Trip Answers

Question answered:24/06/08

We searched the TRIP and Medline databases but found few studies specifically examining the effect of healing time or on inflammation in patients not requiring or no longer needing analgesia.

 

However, a study by Sirkin et al that dates from 1997, compared ketorolac, prednisolone and dexamethasone for post-operative inflammation, The author reports in the abstract of the article:

 

“OBJECTIVE: Ketorolac tromethamine 0.5% and diclofenac sodium 0.1% ophthalmic solutions are approved for use by the U.S. Food and Drug Administration to avoid excessive postoperative inflammation after cataract surgery and implantation of an intraocular lens. This study compares the efficacy and toxicity of these nonsteroidal anti-inflammatory drugs for the first time. DESIGN: Randomized, double-masked, prospective clinical trial. PARTICIPANTS: A total of 120 patients assigned in equal numbers to 1 of the 2 treatment regimens. INTERVENTION: Treatment with either ketorolac 0.5% or diclofenac 0.1% ophthalmic solutions instilled four times daily for 30 days beginning the first postoperative day after surgery. MAIN OUTCOME MEASURES: Objective (Kowa FC 1000 laser cell and flare meter) and subjective (slit-lamp biomicroscope) measurements of inflammation and toxicity were made and compared at three separate post-operative visits. RESULTS: The anti-inflammatory effects of the two treatment regimens were not statistically different at any of the postoperative visits. Patients tolerated both treatments equally well.

 

CONCLUSIONS: This study shows diclofenac sodium 0.1% and ketorolac tromethamine 0.5% ophthalmic solutions are equally effective and safe for the control of postoperative inflammation after uncomplicated cataract surgery performed by phacoemulsification followed by the implantation of a foldable intraocular lens.” [1]

 

Two issues that became apparent during our literature search were the effect of NSAIDs on bone formation and soft tissue healing.

 

The NeLM carried out a review of NSAIDs and their affect on frature healing post-operatively in September 2006. They note:

 

“There have been numerous animal studies detailing a negative effect of NSAIDs on fracture healing, resulting in delayed-union or non-union of bone. Non-union is defined as failure of normal healing of a fractured bone and represents an ongoing failure of initial fracture management. The possibility of an effect on fracture healing in humans has been widely reported and has lead to patients with fractures being denied NSAIDs for pain control. This Medicines Question and Answer examines the evidence for NSAID induced delayed-union and non-union of fractures in humans.”

 

Summary

 

Fracture healing is a complex process which can be affected by numerous factors.  The possibility that NSAIDs could affect this process, resulting in possible non-union and delayed healing has been highlighted by conflicting animal studies; however relevance to short term post-operative use in humans is not known (9,18,22).  The small prospective trials that have been carried out have shown no significant effect on union and fracture healing, and have highlighted the numerous benefits of NSAIDs.  Studies carried out that show negative effects on fracture healing were small and retrospective, with doubts expressed about their methodology. It is possible that the link between NSAIDS and non-union reported in these studies may be due to the need for more NSAIDs to treat these painful unhealed fractures rather than the NSAID being the cause of non-union.  Looking at the evidence available, it seems unreasonable to routinely deny a patient the benefits of a NSAID after surgery on a fracture and an assessment of the risks and benefits of such treatment should be carried out on an individual basis.  If used, NSAIDs should be prescribed at the lowest effective dose for the shortest possible duration to reduce the risk of potential adverse effects.  There is insufficient human evidence available to assess the safety of COX-2 selective agents in fracture healing.  Further study in this area is needed with large prospective, controlled trials.

 

Limitations

 

There are limited data on the effect of NSAIDs on fracture healing in humans and trials available are of poor quality.  There is insufficient information to assess the safety of COX-2 selective inhibitors in fracture healing.  The effect of NSAIDs on wound healing is not considered as a part of this review.” [2]

 

A paper, published this year, assessing the impact of NSAIDs and Cox-2 inhibitors on the bone healing process. Vuolteenaho et al state:

 

“…The present survey reviews current experimental and clinical evidence related to two of those conditions (i.e. on ectopic bone formation and on bone fracture healing). NSAIDs are used clinically to prevent ectopic bone formation (also known as heterotopic ossification) (e.g. after total hip arthroplasty or trauma). The efficacy of NSAIDs in the avoidance of heterotopic ossification has been documented in controlled clinical trials, but the inherent risks (e.g. on healing processes and on loosening of prostheses) need further studies. At the same time, NSAIDs are widely used in the treatment of fracture pain, and their inhibitory effects on the ongoing bone healing process have raised concerns. Results of fracture healing studies in animals treated with NSAIDs or in mice lacking COX-2 gene show that inhibition or deficiency of COX-2 impairs the bone healing process. The limited clinical data also support the assumption that inhibition of COX-2 by non-selective or COX-2-selective NSAIDs delays fracture healing. However, the clinical significance of the effect in various patient groups needs to be carefully assessed and further investigations are needed to characterize the patients at the highest risk for NSAID-induced delayed fracture healing and its complications. In the meantime, use of NSAIDs in fracture patients should be cautious, keeping in mind the benefits of pain relief and inhibition of ectopic bone formation on one hand, and the risks of non-union and retarded union on the other hand.” [3]

 

Concerning the affect of NSAIDs on soft-tissue injuries, Paoloni notes in relation to sports injuries:

 

“The use of non-steroidal anti-inflammatory drugs (NSAIDs) to treat most muscle, ligament and tendon injuries should be reassessed. They have, at best, a mild effect on relieving symptoms and are potentially deleterious to tissue healing.
Soft-tissue injury associated with definite inflammatory conditions such as bursitis or synovitis or involving nerve impingement does warrant short-term treatment with NSAIDs.
Paracetamol has similar efficacy to NSAIDs in soft-tissue injury, is cheaper, and has a lower side-effect profile. It is the analgesic of choice for most soft-tissue injury” [4]

 

References
1. Flach AJ, Dolan BJ and Donahue ME et al.Comparative effects of ketorolac 0.5% or diclofenac 0.1% ophthalmic solutions on inflammation after cataract surgery. Ophthalmology. 1998 Sep;105(9):1775-9. (http://www.hubmed.org/display.cgi?uids=9754191)
2. NeLM. Do Non-Steroidal Anti-Inflammatory Drugs affect fracture healing post-operatively? September 2006. (http://www.druginfozone.nhs.uk/Record%20Viewing/viewRecord.aspx?id=570359)
3. Vuolteenaho K, Moilanen T and Moilanen E. Non-steroidal anti-inflammatory drugs, cyclooxygenase-2 and the bone healing process. Basic Clin Pharmacol Toxicol. 2008 Jan;102(1):10-4. (http://www.hubmed.org/display.cgi?uids=17973900)
4. Paoloni JA et al. The use of therapeutic medications for soft-tissue injuries in sports medicine. MJA 2005; 183 (7): 384-388 (http://www.mja.com.au/public/issues/183_07_031005/pao10246_fm.html)

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