Drugs and recovery: pain relief medication may not be the answer to a speedy recovery

What all athletes need to know about pain relief medication

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.

Inflammation – what happens at tissue level?

  1. Damage to tissue (eg torn ligament, strain or blow to muscle tissue) allows blood to leak into surrounding tissues. This causes a cascade of biochemical events signalling to the body that injury has occurred, and the acute phase of inflammation begins.
  2. One of the first reactions is a widening of the small blood vessels supplying the injured area (vasodilation) resulting in increased blood flow. As well as dilating, these blood vessels also start to become ‘leaky’ to proteins, allowing proteins in the blood to leak through the vessel wall into the surrounding tissue.
  3. The leakage of proteins into surrounding tissue then causes an associated leakage of fluid, which leads to swelling. This swelling often impinges on sensitive nerve endings, causing pain.
  4. At this point, neutrophils (a type of white blood cell) exit from the blood vessels into the tissues, followed by monocytes (another type of white blood cell). Their job is to clean out any bacteria and prevent infection at the injury site. Many of the chemicals released during this phase are broken down into hormones, whose role is to tell cells to become active or inactive during this phase of inflammation. Some of these chemicals are called prostaglandins, which can cause pain at the injury site (more about them later).
  5. The arrival of the macrophages (yet another type of immune cell) at the injury site signals the beginning of the next phase in the healing process. Macrophages begin to clean up the area through a combination of digesting the broken-down cell parts and secreting enzymes, which break down damaged cells. With all this activity occurring, inflammation (and pain) often peaks at this stage.
  6. Once the wound has been successfully cleared of unwanted material it gives way to a process known as granulation, where new tissue is laid down with the help of special cells called fibroblasts and other cells associated with inflammation. Fibroblasts first appear in significant numbers in the wound on the third day post-injury and achieve peak numbers around the seventh day. They are the primary synthetic element in the repair process and are responsible for production of the majority of structural proteins, such as collagen, used during tissue reconstruction. This initial healing phase marks the end of the inflammation phase, although it may take many days or weeks for inflammation to subside completely.
  7. The final phase is called ‘maturation’, whereby the structural proteins in reconstructed tissue are gradually remodelled and strengthened to gain full functionality. This phase can last from a week to a year!

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.

How NSAIDs block the inflammation process

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.

The problem with conventional NSAIDs, such as aspirin and ibuprofen, is that they block both enzymes. Yes, they block the production of inflammatory PG2s by COX-2, but the downside is that they exact a heavy price by simultaneously blocking COX-1 and the production of protective PG2s. Some of these protective PG2s are involved in maintaining the integrity of the stomach lining and protecting the stomach wall against the extremely strong acid secreted in the stomach to digest food. Blocking these protective PG2s increases the risk of this acid attacking the stomach wall, leading to such potentially severe gastrointestinal problems as ulcers and stomach bleeding.

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.

How NSAIDs block protective prostaglandins

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).

Fighting inflammation naturally

After injury, remember the ‘RICE’ acronym – rest, ice, compression, elevation. Applying ice to the affected area during the early stages of injury is particularly effective at reducing the amount of inflammation and subsequent pain that occurs. A compression bandage around the area can also help.

In chronic injuries, nutritional strategies can also help moderate the degree of inflammation:

  • Increasing your intake of omega-3 oils, particularly eicosapentanoeic acid (EPA) found in fish oils (eg salmon, trout, herring, sardines, mackerel, pilchards) helps to block the release of AA from cell membranes and so slows the conversion of AA to inflammatory PG2s. This explains why chronic inflammatory conditions, such as arthritis, are helped by fish oils. Boosting omega-3 oils (found in walnuts, flax and hemp seeds and wheatgerm) will also help because these oils can be transformed into EPA in the body.
  • Evening primrose, borage and blackcurrant seed oils contain a rich source of GLA, which can help boost the body’s levels of prostaglandin E1, a prostaglandin that suppresses inflammation.
  • Antioxidant nutrition is also important, because your body’s antioxidant enzymes help to mop up the ‘collateral’ damage to healthy tissue caused by the release of free radicals in inflammation. Brightly coloured fresh fruits and vegetables are the best source of dietary antioxidants.
  • Glucosamine sulphate can be useful for chronically inflamed joints; recent research has indicated that it’s at least as effective in reducing pain as ibuprofen!

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

Andrew Hamilton BSc, MRSC, trained as a chemist and is now a consultant to the fitness industry and an experienced science writer

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

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