HISTORY OF BENZODIAZEPINES

WHAT THE TEXTBOOKS MAY NOT TELL YOU

Heather Ashton, Newcastle upon Tyne, UK

ANXIOLYTIC DRUGS THROUGH THE AGESAlcohol 8000 yearsOpium1000s of yearsBromides1870sAlso chloral hydrate, paraldehydeBarbiturates 1903-1912Also carbromal, glutethimide, methaqualone etcBenzodiazepines 1960 Librium; 1963 ValiumZ drugs zopiclone 1998; eszopiclone 2005

Morbidity in 50 long-term benzodiazepine users

After starting benzodiazepines:20% - took drug overdose requiring hospital admission20% - developed incapacitating agoraphobia18% - had GI investigations (irritable bowel)10% - had neurological investigations(3 wrongly diagnosed as MS)62% - received other psychotropic drugs (antidepressants)28% - were taking 2 prescribed benzodiazepines

Some Common Acute Benzodiazepine Withdrawal SymptomsSymptoms common to all Symptoms less common inanxiety states anxiety states; relatively specific to benzodiazerpine withdrawalAnxiety, panic attacks, agoraphobia Perceptual disturbances, sense movementInsomnia, nightmares Depersonalisation, derealisationDepression, dysphoria Hallucinations (visual, auditory), Excitability, jumpiness, restlessness misperceptionsPoor memory, concentration Distortion of body image Dizziness, lightheadedness Tingling, numbness, altered sensation Weakness, jelly legs Formication Tremor Sensory hypersensitivity (light, sound, Muscle pain, stiffness taste, smell) (limbs, back, neck, jaw, head) Muscle twitches, jerks, fasiculation Sweating, night sweats Tinnitus Palpitations Psychotic symptoms Confusion, delirium Fits

SOME PROTRACTED BENZODIAZEPINE WITHDRAWAL SYMPTOMSAnxietyDepressionGastrointestinalNeurologicaltinnitus?peripheral neuropathymotor - muscle spasms, ticks, jerks restless legs syndrome?cognitive impairment

SOCIOECONOMIC COSTS OF INAPPROPRIATE BENZODIAZEPINE PRESCRIBING

1. Increased mortality from overdose, suicide2. Increased risk of accidentstraffic. Home, work, falls and fractures in elderly3. Increased risk of aggressive behaviour, assault, antisocial acts4. Contribution to marital/domestic disharmony5. Increased risk to foetus, infants, children6. Contribution to job loss, unemployment, loss of work through illness7. Cost of medical consultations, hospital admissions/ investigations8. Dependence and withdrawal reactions9. Recreational abuse - AIDS, hepatitis, unwanted pregnancy10. Costs of drug NHS prescriptions11. Costs to DHSS due to disability12. Costs of litigation

THERAPEUTIC ACTIONS OF BENZODIAZEPINESActionsClinical usesHypnoticShort-term treatment of insomniaAnxiolytic (tranquillising)Short-term treatment of severe anxietyShort-term aid to alcohol withdrawalAcute treatment of violent psychoticstatesAnticonvulsantEpileptic and drug-induced convulsionsAmnesicPremedication before surgeryMuscle relaxantMuscle spasms, dystonias

ADVERSE EFFECTS OF BENZODIAZEPINES1. Over-sedation Depressed psychomotor performance, poor memory, ataxiacontribute to car accidents, shoplifting Most marked in the elderly, may produce mental confusioncontribute to falls and fractures2. Additive effects with other CNS depressants e.g. alcohol, drug overdose3. Disinhibition Aggressiveness ? Contribute to baby battering, wife beatingDepression, emotional bluntingCognitive impairment6. Adverse effects in pregnancy Neonatal depression7. Abuse8. Tolerance, dependence, withdrawal effects

HALF-LIVES AND EQUIVALENT POTENCIES OF BENZODIAZEPINE ANXIOLYTICSBenzodiazepine Half-life (hrs) Approximate [active equivalent metabolite]oral dosages (mg)_______________________________________________________Alprazolam (Xanax)6-120.5Clonazepam (Klonepin) 18-500.5Lorazepam (Ativan) 10-20 1Diazepam (Valium) 20-100 10 [26-200]Chlordiazepoxide (Librium) 5-30 25Clorazepate (Tranxene) [36-200] 15Oxazepam (Serax)4-15 20

HALF-LIVES AND EQUIVALENT POTENCIES OF BENZODIAZEPINE HYPNOTICSBenzodiazepineHalf-life (hrs) Approximate [active metabolite] equivalent oral dosages (mg)______________________________________________________Triazolam (Halcion) 20.5Flunitrazepam (Rohypnol) 18-26 1 [36-200]Nitrazepam (Mogadon) 15-38 10Temazepam (Restoril) 8-22 20Flunitrazepam (Dalmane) [40-250]15-30Diazepam (Valium) 20-100 10 [36-200]

PATIENTS VULNERABLE TO INCREASED RISKS OF BENZODIAZEPINESConditionRisks________________________________________Older age (>65yrs) Mental confusion, amnesia, fallsand fracturesChronic respiratory disease Respiratory depressionLiver diseaseOversedationDepressionExacerbation, suicide riskOther sedative drugsAdditive effectsPregnancyNeonatal depression, withdrawalAlcohol/drug abuseIncreased risk of dependenceGenetic factorsSlow metabolisers

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HALF-LIVES AND EQUIVALENT POTENCIES OF Z-DRUGS Z drugHalf-life (hrs) Approximate [active metabolite] equivalent oral dosages (mg)________________________________________________________Zaleplon (Sonata) 1-220Zolpidem (Ambien) 220Zopiclone (Zimovane) 5-615Eszopiclone (Lunesta) 6 3 (9 in elderly)

Diazepam (Valium) 20-10010 [36-200]

Basic principles1. Gradual dosage reduction- individual withdrawal rate- adjuvant drugs2. Psychological support- simple encouragement to psychological therapies- long term- information- motivation

BENZODIAZEPINE WITHDRAWAL

ADJUVANT DRUGS IN BENZODIAZEPINE WITHDRAWALSometimes indicatedantidepressants- depression, agoraphobia, sedation-blockers- tremor, palpitationscarbamazepine- fits (high dose Bz)sedative antihistaminesNot helpfulbuspirone, clonidine, nifedipine, ? Alpidem, ? Gabapentin

SOME STEPS NEEDED TO REDUCE BENZODIAZEPINE PRESCRIBING (1)New PatientsShort-term prescriptions (2-4 weeks only) in minimal dosageAvoid potent benzodiazepines (alprazolam, lorazepam, clonazepam)Consider rescheduling benzodiazepinesDevelop non-drug treatments for anxiety and insomnia with suitable training and provision of staffEducate doctors and health care workers about potential dangers of new drugs (e.g. Z drugs and others)

SOME STEPS NEEDED TO REDUCE BENZODIAZEPINE PRESCRIBING (2)Long-term patients (already dependent)Educate doctors and health care workers in withdrawal methodsFinancial aid for patient support groups and dedicated withdrawal clinicsGeneral measuresResearch into long-term effects of benzodiazepinesGreater openness about results of drug-company sponsored clinical trialsKeep up pressure on government health authorities and the public