14 Sep  Reducing prescribing cascades
Case vignette: A 70-year-old woman is diagnosed with COPD, obstructive sleep apnea, left ventricular dysfunction with outflow obstruction, hypertension, prior pulmonary embolism, insomnia, anxiety, depression, mild cognitive impairment, and unexplained laryngitis. She takes 14 prescription drugs and 4 supplements, but would prefer fewer. Her primary care nurse practitioner consults an outpatient clinical pharmacist for a comprehensive medication review.
|1. spironolactone 25mg/d morning|
|2. diltiazem 180mg/d (ER) morning|
|3. bisoprolol 2.5mg/d morning|
|4. furosemide 40mg q2d morning|
|5. rosuvastatin 10mg/d bedtime|
|6. rivaroxaban 20mg/d evening|
|Suspected acid reflux (no GI bleed)|
|7. pantoprazole 40mg/d morning|
|8. tiotropium 2.5mcg (2 inh) morning|
|9. budesonide 100mcg/formoterol 6mcg (2) bid|
|10. salbutamol 100mcg 2 puffs tid prn|
|11. venlafaxine 300mg/d morning|
|12. mirtazapine 30mg/d bedtime|
|13. clonazepam 0.25mg/d bedtime|
|14. melatonin 3mg/d bedtime|
|15-18. iron, calcium, Vitamin C, Vitamin D|
Are prescribing cascades hiding in plain sight?
Once unimaginable, intimidating drug lists are now common.1 Mitigation may be easier if prescribers and dispensing pharmacists recognize the potential for “prescribing cascades”. Coined by 2 geriatricians in 1995,2 “a prescribing cascade begins when a drug is prescribed, an adverse drug event occurs that is misinterpreted as a new medical condition, and a subsequent drug is prescribed to treat this drug-induced adverse event.”3 Sequelae also include over the counter medicines or medical devices (e.g. cardiac pacemaker insertion).
Potential prescribing cascades in this vignette include:
|Drug||Common adverse effect||Possible cascade prescriptions|
|Diltiazem||Peripheral edema||Furosemide for edema mistaken as volume overload or right heart failure|
|Tiotropium||Anticholinergic: hoarseness/laryngitis||Pantoprazole to reduce stomach acid (but not reflux)|
|Mirtazapine||Anticholinergic: impaired stomach emptying; hoarseness/laryngitis||Pantoprazole|
|Venlafaxine||Nausea, “indigestion”, gastric upset||Pantoprazole|
|Venlafaxine||Insomnia, agitation, anxiety||Clonazepam, melatonin, mirtazapine|
|Venlafaxine||Tachycardia/palpitations||Increased dose of bisoprolol|
|Pantoprazole||Impairment of iron absorption||Iron supplement|
Prescriptions added to counter one or more drug effects could induce falls from oversedation, “mild cognitive disorder” or other long-term anticholinergic (antimuscarinic) effects, or adverse effects of a PPI. Given this woman’s interest in deprescribing, the clinical pharmacist also questioned other drugs in her list.
What is known about “prescribing cascades”?
Published studies of prescribing cascades focus on several drug classes.4 Those previously identified include some of the 200 drugs most often prescribed to people in BC.
Seven prevalent examples
1. Anticholinergic drugs ➜ cognitive dysfunction ➜ drugs for dementia
Anticholinergics (e.g. tricyclic antidepressants, cyclobenzaprine, mirtazapine, quetiapine, oxybutynin)5 block acetylcholinergic neurotransmission in the brain, impairing cognition and memory even in the presence of acetylcholinesterase inhibitors (AChE-I: donepezil, galantamine, rivastigmine).6,7 Cognitive decline perceived as a new condition or worsening dementia can lead to new prescriptions or increased doses of AChE-I.8,9
2. Drugs for dementia ➜ incontinence ➜ anticholinergics
Conversely, AChE-I can cause urinary or fecal incontinence, that may “cascade” to prescription of an anticholinergic. Two studies found increased use of antimuscarinic bladder drugs (e.g. oxybutynin) after prescription of cholinesterase inhibitors for dementia.10 Bradycardia or syncope (muscarinic) or muscle cramps (nicotinic) are other cholinergic effects that may precipitate new treatments.11,12,13
3. Anticholinergics ➜ dyspepsia/reflux (“GERD”) ➜ PPI
Dyspepsia or heartburn due to delayed gastric emptying can be mistaken for spontaneous gastrointestinal reflux, or labeled loosely as “GERD”. This association was suggested as a possible cascade in a study evaluating longstanding (“legacy”) prescriptions of PPIs.14 In a U.S. study of 248 nursing home residents, the likelihood of receiving a PPI increased with anticholinergic burden.15 Similarly, a large Nova Scotia cohort study of seniors with dementia suggested that anticholinergics increased PPI dispensing “consistent with a prescribing cascade.”16
4. Anticholinergics ➜ constipation ➜ laxatives
Drug-induced constipation is well recognized, an association confirmed by a 2021 systematic review.17 Amongst Italian nursing home residents, tricyclics increased laxative use (OR 2.98, 95% CI 1.31-6.77), as did other antidepressants, especially mirtazapine (OR 1.37, 95%CI 1.09-1.71.18
5. Calcium channel blockers/gabapentin/pregabalin ➜ edema ➜ diuretics
Dihydropyridine calcium channel blockers (CCB) frequently cause dose-dependent edema, affecting up to 30% of older patients.19,20 Two recent cohort studies found that furosemide prescriptions increased in people taking CCBs, compared with other antihypertensives.21,22 Reducing or stopping a CCB can be preferable to adding furosemide, given its multiple adverse effects.
Gabapentin and pregabalin also cause dose-dependent peripheral edema. In chronic pain this affects up to 9% of people taking gabapentin, and 10% for pregabalin (up to 4-fold vs placebo).23,24,25 A large Ontario cohort study from 2011-2019 found increased loop diuretic prescriptions following initiation of gabapentin/pregabalin for new onset low back pain in older adults (HR: 1.44, 95% CI: 1.23, 1.70; absolute risk increase 0.7%).26 Both may be associated with inappropriate diagnosis of heart failure.27
6. Drug-induced movement disorders ➜ antiparkinsonian drugs
Most antipsychotics, some antidepressants, and the anti-emetics metoclopramide and prochlorperazine block dopamine receptors, or cause movement disorders by other mechanisms. Such adverse events can be mistaken for Parkinson’s disease.28 While a Canadian study found these prescribing cascades unusual,10 others see more reason for concern. Prescriptions for newer as well as older antipsychotics, antidepressants, and metoclopramide have been associated with increased subsequent prescription of l-DOPA/carbidopa and other anti-Parkinsonian drugs.3,28,29,30,31,32
7. Drug-induced hypertension ➜ antihypertensive drugs
About 15% of American adults (19% of adults with hypertension) take a drug that can raise blood pressure.33 Antidepressants (8.7% of adults) and prescription NSAIDs (6.5%) were the most frequent potential candidates for an under-recognized prescribing cascade.
Reducing prescribing cascades
Preventing, detecting and reversing prescribing cascades is not easy.34 Researchers cited in this Letter propose a comprehensive approach, while the Canadian Deprescribing Network offers a simpler one for the public.4,35,36 Recognizing and intercepting cascades still requires knowledge and expert medication review, including attention to known cascades.37 As a rural medical reviewer of this Letter wrote: “The problem is largely our mindset of reflexively treating new symptoms with medications, without first thinking of drug-induced side effects in patients already taking many. We need to think more, before taking the easy option of reaching for the prescription pad.”
- Prescribing cascades cause avoidable polypharmacy and harms.
- Prevent them by careful indication-based prescribing and screening for cascades during medication reviews. Utilize expert pharmacist or medical consultation when available.
- Start by familiarization with cascades involving drugs common in primary care; reduce doses if deprescribing seems too radical.
- Identifying a prescribing cascade is a teachable moment: use it.
- Lee GB, Etherton-Beer C, Hosking SM, et al. The patterns and implications of potentially suboptimal medicine regimens among older adults: a narrative review. Therapeutic Advances in Drug Safety 2022; 13:20420986221100117. DOI:
- Rochon PA, Gurwitz JH. Drug therapy. Lancet 1995; 346(8966):32-36. DOI: 10.1016/s0140-6736(95)92656-9
- Rochon PA, Gurwitz JH. The prescribing cascade revisited. Lancet 2017; 389(10081):1778-1780. DOI:
- McCarthy LM, Savage R, et al. Think cascades: A tool for identifying clinically important prescribing cascades affecting older people. Drugs & Aging 2022; (in press) https://www.springer.com/journal/40266
- Therapeutics Initiative. How well do you know your anticholinergic (antimuscarinic) drugs? Therapeutics Letter. Issue 113, July-August 2018. https://ti.ubc.ca/letter113
- Lu CJ, Tune LE. Chronic exposure to anticholinergic medications adversely affects the course of Alzheimer Disease. American Journal of Geriatric Psychiatry 2003; 11(4):458-61. PMID: 12837675
- Taylor-Rowan M, Edwards S, Noel-Storr AH, et al. Anticholinergic burden (prognostic factor) for prediction of dementia or cognitive decline in older adults with no known cognitive syndrome. Cochrane Database of Systematic Reviews 2021, Issue 5. Art. No.: CD013540. DOI: 10.1002/14651858.CD013540.pub2
- Kurata K, Taniai E, Nishimura K, et al. A prescription survey about combined use of acetylcholinesterase inhibitors and anticholinergic medicines in the dementia outpatient using electronic medication history data from community pharmacies. Integrated Pharmacy Research & Practice 2015; 4:133-141. DOI: 10.2147/IPRP.S86661
- Gill SS, Mamdani M, Naglie G, et al. A prescribing cascade involving cholinesterase inhibitors and anticholinergic drugs. Arch Intern Med 2005; 165(7):808-13. DOI: 10.1001/archinte.165.7.808
- Trenaman SC, Bowles SK, Kirkland S, Andrew MK. An examination of three prescribing cascades in a cohort of older adults with dementia. BMC Geriatrics 2021; 21(1):297. DOI: 10.1186/s12877-021-02246-2
- Gill SS, Anderson GM, Fischer HD, et al. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: a population-based cohort study. Arch Intern Med 2009; 169(9):867-73. DOI: 10.1001/archinternmed.2009.43
- Ruangritchankul S, Chantharit P, Srisuma S, Gray LC. Adverse drug reactions of acetylcholinesterase inhibitors in older people Living with dementia: A comprehensive literature review. Ther Clin Risk Manag 2021; 17:927-949. DOI: 10.2147/TCRM.S323387
- Pfizer Canada. Aricept (donepezil hydrochloride) product monograph, revised Dec. 18, 2014; https://www.pfizer.ca/sites/default/files/201612/ARICEPT_PM_E_177353_18Dec2014_R.pdf
- Mangin D, Lawson J, Cuppage J, et al. Legacy drug-prescribing patterns in primary care. Annals of Family Medicine 2018; 16(6):515-520. DOI: 10.1370/afm.2315
- Rababa M, Al-Ghassani AA, Kovach CR, Dyer EM. Proton pump inhibitors and the prescribing cascade. Journal of Gerontological Nursing 2016; 42(4):23-31. DOI: 10.3928/00989134-20151218-04
- Trenaman SC, Harding A, Bowles SK, et al. A prescribing cascade of proton pump inhibitors following anticholinergic medications in older adults with dementia. Frontiers in Pharmacology 2022; 13:878092. DOI: 10.3389/fphar.2022.878092
- Rodriguez-Ramallo H, Baez-Gutierrez N, Prado-Mel E, et al. Association between anticholinergic burden and constipation: A systematic review. Healthcare 2021; 9(5). DOI: 10.3390/healthcare9050581
- Elli C, Novella A, Nobili A, et al. Laxative agents in nursing homes: An example of prescribing cascade. Journal of the American Medical Directors Association 2021; 22(12):2559-2564. DOI: 10.1016/j.jamda.2021.04.021
- Makani H, Bangalore S, Romero J, et al. Peripheral edema associated with calcium channel blockers: incidence and withdrawal rate – a meta-analysis of randomized trials. Journal of Hypertension 2011; 29(7):1270-1280. DOI: 10.1097/HJH.0b013e3283472643
- AstraZeneca Canada. Plendil (felodipine) product monograph, revised Jan. 15, 2015; https://www.astrazeneca.ca/content/dam/az-ca/downloads/productinformation/plendil-product-monograph-en.pdf
- Savage RD, Visentin JD, Bronskill SE, et al. Evaluation of a common prescribing cascade of calcium channel blockers and diuretics in older adults with hypertension. JAMA Internal Medicine 2020; 180(5):643-651. DOI: 10.1001/jamainternmed.2019.7087
- Vouri SM, Jiang X, Manini TM, et al. Magnitude of and characteristics associated with the treatment of calcium channel blocker–induced lower-extremity edema with loop diuretics. JAMA Network Open 2019; 2(12):e1918425. DOI: 10.1001/jamanetworkopen.2019.18425
- Therapeutics Initiative. Gabapentin for pain: New evidence from hidden data. Therapeutics Letter 75, July-December 2009; https://ti.ubc.ca/letter75
- Falk J, Thomas B, Kirkwood J, et al. PEER systematic review of randomized controlled trials. Management of chronic neuropathic pain in primary care. Canadian Family Physician 2021; 67(5):e130-e140. DOI: 10.46747/cfp.6705e130 Appendix 2 available at: https://www.cfp.ca/content/cfp/suppl/2021/05/03/67.5.e130.DC1/Neuropathic_Pain_Appendix_2.pdf
- Zaccara G, Gangemi P, Perucca P, Specchio L. The adverse event profile of pregabalin: a systematic review and meta-analysis of randomized controlled trials. Epilepsia 2011; 52(4):826–36, 2011. DOI: 10.1111/j.1528-1167.2010.02966.x
- Read SH, Giannakeas V, Pop P, et al. Evidence of a gabapentinoid and diuretic prescribing cascade among older adults with lower back pain. Journal of the American Geriatrics Society 2021; 69(10):2842-2850. DOI: 10.1111/jgs.17312
- Ho JM, Macdonald EM, Luo J, et al. Pregabalin and heart failure: A population-based study. Pharmacoepidemiology & Drug Safety 2017; 26(9):1087-1092. DOI: 10.1002/pds.4239
- Rochon PA, Stukel TA, Sykora K, et al. Atypical antipsychotics and parkinsonism. Archives of Internal Medicine 2005; 165(16):1882-1888. DOI: 10.1001/archinte.165.16.1882
- Avorn J, Bohn RL, Mogun H, et al. Neuroleptic drug exposure and treatment of parkinsonism in the elderly: a case-control study. American Journal of Medicine 1995; 99(1):48-54. DOI: 10.1016/s0002-9343(99)80104-1
- Tsai SC, Sheu SY, Chien LN, et al. High exposure compared with standard exposure to metoclopramide associated with a higher risk of parkinsonism: a nationwide population-based cohort study. British Journal of Clinical Pharmacology 2018; 84(9):2000-2009. DOI: 10.1111/bcp.13630
- Avorn J, Gurwitz JH, Bohn RL, et al. Increased incidence of levodopa therapy following metoclopramide use. JAMA 1995; 274(22):1780-2. PMID: 7500509
- Huh Y, Kim DH, Choi M, et al. Metoclopramide and levosulpiride use and subsequent levodopa prescription in the Korean elderly: The prescribing cascade. Journal of Clinical Medicine 2019; 8(9):1496. DOI: 10.3390/jcm8091496
- Vitarello JA, Fitzgerald CJ, Cluett JL, et al. Prevalence of medications that may raise blood pressure among adults with hypertension in the United States. JAMA Internal Medicine 2022; 182(1):90-93. DOI: 10.1001/jamainternmed.2021.6819
- Brath H, Mehta N, Savage RD, et al. What is known about preventing, detecting, and reversing prescribing cascades: A scoping review. Journal of the American Geriatrics Society 2018; 66(11):2079–2085. DOI: 10.1111/jgs.15543
- Farrell B, Galley E, Jeffs L, et al. “Kind of blurry”: Deciphering clues to prevent, investigate and manage prescribing cascades. PLoS One 2022. DOI: 10.1371/journal.pone.0272418
- Gagnon C, Currie J, Trimble J. Are you the victim of a prescribing cascade? Canadian Deprescribing Network 2020; https://www.deprescribingnetwork.ca/blog/prescribing-cascade
- Therapeutics Initiative. Reducing polypharmacy: A logical approach. Therapeutics Letter 90, June-July 2014; https://ti.ubc.ca/letter90