Pharmacology Consult

Antihistamines, part II: Long-term adverse effects?

Edward A. Bell, PharmD, BCPS
Edward A. Bell

The last Pharmacology Consult column, “Antihistamines for the common cold: Where’s the evidence?” (September 2019), reviewed recently published data suggesting that antihistamine product use may be increasing for the treatment of common cold symptoms. Because recent recommendations and regulations have decreased the use of cough/cold products in the pediatric population, pediatric health care providers may be turning to antihistamine-based products instead. Commonly used first-generation antihistamines have strong anticholinergic properties, and recently published data from the adult population have suggested that long-term use of these drugs may increase the risk for developing dementia. As summaries of these publications find their way to the lay media, it is understandable that parents may wonder about the long-term safety of using antihistamines in children. Although the diagnosis of dementia is certainly not associated with the pediatric population, parents may still express concern about the adverse effects and long-term safetyof antihistamines.

As a brief review, antihistamines are commonly classified as first- and second-generation agents. Over-the-counter cough/cold products commonly contain a first-generation antihistamine, such as brompheniramine, chlorpheniramine or diphenhydramine. Although histamine is not an important clinical mediator of symptoms of the common cold, antihistamines are often included in cough/cold products for their “drying” or anticholinergic (antimuscarinic) effects. The first-generation antihistamines additionally exhibit sedating effects (because of their penetration into the central nervous system [CNS]), which some parents may consider desirable. All first-generation antihistamines can be sedating, with diphenhydramine and hydroxyzine being the most sedating agents in this class. First-generation antihistamines are often referred to as “sedating antihistamines.” In addition to a perceived sedative effect, first-generation antihistamine use has also been linked with adverse effects upon cognition and learning in children. Several published studies have demonstrated this, which can be distinct from perceived drowsiness (ie, a child may not feel drowsy or tired, yet may have reduced concentration and learning). These studies have demonstrated negative effects upon attention, memory, coordination and psychomotor performance in children. Academic, cognitive and social growth may be adversely affected as well.

Second-generation antihistamines (eg, cetirizine, loratadine), considered nonsedating because of their relative lack of CNS penetration, are commonly prescribed to children and adults for allergic conditions. Second-generation antihistamines display no significant anticholinergic pharmacologic actions.

Anticholinergic drugs and dementia risk

Several studies have recently been published describing a potential relationship between cumulative anticholinergic drug use and a risk for dementia in adults. This year, Coupland and colleagues published data demonstrating that the use of drugs with anticholinergic effects is associated with an increased risk for dementia in adults aged 55 years or older. This case-control study used information from a primary care database of patients in England. A total of 58,769 patients diagnosed with dementia were matched to 225,574 controls and evaluated over a 12-year period. Cumulative anticholinergic drug exposure was assessed by monitoring 56 preidentified drugs with strong anticholinergic properties (including antihistamines as a class). The adjusted OR for dementia ranged from 1.06 (95% CI, 1.03-1.09) to 1.49 (95% CI, 1.44-1.54) for the lowest to the highest anticholinergic exposure category, compared with no anticholinergic drug use. Drug classes associated with significant increases in dementia risk included antidepressants, antiparkinson drugs, antipsychotics, bladder antimuscarinics, and antiepileptic drugs. There were no significant increases in dementia risk associated with antihistamines, skeletal muscle relaxants, gastrointestinal antispasmodics, antiarrhythmics or antimuscarinic bronchodilators. Although this large case-control study demonstrated an increased risk for dementia associated with the use of anticholinergic drugs, it does not prove causation.

Additional recent studies have evaluated a potential risk for dementia with anticholinergic drugs. Richardson and colleagues identified the association between anticholinergic drugs and dementia in a case-control study. Patients aged 65 to 99 years with a diagnosis of dementia (n = 40,770) enrolled in a research database in England were compared with 283,933 controls without dementia. The researchers evaluated drugs recognized for having anticholinergic actions that were prescribed 4 to 20 years before a diagnosis of dementia. The adjusted OR for any drug with “definite anticholinergic activity” was 1.11 (95% CI, 1.08-1.14). In terms of drug classes, the researchers found a significant association between dementia and antidepressant, antiparkinson and urologic drugs. They found no association between dementia and antispasmodic, antipsychotic or antihistamine drugs.

Gray and colleagues evaluated 3,434 individuals aged 65 years and older in a prospective population-based cohort study. The participants, who did not have a diagnosis of dementia at study entry, were followed for a mean of 7.3 years. The most commonly used drug classes with anticholinergic actions included tricyclic antidepressants, antihistamines and bladder antimuscarinics. The researchers found that higher cumulative anticholinergic drug exposure was associated with dementia.

Conclusions

The conclusion of this month’s Pharmacology Consult column is not to infer that the use of first-generation antihistamines in the pediatric population will result in dementia as these children age into adulthood. Data from the adult studies described earlier have not definitively proven this risk, although an association between the use of drugs with anticholinergic actions and an increasing risk for dementia has been demonstrated. It is encouraging that a specific association between the use of antihistamines and dementia was not demonstrated in several of these studies, although the additional use of OTC antihistamine drugs may not have been fully evaluated. Experts have suggested that prospective controlled trials (“deprescribing” drugs) are needed to further define the potential for permanent negative cognitive effects of drugs with anticholinergic actions. Although it is known that drugs with anticholinergic actions, such as first-generation antihistamines, impair cognition in children and adults, the duration and reversibility of these effects is not well known. Animal and pathologic studies have shown that drugs with anticholinergic activity display neurodegenerative effects. The clinical implications for adverse cognitive changes are thus concerning. Perhaps the summary conclusion for this month’s column — as well as September’s column — is one that has been repeated in many of the Pharmacology Consult columns over the past 20 years: When considering the use of any medication, the balance between drug benefit and risk must be assessed. If evidence for a drug’s therapeutic benefit does not exist, it is best not given. Prescribers and patients alike must always weigh the potential for adverse effects that all drugs possess.

References:

Campbell NL, Boustani MA. JAMA Intern Med. 2015;doi:10.1001/jamainternmed.2014.7667.

Campbell NL, et al. JAMA Intern Med. 2019;doi:10.1001/jamainternmed.2019.0676.

Coupland CA, et al. JAMA Intern Med. 2019;doi:10.1001/jamaintermed.2019.0677.

Gray SL, et al. JAMA Intern Med. 2015;doi:10.1001/jamainternmed.2014.7663.

Richardson K, et al. BMJ. 2018;doi:10.1136/bmj.k1315.

Ten Eick AP, et al. Drug Safety. 2001;doi:10.2165/00002018-200124020-00003.

For more information:

Edward A. Bell, PharmD, BCPS, is a professor of pharmacy practice at Drake University College of Pharmacy and Health Sciences and Blank Children’s Hospital and Clinics in Des Moines, Iowa. He also is a member of the Infectious Diseases in Children Editorial Board. Bell can be reached at ed.bell@drake.edu.

Disclosure: Bell reports no relevant financial disclosures.

Edward A. Bell, PharmD, BCPS
Edward A. Bell

The last Pharmacology Consult column, “Antihistamines for the common cold: Where’s the evidence?” (September 2019), reviewed recently published data suggesting that antihistamine product use may be increasing for the treatment of common cold symptoms. Because recent recommendations and regulations have decreased the use of cough/cold products in the pediatric population, pediatric health care providers may be turning to antihistamine-based products instead. Commonly used first-generation antihistamines have strong anticholinergic properties, and recently published data from the adult population have suggested that long-term use of these drugs may increase the risk for developing dementia. As summaries of these publications find their way to the lay media, it is understandable that parents may wonder about the long-term safety of using antihistamines in children. Although the diagnosis of dementia is certainly not associated with the pediatric population, parents may still express concern about the adverse effects and long-term safetyof antihistamines.

As a brief review, antihistamines are commonly classified as first- and second-generation agents. Over-the-counter cough/cold products commonly contain a first-generation antihistamine, such as brompheniramine, chlorpheniramine or diphenhydramine. Although histamine is not an important clinical mediator of symptoms of the common cold, antihistamines are often included in cough/cold products for their “drying” or anticholinergic (antimuscarinic) effects. The first-generation antihistamines additionally exhibit sedating effects (because of their penetration into the central nervous system [CNS]), which some parents may consider desirable. All first-generation antihistamines can be sedating, with diphenhydramine and hydroxyzine being the most sedating agents in this class. First-generation antihistamines are often referred to as “sedating antihistamines.” In addition to a perceived sedative effect, first-generation antihistamine use has also been linked with adverse effects upon cognition and learning in children. Several published studies have demonstrated this, which can be distinct from perceived drowsiness (ie, a child may not feel drowsy or tired, yet may have reduced concentration and learning). These studies have demonstrated negative effects upon attention, memory, coordination and psychomotor performance in children. Academic, cognitive and social growth may be adversely affected as well.

Second-generation antihistamines (eg, cetirizine, loratadine), considered nonsedating because of their relative lack of CNS penetration, are commonly prescribed to children and adults for allergic conditions. Second-generation antihistamines display no significant anticholinergic pharmacologic actions.

Anticholinergic drugs and dementia risk

Several studies have recently been published describing a potential relationship between cumulative anticholinergic drug use and a risk for dementia in adults. This year, Coupland and colleagues published data demonstrating that the use of drugs with anticholinergic effects is associated with an increased risk for dementia in adults aged 55 years or older. This case-control study used information from a primary care database of patients in England. A total of 58,769 patients diagnosed with dementia were matched to 225,574 controls and evaluated over a 12-year period. Cumulative anticholinergic drug exposure was assessed by monitoring 56 preidentified drugs with strong anticholinergic properties (including antihistamines as a class). The adjusted OR for dementia ranged from 1.06 (95% CI, 1.03-1.09) to 1.49 (95% CI, 1.44-1.54) for the lowest to the highest anticholinergic exposure category, compared with no anticholinergic drug use. Drug classes associated with significant increases in dementia risk included antidepressants, antiparkinson drugs, antipsychotics, bladder antimuscarinics, and antiepileptic drugs. There were no significant increases in dementia risk associated with antihistamines, skeletal muscle relaxants, gastrointestinal antispasmodics, antiarrhythmics or antimuscarinic bronchodilators. Although this large case-control study demonstrated an increased risk for dementia associated with the use of anticholinergic drugs, it does not prove causation.

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Additional recent studies have evaluated a potential risk for dementia with anticholinergic drugs. Richardson and colleagues identified the association between anticholinergic drugs and dementia in a case-control study. Patients aged 65 to 99 years with a diagnosis of dementia (n = 40,770) enrolled in a research database in England were compared with 283,933 controls without dementia. The researchers evaluated drugs recognized for having anticholinergic actions that were prescribed 4 to 20 years before a diagnosis of dementia. The adjusted OR for any drug with “definite anticholinergic activity” was 1.11 (95% CI, 1.08-1.14). In terms of drug classes, the researchers found a significant association between dementia and antidepressant, antiparkinson and urologic drugs. They found no association between dementia and antispasmodic, antipsychotic or antihistamine drugs.

Gray and colleagues evaluated 3,434 individuals aged 65 years and older in a prospective population-based cohort study. The participants, who did not have a diagnosis of dementia at study entry, were followed for a mean of 7.3 years. The most commonly used drug classes with anticholinergic actions included tricyclic antidepressants, antihistamines and bladder antimuscarinics. The researchers found that higher cumulative anticholinergic drug exposure was associated with dementia.

Conclusions

The conclusion of this month’s Pharmacology Consult column is not to infer that the use of first-generation antihistamines in the pediatric population will result in dementia as these children age into adulthood. Data from the adult studies described earlier have not definitively proven this risk, although an association between the use of drugs with anticholinergic actions and an increasing risk for dementia has been demonstrated. It is encouraging that a specific association between the use of antihistamines and dementia was not demonstrated in several of these studies, although the additional use of OTC antihistamine drugs may not have been fully evaluated. Experts have suggested that prospective controlled trials (“deprescribing” drugs) are needed to further define the potential for permanent negative cognitive effects of drugs with anticholinergic actions. Although it is known that drugs with anticholinergic actions, such as first-generation antihistamines, impair cognition in children and adults, the duration and reversibility of these effects is not well known. Animal and pathologic studies have shown that drugs with anticholinergic activity display neurodegenerative effects. The clinical implications for adverse cognitive changes are thus concerning. Perhaps the summary conclusion for this month’s column — as well as September’s column — is one that has been repeated in many of the Pharmacology Consult columns over the past 20 years: When considering the use of any medication, the balance between drug benefit and risk must be assessed. If evidence for a drug’s therapeutic benefit does not exist, it is best not given. Prescribers and patients alike must always weigh the potential for adverse effects that all drugs possess.

References:

Campbell NL, Boustani MA. JAMA Intern Med. 2015;doi:10.1001/jamainternmed.2014.7667.

Campbell NL, et al. JAMA Intern Med. 2019;doi:10.1001/jamainternmed.2019.0676.

Coupland CA, et al. JAMA Intern Med. 2019;doi:10.1001/jamaintermed.2019.0677.

Gray SL, et al. JAMA Intern Med. 2015;doi:10.1001/jamainternmed.2014.7663.

Richardson K, et al. BMJ. 2018;doi:10.1136/bmj.k1315.

Ten Eick AP, et al. Drug Safety. 2001;doi:10.2165/00002018-200124020-00003.

For more information:

Edward A. Bell, PharmD, BCPS, is a professor of pharmacy practice at Drake University College of Pharmacy and Health Sciences and Blank Children’s Hospital and Clinics in Des Moines, Iowa. He also is a member of the Infectious Diseases in Children Editorial Board. Bell can be reached at ed.bell@drake.edu.

Disclosure: Bell reports no relevant financial disclosures.