Clonazepam (Klonopin®) versus Lorazepam (Ativan®)

Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD

Difference between Clonazepam and Lorazepam

Both clonazepam and lorazepam are long-acting benzodiazepines. These two benzodiazepines differ in their effects on GABA-A receptors, route of metabolism, and elimination half-life.


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Clonazepam
Lorazepam
Brand name/Year of initial approval Klonopin®, 1975 Ativan®, 1977
Formulations Oral Oral, IM, IV
Legal status Schedule IV
Controlled substance
Drug class Benzodiazepine
Long acting Intermediate acting
FDA-approved Indications • Panic disorder
• Lennox-Gastaut syndrome
• Akinetic seizure
• Myoclonic seizure
• Acute mania
• Acute psychosis
• Excessive anxiety
• Status epilepticus
• Preanesthetic
Off-label uses • Insomnia 5
• Status epilepticus • Acute mania
• Psychotic agitation 6
• Muscle spasm
• Catatonia8
Mechanism of action • Anxiolytic, sedative, anticonvulsant activity
• Benzodiazepines work by stimulating the action of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS.
Half-life 30-40 hours 12-15 hours
Oral bioavailability 90% 90%
Metabolism, Elimination Clonazepam is metabolized in the liver (CYP3A4). The drug is metabolized principally by reduction of the nitro group to produce inactive 7-amino derivatives. Less than 1% of the drug is excreted unchanged in the urine. Lorazepam is extensively conjugated to the 3- O-phenolic glucuronide in the liver and undergoes enterohepatic recirculation.
88% of lorazepam is excreted in the urine (with 75% excreted as the glucuronide) and 7% in feces.
Contraindications • Significant liver disease
• Myasthenia gravis
• Sleep apnea syndrome
• Not recommended for depressive neurosis or in psychotic reactions
• Severe respiratory insufficiency
• Acute narrow angle glaucoma
• History of sensitivity to benzodiazepines
Warnings & precautions • Abuse, physical dependence, tolerance
• Impairment of cognitive and motor skills3
• Abnormal thinking or behavioral changes
Side effects • Drowsiness
• Sedation
• Somnolence
• Fatigue
• Depression
• Ataxia
• Incoordination
• Hypersalivation
• Hypotension
• Respiratory depression (particularly injection)
• Apnea
Drug interactions • Increased depressive effects when taken with other CNS depressants or alcohol
Pregnancy category D
Advantages • Broad anti-seizure properties
• High lipophilicity
• Has a role in long-term treatment of epilepsy
• Availability of oral liquid and injectable formulation
• Important drug in the ICU 4
• Useful sedative properties
• Lorazepam activity is less affected by variables such as advanced age, hepatic dysfunction, or drug-drug interactions7.
Disadvantages • Not available for parenteral administration in U.S. • May cause excessive sedation

Lorazepam is one of the more sedating benzodiazepines with strong anti-anxiety, sedative, and hypnotic properties. Lorazepam produces profound amnesia and long-term sedation4. Clonazepam has more selective anticonvulsant activity.

Status epilepticus (SE)

Status epilepticus is a serious neurologic emergency. Intravenous benzodiazepines are recognized as the first line treatment for SE.

According to multicenter comparison 1 lorazepam is associated with a higher risk of refractoriness and a greater number of side effects compared to the clonazepam. The superior efficacy of clonazepam for control of status epilepticus may be at least in part because of its simpler dosing.

Acute mania

Meta-analysis2 found out that clonazepam is effective and safe in the treatment of acute mania, whereas for lorazepam results were inconclusive.


Results of double-blind comparison of clonazepam and lorazepam in acute mania 9 Clonazepam Lorazepam
Regimen 14 days therapy
Response rate 18.2% 61%
Remission rate 0% 38.5%

Further reading

References

  • 1. Alvarez V, Lee JW, Drislane FW, Westover MB, Novy J, Dworetzky BA, Rossetti AO. Practice variability and efficacy of clonazepam, lorazepam, and midazolam in status epilepticus: A multicenter comparison. Epilepsia. 2015 Aug;56(8):1275-85. PubMed
  • 2. Curtin F, Schulz P. Clonazepam and lorazepam in acute mania: a Bayesian meta-analysis. J Affect Disord. 2004 Mar;78(3):201-8. PubMed
  • 3. Ellinwood EH Jr, Nikaido AM, Gupta SK, Heatherly DG, Hege S. Comparison of the relationship between structure and CNS effects for lorazepam, clonazepam and alprazolam. J Psychopharmacol. 1993 Jan;7(1 Suppl):24-32. PubMed
  • 4. Young CC, Prielipp RC. Benzodiazepines in the intensive care unit. Crit Care Clin. 2001 Oct;17(4):843-62. pubMed
  • 5. McClure DJ, Walsh J, Chang H, Olah A, Wilson R, Pecknold JC. Comparison of lorazepam and flurazepam as hypnotic agents in chronic insomniacs. J Clin Pharmacol. 1988 Jan;28(1):52-63. PubMed
  • 6. Ward ME, Saklad SR, Ereshefsky L. Lorazepam for the treatment of psychotic agitation. Am J Psychiatry. 1986 Sep;143(9):1195-6.
  • 7. Donaldson M, Gizzarelli G, Chanpong B. Oral Sedation: A Primer on Anxiolysis for the Adult Patient. Anesth Prog. 2007 Fall;54(3):118-28;
  • 8. Bush G, Fink M, Petrides G, Dowling F, Francis A. Catatonia. II. Treatment with lorazepam and electroconvulsive therapy. Acta Psychiatr Scand. 1996 Feb;93(2):137-43. PubMed
  • 9. Bradwejn J, Shriqui C, Koszycki D, Meterissian G. Double-blind comparison of the effects of clonazepam and lorazepam in acute mania. J Clin Psychopharmacol. 1990 Dec;10(6):403-8. PubMed

Published: December 02, 2016
Last updated: April 04, 2018

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