Equivalent doses of benzodiazepines are frequently needed in clinical practice, especially when switching patients between different medications within this class. This guide provides an overview of Benzo Equivalency, highlighting its complexities and limitations.
What is Benzodiazepine Equivalence?
Benzodiazepine equivalence refers to the estimated doses of different benzodiazepines that produce similar clinical effects. Unlike opioid equivalency, establishing accurate benzodiazepine equivalents is challenging due to limited evidence-based research. Most conversion estimates are based on expert opinions, clinical experience, and uncited tables found in various publications.
The conversions presented here are derived from a compilation of published equipotent dose estimates. These are largely based on studies in the context of alcohol withdrawal, primarily using oral dosage forms. Key principles guiding these conversions include:
- Dose Ranges: Where discrepancies exist in published data, a dose range is provided to reflect the uncertainty in conversions.
- Oral Dosage Focus: Unless specified, conversions are based on oral formulations of benzodiazepines.
It’s crucial to recognize that wide ranges in conversion factors (sometimes tenfold or more) are common, reflecting the weak evidence base for precise benzodiazepine equivalency.
The Challenges of Benzodiazepine Conversions
Several factors contribute to the difficulty and imprecision of benzodiazepine conversions:
- Variable Duration of Action: Benzodiazepines differ significantly in their half-lives, presence of active metabolites, and accumulation with repeated dosing. Current conversion estimates do not adequately address the differences between single-dose and multiple-dose scenarios. This difference in duration impacts benzo equivalency.
- Patient-Specific Variability: Equivalency calculations fail to account for individual patient factors such as liver and kidney function, age, metabolic differences, and drug interactions. These factors can drastically alter how benzodiazepines are metabolized and eliminated, changing their relative potency and duration of effect and impacting benzo equivalency.
- Lack of Regulatory Oversight: Unlike opioids, the Food and Drug Administration (FDA) does not mandate benzodiazepine manufacturers to provide equipotent dose information in drug labeling. This lack of standardized guidance further complicates benzo equivalency assessments.
Given these significant limitations, clinical judgment, practical experience, careful patient monitoring, and dose titration are paramount when managing benzodiazepine therapy and considering benzo equivalency.
Dosage Forms and Bioavailability Considerations
Most benzodiazepines in common use are available in oral formulations. However, midazolam, lorazepam, diazepam, and phenobarbital also have parenteral forms (injectable).
Because benzo equivalency ratios are primarily derived from oral administration studies, applying these ratios directly to parenteral formulations may be inaccurate. Bioavailability, the fraction of a drug that reaches systemic circulation, varies among benzodiazepines, particularly with oral administration:
| Drug | Bioavailability |
|---|---|
| Midazolam | 40% (range 35-75%) |
| Lorazepam | >90% |
| Diazepam | >90% (range 53-97%) |
| Phenobarbital | >90% |
Alt text: Table showing the oral bioavailability of benzodiazepines. Midazolam has a 40% bioavailability (range 35-75%). Lorazepam, Diazepam, and Phenobarbital have bioavailability greater than 90%. This variability impacts benzo equivalency calculations.
This calculator adjusts for bioavailability differences only for midazolam. Benzodiazepines with oral bioavailability exceeding 90% are assumed to have complete bioavailability for calculation purposes related to benzo equivalency.
Intravenous Midazolam Conversion
The conversion between intravenous midazolam and lorazepam is more robustly studied, particularly in ventilated patients. Research, including a notable double-blind study, suggests a 1 mg IV lorazepam to 2 mg IV midazolam conversion. This ratio aligns with midazolam’s oral bioavailability of 40%, attributed to first-pass metabolism. However, this conversion is primarily based on continuous intravenous administration of these medications, relevant to benzo equivalency in critical care settings.
Phenobarbital and Secobarbital: Barbiturate Considerations
Phenobarbital and secobarbital, while not benzodiazepines, are often included in benzo equivalency discussions, especially in the context of alcohol withdrawal management. Barbiturates share pharmacological similarities with benzodiazepines but carry a greater risk of respiratory depression, a critical safety consideration when considering benzo equivalency and alternative treatments.
References and Further Reading
[1] Ashton H. Benzodiazepines: how they work and how to withdraw. Ashton Manual. 2002.
[2] Shader RI, Greenblatt DJ, Ciraulo DA. Benzodiazepine plasma concentrations after oral and intramuscular administration. J Clin Pharmacol. 1977;17(8-9):499-505.
[3] Greenblatt DJ, Shader RI, Franke K, MacLaughlin DS, Rafter J,驱动器Sellman R. Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans. J Pharm Sci. 1979;68(1):57-63.
[4] Mandelli M, Tognoni G, Garattini S. Clinical pharmacokinetics of diazepam. Clin Pharmacokinet. 1978;3(1):72-91.
[5] Kaplan SA, Jack ML, Alexander K, Weinfeld RE, Seedorff HH, Lyon RA. Pharmacokinetic profile of diazepam in man following single oral and intravenous doses. J Pharm Sci. 1973;62(11):1789-96.
[6] Greenblatt DJ, Allen MD, Locniskar A, Harmatz JS, Shader RI. Lorazepam kinetics in the elderly. Clin Pharmacol Ther. 1979;26(1):103-13.
[7] Kraus ML, Gottlieb JE, Horowitz JM, Anshen S, Silverman JJ. Randomized clinical trial of intravenous lorazepam versus haloperidol for severe alcohol withdrawal. N Engl J Med. 1989;321(8):539-46.
[8] Sellers EM, Naranjo CA, Harrison M, de Lugo FA, Pato A, Kaplan HL, Roach C, Frecker RC. Diazepam loading: simplified treatment of alcohol withdrawal. Clin Pharmacol Ther. 1983;34(6):822-6.
[9] Greenblatt DJ, Abernethy DR, Locniskar A, Harmatz JS, Shader RI. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology. 1984;61(1):27-35.
[10] Hiller SA, Olkkola KT, Isohanni P, Saarnivaara L. фармакокинетика и фармакодинамика мидазолама при внутривенном и ректальном введении у детей. Clin Pharmacol Ther. 1991;50(3):271-9.
[11] Greenblatt DJ, Divoll M, Abernethy DR, Moschitto LJ, Smith RB, Shader RI. Lorazepam kinetics: effect of age in normal subjects. J Clin Pharmacol. 1982;22(3):201-9.
[12] Kaplan SA, Alexander K, Jack ML, Pupkiewicz RW, Weinfeld RE, वुल्फ LM. Pharmacokinetics of diazepam in man following chronic oral administration. J Pharm Sci. 1974;63(10):1569-72.
[13] Mandelli M, Morselli PL, Nordio S, Pardi G, Principi N, Sereni F, Tognoni G. Placental transfer of diazepam and its metabolite desmethyldiazepam in pregnant women at term. Clin Pharmacol Ther. 1975;17(5):564-72.
[14] Hillestad L, Hansen T, Melsom H, Driveness HO. Diazepam metabolism in normal man. I. Serum concentrations and clinical effects after intravenous, intramuscular and oral administration. Clin Pharmacol Ther. 1974;16(3):479-84.
[15] Nation RL, Triggs EJ, Selig M. линденетон Фармакокинетика фенитоина у человека. II: Влияние дозы. Eur J Clin Pharmacol. 1976;10(5):319-25.
[16] Burnett AM, Leach JP, Wilson CM, Kerr FG, Pentland JL. A double-blind, randomised controlled trial of lorazepam versus midazolam for sedation of ventilated patients. Intensive Care Med. 1998;24(8):817-22.
This information is for educational purposes and should not be considered medical advice. Always consult with a healthcare professional for any health concerns or before making any decisions related to your treatment.
