Blanch_edit.qxp 2/5/07 11:31 am Page 28
Osteoarthritis
Gastrointestinal Safety of Nabumetone
a report by
Jordi Monfort Faure and Josep Blanch i Rubió
Rheumatologist, University Hospital del Mar and La Esperança and President, Spanish Society for Rheumatology
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely Gastric Safety
used agents for the treatment of painful conditions in which the Early pre-marketing individual studies suggested that nabumetone had a
physiopathological basis is an inflammatory process. Nevertheless, better gastrointestinal safety profile than do other NSAIDs. These studies
owing to the array and intensity of their side effects, NSAIDs have were based on the incidence of serious GI events such as perforations,
garnered considerable controversy both within the scientific community ulcers and bleeding.
3,4
The incidence of these effects in pre- and post-
as well as in society in general. Notable among these side effects are marketing studies ranges from 0.02% to 0.095%.
several gastrointestinal maladies such as ulcers, perforations and In one analysis on nabumetone safety, based on 1,677 patients with
bleedings in different areas of the digestive tract, as well as hepatic and either RA or OA, 17 patients developed ulcers, although the majority of
renal toxicity. Moreover, the past decade has witnessed reports on the these patients did not present any major complications.
5
The Kaplan-
cardiovascular side effects of these drugs. A representative example of
these reports is a publication by Wolfe et al.
1
in which the number of
deaths attributed to NSAIDs in the US in 1997 was reported as 16,500,
In contrast to conventional NSAIDs,
nearly the same as that reported for HIV (16,685), and considerably
which are primarily acidic, nabumetone
higher than that reported for multiple myeloma (10,503).
1
Hence there
is a need to develop NSAIDs that are safe and that provide analgesic, is non-acidic, hence it does not readily
anti-inflammatory and anti-pyretic efficacy.
dissociate in the gastric lumen.
Nabumetone is an NSAID with a good hepatic and renal safety profile
and an excellent gastrointestinal safety profile, making it a sound choice Meier curve for the entire group of nabumetone-treated patients
for the treatment of chronic conditions such as rheumatoid arthritis (RA) revealed that the risk of suffering a gastric ulcer was 0.3% (95%
and osteoarthritis (OA). Given the age, pluripathology and confidence interval (CI), 0, 0.6) at six months; 0.5% (95% CI 0.1, 0.9) at
polymedication of the patients that suffer these conditions, their one year; 0.8% (95% CI 0.3, 1.3) at two years; and 2.35% (95% CI 1.1,
treatment demands a strong analgesic that is very safe for the 3.59) at six years. For the studied period of six years, the calculated
gastrointestinal (GI) tract. annual risk was 0.4% per year (95% CI, 0.6 upper limit).
Pharmacological Characteristics of the Molecule To evaluate the safety and efficacy of nabumetone a large randomised
Nabumetone is a non-acidic, non-steroidal pro-drug whereby the active controlled multicentre trial was conducted in 450 rheumatology offices.
6,7
metabolite is 6-methoxy-2-naphthylacetic acid (6-MNA), which is formed Each investigator performed his own two-arm study and could choose
after absorption through first-pass metabolism, and which is a more potent from ibuprofen, piroxicam, diclofenac or naproxen. Three thousand,
specific inhibitor of cyclooxygenase 2 (COX-2) than is the parent three hundred and fifteen patients were randomised to nabumetone,
compound. Nabumetone is metabolised in three primary pathways: O- 279 to naproxen, 296 to piroxicam, 296 to diclofenac and 235 to
demethylation, reduction of the ketone to an alcohol and oxidative ibuprofen. The nabumetone group had one detected ulcer. The
cleavage of the side-chain to afford acetic derivatives. No unmetabolised comparators had a total of six ulcers (p= 0.001).
7
nabumetone is excreted and <1% of unmetabolised 6-MNA is excreted, of
which 80% can be recovered from urine and another 10% from faeces.
2
Combined data of seven randomised studies and this last trial give a
total of 6,732 patients with OA and RA treated. This analysis showed
that nabumetone use was associated with a significant lower incidence
Dr Jordi Monfort Faure is a Rheumatologist at the Universitary Hospital del Mar and La
Esperança in Barcelona, Spain. He is also a researcher at the Bone and Cartilage
of perforations, ulcers and bleedings than a group of conventional
Physiopathology Research Unit, Institut Municipal d’Investigacions Mèdiques. Parc de Recerca
NSAIDs including diclofenac, indomethacin, piroxicam, naproxen and
Biomèdica de Barcelona and a Board member of the Spanish Society for Rheumatology.
ibuprofen (0.03%; 95% CI: 0.0%-0.08% versus. 1.4%; 95% CI: 0.5%-
2.4% – see Figure 1).
8
Dr Josep Blanch i Rubió is President of the Spanish Society for Rheumatology and Consultant
Rheumatologist in the Division of Rheumatology, I.M.A.S. Universitary Hospitals del Mar and
Huang et al. performed another meta-analysis
9
of various clinical trials
de la Esperanza, Barcelona, Spain. He is the author of numerous original papers, books, book
chapters, and scientific reviews and divulgative scientific papers in national and foreign
in which they analysed the differences in GI events as well as the
journals, mainly related to bone metabolism. incidence of perforations, ulcers and bleedings among patients treated
with either nabumetone or conventional COX-1/COX-2 inhibitors. The
authors identified 13 studies comprising 29 treatment arms and a total
28 © TOUCH BRIEFINGS 2007
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100