Avoiding the prescribing cascade

When it comes to pharmacological treatments, clinical knowledge is always changing. Over the years, the Medical Post has worked to set the record straight on various pharmacological findings, from the effects of cough suppressants in children to treatments that are safe in pregnancy.The number of medications per patient has skyrocketed since the Medical Post’s early days, noted Dr. Thomas Perry, editor-in-chief of the Therapeutics Letter from the Therapeutics Initiative, an independent organization within the University of British Columbia that provides evidence-based information on healthcare interventions. It’s not unusual to have a patient with 10 medications. Often, they’re added inappropriately or not taken away, leading to possible adverse events or drug-drug interactions.Here are four reminders to help physicians prescribe appropriately.Anticholinergic medication and PPIsWhile there’s little evidence showing the most common prescribing cascades in Canada, Aaron Tejani, a pharmacist and researcher at Therapeutics Initiative, said he suspects a common one involves anticholinergic medications and proton pump inhibitors (PPIs).Commonly prescribed anticholinergics include antidepressants (i.e., amitriptyline, bupropion, citalopram, escitalopram, fluoxetine, mirtazapine, paroxetine, sertraline, venlafaxine) antipsychotics (i.e., aripiprazole, clozapine, olanzapine, quetiapine, risperidone) and medications for insomnia and pain and others. Anticholinergic medications can cause an increase in saliva and a decrease in gastric emptying, Tejani said, citing a Therapeutics Initiative letter from 2018 that provides more evidence. The patient may have dyspepsia, which could be mistaken as a symptom of reflux disease, leading a physician to prescribe a PPI.Dr. Melissa Andrew, a geriatrician, and colleagues at Dalhousie University looked at 28,952 Nova Scotia Seniors’ Pharmacare program beneficiaries with dementia and found 63.4% were dispensed at least one anticholinergic medicine between 2010 and 2015. Of these patients, 6.4% were prescribed a PPI within 180 days. Their analysis suggests that a prescription for an anticholinergic medicine increased the risk of being prescribed a PPI. The study was published in Frontiers in Pharmacology in 2022.Of course, the PPI prescription could be appropriate (e.g., the researchers give the example of gastroprotection after an SSRI), but the findings support work published in the Journal of Gerontological Nursing where a long-term home residents’ anticholinergic burden increased the risk of a PPI prescription. The level of anticholinergic activity differs between agents.Prescribing cascades such as this one can occur because adverse effects don’t always appear in the first few weeks of taking a new medication. At times, the patient initially tolerates the medication, but adverse effects appear later, so the prescriber and the patient don’t attribute the symptoms to the drug. “It appears as a new condition,” explained Tejani. There’s a belief about adverse reactions that, “If it’s going to happen, it’ll happen right away,” and if nothing happens early-on, then the prescriber stops worrying about it.“It’s quite likely that someone taking an anticholinergic is likely to get a PPI,” Dr. Perry said. “And once you get on those, you don’t stop.” Dr. Perry is a clinical associate professor in the department of anesthesiology, pharmacology and therapeutics at the University of British Columbia.Deprescribing a PPI is rare, he said, because PPIs are inexpensive and thought to be innocuous. But deprescribing PPIs is recommended by experts. The medications are associated with increased risk of pneumonia, negative effect on the gut microbiome and poor outcome following a fracture, COVID-19 or Clostridium difficile infection, the Nova Scotian researchers noted in their paper.The deprescribing.org website has resources on how to deprescribe a PPI.Anticholinergics and cholinesterase inhibitorsAnticholinergic medications can also cause cognitive problems, including an inability to focus (“brain fog”). “There are cognitive issues that have subtle manifestations from anticholinergics that might be missed,” Tejani said. These symptoms may lead to physicians prescribing medications thought to slow cognitive decline, such as cholinesterase inhibitors.The prescribing cascade can also go the other way. In a 2021 paper, Dr. Andrew and colleagues suggested that older adults on cholinesterase inhibitors were at higher risk of getting a prescription for bladder anticholinergic medication. Centrally acting anticholinergic drugs used to treat these urinary conditions are linked to worse outcomes in people with dementia, studies suggest.Gabapentin, pregabalin and diureticsAn established adverse event of gabapentinoids is edema, leading physicians to sometimes prescribe a diuretic. This could then lead to adverse events from the diuretic, which in turn could promote another prescribing cascade. A cohort study of Ontario older adults with low back pain showed those who took gabapentinoids within a week of a low back pain diagnosis were at a higher risk of getting a diuretic within 90 days compared to those who did not get a gabapentinoid prescription. The risk increases with a higher dose of gabapentinoid, the 2021 study suggests.The edema could also be confused as a symptom of heart failure, Dr. Perry said. This could then lead to another “horrific cascade” with four to six more medications if heart failure is misdiagnosed. One of the medications could be a calcium channel blocker, which can also cause edema.The first step is to recognize prescribing cascades. ThinkCascades is a nine-item list of common prescribing cascades in older adults, published in Drugs and Aging. An international group of experts recently identified 65 potentially inappropriate prescribing cascades, a list endorsed by the European Geriatric Medicine Society. It was published in European Geriatric Medicine. Both include the gabapentinoid and diuretic prescribing cascade.SSRIs/SNRIs and triptansAn attendee at the Canadian Neurological Sciences Federation congress in June 2025 asked about the risk of serotonin syndrome when patients are taking both selective serotonin reuptake inhibitors (SSRI)s or serotonin and norepinephrine reuptake inhibitors (SNRIs) and triptans. This is a case where the concern may have been misunderstood. The U.S. Food and Drug Administration released a warning in 2006 based on certain cases, but an American Headache Society investigation into the cases was outlined in a 2010 position paper. The researchers found few of the cases represented true serotonin syndrome, and there did not seem to be an increased risk. Despite the 15 years since the publication of the paper, there are still some healthcare professionals who hesitate at prescribing both.“I have a lot of patients on both, because depression and anxiety is a common comorbidity for patients with migraine, both in adults and pediatric patients,” said Dr. Marissa Lagman-Bartolome, director of the education program in pediatric neurology at the Children’s Hospital at London Health Sciences Centre in London, Ont.While combining SSRIs or SNRIs and triptans may not pose a risk, physicians should avoid adding amitriptyline to the mix.“We are going to be very very careful if they’re on amitriptyline, which is also acting on serotonin, and a triptan and an SSRI or SNRI,” Dr. Lagman-Bartolome said when asked about the issue. “That one increases the risk of serotonin syndrome for sure.” If she prescribes all three (which is rare), she ensures the patients are closely monitored.Pediatric Canadian Headache Network publishes a dosing guide for treating pediatric headache, although it does not specifically mention SSRIs and SNRIs with triptan use. When it is time to stop antidepressants in these patients, Therapeutics Initiative’s Therapeutics Letter number 157 has evidence-based information on the topic, as does the Canadian Medication Appropriateness and Deprescribing Network.There are a number of resources to help keep prescribing appropriate. Physicians in B.C. can benefit from Therapeutics Initiative’s prescribing portrait, which provides personalized data on prescribing habits in certain areas (e.g., the 2020 portrait on PPIs for heartburn). All Canadian physicians can find information from 11 organizations that make up the new Appropriate Use Coalition, focused on appropriate prescribing.

Avoiding the prescribing cascade

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