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Benzodiazepine Withdrawal Tied to Serious Long-Term Harms

The findings of a large survey support the FDA’s “boxed warning” from 2020.

Key points

  • More than 92 million benzodiazepine prescriptions are yearly dispensed in the US, yet little is known about the experiences of those taking them.
  • An Internet survey of 1,207 benzodiazepine users found more than half reported suicidal thoughts or had attempted suicide.
  • Most (76.2 percent) had not been informed that benzodiazepines are approved for short-term use only and that discontinuation might be difficult.
luchschenF/Shutterstock
Source: luchschenF/Shutterstock

“Over 92 million prescriptions for benzodiazepines are dispensed in the United States annually,” note Vanderbilt University psychiatrist Alistair J. Reid Finlayson and four colleagues in the April issue of Therapeutic Advances in Psychopharmacology, “yet little is known about the experiences of those taking and discontinuing them.”

Signs of a Disconnect

Signs of a disconnect between the widespread prescribing of drugs approved only for short-term (2–4 week) use and their rarely studied long-term consequences underline the importance of the survey, especially on the prevalence and severity of protracted benzodiazepine withdrawal.

Drawing from an Internet survey of 1,207 participants, 71 percent of them identifying as female, Finlayson and colleagues found that “82.9 percent reported work problems, 86.3 percent had problems with social interactions and friendships, and 88.8 percent had problems with fun, recreation, and hobbies.” More than half (54.4 percent) reported suicidal thoughts or had attempted suicide, and 46.8 percent said benzodiazepines had caused lost employment.

In addition, 76.2 percent of respondents had not been informed that benzodiazepines are approved for short-term use only and that discontinuation might be difficult. And 5.6 percent said they had “probably not” been warned.

Benzodiazepines represented in the survey included clonazepam (taken by 52.9 percent), alprazolam (41.7 percent), lorazepam (36.1 percent), and diazepam (32.1 percent). Of those surveyed, 43.7 percent said “situational anxiety” was the leading reason for their prescription, with insomnia or sleep disturbances second at 40.3 percent, and panic attacks third at 39.3 percent.

Among those fully discontinuing benzodiazepines, 10.4 percent had taken a year or longer to taper, though their symptoms persisted beyond discontinuation, sometimes for months and years. Many had attempted tapering more than once, with 17.6 percent adding that against US Food and Drug Administration (FDA) guidelines they “did not taper, quite abruptly, but with consequences.”

Fully 98.6 percent of respondents reported taking the benzodiazepine as prescribed, yet roughly a third (31.5 percent) described food allergies and/or seasonal allergies arising only after benzodiazepine use, and more than 4 in 10 (41.2 percent) had heightened sensitivity to food additives and other chemicals. Roughly a third said that after discontinuation they had experienced balance problems and associated falls and fractures, with 21 percent indicating that the problems began after starting benzodiazepines.

More than half (51.6 percent) of respondents reported low energy months and even years after discontinuation, with similarly prevalent conditions including nervousness, anxiety, and fear (50.2 percent), sleep disturbances (49.0 percent), and difficulty focusing or feeling distracted (49.7 percent). One in five (20.6 percent) had difficulty breathing or swallowing on a protracted basis, and more than one in four (28.3 percent) reported periods of uncontrollable crying or anger.

Other reported symptoms during or after benzodiazepine tapering included muscle weakness (36 percent); balance problems (31.0 percent); akathisia or constant pacing (19.1 percent); the whole body trembling uncontrollably (12.8 percent); acute sensitivity to light, noise, talk, and smell (42.8 percent); and “stabbing pain, burning, aching sensations, or joint pain” (34.7 percent).

Earlier Studies

“Benzodiazepine withdrawal symptoms are more common than most clinicians realize,” Reid Finlayson and colleagues report, citing a 1990 study in the Archives of General Psychiatry that found “58–100 percent (criteria dependent) of benzodiazepine users experience some type of withdrawal reactions upon discontinuation” (Rickels et al., 1990). Further studies from 2000 and 2011 determined that “Up to 44% of long-term benzodiazepine users have persistent moderate to severe withdrawal symptoms when they attempt to discontinue the drug” (De las Cuevas et al., 2000; Lader, 2011).

Yet, the FDA waited until 2020 to add a "boxed warning" of “serious risks associated with their use,” adding: “continued use of benzodiazepines” beyond two to four weeks “had the potential to lead to clinically significant physiological dependence.” The risks also “increased with longer treatment duration and/or higher doses” (Reid Finlayson et al., 2022). Despite the withdrawal studies from 1990, 2000, and 2011—and the evidence of harms documented in 2010 and 2015 by thousands of service users and concerned professionals urging rapid action—the FDA passed on prior evidence of serious adverse events after extended use and abrupt discontinuation.

Benzodiazepine withdrawal was first recognized more than six decades ago, in 1961, two years after the first studies of tricyclic antidepressant withdrawal in 1959. At Palo Alto’s Veterans Hospital in California, Leo Hollister and two other psychiatrists studied the reactions of 36 hospitalized patients to withdrawn chlordiazepoxide (Librium). The patients—said to be chronically ill from anxiety and schizophrenic reactions—had been treated with up to 600 milligrams of the benzodiazepine daily “for one to seven months (most for more than three months).”

Although 9 of the 36 were said to indicate a “clinically significant improvement” when the trial concluded, 10 of the 11 patients who were abruptly switched without their knowledge to placebo, following five months or more of drug treatment, experienced “new symptoms or signs following withdrawal.” “Six patients became depressed after being switched to placebos. Psychoses were aggravated in 5, insomnia and agitation appeared in 5, 4 had loss of appetite, and 1 was nauseated.”

In addition, Hollister and colleagues warned:

Two patients had major convulsions on the seventh and on the eighth day following drug withdrawal. One patient had a single previous seizure associated with earlier drug therapy; the other had no known seizures before. Another patient, not in the formal withdrawal study, experienced two new major seizures twelve days after abrupt withdrawal from a daily dose of 300 mg. He had been treated with chlordiazepoxide for three months but had become agitated at the higher dose range. One patient developed twitching and excessive perspiration on the eighth day after withdrawal.

They concluded:

Although differentiating withdrawal reactions from recrudescent psychiatric symptoms after drug withdrawal is always difficult, a number of factors favored the former interpretation of the newly-appearing symptoms and signs. First, the frequency (10 of 11 patients) of new symptoms or signs soon after withdrawal. Second, their coincidence with decreasing plasma levels of drug. Third, [the existence of] post-withdrawal seizures in 2 patients. Fourth, a slower onset and subtler development of this syndrome than that from meprobamate or barbiturates....If large doses of chlordiazepoxide are used, the drug should not be abruptly discontinued.

Patient Accounts

Why would the same outcomes not hold for benzodiazepines across the board?

Reporting on their own experiences taking and discontinuing the drugs, respondents to the 2022 survey were blunter about the now known harms: “If I could think of one of the worst possible things you could do to a person,” one wrote, “it would be benzo withdrawal.” A second: “This is by far the worst thing to ever happen to me.” A third: “Doctors misled me about my health and never once acknowledged the pills could be the reason behind any of my issues.” Yet it was “very difficult to find a health provider that will taper me off these awful chemicals.”

In warning against abrupt discontinuation, the researchers confirm a worrying lack of support over supervised tapering and deprescribing: “Many of the large number of write-in comments from respondents described attempting to quit benzodiazepines with minimal to no support from the health care system. A few were harshly critical of health care professionals who minimized their distress or disbelieved their symptoms.”

“I’m treated like I did something wrong for taking the prescription as prescribed,” one respondent is quoted as saying, “and when I looked at medical information years ago, [my doctor] told me not to because I was [said to be] making up symptoms by reading medical information.”

In sharp contrast, the researchers note, one 2014 “systematic review of benzodiazepine taper protocols (28 studies) suggested that for older adults, a taper should reduce the dose by 25 percent every 1 or 2 weeks until the patient is drug-free” (Paquin et al 2014) and even that reduction was “probably too-rapid a tapering plan based on the experience of the respondents in this survey.”

While the 2022 survey on benzodiazepine withdrawal adds significantly to clinical understanding of the medical condition and its longer-term effects, it did not include a control group or try to account for a possible nocebo effect, where symptoms are developed precisely because they are expected. Respondents to the survey were also self-selected, meaning their data may not align perfectly with a larger population of all people taking benzodiazepines. Nevertheless, the survey findings support and bolster earlier research on the condition dating from the 1960s and repeated as factors of concern in the 1970s and 1980s.

Randomized controlled studies verifying prevalence and severity months after benzodiazepine discontinuation are still badly needed. As Reid Finlayson and colleagues establish clearly from their survey, protracted withdrawal symptoms from benzodiazepines are “more common than previously appreciated,” with “many patients experienc[ing] a range of protracted and severe symptoms even years after benzodiazepines were completely discontinued.”

References

De las Cuevas C, Sanz EJ, De La Fuente JA, et al. (2000) The Severity of Dependence Scale (SDS) as screening test for benzodiazepine dependence: SDS validation study. Addiction 95: 245-250. [Link]

Hollister LE, Motzenbecker FP and Degan RO. (1961) Withdrawal reactions from chlordiazepoxide (‘Librium’). Psychopharmacologia 2: 63–68. [Link]

Lader M. (2011) Benzodiazepines revisited – will we ever learn? Addiction 106: 2086-2109. [Link]

Paquin AM, Zimmerman K and Rudolph JL. (2014) Risk versus risk: a review of benzodiazepine reduction in older adults. Expert Opin Drug Saf 13: 919-34. [Link]

Reid Finlayson AJ, Macoubrie J, Huff C, Foster D, and Martin PR. (2022). Experiences with benzodiazepine use, tapering, and discontinuation: an Internet survey. Therapeutic Advances in Psychopharmacology 12, 204512532210823. https://doi.org/10.1177/20451253221082386 [Link]

Rickels K, Schweizer E, Case WG, et al. (1990) Longterm therapeutic use of benzodiazepines. I. Effects of abrupt discontinuation. Arch Gen Psychiatry 47: 899-907. [Link]

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