Article Review: The Effect of NSAIDs towards Ligament Healing

by: Rudy Dewantara MD

Abstract
Ligament injury so far has been a common problem especially for atheletes. In United States alone the incidence is 850.000 per year, 70.833 per month, 16.346 per week, 2.328 per day, 97 per hour, 1 per minute, 0 per second. Ankle and knee are the most common sites for ligament injury in atheletes and render special consideration due to the high morbidity it brought. In general there are three grade of ligament injury, according to AAOS (American Academy of Orthopaedic Surgeon), grade 1 is of the lightest with only miscroscopic tearing of collagen fibers, grade II is partial tears of the ligament and grade III being the severe with complete or total rupture of the ligament. The principle of RICE (rest, ice, compression and elevation) remains the gold standard for acute phase and most of the times is accompanied with the administration of NSAIDs (non steroidal anti inflammatory drugs) to relieve pain and edema. However there are some controversy rise up related to the use of NSAIDs in ligament injury. Many studies were performed in order to determine the effect of NSAIDs to ligament healing. Some agents have been studied in clinical trial such as piroxicam, ibuprofen, indomethacin, celecoxib and others. Some studies suggest that NSAIDs do delay ligament healing, some others do not, and few of them advise us to be careful in selecting NSAIDs. This article review will explore some of those studies in order to determine the effect of NSAIDs towards ligament healing.

Ligament Healing
Ligament is a tough band of white fibrous connective tissue that links two bones together at a joint. Ligament is composed primarily of type I collagen, but they contain small amounts of types III and V. The type III collagen content has been reported to be 10% for ligament as opposed to 5% for tendon. Collagen types II, VI, XII, and XIV have also been reported to be in the ligament and capsule. However, these collagens appear to be associated with fibrocartilage that is found at the junction with bone, not in the midsubstance. The high content of type I collagen in these joint tissues not only leads to mechanical stability, but it also promotes elastic energy storage10.
The first phase of ligament healing is considered the inflammatory phase and occurs in the first week following injury. It starts with the migration of macrophages from tissues surrounding the injury. During this phase, the macrophages remove necrotic tissue and hematoma from the area of the injury thereby preparing the tissue bed for reconstruction. Collagenases and matrix metalloproteinases have a key role in removing not only collagen debris, but also matrix components from the site of injury. The last phase has been termed the remodeling phase. At approximately 8 week after injury, the recently laid down collagen fibers are brought into orientation along the axis of the ligament. The collagen fibers are originally oriented perpendicular to the long axis of the ligament. It is during this period that adhesions may become more numerous and tenacious. Older individuals have a lower metabolic activity within these structures that may be responsible for the diminished age-related tendon-healing capacity observed10.


What Are NSAIDs and How Do They Work?

NSAIDs stands for non steroidal anti inflammatory drugs. It has analgesic, antipyretic and, in higher doses, anti-inflammatory effects. They reduce pain, fever and inflammation. The term “non-steroidal” is used to distinguish these drugs from steroids, which (among a broad range of other effects) have a similar eicosanoid-depressing, anti-inflammatory action5.
Prostaglandins are a related family of chemicals that are produced by the cells of the body and have several important functions. They promote inflammation, pain, and fever, support the function of platelets that are necessary for the clotting of blood, and protect the lining of the stomach from the damaging effects of acid. Prostaglandins are produced within the body’s cells by the enzyme cyclooxygenase (Cox). There actually are two Cox enzymes, Cox-1 and Cox-2. Both enzymes produce prostaglandins that promote inflammation, pain, and fever. However, only Cox-1 produces prostaglandins that support platelets and protect the stomach. Nonsteroidal anti-inflammatory drugs (NSAIDs) block the Cox enzymes and reduce prostaglandins throughout the body. As a consequence, ongoing inflammation, pain, and fever are reduced. Since the prostaglandins that protect the stomach and support the platelets and blood clotting also are reduced, NSAIDs can cause ulcers in the stomach and promote bleeding. NSAIDs differ in how strongly they inhibit Cox-1 and, therefore, in their tendency to cause ulcers and promote bleeding5.

Studies on Non Specific NSAIDs
Many physicians sports medicine specialist even trainers of atheletes believe that aggressive early intervention in the management of acute ankle sprains can significantly improve outcome and reduce subsequent disability. An integral part of this intervention is pain relief, especially through the use of nonsteroidal antiinflammatory drugs (NSAIDs). Despite their widespread use in the treatment of acute musculoskeletal injuries in sports medicine, general, and orthopaedic practices, their efficacy has not been firmly established. Most of the available evidence relates to the treatment of rheumatoid arthritis
rather than to acute sports injuries. There are reasons to expect that antiinflammatory drugs might have an adverse effect on healing. Inflammation is an early sequela of injury and results in the recruitment of cells into the area of injury for the removal of necrotic debris and the initiation of the healing process. There were also an articles documented that ibuprofen has an adverse effect on the recovery of bone strength after the drilling of holes in bones8,9. Many others studies have been performed since then to explore the possibility of NSAIDs adverse effects towards ligament healing.
In 1988 at the University of North Carolina, Division of Orthopaedics, dr. Laurence E. Dahners and associate studied the effect of NSAIDs on healing of ligaments. The agent used in the study is piroxicam. Piroxicam-treated rats were compared to placebo-treated rats in terms of the drug’s effect on the mechanical strength of the healing
ligament. Administration of piroxicam on day 1 to 6 postinjury resulted in a 42% increase in strength at day 14 postinjury for the piroxicam-treated ligaments (P < 0.01) when compared with the placebo-treated controls. Neither doubling nor halving the standard piroxicam dose significantly altered this increased healing strength. Biochemical analysis of collagen synthesis demonstrated a suggestive, although not statistically significant, increase in collagen synthesis and collagen content in the piroxicam-treated healing ligament. In separate experiments, piroxicam had no effect on the healed ligament at 21 days or on the strength of uninjured ligaments. In conclusion, piroxicam increased the early strength of healing ligaments in the rat when the drug was administered for short periods of time after injury. It did not affect the final strength when healing was complete, nor did it alter the strength of uninjured ligaments2.
Another study was done on the use of Piroxicam (NSAID) in the treatment of acute ankle sprains in the Australian military. Compared with the placebo group, the subjects treated with Piroxicam had less pain, were able to resume training more rapidly, were treated at lower cost, and were found to have increased exercise endurance on resumption of activity. Interestingly, subjects treated with piroxicam showed some evidence of local abnormalities such as instability and reduced range of movement. In addition, this was the first study to use anterior drawer test as clinical measure of ankle instability in a clinical trial. The anterior drawer test demonstrated greater instability in the piroxicam group. However this study concluded that the systematic use of the piroxicam produced better recovery at lower cost. The effects of piroxicam were impressive; they reduced subject pain, time lost from training, and the cost of treatment, and they increased exercise endurance after ankle sprain. However, subjects treated with piroxicam also had greater instability, less range of motion, and increased swelling. It is possible that the analgesic effects of NSAIDs actually allowed subjects to resume activity prematurely, before there had been sufficient tissue healing to prevent further swelling and interference with healing that leads to increased instability and possibly to reduced range of motion. Having introduced this note of caution, however, it must be reiterated that the treatment group had a favorable outcome in the long term, both in terms of morbidity and cost and that, on balance, the overall result of the use of NSAIDs was beneficial7.
Based on studies aforementioned, piroxicam, probably the most-studied NSAIDs agent, has a beneficial effect towards ligament healing. In 2006, once again another study suggest that piroxicam should be the drug of choice for ligament injury. The study was performed by Curtis A. Hanson and he concluded that Piroxicam improves ligament healing, but this effect cannot be attributed to all nonselective nonsteroidal antiinflammatory drugs. Opiate analgesics, acetaminophen, and cyclooxygenase-2 inhibitors do not appear to categorically affect ligament healing4.
A study on other NSAIDs agent, ibuprofen, was performed by Claude T. Moorman MD and associates from the Sports Medicine Program and Orthopaedic Biomechanics Laboratory, University of Maryland, Baltimore, in 1999, in which 24 New Zealand White rabbits, the medial collateral ligament of one hindlimb was ruptured; the contralateral ligament served as an internal control. The rabbits were treated orally, twice daily, with a 14-day course of either 35 mg of ibuprofen per kilogram of body weight or a placebo. The rabbits were sacrificed at 14 or 28 days, and the ligaments were tested in tension to failure at 0.15 mm/sec. There was no statistically significant difference in the values of mechanical properties of ligaments from rabbits treated with ibuprofen versus those treated with placebo at either 14 or 28 days after injury. The conclusion was there is no early deleterious effect of a short course of ibuprofen on the mechanical behavior of medial collateral ligaments6.

Studies on COX-2 Selective Inhibitor
All the above studies used piroxicam and ibuprofen, but what about the effect of other NSAIDs group namely Cox-2 selective inhibitor? Celecoxib was the first of a new class of nonsteroidal antiinflammatory drugs, the cyclooxygenase-2 (Cox-2) specific inhibitors, marketed as having the same antiinflammatory efficacy as other nonsteroidal antiinflammatory drugs without their increased risk of gastrointestinal ulceration. Although the benefits of celecoxib have been shown when used for rheumatoid arthritis and osteoarthritis, we are still unaware of any studies concerning its effect on soft tissues. Christopher L. Elder et al used the surgically incised medial collateral ligament of male Sprague-Dawley rats as an experimental model for acute ligament injuries to investigate the effects of celecoxib on ligament healing. Fifty rats underwent surgical transection of the right medial collateral ligament. Postoperatively, half were given celecoxib for the first 6 days of recovery, the other half were not. The animals were sacrificed 14 days after the operation, and both the injured and uninjured medial collateral ligaments were mechanically tested to failure in tension. Celecoxib-treated/injured ligaments were found to have a 32% lower load to failure than untreated/injured ligaments. The results of this study do not support use of cyclooxygenase-2 specific inhibitors in the treatment of ligament injuries3.
Stuart J. Warden et al studied the use of celecoxib and low-intensity pulsed ultrasound, either used alone or combined. The result is low-intensity pulsed ultrasound accelerated but did not improve ligament healing, whereas celecoxib delayed but did not impair healing. When used in combination, the beneficial low-intensity pulsed ultrasound
effect was cancelled by the detrimental celecoxib effect11.

Studies on COX-1 Selective Inhibitor
As already mentioned, COX-1 produces prostaglandins important for homeostasis and certain physiologic functions but that it does not play a big role in producing inflammation. On the other hand, COX-2, which is found in most tissues, is an inducible enzyme, but it is usually not produced under normal conditions. Studies have shown us the adverse effect of COX-2 towards ligament healing. Based on those results, Victor B. Bogatov et al tried to determine the effect of COX-1 selective inhibitor either on injured or uninjured ligaments in rat. No significant differences in the strength of injured ligaments were found between drug and placebo treatment. However, the contralateral uninjured ligaments in the SC-560-treated groups failed at 27% higher energy and 22% higher load. The conclusion of the study is cyclooxygenase-1 inhibitor did not improve the strength of ligament healing but did significantly improve the strength of the contralateral uninjured ligament. It also suggest that a pure cyclooxygenase-1 inhibitor is probably not indicated as a positive influence on ligament healing but might provide benefits in ligament injury prevention1.

Discussion
Nonselective nonsteroidal antiinflammatory drugs are widely used to treat acute ligament injuries because of their effect on pain and swelling. It is expected that once the pain and swelling diminished, patient is able to return their activity as soon as possible. However, early agressive treatment with analgesic and anti inflammatory agent will also prevent the recruitment of cells into the area of injury for the removal of necrotic debris and the initiation of the healing process. Therefore, some studies have been performed to determine whether NSAIDs, a commonly used agent, have adverse effects towards ligament healing.
Piroxicam and ibuprofen were two agents of non spesific NSAIDs (it blocks both Cox-1 and Cox-2 enzymes) used in some studies. Studies have shown that both agents have no detrimental effect on ligament healing. One studies conducted by Laurens even showed that piroxicam increased the early strength of healing ligaments in the rat when the drug was administered for short periods of time after injury. Since many studies with non spesific NSAIDs have shown similar results, it should be the integral part in treating acute ligament injury. On contrary, other group of NSAIDs, Cox-2 selective inhibitor have been proven to delay ligament healing, therefore it is wise not to prescribe it.
Since Cox-2 selective inhibitor did impair ligament healing, it was hypothesized that the beneficial effect of nonselective nonsteroidal antiinflammatory drugs on ligament healing is due to their Cox-1 component. However, the study from Victor B. Bogatov did not support this hypothesis. Instead, the study suggested that Cox-1 selective inhibitor may be useful in strengthening musculoskeletal soft tissue to prevent injury.

References

1. Bogatov VB, Weinhold P, Dahners LE. The Influence of a Cyclooxygenase-1 Inhibitor on Injured and Uninjured Ligaments in the Rat. American Journal of Sports Medicine. 2006.

2. Dahners LE, Gilbert JA, Lester GE, et al. The effect of a nonsteroidal
antiinflammatory drug on the healing of ligaments. American Journal of Sports Medicine. 1988

3. Elder CL, Dahners LE, Weinhold PS. A Cyclooxygenase-2 Inhibitor Impairs Ligament Healing in the Rat. American Journal of Sports Medicine. 2001.

4. Hanson CA, Weinhold PS, Afshari HM, et al. The Effect of Analgesic Agents on the Healing Rat Medial Collateral Ligament. American Journal of Sports Medicine. 2005

5.Katzung BG. Basic and Clinical Pharmacology 8th Edition. McGraw Hill Companies Inc. 2001.

6. Moorman CT, Kukreti U, Fenton DC. The Early Effect of Ibuprofen on the Mechanical Properties of Healing Medial Collateral Ligament. American Journal of Sports Medicine. 1999.

7. Slatyer, M. A randomized controlled trial of Piroxicam in the management of acute ankle sprain in Australian regular army recruits. American Journal of Sports Medicine. 1997.

8. Tornkvist H, Lindholm TS, Netz P, et al. Effect of ibuprofen and indomethacin on bone metabolism reflected in bone strength. 1984

9. Vogel HG: Mechanical and chemical propertes of various connective tissue organs in rats as influenced by nonsteoridal antirheumatic drugs. 1977

10. Walsh WR. Repair and Regeneration of Ligaments, Tendons, and Joint Capsule. 2005

11. Warden SJ, Avin KG, Beck EM, et al. Low-Intensity Pulsed Ultrasound Accelerates and a Nonsteroidal Anti-inflammatory Drug Delays Knee Ligament Healing. American Journal of Sports Medicine. 2006.

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