Benzodiazepines: Recognizing Their Legitimate Indications

The Affordable Care Act prevents any health care plan from excluding coverage for benzodiazepines.

Benzodiazepines, first marketed in the early 1960s, allowed physicians to breathe a sigh of relief. Chlordiazepoxide and diazepam (both Hoffman-LaRoche products approved in 1960 and 1963, respectively) were the answer to a question researchers pursued vigorously in the 1950s: could a less toxic, less addictive drug or class of drugs be developed to replace available but risky tranquilizers? At the time, few drugs were available to treat anxiety, depression, and insomnia. Most available agents were controlled substances and acknowledged as likely to be “habit forming” (a buzzword at the time), cause dependence, and sometimes lead to addiction. In addition, these agents were plagued with side effects (Table 1).^1-3

Table 1: The 1950s Armamentarium of Drugs for Anxiety, Depression, and Insomnia

Drug or Drug Class

Side Effects and Concerns

Chloral hydrate

• Use limited by potential dependence
• Symptoms of acute toxicosis include nausea, vomiting, confusion, convulsions, slow and irregular breathing, and cardiac arrhythmia, ultimately progressing to coma with an overdose

Reserpine

• Many common side effects: abdominal pain, diarrhea, nausea, vomiting, xerostomia, dizziness, headache, lethargy, somnolence, vertigo, depression (in 6% to 30% of patients), nasal congestion
• Nightmares: can be bizarre and disabling

Barbiturates

• Sleepiness and somnolence are serious side effects
• Respiratory depression is a serious concern
• Habit forming (dependence and addiction possible)
• Accidental and suicidal overdose were common

Meprobamate

• Habit forming
• Plagued with neurologic side effects (asthenia, ataxia, dizziness, abnormal electroencephalogram, paradoxical excitement, headache, Paresthesia, slurred speech, somnolence, vertigo)
• Lethal overdose can be as little as 12 g

Initially, benzodiazepines appeared less likely to cause dependence than the older drugs. Additionally, benzodiazepines do not cause respiratory depression, the most significant safety concern with barbiturates.^4,6,7 Initially, medical professionals were relieved to have a safer alternative to the older drugs, and benzodiazepines immediately became blockbuster products.^8,9

Better Coping Through Chemistry

Benzodiazepines, especially Valium, became symbols of our fast-paced, heavily stressed society. Stressed? Pop a benzo! These drugs assumed central roles in books (eg, Valley of the Dolls), movies (eg, Starting Over), television shows, rock ‘n’ roll hits, and comedy routines. Many celebrities have publicly admitted addiction, and several have died of overdose after taking benzodiazepines with other drugs, including alcohol. Marilyn Monroe, Anna Nicole Smith, and Heath Ledger are just a few celebrities whose deaths were suspected of being associated with benzodiazepines.^10-13

In addition, a controversial case unfolded in the mid-1970s concerning the fate of a young woman, Karen Ann Quinlan, who became comatose after a benzodiazepine overdose. Her situation challenged the way we think about end-of-life care. As a result of a diazepam—alcohol overdose, Quinlan went into a coma—a persistent vegetative state—and remained unresponsive for 10 years. Early on after she became comatose, her family worked through the court systems to be allowed to disconnect her supportive care. At the time, the New Jersey Supreme Court ruled that her family should be allowed to decide whether to remove her from life support, which the family did. Multiple iterations of the end-of-life care decision have been revisited by the New Jersey Court since. However, Americans in all parts of the country followed her case.¹⁴

Today, benzodiazepines are so widely used, researchers have found trace residues of the drugs in many bodies of water worldwide.¹⁴

Over the Years

We now have more than 50 years of experience with benzodiazepines. Pharmaceutical innovators looked for molecular modifications of chlordiazepoxide and diazepam and found numerous drugs that use the same mechanism of action (gamma amino benzoic acid enhancement). By the mid to late 1970s, benzodiazepines topped every “most frequently prescribed” list. By the 1980s, medicine’s thought leaders and law enforcement voiced new concerns after seeing adverse consequences of benzodiazepine use: abuse and dependence. Legislators took action, as did many professional associations. They began (1) regulating or recommending against prescribing benzodiazepines in many circumstances and (2) creating mechanisms to increase prescriber caution.^15-20 For example:

• The American Geriatrics Society Beers Criteria and its updates identify drugs that, when used in older patients, are associated with poor outcomes. The Criteria recommend avoiding the use of most benzodiazepines in older patients, but the criteria list some specific conditions in which benzodiazepines are useful.¹⁵
• The 2003 Medicare Modernization Act overhauled Medicare. In 2006, revisions created an entitlement benefit for prescription drugs starting in 2006. It excluded all benzodiazepines, regardless of diagnosis or justification. Only Medicare beneficiaries with supplemental drug insurance (dual eligibles or insureds with private secondary insurance) or who were willing to pay out of pocket could have a benzodiazepine prescription covered.²¹ (This has since been overturned; see the discussion below.)
• The Drug-Induced Rape Prevention and Punishment Act of 1996 amended the Controlled Substances Act (CSA) to impose penalties of up to 20 years’ imprisonment and a fine for violating CSA provisions. Targeting flunitrazepam (or “roofies,” a date-rape drug), the act made it illegal to distribute a controlled substance to any individual without that individual’s knowledge, with intent to commit a crime of violence (including rape) against the individual.²²

Alternatively, the World Health Organization’s (WHO’s) Essential Drugs List includes several benzodiazepines. The WHO, acknowledging these drugs’ significant contributions, recommends that these drugs should be available at all times and in sufficient amounts in key hospital settings.²³

The Affordable Care Act

The Patient Protection and Affordable Care Act (ACA) of 2010 significantly expanded government’s role in health care and created regulatory overhaul of the US health care system. One significant change concerns benzodiazepines. The ACA includes language that prevents any health care plan, including Medicare, from excluding benzodiazepines. This action recognizes benzodiazepines’ legitimate and important indications (Online Table 2).²⁴ This reversal is welcome news for patients who legitimately need benzodiazepines but were not covered before.

Table 2: Most Appropriate Uses for Benzodiazepines (if Benefits Outweigh Risks)

Use

Commonly used Benzodiazepine

Alcohol and barbiturate withdrawal

Diazepam

End-of-life anxiety or insomnia

Diazepam, lorazepam, temazepam, triazolam

Muscle relaxation

Diazepam

Panic disorder

Alprazolam

Perioperative anesthesia

Midazolam

Seizure

Clonazepam, diazepam

Status epilepticus

Diazepam (rectal, intravenous)

Closing Thoughts

Benzodiazepines changed society, health care, and the way pharmacists practice. While offering benefits that far surpassed those of previous drugs, benzodiazepines created a need for health care provider vigilance. Used judiciously, benzodiazepines can relieve serious symptoms. Used recreationally, they create risks that endanger abusers and society’s safety. Fortunately, recent changes give Medicare beneficiaries and all insured patients access to these drugs when they need them.

Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy with interests in medical history and how society views and addresses issues related to prescription drugs.

References

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• Sternbach LH. The discovery of librium. Agents Actions. 1972;2:193-196.
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• Marantz Henig R. Valium’s contribution to our new normal. The New York Times. www.nytimes.com/2012/09/30/sunday-review/valium-and-the-new-normal.html?_r=0. September 29, 2012. Accessed November 4, 2013.
• Susann J. Valley of the Dolls. 6th ed. New York, NY: Grove Press; 1997.
• Gordon B. I’m Dancing as Fast as I Can. 2nd ed. New York, NY: Moyer Bell; 2011.
• Ledray LE. Date rape drug alert. J Emerg Nurs. 1996;22:80.
• Karen Ann Quinlan Memorial Foundation. Karen Ann Quinlan, 1954-1985. www.karenannquinlanhospice.org/history/. Accessed November 4, 2013.
• American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012;60:616-631.
• Keston M, Brocklehurst JC. Flurazepam and meprobamate: a clinical trial. Age Ageing. 1974;3:54-58.
• Rummans TA, Davis LJ Jr, Morse RM, Ivnik RJ. Learning and memory impairment in older, detoxified benzodiazepine-dependent patients. Mayo Clin Proc. 1993;68:731-737.
• Ray WA, Griffin MR, Downey W. Benzodiazepines of long and short elimination half-life and the risk of hip fracture. JAMA. 1989;262:3303-3307.
• Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women: study of Osteoporotic Fractures Research Group. N Engl J Med. 1995;332:767-773.
• 20. Barbone F, McMahon AD, Davey PG, et al. Association of road traffic accidents with benzodiazepine use. Lancet. 1998;352:1331-1336.
• H.R. 1 (108th): Medicare Prescription Drug, Improvement, and Modernization Act of 2003. Govtrack website. https://www.govtrack.us/congress/bills/108/hr1. Accessed November 4, 2013.
• Lott T. Drug-Induced Rape Prevention And Punishment Act of 1996. Sunlight Foundation website. http://capitolwords.org/date/1996/10/03/S12376_drug-induced-rape-prevention-and-punishment-act-of/. Accessed November 4, 2013.
• World Health Organization. WHO model list of essential mediations: 17th list, March 2011. http://whqlibdoc.who.int/hq/2011/a95053_eng.pdf. Accessed November 4, 2013.
• Patient Protection and Affordable Care Act of 2010, Pub. L. No. 111-148, § 2502, 124 Stat. 119, amended by Health Care and Education Reconciliation Act of 2010, Pub. L. No. 111-152, 124 Stat. 1029 (to be codified as amended at 42 U.S.C. § 1396r-8(d)) (adding “benzodiazepines” to drugs that cannot be excluded).
• Benzodiazepines. Hospice Education Institute website. www.hospiceworld.org/book/benzodiazepines.htm. Accessed November 4, 2013.