Flexibility is warranted in applying prescribing guidelines

“And though she’s not really ill/There’s a little yellow pill

She goes running for the shelter of a mother’s little helper

And it helps her on her way, gets her through her busy day…

Doctor please, some more of these/Outside the door, she took four more”¹

In this issue of the Journal, Kaur et al² note the benefits of and pragmatic concerns about the use of benzodiazepines, and suggest keeping an open mind about recent directives encouraging marked diminution (or elimination) of their use in most patients. Reading this, I wondered whether we should also be taking a moment for reflection regarding the current espoused generic directives on markedly limiting narcotic prescriptions as we treat the patient in front of us. There seems to be an accepted assumption that if a nonlifesaving medication is associated with harmful effects within a population of “users,” then there should be a clear net benefit in discontinuing chronic use and markedly limiting prescribing for virtually everyone. There are certainly kernels of truth in this approach, but I would argue that it cannot necessarily be applied in individual patients. It’s hard to know whether data or social constructs are primarily driving current efforts to markedly curtail prescribing at an individual level. Is limiting prescribing the right approach, or is it overly intrusive and paternalistic?

Time will tell, but my own encounter as a patient left me scratching my head. Several years ago, after a confusing and quite uncomfortable prelude, I had bilateral obstructing kidney stones surgically fished out. They were temporarily replaced by stents the size of Michigan. Not the most pleasant overall experience, and nocturnal narcotics were the only way I was able to sleep. A year or so later, right before I was scheduled to travel to give some lectures, I had the return of a readily recognized flank pain. I called my urologist and asked for a few narcotics to take with me, and I was told that their department policy forbade him to prescribe them.

Benzodiazepines were first introduced in the 1950s with chlordiazepoxide followed by diazepam (Valium) and others. Their mechanism of action involves allosteric modulation of the gamma-aminobutyric acid receptor, enhancing neural inhibition resulting in clinical anxiolytic, sedative, muscle relaxant, and anticonvulsant effects. Clinical trials showed efficacy for all of these and patient acceptance was enthusiastic, to say the least. But safety results from long-term studies were not initially available.

Chlordiazepoxide, initially named methaminodiazepoxide, was patented in 1958 and introduced to clinics in 1960 as Librium. The benzodiazepines, particularly diazepam, rapidly replaced barbiturates and other hypnotics as treatment for anxiety and were used by many as a sleep aid. The benzodiazepines had fewer acute side effects than barbiturates, the alternative available at the time. For a while, “benzos” were the most widely prescribed drugs in the world, estimated in the early 1970s to be used by up to 20% of the population.³ Their popularity was so high in the United Kingdom that in 1973 legal class action was taken against Hoffman–La Roche, the manufacturer, after a report demonstrated the extremely high cost of the mass consumption of benzodiazepines and questions were raised regarding appropriate prescription and issues of dependency or addiction. Financial support for this suit ultimately was withdrawn without any final legal decision, but millions of British pounds were spent in legal costs.

Patient acceptance and demand soared around the world. Culturally, benzodiazepines became a way of life, working their way into novels and movies, and famously into music. The Rolling Stones’ “Mother’s Little Helper” was dropped first on the UK version of their album Aftermath and a bit later as a single (“Lady Jane” was the B side) in the more drug-lingo–averse United States.

But despite wide patient acceptance, long-term use became recognized as a potential source of significant risk: dependence, withdrawal syndromes, cognitive impairment, increased risk of falls and fractures (especially in the elderly), and potential for overdose, particularly when combined with other central nervous system depressants. Current clinical guidelines recommend benzodiazepines primarily for short-term or intermittent use, with antidepressants and behavioral therapies preferred for chronic anxiety and insomnia. These guidelines and restrictive US Food and Drug Administration and legal restrictions have had variable success over time in limiting the number of prescriptions. By the 1980s, the number of prescriptions had decreased, but prescriptions for alternative, often less effective and not necessarily safer medications increased.³ In the United States, benzodiazepine prescriptions increased from the late 1990s through the early 2010s, with a slight decline more recently, but long-term use remains common, especially among older adults and women. Most prescriptions are written by primary care physicians.⁴

Recent attention has been focused on deprescribing benzodiazepines in patients taking the drugs chronically, even if they have been doing well and achieving the desired behavioral effects of the medications. It is reasonable to ask whether there are strong data supporting this as a uniform practice.

As noted by Kaur et al,² the supporting data for this approach are limited. A comparative effectiveness study that analyzed data from a US health claims database on patients prescribed long-term benzodiazepine therapy who had commercial or Medicare Advantage insurance between 2013 and 2017 did not demonstrate any safety advantage to discontinuation.⁵ Instead, discontinuation of benzodiazepines in chronic users was associated with a small increase in mortality and a higher risk of adverse events, especially in the short term after cessation. Interestingly, there is a review demonstrating similar outcomes when withdrawing narcotics from patients chronically prescribed narcotics.⁶ Gradual, informed, individualized tapering with nonpharmacologic support is likely the safest and most effective strategy to minimize withdrawal and adverse outcomes. But I believe it remains an open question as to whether this is the best strategy for all.

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