Flurazepam: Effect as a long-acting benzodiazepine

Flurazepam (brand name Dalmadorm) is a first-generation benzodiazepine with long duration of action, used as a sleep aid. It was introduced in the early 1970s and is among the classical sleep medications due to its pronounced hypnotic effect lasting several hours. In Germany, flurazepam is prescription only and falls under the provisions of the Medicines Act for substances with abuse potential. In modern sleep medicine, flurazepam is prescribed only cautiously due to the long elimination half-life of active metabolites and associated hangover effects and fall risk.

Flurazepam differs from short and intermediate acting benzodiazepines through a particularly long duration of action. This can be advantageous for patients with sleep maintenance problems because nighttime awakenings are reduced. However, the long duration of action also leads to daytime residual effects with drowsiness, cognitive impairment and increased fall risk, especially in elderly patients. Therefore, flurazepam is on the PRISCUS list of potentially inappropriate medications for older patients.

Mechanism of Action

Flurazepam, like all benzodiazepines, acts as a positive allosteric modulator at the GABA A receptor. By binding to the benzodiazepine binding site of the receptor, it enhances the effect of GABA, the most important inhibitory neurotransmitter in the central nervous system. This results in sedation, sleep induction, anxiolysis, anticonvulsive and muscle relaxing effects. Flurazepam increases the frequency with which GABA-induced chloride channels open, leading to hyperpolarization of the neuronal membrane and reducing excitability.

Pharmacologically, flurazepam enhances the sleep-promoting effect of GABA receptors in the sleep centers of the hypothalamus and brainstem. The substance reduces sleep latency, prolongs total sleep duration and reduces nighttime awakenings. However, there is a shift in sleep stages with reduction of deep sleep (REM sleep) and restorative phases, which can impair sleep quality despite longer sleep duration.

Pharmacokinetically, flurazepam is rapidly converted after oral administration in the liver to pharmacologically active metabolites. The main metabolite is N-desalkylflurazepam, which has an elimination half-life of 47 to 100 hours. This very long half-life explains the accumulation with repeated use and persistent daytime residual effects. The duration of a single dose is 7 to 8 hours, but the effect of the metabolites lasts significantly longer.

Indications

• Short-term treatment of sleep initiation and sleep maintenance problems in adults, especially when nighttime awakening is a main problem
• Sleep disorders related to psychological stress temporarily for bridging therapy
• Sleep disorders during inpatient treatment in hospital or nursing home, however used cautiously here due to fall risk

Due to significant risks with chronic use, dependence potential and modern availability of shorter acting Z-drugs such as zolpidem or zopiclone, flurazepam is rarely prescribed in outpatient sleep medicine today. For chronic sleep disorders, non-pharmacological therapies (sleep hygiene, cognitive behavioral therapy for insomnia) are the primary recommendation.

Dosage and Administration

Adults: 15 to 30 mg of flurazepam approximately 30 minutes before bedtime.

Elderly or debilitated patients: 15 mg, adjust according to tolerability if needed.

Duration of use: not longer than 2 to 4 weeks, including gradual discontinuation, to prevent dependence. Chronic use only in justified exceptional cases under medical supervision.

Administration: take with water, ideally on an empty stomach, as a meal may delay onset of action. Take directly before bedtime and allow 7 to 8 hours for sleep.

Upon discontinuation: slow dose reduction over several weeks to avoid withdrawal symptoms such as rebound insomnia, anxiety, tremor, sweating.

Renal impairment: use caution with moderate to severe impairment and consider dose reduction. Hepatic impairment: with moderate to severe impairment, prolonged duration of action and higher levels of active metabolites, therefore dose reduction required or avoidance.

Important: after taking the medication until the next restorative sleep phase, do not engage in safety-critical activities.

Side Effects

Very common: daytime drowsiness, sedation, dizziness, reduced concentration, cognitive impairment, hangover effects on the following day.

Common: muscle weakness, coordination disorder with fall risk, headache, confusion (especially in elderly patients), depressive mood, dry mouth, paradoxical reactions with agitation instead of sedation (especially in elderly patients and children).

Occasional: respiratory depression, anterograde amnesia (memory gaps after taking the medication), hallucinations, paradoxical agitation, aggression, sexual dysfunction.

Rare to very rare: severe allergic reactions including anaphylaxis, rash, hepatotoxicity, leukopenia, jaundice, respiratory arrest from overdose in combination with other central depressants.

Dependence: physical and psychological dependence can develop after just a few weeks of use. Upon discontinuation, withdrawal symptoms such as rebound insomnia, anxiety, tremor, sweating, tachycardia, seizures (with abrupt discontinuation).

Fall risk: significantly increased, especially in elderly patients, due to nighttime or morning residual effects.

Drug Interactions

• Other central depressants (alcohol, opioids, other benzodiazepines, sedating antihistamines, antipsychotics): potentially fatal respiratory depression, use caution and avoid combination.
• CYP3A4 inhibitors (ketoconazole, erythromycin, cimetidine, ritonavir): increased levels and enhanced effects.
• CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St. John's wort): reduced effects.
• Anticoagulants such as phenprocoumon: theoretical interactions, monitoring required.
• Muscle relaxants: enhanced muscle relaxing effect.
• Antidepressants with central depressant effects: enhanced sedation.
• Methadone: enhanced respiratory depression in opioid substitution.

Special Information

Pregnancy: not recommended, especially in the first trimester (risk of birth defects) and shortly before delivery (respiratory depression in newborns, floppy infant syndrome). Nursing: transfer into breast milk, risk of sedation in infants, therefore not recommended.

Children: not recommended because risks outweigh benefits.

Elderly patients: use caution due to increased fall risk, cognitive side effects, paradoxical reactions. Flurazepam is on the PRISCUS list.

Contraindications: known hypersensitivity, myasthenia gravis, severe respiratory insufficiency, severe obstructive sleep apnea syndrome, severe hepatic insufficiency, acute intoxication with alcohol or central depressants, substance abuse history (relative).

Before therapy: detailed history of sleep disorders with clear therapy goals, substance abuse history, concomitant medications, cardiopulmonary comorbidities, sleep hygiene counseling.

During therapy: regular reevaluation of indication, efficacy and side effects, attention to fall risk.

Lifestyle: no alcohol, good sleep hygiene, regular sleep-wake rhythm, physical activity during the day, avoid caffeine in the evening. For chronic insomnia, cognitive behavioral therapy as targeted treatment.

Driving ability: flurazepam significantly impairs reaction ability. Due to the long half-life, relevant residual effects also on the following day. Therefore, do not drive or operate heavy machinery after taking it, individual assessment required.

You May Also Be Interested In

• Zolpidem, short-acting Z-drug sleep aid
• Zopiclone, another Z-drug sleep aid
• Lormetazepam, intermediate-acting benzodiazepine
• Lorazepam, intermediate-acting benzodiazepine
• Melatonin, endogenous hormone as mild sleep aid

Frequently Asked Questions

Sources

• Gelbe Liste, Flurazepam active ingredient profile
• BfArM, Federal Institute for Drugs and Medical Devices
• German Society for Sleep Research and Sleep Medicine (DGSM)
• German Society for Psychiatry, Psychotherapy and Neurology
• AWMF S3 guideline on non-restorative sleep and insomnia