Drugs and recovery: why pain-relief medication may inhibit your recovery

Sooner or later the dreaded ‘I’ word becomes part and parcel of virtually every athlete’s vocabulary. If you’re exploring your physical limits, or your sport involves the risk of impact, it’s only a matter of time before injury strikes, delivering a double whammy. Quite apart from the pain and discomfort of the injury itself, there’s the frustration and depression of seeing your hard-earned fitness gains slip away as each inactive day passes. Hardly surprising then that athletes seeking to return to training as soon as possible frequently turn to painkillers, and particularly to anti-inflammatory medication. However, contrary to popular belief, this type of medication can cause potentially serious side effects, and new research indicates that it may even slow down healing and increase susceptibility to injury in the longer term, writes Andrew Hamilton.If you’ve ever been injured, you’ll be well aware of the associated pain and discomfort that injury brings. But injury also results in inflammation. Sometimes this inflammation is all too apparent (for example a twisted ankle that swells up like a balloon), while at other times it’s hidden from view (such as with a shoulder impingement injury, where the inflammation occurs deep in the joint). Inflammation is responsible for much of the pain and discomfort that occurs after injury – but why does it happen?

Inflammation is the body’s basic response to injury. When an injury occurs, your body immediately recognises the damaged tissue as ‘foreign’, and a sequence of complicated and interrelated events are set in motion to defend the body and eradicate the damaged tissue by a process of destruction, followed by renewal. It’s a bit like warfare: if you want your body to be healthy, it must be able to mount an inflammatory response! The general sequence of events following an injury is shown in the box overleaf.

The downside of inflammation, however, is that it invariably causes pain and discomfort. Sometimes this can actually be advantageous because the pain forces us to limit the movement in the affected area, and that can help healing; damaged unrepaired tissue is weak tissue and further movement may worsen the injury.

However, there are also times when inflammation can be detrimental, especially when it becomes chronic. For example, joint inflammation due to arthritis may limit motion in a joint, yet maintaining mobility in arthritic joints is crucial for the long-term health of those joints. Although painkillers like codeine and paracetamol can offer pain relief, tackling the inflammation itself is a far more effective strategy, which is where anti-inflammatory medication comes in.

Anti-inflammatory medications are by far the most commonly prescribed medication for pain involving inflammation. They fall into two main categories: steroidal and non-steroidal. Steroidal anti-inflammatories, such as hydrocortisone, are very effective but carry health risks, especially when used for extended periods of time. These risks include skin and blood sugar abnormalities, weakened bones, and even disruption of the body’s own steroid production capability, which is why they’re only used as a last resort.

By contrast, and as their name suggests, nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen and diclofenac, among others, don’t carry the risks of steroid use and are therefore much preferred by doctors. This also explains why the less potent types of NSAIDs, such as aspirin and ibuprofen, can be freely purchased over the counter. So commonly prescribed and purchased are these drugs that in the UK alone it is estimated that there are between five and eight million regular users!

One of the crucial steps in regulating the process of inflammation involves naturally occurring substances called prostaglandins, which are synthesised in our bodies from fatty acids that we consume in our diet. These prostaglandins possess hormone-like properties – ie they act as chemical messengers, telling cells what to do, and by so doing play a pivotal role in regulating a number of aspects of our body’s chemistry.

There are actually three types, or families, of prostaglandins: series 1 (PG1), series 2 (PG2) and series 3 (PG3 – we don’t need to worry about these here). Although PG1 and PG2 prostaglandins are both synthesised from metabolites of linoleic acid (omega-6 – one of the essential fatty acids we eat in our diet), they have very different roles.

• The PG1 family of prostaglandins can be thought of as ‘the good guys’, helping blood to become less sticky, relaxing blood vessels, improving circulation and lowering blood pressure, enhancing the function of immune T-cells and helping insulin work more effectively in the body. PG1 also helps prevent the release of the fatty acid arachidonic acid (AA) from our cell membranes, where it is normally stored. This is important because AA is the building block from which the PG2 series of prostaglandins are synthesised.
• PG2 prostaglandins are responsible for a number of biochemical ‘fight or flight’ responses in the body. For example, they increase stickiness of blood (useful for clotting and wound healing), increase blood pressure by stimulating water retention and are responsible for inflammation. But, while they have their role in emergency conditions, under ‘normal’ conditions many of their effects can be undesirable, which is why they’re often referred to as ‘the bad guys’ of prostaglandins!

NSAIDs work by helping to block the conversion of AA to certain types of PG2s, prostaglandins that orchestrate the process of inflammation, as illustrated graphically in the flow chart below.



So far, so good, but there’s a big problem for sportsmen and women who use NSAIDs, and that is the fact that many of these drugs can play havoc with the delicate lining of the stomach, with the potential to cause such serious gastric problems as ulcers and bleeding.

The risks involved are considerable: in the USA, NSAIDs cause more deaths than bone marrow cancers, asthma, cervical cancer or Hodgkin’s disease (cancer of the lymphatic tissues) and about as many as HIV/AIDS ⁽¹⁾. On average, one in every 1,200 patients taking NSAIDs for at least two months will die from gastrointestinal complications – people who would not have died if they had not taken NSAIDs ⁽²⁾! A large UK study also showed that the risk of NSAID-induced gastric bleeding increases rapidly with age, as does death from complications (see table below)⁽³⁾.

Table: age-related risk of problems with NSAIDs

Age range (years)	Chance of GI bleed due to NSAID	Chance of dying from GI bleed due to NSAID
Risk in any one year is 1 in:
16-45	2,100	12,353
45-64	646	3,800
65-74	570	3,353
Ž 75	110	647

Of course, no medication is totally without side effects or risks, but the fact is that many people, including sportsmen and women, are completely unaware of the risks relating to NSAIDs.

The reason why many NSAIDs can be so harmful to the stomach lining is to do with the way they block the conversion of AA to PG2s, as illustrated in the diagram above right.

Before the 1990s, scientists believed that the conversion of AA to PG2s involved a single enzyme called cyclooxygenase. But then it was discovered that this conversion actually involves two very closely related enzymes – cyclooxygenase 1 and cyclooxygenase 2, or more simply COX-1 and COX-2. However COX-1 and COX-2 have different functions. COX-1 synthesises PG2s that do ‘housekeeping’ work around a number of organs, such as maintaining the health of the stomach, intestines and kidneys, while COX-2 synthesises the potentially troublesome inflammatory PG2s and oxygen free radicals that enhance inflammation.

A new generation of NSAIDs

A new generation of NSAIDs, called ‘COX-2 inhibitors’, has recently appeared on the market. These include such products as rofecoxib, celecoxib and valdecoxib. As the name suggests, these block the COX-2 enzyme, but not the COX-1 enzyme. In other words, they dramatically reduce inflammation without the harmful gastric effects and risks of conventional NSAIDs. In short, this type of NSAID seems to be the answer to an injured athlete’s prayer!

However, some new research on COX-2 inhibitors makes disturbing reading. A group of American scientists examined the effects of COX-2 inhibitors on mice with bone fractures and found that, by comparison with untreated mice, COX-2-treated mice suffered from profoundly compromised bone healing ⁽⁴⁾. In particular, the bone nodules that formed (small bony growths that form the first stage of healing) were smaller and did not respond to growth factors that would stimulate bone healing in untreated mice. Moreover, when the COX-2-treated mice were then given a dose of the inflammatory PG2s (which had been blocked by the COX-2 drug), the bone healing process was restored, indicating that these inflammatory PG2s may play an essential role in bone healing.



In addition, several studies have shown that the COX-2 inhibitors celecoxib and rofecoxib either delay or inhibit fracture healing in rats ^(5,6); another study found that COX-2 inhibitors decreased the strength of fracture healing at 21 days ⁽⁷⁾; and a paper published earlier this year points to evidence that these drugs impair the return of mechanical strength following acute injury to ligaments and tendons as well as bone ⁽⁸⁾.

Given that it’s the blocking of inflammatory PG2 production that seems to be the cause of this delayed healing, eagle-eyed readers out there might be wondering whether traditional NSAIDs (which block both COX-2 and COX-1) also diminish the rate of healing? The answer appears to be ‘yes’. A study on rabbits compared the effect of a COX-2 NSAID (celecoxib) with a conventional NSAID (Toradol) on bone healing following a fracture and found no statistical difference ⁽⁹⁾.

Meanwhile, in a human study, researchers looked at patients who had undergone spinal fusion treatment, where two or more vertebrae are fused together, and discovered that patients who had taken a conventional NSAID (Toradol) were five times less likely to achieve successful union of the vertebrae than those who had taken no NSAID ⁽¹⁰⁾.

However, some researchers believe that the extent of healing impairment is far more severe with COX-2 inhibitors. In the COX-2 rat study mentioned above, 253 young rats with broken legs were given either one of two types of COX-2 NSAIDs (Vioxx, Celebrex) or indomethacin, which is a traditional NSAID ⁽⁵⁾. The indomethacin-treated rats took a week longer to heal than untreated rats, but the new bone was just as strong. However, rats given Vioxx or Celebrex had not fully healed after two months and the researchers likened the new bone to a ‘weakened shell’.

There have been anecdotal reports of impaired bone healing in patients taking traditional NSAIDs for years, but this side effect may have escaped attention because traditional NSAIDs, such as ibuprofen and indomethacin, appear to delay healing instead of blocking it. Interestingly, the report also says aspirin appears to be one of the few NSAIDs that kill pain without this side effect!

Finally, long-term use of some COX-2 NSAIDs may pose other health problems. In 2004, Merck’s product Vioxx was withdrawn because of new evidence indicating an increased risk of stroke and heart attack. And just two months ago, Pfizer agreed to suspend sales of another COX-2 drug (Bextra) after US and European regulators said the risk of serious side effects, including a potentially fatal skin allergy, outweighed the benefits. In addition, the US Food and Drug Administration also asked Pfizer to add a ‘black box’ warning – the strongest possible – to the label of its COX-2 antiinflammatory painkiller Celebrex.

There is no doubt that NSAIDs can help you return to training and competition more rapidly, and provide effective pain relief in the process. It is also true that the new generation COX-2 inhibiting NSAIDs are much less risky in terms of gastric health. However, every silver lining has a cloud and NSAIDs are no exception! Although more research is needed, there’s genuine concern that (aspirin aside) NSAIDs may impair injury healing, especially of bone and ligament. And COX-2 NSAIDs may present more of a problem in this respect than traditional NSAIDs. However, to date there’s little evidence about the possible effects of NSAIDs on soft tissue injury healing.

If you’re suffering from a soft tissue injury, there’s no reason as yet to believe that COX-2 NSAIDs will harm the healing process, and they could be the best option. Injuries involving ligaments or bone are more problematical because some evidence indicates that COX-2 NSAIDs could seriously delay and impair healing, leaving you more vulnerable to re-injury.

On the other hand, if you have a sensitive stomach, a traditional NSAID may cause gastric problems, especially when taken for extended periods of time, and even these NSAIDs appear to delay healing. Ideally you should talk to your GP before rushing into the nearest chemist and buying anti-inflammatories. There are also some very simple guidelines you can use to help reduce inflammation naturally, without resorting to NSAIDs (see box below).

The take-home message is that all NSAIDs pose considerable risks and you should use them as a last resort, not a first!

References

1. Journal of Rheumatology 1999; 26 Supp 56:18-24
2. Pain 2000; 85: 169-182
3. Aliment Pharmacol Ther 1997; 11: 283-91
4. Journal of Clinical Investigation 2002; 109(11): 1405-1415
5. Journal of Bone and Mineral Research 2002;17(6): 963-976
6. J Bone Joint Surg Am 2004; 86-A(1): 116-23
7. Journal of Orthopaedic Research 2003; 21: 670-675
8. Sports Med 2005; 35(4): 271-83
9. JBJS-Am 2002; 84A(10): 1763-1768
10. Spine 1998; 23(7): 834-838