New trials show acetaminophen better than placebo for OA

July 20, 2004

Jul 20, 2004 Nainggolan

Sutton-in-Ashfield, UK - Acetaminophen (paracetamol) is more effective than

placebo in relieving the pain of large joint osteoarthritis (OA), according

to a Leader in the August 2004 issue of the ls of the Rheumatic Diseases

[1]. But NSAIDs and coxibs are superior to acetaminophen, it adds.

Three new papers on acetaminophen and OA accompany this Leader, an

unprecedented occurrence. " Never in the 127 years history of acetaminophen's

existence have so much trial data on OA been reported, " say Dr R Neame

(King's Mill Hospital, Sutton-in-Ashfield, UK) and colleagues.

The new papers consist of a meta-analysis and 2 large-placebo-controlled

studies of the efficacy of acetaminophen in OA.

Meta-analysis: acetaminophen should remain first-line therapy

Although current EULAR and ACR guidelines both support acetaminophen as the

first-line oral analgesic for patients with knee OA, " until now there has

been a paucity of clinical trial data to confirm the efficacy of paracetamol

in large joint OA, " Neame et al say in their Leader.

Until now there has been a paucity of clinical trial data to confirm the

efficacy of paracetamol in large joint OA.

There have been only 4 placebo-controlled trials of this drug in OA, they

note. The first 2 showed the superiority of acetaminophen over placebo, but

they were small. A third, slightly larger, study was negative, however,

while a fourth crossover study showed that acetaminophen was effective for

pain but was no better than placebo for total WOMAC scores.

In the light of these heterogeneous data, Dr Weiya Zhang (University of

Nottingham, UK) et al have undertaken a new meta-analysis of evidence

available to July 2003 [2].

This included 10 randomized controlled trials and shows that acetaminophen

gives pain relief in OA that is better than placebo (effect size 0.21; 95%

CI 0.02-0.41).

However, NSAIDs were better than acetaminophen for pain relief, and clinical

response rate was higher with NSAIDS than with acetaminophen. Also, the

number of patients who preferred NSAIDs was more than twice the number

preferring acetaminophen, Zhang et al note.

Professor Doherty (University of Nottingham, UK)an author of the

Leader and the meta-analysistold rheumawire that " despite the findings that

NSAIDs are more efficacious than paracetamol, the latter should remain

first-line therapy for knee OA. "

[Paracetamol] should remain first-line therapy for knee OA.

The safety record of acetaminophen at the recommended dosage " is excellent, "

and " it is very cheap and widely available, " he says. Only if acetaminophen

proves insufficient should NSAIDs be considered, he believes, because they

" can kill you! "

" Most patients with OA are old or elderly and are at increased risk of

NSAID-associated peptic ulceration/bleeding/perforation. If they are given

NSAIDs they should be considered for prophylaxis (combined proton pump

inhibitors [PPIs] or misoprostol) or be given a coxib, " he says.

Two new placebo-controlled studies: the first is negative

Also in this issue are 2 new placebo-controlled studies of acetaminophen.

The first, by Dr Corinne Miceli- (Cochin Hospital, Paris, France) et

al [3], did not find any effect of acetaminophen over placebo in 779

patients with OA of the knee (52.6% of those taking acetaminophen and 51.9%

of those taking placebo reached the primary end pointa 30% decrease in

global knee pain during physical activity in the past 24 hours).

" At first sight, this is a very strong negative result suggesting that

paracetamol is no better than placebo, " say Neame et al. " However, there are

several unusual features and caveats to this study, " they add.

The relevance of the [French] study result for clinical management of

common knee OA is questionable.

First, patients had high pain scores at baseline, " which is unrepresentative

of the usual clinical status in patients with knee OA, " they say. This, in

turn, could have led to the unexpectedly high placebo response and high

dropout rate, which also make this study difficult to interpret. As a

result, " the relevance of the study result for clinical management of common

knee OA is questionable, " they conclude.

Second US study: celecoxib better than acetaminophen

The second study, by Dr Theodore Pincus (Vanderbilt University Medical

Center, Nashville, TN) and colleagues, consists of 2 randomized

double-blind, placebo-controlled, double-dummy crossover trials (PACES-a and

PACES- in patients with knee or hip OA [4].

PACES-a and PACES-b both enrolled just over 500 patients and were both of

identical designpatients were assigned randomly to 1 of 6 treatment sequence

groups to receive a sequence of 2 of 3 treatments, each for 6 weekscelecoxib

(Celebrex, Pfizer), 200 mg/day, acetaminophen 1000 mg 4 times a day, or

placebo. Each patient received a drug and a placebo or 2 placebos in each

period.

Celecoxib was more efficacious than acetaminophen in both periods in both

studies, and acetaminophen was more efficacious than placebo in both

studies, the authors say. No differences were seen in adverse events or

tolerability between the 3 treatment groups. Also, more patients preferred

celecoxib than acetaminophen, and more preferred acetaminophen than placebo

in the 2 studies.

Neame et al say it is " unfortunate " that the data for patients with knee OA

and hip OA in this US study were combined. " The prevalence, risk factors,

natural history, and outcome of hip and knee OA show a number of differences

and it cannot be assumed that outcomes from the same treatment will be

identical, " they state.

And overall, it is " disappointing " that both of the new studies were only 6

weeks long and that, in both, there is a lack of information about key

aspects of the study design, " which creates difficulties in the

interpretation of the results, " they say. They urge future researchers in

this field to consider the CONSORT agreement [5]an attempt to improve the

full and unambiguous reporting of key information in clinical trials.

Better than placebo, but NSAIDs are superior

In conclusion, Neame et al say that " despite a second negative clinical

trial, the aggregated research data still support paracetamol as being more

effective than placebo in relieving pain of large joint OA. " But NSAIDs and

coxibs " show superior efficacy to paracetamol and are also effective for

stiffness, " they note.

Nevertheless, long-term studies of acetaminophen, as well as many other

treatments for OA, " are still required. " For such trials, participants

should be representative of OA patients in general and the CONSORT agreement

for the full reporting of clinical trials " should be consistently applied by

authors and editors. "