As US physicians have slowly moved away from the reflexive use of opioids for back and other forms of pain, they have often substituted other addictive drugs with unfavorable risk/benefit profiles—increasing the incidence of onerous side effects, including overdose and death.
For example, recent studies have documented major overuse of benzodiazepines for chronic pain and other indications—alone, in combination with opioids, and with other sedating medications. They are commonly prescribed for the wrong conditions, the wrong patients, and the wrong duration.
They are exacting a sad death toll—contributing to almost 12,000 deaths in 2017, according to the National Institute on Drug Abuse (NIDA). (See NIDA, 2019). While benzodiazepines can and do lead to lethal overdose on their own, most deaths stem from combinations of medications.
Stanford psychiatrist and addiction specialist Anna Lembke, MD, and colleagues recently termed the widespread prescription of benzodiazepines “our other prescription drug problem.” (See Lembke et al., 2018.)
“Between 1996 and 2013, the number of adults who filled a benzodiazepine prescription increased by 67%, from 8.1 million to 13.5 million, and the quantity of benzodiazepines they obtained more than tripled during that period, from 1.1-kg to 3.6-kg lorazepam-equivalents per 100,000 adults,” they noted in the New England Journal of Medicine.
They cited an eight-fold increased incidence in overdose deaths involving benzodiazepines among men and women from 1999 to 2015. Most but not all of the overdose deaths—about 75%—stemmed from taking benzodiazepines with opioids.
“It would be a tragedy if measures to target overprescribing and overuse of opioids diverted people from one class of life-threatening drugs to another, according to these researchers.
Both sexes are vulnerable to the adverse effects of benzodiazepines, particularly women. The US Centers for Disease Control and Prevention recently updated overdose death rate statistics for women aged 30 to 64 years from 1999 to 2017. During this time frame death rates related to benzodiazepines increased a stunning 830%.
“Rates of overdose deaths involving benzodiazepines increased in every age group examined,” according to Jacob P. VanHouten, MD, PhD, and colleagues. They found a 1225% increase in women aged 30 to 34 years and a 534% increase among women aged 40 to 44 years. (See VanHouten et al., 2019.)
Physicians, patients, and the general public have consistently underestimated the dangers of these sedating drugs.
“The benzodiazepine overprescribing problem is at least five years behind the opioid overprescribing problem in terms of public awareness and response,” said Lembke in a recent email. “Yet the two are almost parallel epidemics, in that both result from prescribing these drugs long term at high doses contrary to the evidence (which does not support long-term use in either case), both are addictive, and both are potentially lethal (opioids more so, although benzodiazepines with or without opioids can kill). Another interesting and important parallel is the rise of high-potency, illicit benzodiazepines, not unlike illicit fentanyl and carfentanyl, now available through illegal online pharmacies and other dark web sources. These new amalgams, for example “clonazalam,” a synthetic combination of Klonopin and Xanax, are highly lethal, requiring a microgram scale to avoid overdose,” she warned.
Study of a Nationally Representative Sample
The most recent data on the overuse of benzodiazepines come from a cross-sectional study of a nationally representative sample. Sumit D. Agarwal, MD, and Bruce Landon, MD, analyzed patient visits from the National Ambulatory Medical Care Survey (NAMCS) from January 1, 2003, through December 31, 2015. The NAMCS is an annual cross-sectional survey of ambulatory care visits in the United States. (See Agarwal and Landon, 2019.)
They found a total of 27.6 million benzodiazepine visits in 2003 and 62.6 million visits in 2015. The overall benzodiazepine visit rate doubled from 3.8% to 7.4% of overall visits. Most benzodiazepines were prescribed in primary care settings.
Benzodiazepines are widely prescribed for anxiety, depression, and insomnia—where there they can be beneficial, but only with short-term or careful intermittent use.
“Many prescribers don't realize that benzodiazepines can be addictive and when taken daily can worsen anxiety, contribute to persistent insomnia, and cause death. Other risks associated with benzodiazepines include cognitive decline, accidental injuries and falls, and increased rates of hospital admission and emergency department visits,” according to Lembke et al. in the New England Journal of Medicine.
However, the study by Agarwal and Landon showed that the growth in benzodiazepine visit rates increased only slightly for anxiety and depression and did not change at all among patients treated for insomnia.
However, there was a major increase in the use of benzodiazepines for back and/or chronic pain, where the benzodiazepine visit rate more than doubled from 3.6% in 2003 to 8.5% in 2015.
And, ominously, the coprescribing rate of benzodiazepines with opioids quadrupled from 0.5% (95% CI, 0.3%-0.7%) in 2003 to 2.0% (95% CI, 1.4%-2.7%) in 2015 (P < .001); the coprescribing rate with other sedating medications doubled from 0.7% (95% CI, 0.5%-0.9%) to 1.5% (95% CI, 1.1%-1.9%) (P < .001), according to Agarwal and Landon.
Unfortunately, the study by Agarwal and Landon suggested that the greatest increase in benzodiazepine use involved long-term use—where there are scant benefits and lethal risks.
“The increase in the number of benzodiazepine visits likely reflects not only a growing number of unique individuals receiving benzodiazepines, but also an increase in those who are receiving benzodiazepines on a long-term basis. Other studies using pharmaceutical claims data and the National Health and Nutrition Examination Survey support the conclusion that long-term benzodiazepine use may be a larger driver of the increased use of this class of medications. This finding is of even greater concern because little evidence supports the use of benzodiazepines past 8 or 10 weeks, as suggested by US Food and Drug Administration labeling and several disease specific clinical guidelines,” according to Agarwal and Landon.
Why Is There Such an Increase in Benzodiazepine Prescription?
So why is there such an increase in the use of benzodiazepines for back and other forms of chronic pain? Is it a matter of overworked MDs moving away from opioids towards another medication without realizing its significant dangers? Could the structure of primary care be an issue—since most healthcare systems do not offer many of the nondrug therapies recommended in the American College of Physicians guideline on the management of low back pain.
“Yes to all of the above,” said coauthor Landon, a professor of healthcare policy at Harvard Medical School. “Physicians in general, and primary care physicians specifically, have few arrows in their quivers that effectively treat pain. Moreover, chronic pain often is confounded by other coexisting mental health issues that are poorly covered and undertreated in our current health care system,” he added.
“In the absence of better treatment modalities and being stuck in payment systems that minimize the value of counseling and other non-medical approaches, it is no wonder that physicians reach for anything they can try that is not an opioid. Also, as is often the case, “fill in an expletive” rolls downhill, and other physicians often just refer these patients back to primary care to figure out an approach.”
“‘These are great questions,’” said lead author Agarwal, a research fellow at Brigham and Women's Hospital in Boston. Our study doesn't directly answer these but in the discussion section of the paper, we tried to make some conjectures:”
- The benefits of benzodiazepines are immediately obvious (i.e. patients get immediate relief, even if it is only temporary) but the harms are much more indolent. This results in an over-appreciation of the benefits of benzodiazepines and under-appreciation of their risks among prescribers. This harkens back to the opioid epidemic which was at least partially driven by prescribers' under-appreciation of their risks.
- This [crisis] may be reflective of larger societal forces. In other words, patients with anxiety and other “diseases of despair,” which often co-manifest with somatic complaints such as pain, may be presenting to primary care with increasing frequency.
- As you mention, there may also be poor access to or availability of other good alternatives. Lidocaine patches, for example, which work well for pain, but are only covered by Medicare for post-herpetic neuralgia; otherwise they are very expensive. Physical therapy and other non-drug modalities aren't always readily available.
- To the point you're making, the current attention on opioids may certainly have impacted benzodiazepine prescribing. On the one hand, it could also have led to the replacement of opioids with benzodiazepines. On the other hand, I certainly hope that the current crisis has led to a more general recognition of the potential dangers of other prescription drugs like benzodiazepines. The next few years of data will be telling in this regard,” Agarwal suggested.
Several Ways to Interpret the New Study
The reasons for the dramatically increased prescription of benzodiazepines for chronic pain aren't clear, said Lembke via email.
“It's hard to know, based on the data, whether doctors are prescribing more benzodiazepines for chronic pain, using them to replace opioids, seeing patients more often to manage benzodiazepines (which would actually be a good thing), or whether some other phenomenon is taking place,” she explained.
“Anecdotally, I have seen doctors use benzodiazepines to help patients get off of opioids, which may be going from the frying pan into the fire. Just as the opioid epidemic itself is in part a result of our faltering health care system, so too has the response been emblematic of that.
Major Need for Non-Drug Therapies
“In short, we want to find the pill that's going to fix the opioid problem, when what we really need to do is tackle the bigger problem of providing non-medication treatments for chronic pain (physical therapy, massage, psychotherapy, other mind-body interventions) and naming and treating addiction.
“For chronic medical conditions, like chronic low back pain, the best medicine is slow medicine. But the system is designed for quick fixes in the form, often, of a pill. To change this, educating prescribers is important, but will never be enough. We need to incentivize slow medicine at the systems level if we want to get patients and prescribers to engage in a different way,” Lembke asserted.
Should Benzodiazepines Have Any Role in the Treatment of Back Pain?
Lembke suggested that the combination of benzodiazepines and opioids probably shouldn't have any role in the treatment of chronic back pain.
“The FDA issued the black box warning against opioid and benzodiazepine co-prescribing for good reason: the risk of overdose is significantly higher when these drugs are used in combination. Benzodiazepines also potentiate the euphoria produced by opioids, something we know from patients with addiction, who describe using those drugs in combination to augment the high. I do not think opioids and benzodiazepines should be used in combination or monotherapy to treat chronic pain. I would also argue that patients on buprenorphine or methadone maintenance for opioid addiction, who have been on long term benzodiazepines, should be tapered slowly and compassionately down and off of benzodiazepines. In other words, I don't think people with addiction should get a pass on opioid and benzodiazepine co-prescribing unless compelling evidence emerges to demonstrate that the benefits outweigh the harms. As far as I know, we don't have evidence like that,” said Lembke.
Disclosures: None declared.
Agarwal SD, Landon BE, Patterns in outpatient benzodiazepine prescribing in the United States, JAMA Network Open, 2019; 2(1):e187399. doi:10.1001/jamanetworkopen.2018.7399.
Lembke A, et al, Our other prescription drug problem, The New England Journal of Medicine, 2018; 378(8):693–5. doi:10.1056/NEJMp1715050.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
VanHouten J, et al, Drug overdose deaths among women aged 30–64 years—United States, 1999–2017, Morbidity and Mortality Weekly Report, January 11, 2019;68(1):1–5.