between the dates of 30 October 1980 and 03 April 1981. The meeting was classified under the Public Records Act 1958 until 2014 but became available in 2005 as a result of the Freedom of Information Act. The meeting was called due to concerns that 10-100,000 people could be dependent; meeting chairman Professor Malcolm Lader later revised this estimate to include approximately half a million members of the British public suspected of being dependent on therapeutic dose levels of benzodiazepines, with about half of those on long-term benzodiazepines. It was reported that benzodiazepines may be the third- or fourth-largest drug problem in the UK (the largest being alcohol and tobacco). The Chairman of the meeting followed up after the meeting with additional information, which was forwarded to the Medical Research Council neuroscience board, raising concerns regarding tests that showed definite cortical atrophy in 2 of 14 individuals tested and borderline abnormality in five others. He felt that, due to the methodology used in assessing the scans, the abnormalities were likely an underestimate, and more refined techniques would be more accurate. Also discussed were findings that tolerance to benzodiazepines can be demonstrated by injecting diazepam into long-term users; in normal subjects, increases in growth hormone occurs, whereas in benzodiazepine-tolerant individuals this effect is blunted. Also raised were findings in animal studies that showed the development of tolerance in the form of a 15 percent reduction in binding capacity of benzodiazepines after seven days administration of high doses of the partial agonist benzodiazepine drug flurazepam and a 50% reduction in binding capacity after 30 days of a low dose of diazepam. The Chairman was concerned that papers soon to be published would “stir the whole matter up” and wanted to be able to say that the Medical Research Council “had matters under consideration if questions were asked in parliament”. The Chairman felt that it “was very important, politically that the MRC should be ‘one step ahead'” and recommended epidemiological studies be funded and carried out by Roche Pharmaceuticals and MRC sponsored research conducted into the biochemical effects of long-term use of benzodiazepines. The meeting aimed to identify issues that were likely to arise, alert the Department of Health to the scale of the problem and identify the pharmacology and nature of benzodiazepine dependence and the volume of benzodiazepines being prescribed. The World Health Organisation (WHO) was also interested in the problem and it was felt the meeting would demonstrate to the WHO that the MRC was taking the issue seriously. Among the psychological effects of long-term use of benzodiazepines discussed was a reduced ability to cope with stress. The Chairman stated that the “withdrawal symptoms from valium were much worse than many other drugs including, e.g., heroin”. It was stated that the likelihood of withdrawing from benzodiazepines was “reduced enormously” if benzodiazepines were prescribed for longer than four months. It was concluded that benzodiazepines are often prescribed inappropriately, for a wide range of conditions and situations. Dr Mason (DHSS) and Dr Moir (SHHD) felt that, due to the large numbers of people using benzodiazepines for long periods of time, it was important to determine the effectiveness and toxicity of benzodiazepines before deciding what regulatory action to take.

Controversy resulted in 2010 when the previously secret files came to light over the fact that the Medical Research Council was warned that benzodiazepines prescribed to millions of patients appeared to cause cerebral atrophy similar to hazardous alcohol use in some patients and failed to carry out larger and more rigorous studies. The Independent on Sunday reported allegations that “scores” of the 1.5 million members of the UK public who use benzodiazepines long-term have symptoms that are consistent with brain damage. It has been described as a “huge scandal” by Jim Dobbin, and legal experts and MPs have predicted a class action lawsuit. A solicitor said she was aware of the past failed litigation against the drug companies and the relevance the documents had to that court case and said it was strange that the documents were kept ‘hidden’ by the MRC.

Professor Lader, who chaired the MRC meeting, declined to speculate as to why the MRC declined to support his request to set up a unit to further research benzodiazepines and why they did not set up a special safety committee to look into these concerns. Professor Lader stated that he regrets not being more proactive on pursuing the issue, stating that he did not want to be labelled as the guy who pushed only issues with benzos. Professor Ashton also submitted proposals for grant-funded research using MRI, EEG, and cognitive testing in a randomized controlled trial to assess whether benzodiazepines cause permanent damage to the brain, but similarly to Professor Lader was turned down by the MRC.

The MRC spokesperson said they accept the conclusions of Professor Lader’s research and said that they fund only research that meets required quality standards of scientific research, and stated that they were and continue to remain receptive to applications for research in this area. No explanation was reported for why the documents were sealed by the Public Records Act.

Jim Dobbin, who chaired the All-Party Parliamentary Group for Involuntary Tranquilliser Addiction, stated that:

Many victims have lasting physical, cognitive and psychological problems even after they have withdrawn. We are seeking legal advice because we believe these documents are the bombshell they have been waiting for. The MRC must justify why there was no proper follow-up to Professor Lader’s research, no safety committee, no study, nothing to further explore the results. We are talking about a huge scandal here.

The legal director of Action Against Medical Accidents said urgent research must be carried out and said that, if the results of larger studies confirm Professor Lader’s research, the government and MRC could be faced with one of the biggest group actions for damages the courts have ever seen, given the large number of people potentially affected. People who report enduring symptoms post-withdrawal such as neurological pain, headaches, cognitive impairment, and memory loss have been left in the dark as to whether these symptoms are drug-induced damage or not due to the MRC’s inaction, it was reported. Professor Lader reported that the results of his research did not surprise his research group given that it was already known that alcohol could cause permanent brain changes.

Class-Action Lawsuit

Benzodiazepines spurred the largest-ever class-action lawsuit against drug manufacturers in the United Kingdom, in the 1980s and early 1990s, involving 14,000 patients and 1,800 law firms that alleged the manufacturers knew of the potential for dependence but intentionally withheld this information from doctors. At the same time, 117 general practitioners and 50 health authorities were sued by patients to recover damages for the harmful effects of dependence and withdrawal. This led some doctors to require a signed consent form from their patients and to recommend that all patients be adequately warned of the risks of dependence and withdrawal before starting treatment with benzodiazepines. The court case against the drug manufacturers never reached a verdict; legal aid had been withdrawn, leading to the collapse of the trial, and there were allegations that the consultant psychiatrists, the expert witnesses, had a conflict of interest. This litigation led to changes in British law, making class-action lawsuits more difficult.

Symptoms

Effects of long-term benzodiazepine use may include disinhibition, impaired concentration and memory, depression, as well as sexual dysfunction. The long-term effects of benzodiazepines may differ from the adverse effects seen after acute administration of benzodiazepines. An analysis of cancer patients found that those who took tranquillisers or sleeping tablets had a substantially poorer quality of life on all measurements conducted, as well as a worse clinical picture of symptomatology. Worsening of symptoms such as fatigue, insomnia, pain, dyspnoea and constipation was found when compared against those who did not take tranquillisers or sleeping tablets. Most individuals who successfully discontinue hypnotic therapy after a gradual taper and do not take benzodiazepines for 6 months have less severe sleep and anxiety problems, are less distressed and have a general feeling of improved health at 6-month follow-up. The use of benzodiazepines for the treatment of anxiety has been found to lead to a significant increase in healthcare costs due to accidents and other adverse effects associated with the long-term use of benzodiazepines.

Cognitive Status

Long-term benzodiazepine use can lead to a generalised impairment of cognition, including sustained attention, verbal learning and memory and psychomotor, visuo-motor and visuo-conceptual abilities. Transient changes in the brain have been found using neuroimaging studies, but no brain abnormalities have been found in patients treated long term with benzodiazepines. When benzodiazepine users cease long-term benzodiazepine therapy, their cognitive function improves in the first six months, although deficits may be permanent or take longer than six months to return to baseline. In the elderly, long-term benzodiazepine therapy is a risk factor for amplifying cognitive decline, although gradual withdrawal is associated with improved cognitive status. A study of alprazolam found that 8 weeks administration of alprazolam resulted in deficits that were detectable after several weeks but not after 3.5 years.

Effect on Sleep

Sleep architecture can be adversely affected by benzodiazepine dependence. Possible adverse effects on sleep include induction or worsening of sleep disordered breathing. Like alcohol, benzodiazepines are commonly used to treat insomnia in the short term (both prescribed and self-medicated), but worsen sleep in the long term. Although benzodiazepines can put people to sleep, while asleep, the drugs disrupt sleep architecture, decreasing sleep time, delayed and decreased REM sleep, increased alpha and beta activity, decreased K complexes and delta activity, and decreased deep slow-wave sleep (i.e. NREM stages 3 and 4, the most restorative part of sleep for both energy and mood).

Mental and Physical Health

The long-term use of benzodiazepines may have a similar effect on the brain as alcohol, and is also implicated in depression, anxiety, post-traumatic stress disorder (PTSD), mania, psychosis, sleep disorders, sexual dysfunction, delirium, and neurocognitive disorders. However a 2016 study found no association between long-term usage and dementia. As with alcohol, the effects of benzodiazepine on neurochemistry, such as decreased levels of serotonin and norepinephrine, are believed to be responsible for their effects on mood and anxiety.[39] Additionally, benzodiazepines can indirectly cause or worsen other psychiatric symptoms (e.g. mood, anxiety, psychosis, irritability) by worsening sleep (i.e. benzodiazepine-induced sleep disorder).

Long-term benzodiazepine use may lead to the creation or exacerbation of physical and mental health conditions, which improve after six or more months of abstinence. After a period of about 3 to 6 months of abstinence after completion of a gradual-reduction regimen, marked improvements in mental and physical wellbeing become apparent. For example, one study of hypnotic users gradually withdrawn from their hypnotic medication reported after six months of abstinence that they had less severe sleep and anxiety problems, were less distressed, and had a general feeling of improved health. Those who remained on hypnotic medication had no improvements in their insomnia, anxiety, or general health ratings. A study found that individuals having withdrawn from benzodiazepines showed a marked reduction in use of medical and mental health services.

Approximately half of patients attending mental health services for conditions including anxiety disorders such as panic disorder or social phobia may be the result of alcohol or benzodiazepine dependence. Sometimes anxiety disorders precede alcohol or benzodiazepine dependence but the alcohol or benzodiazepine dependence often acts to keep the anxiety disorders going and often progressively makes them worse. Many people who are addicted to alcohol or prescribed benzodiazepines decide to quit when it is explained to them they have a choice between ongoing ill mental health or quitting and recovering from their symptoms. It was noted that because every individual has an individual sensitivity level to alcohol or sedative hypnotic drugs, what one person can tolerate without ill health will cause another to suffer very ill health, and that even moderate drinking in sensitive individuals can cause rebound anxiety syndromes and sleep disorders. A person who is suffering the toxic effects of alcohol or benzodiazepines will not benefit from other therapies or medications as they do not address the root cause of the symptoms. Recovery from benzodiazepine dependence tends to take a lot longer than recovery from alcohol, but people can regain their previous good health. A review of the literature regarding benzodiazepine hypnotic drugs concluded that these drugs cause an unjustifiable risk to the individual and to public health. The risks include dependence, accidents and other adverse effects. Gradual discontinuation of hypnotics leads to improved health without worsening of sleep.

Daily users of benzodiazepines are also at a higher risk of experiencing psychotic symptomatology such as delusions and hallucinations. A study found that of 42 patients treated with alprazolam, up to a third of long-term users of the benzodiazepine drug alprazolam (Xanax) develop depression. Studies have shown that long-term use of benzodiazepines and the benzodiazepine receptor agonist nonbenzodiazepine Z drugs are associated with causing depression as well as a markedly raised suicide risk and an overall increased mortality risk.

A study of 50 patients who attended a benzodiazepine withdrawal clinic found that, after several years of chronic benzodiazepine use, a large portion of patients developed health problems including agoraphobia, irritable bowel syndrome, paraesthesia, increasing anxiety, and panic attacks, which were not pre-existing. The mental health and physical health symptoms induced by long-term benzodiazepine use gradually improved significantly over a period of a year following completion of a slow withdrawal. Three of the 50 patients had wrongly been given a preliminary diagnosis of multiple sclerosis when the symptoms were actually due to chronic benzodiazepine use. Ten of the patients had taken drug overdoses whilst on benzodiazepines, despite the fact that only two of the patients had any prior history of depressive symptomatology. After withdrawal, no patients took any further overdoses after one year post-withdrawal. The cause of the deteriorating mental and physical health in a significant proportion of patients was hypothesised to be caused by increasing tolerance where withdrawal-type symptoms emerged, despite the administration of stable prescribed doses. Another theory is that chronic benzodiazepine use causes subtle increasing toxicity, which in turn leads to increasing psychopathology in long-term users of benzodiazepines.

Long-term use of benzodiazepines can induce perceptual disturbances and depersonalisation in some people, even in those taking a stable daily dosage, and it can also become a protracted withdrawal feature of the benzodiazepine withdrawal syndrome.

In addition, chronic use of benzodiazepines is a risk factor for blepharospasm. Drug-induced symptoms that resemble withdrawal-like effects can occur on a set dosage as a result of prolonged use, also documented with barbiturate-like substances, as well as alcohol and benzodiazepines. This demonstrates that the effects from chronic use of benzodiazepine drugs are not unique but occur with other GABAergic sedative hypnotic drugs, i.e. alcohol and barbiturates.

Immune System

Chronic use of benzodiazepines seemed to cause significant immunological disorders in a study of selected outpatients attending a psychopharmacology department. Diazepam and clonazepam have been found to have long-lasting, but not permanent, immunotoxic effects in foetuses of rats. However, single very high doses of diazepam have been found to cause lifelong immunosuppression in neonatal rats. No studies have been done to assess the immunotoxic effects of diazepam in humans; however, high prescribed doses of diazepam, in humans, have been found to be a major risk of pneumonia, based on a study of people with tetanus. It have been proposed that diazepam may cause long-lasting changes to the GABAA receptors with resultant long-lasting disturbances to behaviour, endocrine function and immune function.

Suicide and Self-Harm

Use of prescribed benzodiazepines is associated with an increased rate of attempted and completed suicide. The prosuicidal effects of benzodiazepines are suspected to be due to a psychiatric disturbance caused by side effects or withdrawal symptoms. Because benzodiazepines in general may be associated with increased suicide risk, care should be taken when prescribing, especially to at-risk patients. Depressed adolescents who were taking benzodiazepines were found to have a greatly increased risk of self-harm or suicide, although the sample size was small. The effects of benzodiazepines in individuals under the age of 18 requires further research. Additional caution is required in using benzodiazepines in depressed adolescents. Benzodiazepine dependence often results in an increasingly deteriorating clinical picture, which includes social deterioration leading to comorbid alcohol use disorder and substance use disorder. Benzodiazepine misuse or misuse of other CNS depressants increases the risk of suicide in drug misusers. Benzodiazepine has several risks based on its biochemical function and symptoms associated with this medication like exacerbation of sleep apnoea, sedation, suppression of self-care functions, amnesia and disinhibition are suggested as a possible explanation to the increase in mortality. Studies also demonstrate that an increased mortality associated with benzodiazepine use has been clearly documented among ‘drug misusers’.

Carcinogenicity

There has been some controversy around the possible link between benzodiazepine use and development of cancer; early cohort studies in the 1980s suggested a possible link, but follow-up case-control studies have found no link between benzodiazepines and cancer. In the second U.S. national cancer study in 1982, the American Cancer Society conducted a survey of over 1.1 million participants. A markedly increased risk of cancer was found in users of sleeping pills, mainly benzodiazepines. Fifteen epidemiologic studies have suggested that benzodiazepine or nonbenzodiazepine hypnotic drug use is associated with increased mortality, mainly due to increased cancer death. The cancers included cancer of the brain, lung, bowel, breast, and bladder, and other neoplasms. It has been hypothesised that benzodiazepines depress immune function and increase viral infections and could be the cause or trigger of the increased rate of cancer. While initially US Food and Drug Administration (FDA) reviewers expressed concerns about approving the nonbenzodiazepine Z drugs due to concerns of cancer, ultimately they changed their minds and approved the drugs. A 2017 meta-analysis of multiple observational studies found that benzodiazepine use is associated with increased cancer risk.

Brain Damage

In a study in 1980 in a group of 55 consecutively admitted patients having engaged in non-medical use of exclusively sedatives or hypnotics, neuropsychological performance was significantly lower and signs of intellectual impairment significantly more often diagnosed than in a matched control group taken from the general population. These results suggested a relationship between non-medical use of sedatives or hypnotics and cerebral disorder.

A publication asked in 1981 if lorazepam is more toxic than diazepam.

In a study in 1984, 20 patients having taken long-term benzodiazepines were submitted to brain CT scan examinations. Some scans appeared abnormal. The mean ventricular-brain ratio measured by planimetry was increased over mean values in an age- and sex-matched group of control subjects but was less than that in a group of alcoholics. There was no significant relationship between CT scan appearances and the duration of benzodiazepine therapy. The clinical significance of the findings was unclear.

In 1986, it was presumed that permanent brain damage may result from chronic use of benzodiazepines similar to alcohol-related brain damage.

In 1987, 17 inpatient people who used high doses of benzodiazepines non-medically have anecdotally shown enlarged cerebrospinal fluid spaces with associated cerebral atrophy. Cerebral atrophy reportedly appeared to be dose dependent with low-dose users having less atrophy than higher-dose users.

However, a CT study in 1987 found no evidence of cerebral atrophy in prescribed benzodiazepine users.

In 1989, in a 4- to 6-year follow-up study of 30 inpatient people who used benzodiazepines non-medically, Neuropsychological function was found to be permanently affected in some people long-term high dose non-medical use of benzodiazepines. Brain damage similar to alcoholic brain damage was observed. The CT scan abnormalities showed dilatation of the ventricular system. However, unlike people who consume excessive alcohol, people who use sedative hypnotic agents non-medically showed no evidence of widened cortical sulci. The study concluded that, when cerebral disorder is diagnosed in people who use high doses of sedative hypnotic benzodiazepines, it is often permanent.

A CT study in 1993 investigated brain damage in benzodiazepine users and found no overall differences to a healthy control group.

A study in 2000 found that long-term benzodiazepine therapy does not result in brain abnormalities.

Withdrawal from high-dose use of nitrazepam anecdotally was alleged in 2001 to have caused severe shock of the whole brain with diffuse slow activity on EEG in one patient after 25 years of use. After withdrawal, abnormalities in hypofrontal brain wave patterns persisted beyond the withdrawal syndrome, which suggested to the authors that organic brain damage occurred from chronic high-dose use of nitrazepam.

Professor Heather Ashton, a leading expert on benzodiazepines from Newcastle University Institute of Neuroscience, has stated that there is no structural damage from benzodiazepines, and advocates for further research into long-lasting or possibly permanent symptoms of long-term use of benzodiazepines as of 1996. She has stated that she believes that the most likely explanation for lasting symptoms is persisting but slowly resolving functional changes at the GABAA benzodiazepine receptor level. Newer and more detailed brain scanning technologies such as PET scans and MRI scans had as of 2002 to her knowledge never been used to investigate the question of whether benzodiazepines cause functional or structural brain damage.

A 2018 review of the research found a likely causative role between the use of benzodiazepines and an increased risk of dementia, but the exact nature of the relationship is still a matter of debate.

Special Populations

Neonatal Effects

Benzodiazepines have been found to cause teratogenic malformations. The literature concerning the safety of benzodiazepines in pregnancy is unclear and controversial. Initial concerns regarding benzodiazepines in pregnancy began with alarming findings in animals but these do not necessarily cross over to humans. Conflicting findings have been found in babies exposed to benzodiazepines. A recent analysis of the Swedish Medical Birth Register found an association with preterm births, low birth weight and a moderate increased risk for congenital malformations. An increase in pylorostenosis or alimentary tract atresia was seen. An increase in orofacial clefts was not demonstrated, however, and it was concluded that benzodiazepines are not major teratogens.

Neurodevelopmental disorders and clinical symptoms are commonly found in babies exposed to benzodiazepines in utero. Benzodiazepine-exposed babies have a low birth weight but catch up to normal babies at an early age, but smaller head circumferences found in benzo babies persists. Other adverse effects of benzodiazepines taken during pregnancy are deviating neurodevelopmental and clinical symptoms including craniofacial anomalies, delayed development of pincer grasp, deviations in muscle tone and pattern of movements. Motor impairments in the babies are impeded for up to 1 year after birth. Gross motor development impairments take 18 months to return to normal but fine motor function impairments persist. In addition to the smaller head circumference found in benzodiazepine-exposed babies mental retardation, functional deficits, long-lasting behavioural anomalies, and lower intelligence occurs.

Benzodiazepines, like many other sedative hypnotic drugs, cause apoptotic neuronal cell death. However, benzodiazepines do not cause as severe apoptosis to the developing brain as alcohol does. The prenatal toxicity of benzodiazepines is most likely due to their effects on neurotransmitter systems, cell membranes and protein synthesis. This, however, is complicated in that neuropsychological or neuropsychiatric effects of benzodiazepines, if they occur, may not become apparent until later childhood or even adolescence. A review of the literature found data on long-term follow-up regarding neurobehavioural outcomes is very limited. However, a study was conducted that followed up 550 benzodiazepine-exposed children, which found that, overall, most children developed normally. There was a smaller subset of benzodiazepine-exposed children who were slower to develop, but by four years of age most of this subgroup of children had normalised. There was a small number of benzodiazepine-exposed children who had continuing developmental abnormalities at 4-year follow-up, but it was not possible to conclude whether these deficits were the result of benzodiazepines or whether social and environmental factors explained the continuing deficits.

Concerns regarding whether benzodiazepines during pregnancy cause major malformations, in particular cleft palate, have been hotly debated in the literature. A meta analysis of the data from cohort studies found no link but meta analysis of case-control studies did find a significant increase in major malformations. (However, the cohort studies were homogenous and the case-control studies were heterogeneous, thus reducing the strength of the case-control results). There have also been several reports that suggest that benzodiazepines have the potential to cause a syndrome similar to foetal alcohol syndrome, but this has been disputed by a number of studies. As a result of conflicting findings, use of benzodiazepines during pregnancy is controversial. The best available evidence suggests that benzodiazepines are not a major cause of birth defects, i.e. major malformations or cleft lip or cleft palate.

Elderly

Significant toxicity from benzodiazepines can occur in the elderly as a result of long-term use. Benzodiazepines, along with antihypertensives and drugs affecting the cholinergic system, are the most common cause of drug-induced dementia affecting over 10 percent of patients attending memory clinics. Long-term use of benzodiazepines in the elderly can lead to a pharmacological syndrome with symptoms including drowsiness, ataxia, fatigue, confusion, weakness, dizziness, vertigo, syncope, reversible dementia, depression, impairment of intellect, psychomotor and sexual dysfunction, agitation, auditory and visual hallucinations, paranoid ideation, panic, delirium, depersonalisation, sleepwalking, aggressiveness, orthostatic hypotension and insomnia. Depletion of certain neurotransmitters and cortisol levels and alterations in immune function and biological markers can also occur. Elderly individuals who have been long-term users of benzodiazepines have been found to have a higher incidence of post-operative confusion. Benzodiazepines have been associated with increased body sway in the elderly, which can potentially lead to fatal accidents including falls. Discontinuation of benzodiazepines leads to improvement in the balance of the body and also leads to improvements in cognitive functions in the elderly benzodiazepine hypnotic users without worsening of insomnia.

A review of the evidence has found that whilst long-term use of benzodiazepines impairs memory, its association with causing dementia is not clear and requires further research. A more recent study found that benzodiazepines are associated with an increased risk of dementia and it is recommended that benzodiazepines be avoided in the elderly. A later study, however, found no increase in dementia associated with long-term usage of benzodiazepine.