Prescribing a drug is one of the most common interventions that physicians perform. However, polypharmacy—when five or more drugs are prescribed—is often to blame for adverse drug reactions. These reactions can lead to potential hospitalization, a risk that coincides with increasing rates of polypharmacy, affecting 17.1% of adults and 44.1% of the elderly between 2017–2018.

Wang X, Liu K, Shirai K, et al. Prevalence and trends of polypharmacy in U.S. adults, 1999-2018. Glob Health Res Policy. 2023;8(1):25.

 

Adverse drug reactions and polypharmacy increase the risk of prescribing cascades, which occur when a prescribed or precipitating drug results in an adverse drug reaction for which a second drug is prescribed. This second drug can then precipitate further adverse drug reactions, necessitating the prescription of a third drug, continuing the vicious cycle.

 

Types of prescribing cascades

 

A review by German researchers characterized various types of prescribing cascades.

Dreischulte T, Shahid F, Muth C, et al. Prescribing cascades: How to detect them, prevent them, and use them appropriately. Dtsch Arztebl Int. 2022;119(44):745–752. 

 

In intentional prescribing cascades, an adverse drug reaction is identified and a second drug is purposefully used to treat this adverse drug reaction. With unintentional drug cascades, the adverse drug reaction is identified as a new medical condition and a second drug is prescribed without recognizing the role of the precipitating drug.

Necessary prescribing cascades occur when the relative benefit is so great that non-prescription would be inconsistent with appropriate treatment, and the non-utilization of this cascade would represent undertreatment. The non-utilization of an appropriate prescription cascade, however, would not necessarily represent undertreatment.

Second drugs can also prevent adverse drug reactions, thus representing prophylactic prescribing cascades. PPIs prescribed to prevent gastrointestinal adverse drug reactions from NSAIDs are one example. 

 

Examples of prescribing cascades

 

The first prescribing cascades were discussed in the literature nearly two decades ago. One common example involves the use of diuretics in patients treated with dihydropyridine calcium channel blockers, to ameliorate the adverse effect of peripheral edema. The prevalence of this cascade is 1 of every 22 US patients receiving dihydropyridine calcium channel blockers.

The following are some other examples of prescribing cascades, as noted in a review published in PLoS ONE:

Farrell B, Galley E, Jeffs L, et al. "Kind of blurry": Deciphering clues to prevent, investigate and manage prescribing cascades. PLoS One. 2022;17(8):e0272418.

 

 

Managing prescribing cascades

 

The PLoS ONE authors observed that HCPs and patients both play a role in recognizing the adverse effects that mediate prescribing cascades. 

Patients need to “consciously ask, ‘Could this be caused by a drug?’ as part of an approach to diagnosis,” the authors wrote. “Asking (and answering) this question about a sign, symptom, or apparent new or worsening medical condition before referral to a specialist for additional investigations or adding a new drug treatment could prevent a prescribing cascade. There are calls for all healthcare professionals involved in managing medication therapy to incorporate this type of assessment as part of their clinical practice.”

It’s important to recognize that adverse events could take time to manifest and that regular and long-term monitoring for adverse effects is necessary.

 

Reducing the risk of polypharmacy

 

Medical educators can shift the perspective of trainees to consider drug-related causes of signs/symptoms during the H&P. Heightened awareness will come from acquiring a global knowledge about the adverse effects of medications and age-related changes in medication pharmacokinetics and pharmacodynamics, and this will help develop competencies for deprescribing.

Physicians must determine the reasons for the use of medications, create a timeline of their uses, and document the sequence of events. Deprescribing one or more potentially causative agents can determine whether a sign or symptom is influenced by medication and is integral in treating the sign or symptom.

This information should be available to HCPs, and patients should be engaged in monitoring the effectiveness and safety of the drugs they are taking.

“Such documentation and knowledge will help people make informed decisions about risk-benefit of continuing medications, which ultimately informs discussions about deprescribing as part of both sign and symptom investigation, as well as management of a possible prescribing cascade,” the PLoS ONE authors wrote. “Such decisions are heavily influenced by the patient’s perception of the risk-benefit of each medication and their readiness to make changes, something that may change over time and with additional information. Clinicians must be flexible and persistent in engaging in such discussions as patients’ perceptions change.”

Tools that aid in the recognition of prescribing cascades may also be helpful. To help clinicians recognize the potential for prescription cascades, international researchers developed a nine-item consensus-based list detailed in a study published in Drugs & Aging. They call the tool ThinkCascades.

McCarthy LM, Savage R, Dalton K, et al. ThinkCascades: A tool for identifying clinically important prescribing cascades affecting older people. Drugs Aging. 2022;39(10):829–840.

 

“Panelists’ decisions about what constituted a clinically important prescribing cascade were multi-factorial. This tool not only raises awareness about these cascades but will also help clinicians recognize these and other important prescribing cascades. This list contributes to the prevention and management of polypharmacy and medication-related harm in older people,” the investigators wrote.