Benzodiazepine

Benzodiazepine Use During Pregnancy Increases Miscarriage Risk

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Benzodiazepine use during pregnancy is associated with an increased risk for miscarriage, according to new research published in JAMA Psychiatry. Health care professionals should carefully consider the risk-benefit ratio when considering benzodiazepine treatment for pregnant individuals.

Although benzodiazepines can cross the placental barrier and may potentially impact fetal development, they are still used to treat psychiatric and sleep disorders in pregnancy. Studying the effect of benzodiazepines on pregnancy outcomes is challenging as pregnant women are often precluded from randomized clinical trials and confounding factors can bias results in observational studies. The current study aimed to quantify the risk for miscarriage associated with benzodiazepine use during pregnancy, using a case-time-control design that accounts for confounders.

This nationwide, population-based study was conducted in Taiwan using pregnancy data from the National Health Insurance (NHI) database from 2002 to 2019 and the National Birth Certificate Application (BCA) database from 2004 to 2018. Researchers employed a case-time-control design to investigate the association between benzodiazepine use during pregnancy and the risk for miscarriage, comprising 2 analyses: a case-crossover analysis and an exposure time-trend control crossover analysis. The researchers used a conditional logistic model to estimate the odds ratios (ORs) of miscarriage.

Overall, the study included 3,067,122 pregnancies among 1,957,601 women (mean age=30.61; SD, 5.91). Of those pregnancies, 136,134 (4.4%) resulted in miscarriage. The researchers then matched the case group of individuals who experienced miscarriage with controls (based on age, psychiatric medical conditions, lifestyle factors, chronic comorbidities, medication use, and health care utilization), resulting in 134,864 pairs of pregnant women.

Prescribing benzodiazepines should only be considered following a comprehensive evaluation of the potential benefits and risks for both the mother and the child.

Among the cases cohort, 1502 pregnant women were exposed to benzodiazepines during the risk period only (1 to 28 days before miscarriage), and 2806 were exposed during the reference period only (181 to 208 days before the last menstrual period). Case-time-control ORs confirmed that exposure to benzodiazepines was associated with an increased risk for miscarriage (OR, 1.69; 95% CI, 1.52-1.87). Further, subgroup analyses revealed a dose-response association between benzodiazepine exposure and miscarriage, with the OR increasing from 1.61 (95% CI, 1.43-1.82) for low-dose exposure to 1.86 (95% CI, 1.53-2.25) for high-dose exposure.

This nationwide case-time-control study revealed that benzodiazepine use during pregnancy was associated with an approximately 70% increased risk for miscarriage, even after accounting for measurable confounders. Study authors concluded, “Prescribing benzodiazepines should only be considered following a comprehensive evaluation of the potential benefits and risks for both the mother and the child.”

The primary limitation of the study is the potential bias resulting from the use of birth certificate-based and claims-based databases for pregnancy and benzodiazepine exposure measures.

New Warning About Benzodiazepine Use and Dementia Risk

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Yet another study has linked benzodiazepine use to an increased risk for Alzheimer’s disease (AD).

“Even though the association between benzodiazepine use and Alzheimer’s disease was small in this study, the threshold for prescribing these drugs should be high enough due to their overall adverse effect profile, including higher risk of falls and hip fractures,” lead author Vesa Tapiainen, MD, PhD, a student in the School of Pharmacy, University of Eastern Finland, Kuopio, told Medscape Medical News.

These drugs are often used to treat sleep problems, but their efficacy for this indication diminishes over time, whereas the risks for adverse events remain, she added.

“Physicians should consider the risks and benefits, as well as appropriate duration of treatment, before prescribing these drugs,” said Tapiainen.

Although other studies have linked benzodiazepines with AD risk, Tapiainen believes this one is the largest to date.

The study was published in the August issue of Acta Psychiatrica Scandinavica.

Widely Used

In addition to insomnia, benzodiazepines and other so-called “Z” drugs, such as zolpidem (multiple brands) and zopiclone (Lunesta, Sunovion), are used to treat other neuropsychiatric symptoms of dementia, such as anxiety.

Although these drugs have different molecular structures, they have a similar mechanism of action and similar anxiolytic, anticonvulsive, hypnotic, and relaxing effects. In addition, they have similar adverse effects, including drowsiness, and their use is associated with mobility problems, falls, and fractures.

Benzodiazepines are used in 9% to 32% of older patients, the authors report.

The researchers used the Medication Use and Alzheimer’s Disease (MEDALZ) cohort, which includes all 70,719 residents of Finland. The patients selected for the study had been diagnosed with AD between 2005 and 2011. The patients’ ages ranged from 34 to 105 years. The study also included 282,862 matched control persons from nation-wide registers.

AD diagnoses were based on criteria from the DSM‐IV, as well as from the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association, now known as the Alzheimer’s Association.

Investigators extracted information on drug use from the Finnish Prescription Register. They looked at short-, medium- and long-acting benzodiazepines and related drugs.

In addition, the researchers examined different durations of drug use (1 day to 1 month; 1 month to 1 year; 1 to 5 years; and more than 5 years), and cumulative consumption in defined daily doses (DDDs), divided by tertiles.

“Worrying” Results

To account for reverse causality, the researchers investigated drug use only from 1995 to 5 years before AD diagnosis.

They controlled for various chronic disorders, including asthma/chronic obstructive pulmonary disease, cardiovascular disease, and diabetes, as well as for substance abuse, socioeconomic status (SES), and use of antidepressants and antipsychotics. All confounders were extracted until 5 years before the AD diagnosis.

Results showed that compared to individuals who had not used any of the relevant drugs, any use was associated with an increased risk of AD (odds ratio [OR], 1.19, 95% confidence interval [CI], 1.17 – 1.21).

After adjusting for comorbidities, SES, and use of other psychotropic medications, the association was somewhat lower (OR, 1.06; 95% CI, 1.04 – 1.08).

Using statistical calculations, the authors determined that the proportion of AD cases that could be attributed to exposure to these drugs was 5.7%.

Although the authors acknowledge that the increased absolute risk is modest, they point out that because these drugs are frequently used in older people, even a small increase in risk may be important.

“This is worrying,” the investigators note, not only because these drugs are commonly used by older patients but also because, despite recommendations, they’re often used long term in this population of patients.

In this study, the AD risk with all drugs was highest in patients who used the drugs for longer than a year. In the fully adjusted model, there were no risks for use during periods of less than a month.

The risks and benefits of these drugs should be reevaluated regularly, stressed Tapiainen.

She added that targeting the causes of sleep problems in patients and using nonpharmacologic treatments “should be prioritized.”

The relationships uncovered by the authors were similar for the various drugs and for short-, medium- and long-acting formulations.

Puzzling Finding

Interestingly, lower average doses (<0.5 DDD/day) of many of the drugs increased the AD risk more than higher doses in the unadjusted model.

“We were puzzled by this observation and investigated it in more detail,” said Tapiainen. “This investigation revealed that those who used the highest average doses actually used these drugs for a shorter period of time, and so their total consumption was less.”

In addition, high and low doses may have been used for different indications.

The authors noted that the dose-response relationship that was uncovered for both cumulative consumption and duration was lessened in the highest drug dose category after adjusting for use of other psychotropics.

“This indicates that the association may be partially due to antidepressants and/or antipsychotics, or concomitant use of these medications,” said Tapiainen.

When asked whether the relationship between drug use and AD risk was more pronounced among the oldest patients in the study, Tapiainen said she and her colleagues did not investigate this in the published study.

“But because we found this question interesting, we did further analysis and found that the association was similar regardless of age,” she said.

A limitation of the study was that it did not include data regarding nonreimbursed drugs or drugs used in hospital.

Plausible Risk

Commenting on the findings for Medscape Medical News, David S. Knopman, MD, professor of neurology, Mayo Clinic, Rochester, Minnesota, and a member of the Alzheimer’s Association Medical and Scientific Advisory Council, noted that many studies have suggested that patients who are exposed to certain psychoactive drugs, such as those with cholinomimetic properties, are at increased risk for dementia.

“I therefore find it plausible that benzodiazepines and related drugs could carry the same risks,” he said.

However, he added that the risk uncovered in this current study was “very modest.”

When the authors refer to “risk of Alzheimer’s” they mean “risk of dementia,” said Knopman. “They have no evidence from either neuropathology or biomarkers that the affected individuals had amyloidosis and tauopathy — so Alzheimer’s disease in the biological sense of the word.”

Tapiainen noted that all AD cases in the study were clinically verified with CT/MRI and that the diagnoses were confirmed by a registered neurologist or geriatrician.

The “bottom line” for Knopman is the same — that use of certain psychoactive drugs seems to increase the risk for dementia.

However, it is unclear whether the drugs are temporarily worsening cognition or symptoms are being treated with these drugs, said Knopman.

“In other words, the direction of causality from drugs to dementia could go in either direction, and this study that used administrative data can’t determine the direction of causality,” he said.

Nevertheless, a take-home message is that benzodiazepines and related sleep medications should be avoided “if at all possible” in older individuals, said Knopman.

Also weighing in on the findings for Medscape Medical News, Ronald Petersen, MD, PhD, director, Alzheimer’s Disease Research Center, Mayo Clinic, agreed that it is “appropriate” to be cautious about benzodiazepine use.

Petersen said he found the study “interesting,” although he “would want to be certain the clinical diagnoses were not confounded by benzodiazepine use prior to testing.”

Warnings About Benzodiazepine Use in the Elderly Go Unheeded

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Despite years of warnings about the hazards of prescribing benzodiazepines for the elderly, these drugs continue to be used at a higher rate than what is considered appropriate in older Americans — particularly older women, new data show.

A recent report released by Athena Health shows that individuals older than 65 years are prescribed benzodiazepines — including alprazolam (multiple brands), lorazepam (multiple brands), diazepam (multiple brands), and clonazepam (Klonapin, Roche) — more than other age groups are.

In 2017, 8.4% of individuals aged 65 and older were prescribed one of the drugs, a drop from 8.7% the previous year. Just over 8% of 50- to 64-year-olds were prescribed a benzodiazepine in 2017, compared to 7.5% of those aged 40 to 49 and 6.6% of those aged 30 to 39.

Ten percent of women older than 65 were prescribed a benzodiazepine, compared to just under 6% of men.

The data come from a sample of 3 million patients treated by primary care providers who are part of the Athena Health data network.

The data “are consistent with earlier research that suggests significant benzodiazepine overuse, especially among older adults,” Mark Olfson, MD, MPH, professor of psychiatry and epidemiology, Columbia University, New York City, told Medscape Medical News.

Since 2012, the American Geriatrics Society (AGS) has urged clinicians to avoid use of benzodiazepines in older adults. That recommendation is being reiterated in the AGS 2018 prescribing guidelines (called the Beers Criteria), which are under final review.

Physicians Not Getting the Message

The AGS notes that benzodiazepines increase the risk for cognitive impairment, delirium, falls, fractures, and motor vehicle crashes. The drugs can be appropriate for seizure disorders, rapid eye movement sleep behavior disorder, benzodiazepine withdrawal, ethanol withdrawal, severe generalized anxiety disorder, and periprocedural anesthesia, the AGS says.

Since benzodiazepines were first introduced in the 1960s, prescribing authorities and public health agencies have periodically issued warnings about the potential for addiction and other side effects.

In May, the deprescribing guidelines for the elderly project, based at the Bruyère Research Institute in Ottawa, Ontario, Canada, launched an effort to help clinicians wean long-term users off benzodiazepines and the benzodiazepine receptor agonists zolpidem (multiple brands), zopiclone (Zunesta, Suovion), and zaleplon (Sonata, Pfizer).

“We need to be a little bit more judicious with these,” Nicole Brandt, PharmD, MBA, BCGP, BCPP, FASCP, executive director of the Peter Lamy Center on Drug Therapy and Aging, University of Maryland, Baltimore, told Medscape Medical News. Brandt said she continues to be concerned about the persistence of benzodiazepine use in the face of so many warnings and guidelines.

Robert Roca, MD, chair of the American Psychiatric Association’s Council on Geriatric Psychiatry, said he was surprised — but not entirely — at the Athena data indicating that women received benzodiazepines at twice the rate of men.

“Women are more willing to express distress, and they’re more likely to receive psychotropics of all kinds,” Roca, vice president and chief medical officer, Sheppard Pratt Health System, Baltimore, told Medscape Medical News.

Women also have a higher risk for dementia, and, given the pressure to reduce the use of antipsychotics in patients with dementia, it’s possible that benzodiazepines are being substituted, said Roca. But, he added, benzodiazepines “are not a particularly good alternative.”

Olfson said that women “have higher rates of insomnia, anxiety disorders, and mood disorders, all of which are related to benzodiazepine use.” He also noted, however, that “because women assume more caregiver roles than men, they are under greater stress, which contributes to anxiety and sleep problems.”

Dementia Risk

Brandt agrees that caregiving is a major stressor for women. He noted that “it’s easier to get a medication paid for than to get counseling paid for or respite care paid for.” Benzodiazepines are prescribed for many medical problems, but “there are also lots of psychosocial issues where they may be the go-to agent,” she said.

She added that she’s seen benzodiazepines prescribed to help older people cope with losses, including the loss of mobility and the loss of friends or family members.

“I think benzodiazepines are a surrogate for a much bigger issue,” she said.

Many factors account for the continuing popularity and persistent use of benzodiazepines. Olfson said there is limited access to alternative evidence-based treatments for insomnia and noted that there’s “an unwillingness of some older people to consider reducing or discontinuing” the drugs.

In addition, said Olfson, “for some primary care physicians who have competing clinical demands on their time, given common comorbid medical problems in older adults, pharmacological options for managing insomnia and anxiety may be attractive.”

Roca noted that they are generally safe and effective in reducing anxiety and generally are not abused, although “there is no question they are potentially addictive.”

Benzodiazepines can also be a bridge therapy for patients who need an antidepressant, which can take weeks to start working, said Roca. He favors short-acting benzodiazepines, which, unlike long-acting ones like diazepam, are not taken up by adipose tissue.

But that type of analysis may not be familiar to physicians who more often prescribe the medications to younger people. “They are not so tuned in to the risks of prescribing to older people,” said Roca.

Besides the risks outlined by the AGS, some data now suggest that long-term exposure may increase the risk for dementia, he said. “There are all kinds of reasons to be careful,” said Roca.

Medicare has kept an eye on benzodiazepine use among older people who participate in the federal health plan. The Affordable Care Act initially banned coverage of benzodiazepines through Medicare Part D drug plans. That prohibition was lifted in January 2014; the drug class is now covered under Part D for any medically accepted indication.

A Hidden Epidemic?

The agency has taken an even closer look since it became clear that the drugs were often being prescribed in tandem with opioids. In 2015, the Centers for Medicare & Medicaid Services reported that 17% of Medicare beneficiaries were using benzodiazepines and that about a quarter were using them in conjunction with opioids.

A study published in JAMA Psychiatry in June found that rates of new opioid prescriptions written for adults using a benzodiazepine skyrocketed from 189 to 351 per 1000 persons from 2005 to 2010.

Although it decreased to 172 per 1,000 by 2015, “the likelihood of receiving a new opioid prescription during an ambulatory visit remained higher for patients concurrently using benzodiazepines compared with the general population after adjusting for demographic characteristics, comorbidities, and diagnoses associated with pain,” the authors note.

The dual use — and continued high use of benzodiazepines — has alarmed many clinicians and public health officials.

“Despite the many parallels to the opioid epidemic, there has been little discussion in the media or among clinicians, policymakers, and educators about the problem of overprescribing and overuse of benzodiazepines and z-drugs, or about the harm attributable to these drugs and their illicit analogues,” Anna Lembke, MD, Jennifer Papac, MD, and Keith Humphreys, PhD, wrote in an editorial published in the New England Journal of Medicine in February.

Overdose deaths related to benzodiazepine use continue to rise. Lembke noted that data from the National Institute on Drug Abuse (NIDA) show that overdose deaths involving benzodiazepines increased from 1135 in 1999 to 8791 in 2015. In 2016, NIDA reported 10,684 overdoses in which benzodiazepines were involved. Most of the deaths occurred in people who were also taking opioids, said NIDA.

Brandt said the opioid crisis provides lessons for how benzodiazepines should be monitored and prescribed. Benzodiazepines are not villains, however, she said. Like opioids, they are “a tool to address a problem,” said Brandt. She noted that she would not want to see them blacklisted.

Both Roca and Olfson said they supported adding benzodiazepines to state prescription drug monitoring programs. Including them would help flag those people who are using benzodiazepines and opioids, said Olfson. He also said that because a lot of the risk with the drug class is associated with long-term use, “policies should be considered and evaluated that restrict the days’ supply of benzodiazepines in a single prescription.”

Roca expressed concern about overly restrictive policies. “If you put a target on the back of these medications, you may make it difficult for patients who need them,” he said.

Factors Predicting Long-term Benzodiazepine Use Identified

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Poor-quality sleep, prescribing in an extended manner, and white race are key factors that predict conversion to long-term benzodiazepine use in the elderly, a practice that is strongly tied to poor outcomes, including death.

Dr Lauren Gerlach

 

The results highlight the need to “start with the end in mind” when prescribing a benzodiazepine, author Lauren B. Gerlach, DO, a geriatric psychiatrist and assistant professor in the Department of Psychiatry and the Program for Positive Aging, University of Michigan, Ann Arbor, told Medscape Medical News.

This means “beginning with a short-duration prescription and engaging patients in discussions of when to reevaluate their symptoms and begin tapering the patient off,” she said.

Gerlach said more work is needed to improve access to effective nonpharmacologic treatments, such as cognitive-behavioral therapy, as well as to provide access to education regarding such treatments.

The study was published online September 10 in JAMA Internal Medicine.

A Common Practice

Treatment guidelines recommend that if benzodiazepines are to be used at all, they should be used on a short-term basis. However, research suggests that up to one third of use is long term and that use is most common among older adults.

The investigators point out that the factors that predict extended benzodiazepine use are poorly understood.

To identify these risk factors, the researchers used data from the Supporting Seniors Receiving Treatment and Intervention (SUSTAIN) program, which provides a supplement to a Pennsylvania medication coverage program for low-income older adults.

Program services included detailed interviews to screen for mental health problems, such as anxiety, depression, and sleep problems, as well as pain, and analysis of prescription records and other clinical data.

The investigators examined how many older adults who received a new benzodiazepine prescription from a nonpsychiatric provider went on to long-term use of the medication. They also evaluated patient and clinical characteristics that predicted long-term use.

Long-term use was defined as a medication possession ratio (MPR) greater than 30% in the year following the initial prescription. Gerlach explained that the MPR was calculated by dividing the number of days of medication supplied by 365 days.

The study included 576 older adults (mean age, 78.4 years).

The analysis showed that 1 year after the index prescription, 26.4% of patients met the criteria for long-term use. They were prescribed benzodiazepines for a mean of 232.7 days.

Although treatment guidelines recommend only short-term prescribing, “these long-term patients were prescribed nearly 8 months’ worth of medication after their initial prescription,” said Gerlach.

In adjusted analyses, white race (odds ratio [OR], 4.19; 95% confidence interval [CI] 1.51 – 11.59; P = .006), days supplied in the index prescription (OR, 1.94; 95% CI, 1.52 – 2.47; P < .001), and poor sleep quality (OR for very, very bad vs very good, 4.05; 95% CI, 1.44 – 11.43; P = .008) were factors associated with increased long-term benzodiazepine use.

“Cause for Concern”

It’s a “cause for concern” that nonclinical factors are associated with benzodiazepine prescribing, said Gerlach.

“The decision to prescribe and then continue a benzodiazepine — or any other medical treatment — should be driven by a clinical need,” she said.

Gerlach said it was “particularly striking” that for every 10 additional days of medication prescribed, “a patient’s risk of long-term use nearly doubled over the next year.”

This finding “suggests that providers should pause and think more cautiously when providing a new prescription for benzodiazepines, such as considering a 14-day supply rather than a 30-day supply of medication,” said Gerlach.

Also concerning was the average age of the study participants when they first received a benzodiazepine prescription (78 years), because national guidelines say these drugs “should rarely be given to adults over age 65,” she said.

Of the clinical measures the researchers evaluated, which included depression, anxiety, sleep, and pain, only poor sleep was associated with the likelihood of continued benzodiazepine use.

“This is despite the fact that benzodiazepines are not recommended for long-term use as sleep aids, and may even worsen sleep outcomes the longer they’re used,” said Gerlach.

Because nonpsychiatric clinicians increasingly prescribe psychotropic drugs to older adults, the authors write that it is “critical” to improve access to and education about nonpharmacologic treatments.

The authors note that the study did not account for as-needed medication use, which may have had an effect on the calculation of long-term use. As well, the analysis was limited to low-income older adults from Pennsylvania, which may limit generalizability.

The authors also point out that definitions of long-term benzodiazepine use vary and that it is possible that a different definition of long-term use might have yielded different results. However, the investigators used three alternative definitions, with no significant variation in the findings.

Important Message

Commenting on the article for Medscape Medical News, Peter Yellowlees, MD, professor of psychiatry and vice chair for faculty development, Department of Psychiatry, University of California, Davis, said he was somewhat surprised that not more patients converted to long-term benzodiazepine prescriptions and that whites and not minority groups were more likely to be prescribed these drugs long term.

He said the “single most important message” from the study is that patients should know from the beginning that their benzodiazepine prescription will be short term.

In his own practice, Yellowlees said he “very seldom” prescribes benzodiazepines and “is much more likely” to taper patients off these drugs.

He aims to have patients to take these addictive medicines only three or four times a week — not every day — to avoid “getting hooked on them” and to taper patients off the drugs “extremely slowly” — over 3 to 6 months.

“Most people try to taper patients off in a matter of maybe 2 or 3 weeks; they will go, say, from 10 mg one week, to 5 mg the next, to whatever the next, and honestly, that’s just too hard for many patients,” he said.

The problem is that such a slow tapering approach can be time consuming, and primary care practitioners may have only a 15-minute consult per patient.

Benzodiazepines have been linked to falls and cognitive impairment, said Yellowlees.

“The effects can mimic early dementia. People get confused, and that leads to falling down and not being able to manage at home, with patients then having to go into a nursing home,” he said.

There are also risks of taking these drugs and then driving, said Yellowlees.

In lieu of benzodiazepines, he often uses cognitive-behavioral therapy for patients who have problems sleeping or who have anxiety.

Symptom-Triggered Dosing Is Better Than Fixed Dosing for Treating Alcohol Withdrawal.

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Symptom-triggered dosing leads to lower total benzodiazepine dose and shorter hospital stay than fixed-tapered dosing.

In a retrospective chart review, researchers compared outcomes between 49 patients who received symptom-triggered benzodiazepine dosing and 50 who received standard fixed-tapered dosing for treatment of alcohol withdrawal in an emergency department (ED) clinical decision unit in Ireland during a 2-year period. Patients treated with the symptom-triggered dose regimen were assessed at 90-minute intervals using the Clinical Institute Withdrawal Assessment for Alcohol scoring tool and were given a dose of a benzodiazepine if the score indicated need. Patients treated with the standard regimen received tapered doses of benzodiazepine over 5 to 7 days. Benzodiazepine doses were reported in diazepam dosing equivalents, with 25 mg of chlordiazepoxide considered equivalent to 10 mg of diazepam.

The two groups were comparable in demographics, alcohol use, and reasons for coming to the ED. The symptom-triggered dosing group had a shorter median hospital stay (2 days vs. 3 days) and received a lower median cumulative benzodiazepine dose (equivalent to 80 mg vs. 170 mg of diazepam).

Comment: Many emergency physicians have already adopted the practice of treating alcohol withdrawal based on symptoms with the goal of the patient being calm but able to be aroused. This study suggests that this approach may not only reduce the amount of benzodiazepine needed, but it may also shorten hospital stay.

Source: Journal Watch Emergency Medicine

 

Psychotropic Drug Use Associated with Increased Risk for Car Crashes .

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Antidepressants, benzodiazepines, and so-called “Z-drugs” such as zolpidem (Ambien) and zaleplon (Sonata) are associated with increased risk for motor vehicle accidents, according to a case-control study in the British Journal of Clinical Pharmacology.

Using registry and claims data from Taiwan, researchers assessed use of psychotropic drugs among 5200 people who were drivers during motor vehicle accidents and 31,000 matched controls who were not in accidents.

Relative to nonusers, the risk for motor vehicle accidents was higher among patients who had taken the following classes of drugs within the previous month: antidepressants (adjusted odds ratio, 1.73), benzodiazepines (1.56), and Z-drugs (1.42), but not antipsychotics. Even relatively low doses of antidepressants and benzodiazepines conferred increased risks.

The authors conclude that clinicians should “choose safer, alternative treatments and advise patients not to drive, especially while taking medications, to minimize the risk of causing [traffic accidents] under the influence of psychotropic medications.”

Source: British Journal of Clinical Pharmacology