RESEARCH - Acetaminophen linked to increased risk of asthma and COPD

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Acetaminophen linked to increased risk of asthma and COPD

Rheumawire

May 5,2005

Zosia Chustecka

Nottingham, UK - Use of acetaminophen (paracetamol) is associated with an

increased risk of asthma and chronic obstructive pulmonary disease (COPD)

and with decreased lung function, according to findings from a large

epidemiological study [1]. Aspirin and ibuprofen showed no such linkin fact,

regular use of ibuprofen was associated with higher lung function.

The findings are reported in the May 1, 2005 issue of the American Journal

of Respiratory and Critical Care Medicine by Dr Tricia McKeever (Nottingham

City Hospital, UK) and colleagues at the National Institute of Public

Health, Bilthoven, the Netherlands and Cornell University, Ithaca, NY.

The researchers used data from the US Third National Health and Nutritional

Examination Survey (NHANES III) on the use of pain medications in 13 492

subjects and performed multiple logistic regression analyses. They found a

positive dose-dependent association between increased use of acetaminophen

and asthma (adjusted odds ratio for increasing category of intake 1.20 [95%

CI 1.12-1.28], p for trend <0.001) and COPD (1.16 [95% CI 1.09-1.24],

p<0.001). On the basis of lung-function spirometry tests (forced expiratory

volume [FEV1]), the team also found an inverse nonlinear association between

acetaminophen use and lung function. Daily users of acetaminophen had a mean

adjusted FEV1 that was 61.5 mL (95% CI -97.6 to -25.4) lower than nonusers,

they report.

McKeever et al note that the association of acetaminophen with asthma has

been reported previously, but the association with COPD and with decreased

lung function are novel findings and need further research, ideally from

longitudinal investigations. They speculate that regular use of

acetaminophen may lead to decreased glutathione levels in the airway

epithelial lining fluid, leading to oxidant damage in the lung.

" This is a very new area of research, and the findings with lung function

are demonstrated for the first time, " McKeever tells rheumawire. Asked for

what the new findings may mean for clinicians who have patients taking

acetaminophen on a regular basisas many in rheumatology doshe emphasized the

need for more research to confirm the findings and adds: " I am not medically

trained, so I do not feel comfortable about making suggestions on changes in

practices. "

Should be regarded as hypothesis generating

Approached by rheumawire for their reaction to the new findings,

rheumatologists urged caution. Dr Matteson (Mayo Clinic, Rochester,

MN), who acts as an editorial consultant for www.jointandbone.org,

commented: " The possible association of acetaminophen use and asthma is a

major health concern. Acetaminophen is commonly used for management of pain

in patients who have reactive-airways disease and aspirin sensitivity who

are also at increased risk of worsening of reactive-airways disease with use

of traditional [nonsteroidal anti-inflammatory drugs] NSAIDs. The study by

McKeever is important because it provides evidence of a link between

acetaminophen use and reactive-airways disease. The odds ratio in this study

is small, 1.20, suggesting an increase risk of about 20%. However, the

biological hypothesis of antioxidant activity of acetaminophen remains

untested. The study should be regarded as hypothesis generating and calls

for studies directly examining the effect of acetaminophen on pulmonary

function to confirm it. Until then, clinicians should weigh this association

as a potential concern but evaluate it in individual patients on a

case-by-case basis. "

From the UK, Dr Grove (North Tyneside General Hospital, North

Shields, UK) concurs, pointing out that " cross-sectional studies of this

type are very vulnerable to unexpected confounders. For example, COPD is

caused by smoking, smoking is linked to poorer prognosis in back pain, and

back pain is linked to paracetamol use. " He suggests that back pain,

osteoarthritis, and also rheumatoid arthritis (as seropositive disease is

linked to smoking) should be investigated as potential confounders, but they

weren't in this studythe researchers used a single categorical variable (yes

or no for comorbidity). Also, he comments that " a relative risk of 1.2 is

very small (in epidemiological terms) for this kind of studyanything less

than 2 should be regarded as highly dubious, " although he points out that

the odds ratio is for increasing category of intake and the overall OR

between those who never use paracetamol and those who take in daily would be

about 2 (1.2x1.2x1.2x1.2).

Grove also warns against hyping the data. " I'd say this is dangerous stuff

in the current, rather hysterical climate of public concern regarding

long-term toxicity of painkillers. " Another UK rheumatologist, Dr

Ostor (Addenbrookes Hospital, Cambridge) agrees: " We may end up with no pain

relievers in the current atmosphere of concern regarding the use of

analgesics (specifically the COX-2 debate!). "

Ostor comments that to " make real sense of the observation, I would suggest

a randomized controlled trial of the effect of paracetamol on lung function

compared with traditional NSAIDs and placebo. " At this time, patients should

" certainly not stop taking paracetamol on the results of this study until

further information is at hand. As always, physicians need to tailor

treatment to the individual. "

Confounding variables did not alter results

McKeever et al note that all of the regression analyses were investigated

for possible interactions between exposure to pain medications and

confounding factors, particularly sex, age, smoking, and antioxidant intake.

There was no evidence that any of these modified the association, they

comment. In all their models, adjusting for potential confounding

variablesincluding levels of education, poverty index, body mass index,

comorbidity illness, and serum antioxidants (vitamin C, vitamin E, or

selenium)did not notably alter the results.

There is a possibility of confounding by indication, the researchers

comment. Individuals with asthma may avoid aspirin because of sensitivity or

because of physician recommendation and therefore preferentially use

acetaminophen. When they stratified the study participants into users and

nonusers of aspirin, the team found a dose-response trend only among the

nonusers. However, among the aspirin users, individuals who regularly took

acetaminophen still had a significantly increased risk of asthma (both

statistically significant and biologically significant effect size), they

note.

Acetaminophen bad, ibuprofen good?

Among the study participants (n=13 492), the prevalence of asthma was 6.9%

and COPD was 11.8%, and 2.8% had both respiratory diseases. About 4% of the

participants used acetaminophen on a daily basis, compared with 8.2% for

aspirin and 2.5% for ibuprofen. Approximately 3% of the population reported

using all 3 pain medications in the last month, and 16% of the population

used 2 drugs.

The association between analgesic use and asthma and COPD was significant

only for acetaminophen. The magnitude of the effect was similar for both

respiratory diseases, the researchers comment.

The decrease in lung function in association with acetaminophen was seen

only in individuals who reported a daily (or greater) use of the drug. But

in contrast, the investigation showed an increase in lung function with

regular use of ibuprofen, although a linear dose-response relation was not

observed. " Our data suggest that use of ibuprofen may be beneficial for lung

function, " the researchers comment, adding that a trial in cystic fibrosis

showing a reduction in the annual decline of lung function over 4 years in

patients taking ibuprofen compared with those on placebo [2] supports their

finding.

McKeever et al also note that there have been several reports in the past of

an association between acetaminophen and asthma. The first was a

case-control study of asthma in adults that found an adjusted OR for daily

users of acetaminophen compared with nonusers of 2.4 (95% CI 1.2-4.6) [3];

more recently, a cohort study of adult women found that acetaminophen use

for at least 22 days per month on average was associated with a 1.5-fold

increase in asthma (95% CI 0.95-2.46, p for trend 0.0006) [4].

Sources

a. McKeever TM, SA, Smit HA, et al. The association of

acetaminophen, aspirin and ibuprofen with respiratory disease and lung

function Am J Respir Crit Care Med 2005; 171:966-971.

b. Konstan MW, Byard PJ, Hoppel CL, et al. Effect of

high-dose ibuprofen in patients with cystic fibrosis N Eng J Med 1995;

332:848-854.

c. Shaheen SO, Sterne JA, Songhurst CE, et al Frequent

paracetamol use and asthma in adults. Thorax 2000; 55:266-270.

d. Barr RG, Wentowski CC, Curhan GC, et al. Prospective study

of acetaminophen use and newly diagnosed asthma among women. Am J Respir

Crit Care Med 2004; 169:836-841.

Not an MD

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org