Page 123 Acute Pain Management

Peptic ulceration
A large case‐controlled study using a general practice database identified 10 892 patients over
4 years with a ‘first ever’ diagnosis of an upper GI ulcer or bleeding and compared them with
matched controls (Hippisley‐Cox et al, 2005 Level III‐3). Where individual drugs were specified in
the results, the risks were shown to be significantly increased for patients using naproxen,
diclofenac, ibuprofen, aspirin and rofecoxib, but not those taking celecoxib.
Acute gastroduodenal damage and bleeding can also occur with short‐term nsNSAID use —
the risk is increased with higher doses, a history of peptic ulceration, use for more than 5 days
and in elderly people (Strom et al, 1996 Level IV). After 5 days of naproxen and ketorolac use in
healthy elderly subjects, ulcers were found on gastroscopy in 20% and 31% of cases
respectively (Harris et al, 2001 Level II; Stoltz et al, 2002 Level II; Goldstein et al, 2003 Level II).
The gastric and duodenal epithelia have various protective mechanisms against acid and
enzyme attack and many of these involve prostaglandin production. Chronic nsNSAID use is
associated with peptic ulceration and bleeding and the latter may be exacerbated by the
antiplatelet effect. It has been estimated that the relative risk of perforations, ulcers and
bleeds associated with nsNSAIDs is 2.7 compared with people not consuming nsNSAIDs (Ofman
et al, 2002 Level III‐2). Use of ketorolac and piroxicam carried the highest risk (Lanas et al, 2003
Level III‐3). Concurrent use of a proton‐pump inhibitor (PPI) significantly reduced the incidence
of nsNSAID‐related peptic ulcer disease (Targownik et al, 2008 Level III‐2).
Aspirin‐exacerbated respiratory disease
Precipitation of bronchospasm by aspirin is a recognised phenomenon in individuals with CHAPTER 4
asthma, chronic rhinitis and nasal polyps. Aspirin‐exacerbated respiratory disease (AERD)
affects 10% to 15% of people with asthma, can be severe and there is a cross‐sensitivity with
nsNSAIDs but not coxibs (Simon & Namazy, 2003 Level IV; Szczeklik & Stevenson, 2003 Level IV; West
& Fernandez, 2003 Level I). A history of AERD is a contraindication to nsNSAID use, although
there is no reason to avoid nsNSAIDs in other people with asthma.

Bone healing
Evidence for an effect on bone healing is conflicting. In one study of 88 patients, 30 of whom
were given ketorolac after spinal fusion, the incidence of incomplete union or non‐union was
higher in those given ketorolac; the relative risk was approximately six times higher than
control group of patients who did not receive an NSAID and smoking was said to have had no
effect on the spinal fusion outcome (Park et al, 2005 Level III‐2). In another study of 405 patients,
228 of whom were given ketorolac after similar surgery, there was no significant difference in
the non‐union rates between the two groups; in this study there were no patients who
smoked (Pradhan et al, 2008 Level III‐3).
Cardiovascular
Most publications looking at the risk of cardiovascular side effects associated with nsNSAID
use also include information relating to risks with coxibs. See discussion under Section 4.2.3
below.

4.2.3 Cyclo-oxygenase-2 selective inhibitors (coxibs)
Coxibs selectively inhibit the inducible cyclo‐oxygenase enzyme, COX‐2, and spare constitutive
COX‐1 (see above). The coxibs available at present include celecoxib, etoricoxib and parecoxib,
the injectable precursor of valdecoxib. By sparing physiological tissue prostaglandin
production while inhibiting inflammatory prostaglandin release, coxibs offer the potential for
effective analgesia with fewer side effects than nsNSAIDs.

Acute pain management: scientific evidence 75