Is Ibuprofen Safe?

In the UK nearly 50% of adults take a prescription medication, with non-steroidal anti-inflammatory drugs being one of the most common prescriptions. (1) Recent research has shown that the average Briton takes 373 painkillers per year (2) and that 1 in 20 adults take at least 6 painkillers each time that they get ill. These figures are staggering and suggest that many people think that they are a safe and rational choice to make. 

However, there is a growing body of research showing some serious concern around the long and short-term safety of these common drugs (like Ibuprofen and diclofenac), and it could be time that we adopt a more conservative and cautious view about the way that they are used. Especially when you consider that some 1.4 Billion Ibuprofen pills are swallowed every year in the UK. 

That equates to some £600 million pounds worth of NSAIDs being sold over the counter each year! That doesn’t even take into account the amount from prescription versions of the drug, like diclofenac and naproxen.

In this article, I will show you some of the main concerns surrounding these common painkillers and show you seven powerful natural alternatives which are a lot safer.

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What Are NSAIDs?

Non-Steroidal Anti-Inflammatory Drugs are a type of medication that is widely used to relieve pain, inflammation and bring down high fevers. They are called non-steroidal because they reduce pain and inflammation through a different biochemical process than a steroid-based drug, like corticosteroids would, for example. 

In the UK you can only buy Ibuprofen (also known as Nurofen), and Aspirin over the counter, but others are available by prescription only, like, celecoxib and naproxen (there are several others). Diclofenac (sold as Voltarol) used to be available over the counter but was removed from the shelves in 2015 due to the risk of heart problems. Diclofenac is now only available as Voltarol gel, which is applied topically to the area of pain or injury. 

How Do NSAIDs Work?

NSAIDs all work in the same way, by blocking the cyclooxygenase enzyme that is responsible for producing the prostaglandin messenger molecules that cause inflammation, pain and fever. 

These drugs fall into two categories, COX1 and COX2, which essentially block different prostaglandin pathways and lower pain and inflammation in different but similar ways. Ibuprofen and aspirin an example of cox 1 NSAIDs, whereas celecoxib is a COX2 NSAID.

Is It Safe To Take NSAIDS For Headaches And Back Pain?


These are among the two most common reasons why people painkillers. It might surprise you to learn, however, that the jury is no longer out on the issues of whether or not NSAIDs are safe. The question is not do they work for pain since this has been very well established, they are excellent at reducing pain in the short term. 

Indeed the fact that they are so effective at their job may be the single biggest issue with NSAIDs since they become an easy and obvious choice for many people.

The question that you should be asking yourself is are these a safe and sensible choice for my long-term health. 

The science is strongly suggesting that we shouldn’t be so quick to reach for these pills. They haven’t gotten the name of ‘gut burners’ without good reason. 

Ibuprofen Can Cause Intestinal Bleeding 


One of the known side effects of COX1 NSAIDs is that they are harmful to the gut lining, especially when taken long term. Numerous studies have linked high dose NSAID use with stomach and intestinal perforations which can lead to death through internal bleeding. In the USA it is thought that up to 16000 patients per year die from gastrointestinal tract (GIT) bleeds directly related to the use of prescription NSAIDs, in the UK the number may be as high as 2000 per year. 

The risks of severe GIT bleeds goes up with increasing or long-term consumption of these drugs, but the challenge is that you may not notice the early signs of blood in your stool. There can be small microbleeds over time as the GIT gradually weakens leading it to perforate and become a very serious problem. 

There is now a growing concern that even very short-term use of these drugs for one to two days could result in a stomach lining perforation in susceptible individuals. This is because one of the side effects of COX1 NSAIDS is to interfere with the normal production of the protective mucus layer of the stomach, effectively leaving it vulnerable to erosion by your own powerful stomach acid. Some experts even claim that everyone who takes NSAIDs will get small erosions of the stomach, even after a single dose. (3)

The crazy part about all of this is that it is not even considered controversial to take these drugs, on the contrary, in fact, they are widely thought as being safe! The fact that you can purchase them and take them unsupervised over long periods of time is a real cause for concern. 

I routinely ask my patients which medications they are taking for their pain, and very commonly a combination of both ibuprofen, paracetamol (which is not an NSAID but has its own unique concerns) as well as a prescription based NSAID come up. 

These drugs may be relatively safe for some people when taken in the short term, but they should arguably not be taken lightly either, especially when you consider that they do not address the underlying cause, and may, in fact, as I’ll explain in a moment, impede the normal healing process. 

The Attempt To Reduce Intestinal Bleeding

Once the COX1 NSAIDs were found to cause GI bleeding the newer form of COX2 drugs were developed, because they were found to have reduced GI impact. However, they were soon linked with a higher incidence of cardiovascular problems, like heart attack and stroke. The now infamous COX2 drug Vioxx was removed from the market in 2004 having been attributed to the death of some 60,000 patients worldwide.

The difficulty with nearly all medications is that their mechanisms of action cannot be specifically targeted to just the problem area alone. The human body is like a vast cellular machine of spinning cogs which all turn together, yet each cog while helping the whole is also linked to a specific system itself. You can’t just stop one cog spinning without it affecting the speed of all the other cogs. This is why side-effects exist, and it is an unfortunate reality with many, if not all drugs. 

Ibuprofen Leads To An Increased Risk Of Heart Attacks

Unfortunately, there is now a growing body of evidence that even COX1 NSAIDs can increase your risk of heart attacks, stroke and heart failure.  

The proposed mechanism linking NSAIDs to heart failure is that they cause the kidney to retain sodium, and where sodium goes water follows, leading to an increase in blood pressure. 

A recent study in the British Medical Journal has gained a lot of attention in the press, causing much concern around the world and even an altered stance by the FDA on the safety of these drugs. (4)

In this study, the researchers looked some 37million medical records from five European countries (the Netherlands, Italy, Germany, and the United Kingdom) and found a 19% relative risk increase of heart attacks, with this increased risk occurring almost immediately after the drugs are taken. The risks go up with rising dosages and time but reduce again when the medications are stopped. This study also showed that some NSAIDS carried more significant risks than others, but all were implicated. 

Now this study is by no means a direct cause and effect. It shows a correlation, which is generally not accepted as rock solid science. It’s a bit like saying that 19 per cent of people who take their ice creams to the beach find that they melted faster than expected; therefore beaches are harmful to ice creams. Not necessarily I hear you say! It could be that the beach is warmer than the freezer that the ice creams came from, and that 19% of people were taking too long to eat their ice creams. This is the trouble with correlation. It may or may not be true. 

The actual risk of heart attacks from taking NSAIDs, according to this study, can be calculated to be somewhere between 0.2 to 2% which is still not a small number, considering how many people take these pills. The risks of NSAIDs causing heart attacks become significant if you are already at an increased risk of having a heart attack. This means that if you are a young athlete, your risks are less than if you are in your 60’s, overweight and a smoker. 

NSAIDs Can Slow Tissue Healing

NSAIDs work by inhibiting the natural production of prostaglandins, which are not only involved in the chemistry of pain and inflammation, but also in the chemistry of collagen production. Since collagen is the basic building block of most tissues, a reduced bioavailability may lead to an inferior regenerative healing response. 

It is important to remember that inflammation is required as a part of the typical healing response. Inflammation brings more blood to the area to help initiate healing. Platelets and natural growth factors and immune system molecules are also brought in. The area swells because healing factors are filling the tissue space. The injured area also produces pain which is critically important to let the injured party know not to use the injured area. Its a beautifully intelligent response, and knowing what is going on beneath the surface begs you to ask the question, why would you ever try to reduce the pain to carry on being active in the short term?

Indeed several studies have shown that the use of NSAIDs slows down the healing of injured ligaments, muscles, bones and other tissues.

A recent study looked at the effect of Toradol (ketorolac) on the results of ACL (a ligament in the knee) reconstruction surgery. They found that one injection of Toradol given before the surgery to help control post-operative pain resulted in significantly greater laxity in the repaired knee six weeks after the surgery. That is counterproductive to the desired result. (5)

Further studies have found that NSAID use delays the healing of shoulder rotator cuff surgery, muscle strains and knee ligament injuries. (6, 7)

If you are trying to heal a damaged soft tissue or joint then taking NSAIDs for pain relief could significantly lengthen the time that it takes you to recover, and it could even lead to an inferior repair of the injury. This is an essential factor to take into account if you are one of the many thousands of people who take vitamin I (Ibuprofen) as a preventative measure for pain in sports

Is It Ok To Take NSAIDS For Exercise Related Aches And Pains? 

Pain and sport generally don’t mix very well, understandably it tends to distract an detract from peak performance. So it should be of surprise that the practice of timing a dose of ibuprofen before, during or after an event to either prevent pain or speed up recovery is surprisingly commonplace. Again, just because it is common does not mean it is wise. If you knew what these painkillers were doing to your insides, you would probably think twice before mixing them with your sport.

What About Taking Ibuprofen During My Sporting Event?

If this has been part of your sports performance strategy, then take careful notes of the following 2012 study where the effect of NSAIDS on gut permeability was assessed for the first time. 

The researches looked at 9 healthy athletes over four separate variables 1) taking a standard dose of 400 mg ibuprofen twice before a bike workout. 2) cycling without the ibuprofen; 3) taking 400 mg ibuprofen twice at rest and finally 4) resting without ibuprofen intake.

In each of these scenarios, they measure gut damage by monitoring a protein know as I-FABP or intestinal fatty acid binding protein. They also used mass spectrometry and chromatography to measure pre-ingested sugar probes in the urine to assess gut permeability. 

What did they find out? 

Interestingly they found out that exercise by itself can lead to a “small” degree of increased gut permeability as shown by an increase in I-FABP levels. However, the level of gut damage was found to be greatest in the group that cycled and took ibuprofen. The correlation between ibuprofen and gut barrier dysfunction was very well correlated. The authors concluded that exercise will slightly increase gut permeability, but exercise and ibuprofen will amplify the problem making a more serious health consideration. In fact, the researchers go on to conclude that “NSAID consumption by athletes is not harmless and should be discouraged”. (8)

That is definitely something to consider before you next pop a pill to prevent a sports-induced ache or pain. Remember, pain is often a warning sign that is there because your body requires you to pay attention. At this most basic of philosophical levels, it seems foolish to ignore the signal. 

One of the commonly held beliefs around NSAIDS is that taking them may help improve recovery speed from injuries because they reduce inflammation. Again, from a basic science standpoint, this makes no sense, since inflammation is a required part of the healing process, bringing in immune system messengers and molecules that are necessary to heal the injured tissue. Artificially shutting this process down may make you feel better, but it could negatively impact the depth of your healing.

Remember this always: Drugs are poisons with possible beneficial side effects!

Should I Take Ibuprofen Before My Sporting Event?

Well, if this is your chosen tactic then pay attention to a study by Donnelly et al. (1990) which showed that if you take 400mg of ibuprofen 4 hours before exercise that you will indeed experience reduced soreness, but that there was no prevention of muscle cell damage. Again, this is common sense, since you artificially lower your bodies ability to experience pain through reducing inflammation systemically, yet you are also potentially turning off the biological warning system, possibly leaving you open to more serious repetitive strain type injuries. (9)

Using Ibuprofen While You Exercise Could Cause Kidney Damage

Another study has shown, rather alarmingly, that using ibuprofen during long endurance events like triathlon and marathons can actually decrease your kidney function, leading to problems with regulating sodium, electrolyte and hydration levels. This could have potentially dire ramifications, especially if racing on hot days when the kidney system is already placed under greater strain, thus risking severe long-term kidney damage. (10)

Remember that Ibuprofen has been linked with harmful side effects on the kidneys in many studies now, so this is not new news.

A further study performed on ultra-marathon runners completing a 100-mile race showed that the athletes who used ibuprofen (they tool either 600 mg on the day before as well as race day, or 1200mg on the day before as well as race day) had significantly higher levels of markers for severe muscle damage (including immune system markers like C-reactive protein, plasma cytokines and macrophages) and that this adverse effect increased if the dose of ibuprofen was doubled. (11)

Interestingly when they looked other factors like the athlete’s race time, their post-race muscle soreness as well as their perceived rate of exertion they found that ibuprofen did not help at all. Meaning that the higher rate of inflammation and muscle damage experienced by the ultra-endurance athletes who took the pills was just not worth it, and arguably somewhat regrettable. 

Sport Is A Double-Edged Sword


You may be surprised to learn that sport itself can be quite damaging for your body. Especially intense competition over a long duration. The history books are filled with tales of unfortunate athletes who have passed away in their prime, even though they were physically very fit. 

Fitness does not necessarily equate to good health. In fact the harder you push in your sport, the more damage that your body can sustain. It is well known for example that if you assess the blood chemistry of marathon runners post-race that you will find evidence of heart muscle damage, skeletal muscle damage, gut barrier damage, kidney damage and elevated markers for stress hormones and inflammatory molecules. Thankfully, the use of proper training and nutrition strategies can greatly limit the risks associated with endurance sports. 

Another study showed that 44% of ultramarathon runners had elevated creatinine levels (a byproduct of the kidneys blood filtering process), high enough to indicate acute kidney damage post-race. 

When they assessed athletes from the same race who had taken Ibuprofen at 4-hour intervals, they found that they were 18% more likely to have this acute kidney damage when compared to placebo. (12) 

Once again, the message appears to be quite clear – if you take ibuprofen during sports, you are risking greater damage as your body battles to regulate itself in the face of increased physical stress. 

A Few More Alarming Negative Side Effects Of NSAIDs

With the risk of sounding alarmist, ill bring your attention to a few more articles of evidence that are also sounding the warning bell on NSAIDs. 

Studies have also shown that NSAIDs can more than double the risk of miscarriage when taken during pregnancy (13) as well as increase the risk of birth defects. (14)

Meanwhile, there is a growing body of evidence to show that taking NSAIDs for 4 years or longer increases your risk of developing renal (kidney) cell cancer. (15)

NSAIDs have been linked to a 22 per cent increased risk of erectile dysfunction if taken three times a day for more than three months (16) which is not an atypical dose if people are battling an acute episode of lower back pain, for example. 

How To Eliminate NSAIDs From Your Life

It should be clear by this point that relying on NSAIDs to control your pain is risky business. Avoiding these common painkillers is sometimes easier said than done. Especially when you consider that many of us live demanding lives with hectic schedules and few things scupper productivity as effectively as pain and injury. 

Fortunately, there are many natural approaches to relieving both acute and chronic inflammation. 

NSAID Alternative No.1: Add More Collagen To Your Diet 

At least once per week, I will make a large pot of bone broth using my instant pot and any organic, grass-fed, free-range bones I can get my hands on. Usually, it is a chicken carcass, but I do buy lamb and beef bones online. (Just get them in bulk and keep them in the freezer). Not only is bone broth absolutely delicious in soups, stews, or as a wholesome drink on its own, but it contains large quantities of collagen, glycine, and gelatin, which have all been shown to be essential for joint health. 

Studies have shown that collagen improves the joint comfort in both arm and leg joints as well as the lower back. (17) If you are eating a low protein diet, you will likely benefit even more from the use of a collagen supplement.

A systematic review showed that hydrolysed collagen had positive benefits on osteoporosis and osteoarthritis since it seems to help with bone mineralisation and cartilage health. (18). 

Fortunately, it is easy to get a hold of a quality hydrolysed collagen supplement these days. I like this one and this one. Just add a scoop to smoothies, soups, teas, coffees or just water. Aim to eat anywhere from 10 to 20 grams per day and wait with baited breath as your joint and skin health improve. 

NSAID Alternative No. 2: Reduce Grains And Sugars

By eliminating, or at least radically reducing your consumption of grains and sugars you can help to stabilise your insulin and leptin levels. When these hormones are raised, they can either increase or cause painful inflammation in your body. 

Reducing the amount of sugar and grains that you eat you can significantly reduce the level of inflammatory prostaglandins in your body. 

Weaning yourself onto a very low sugar and low carbohydrate diet is an essential strategy for combating inflammation and boosting your general health. You can learn much more about this in my Wake Up Wellness Program. 

NSAID Alternative No. 3: Stress Relief

Chronic stress can have a significant impact on your immune system and play a role in chronic inflammation. Having a stable daily routine that helps you to unwind and manage both the effects and cause of stress is essential.

Habits like meditation, exercise, journaling and Emotional Freedom Technique can be beneficial in helping to calm the effects of stress in the body. 

My two personal favourite meditation techniques are the Silva Method guided meditation, which can found on YouTube (great for when you are super stressed and just need to reset) and ascension meditation (a fantastic daily practice). 

If you find yourself continuously triggered by the same stressful situations in life, then techniques such as The Work by Byron Kate, or the Demartini Method can be very effective at helping you to re-frame the stress triggers in your mind. When you train your brain to no longer see a trigger as stressful, you may be able to prevent this same stress from recurring in the future. 

Another fantastic option to help your body release the deep-seated cause of stress is a chiropractic technique known as Neuro Emotional Technique, or NET for short. We have recently introduced this to our toolbox at SpineCentral and found it to produce incredible results. Since this is a world wide and popular technique you should be able to find a practitioner who uses it near to you.

NSAID Alternative No. 4: Vitamin D3

Low levels of vitamin D3 have been shown to be an essential factor in inflammation. The sensible use of sun exposure can help to maintain optimal levels of this vital hormone in the summer months, and careful supplementation can help to keep them topped up over the winter. 

It is wise to get your vitamin D levels checked, either at your GP or through a nutritionist or health care practitioner or even with a simple home test kit. The jury is still out on exactly what an ideal healthy level of Vit D3 should be, but the range of 40 and 80 ng/mL is thought to be safe. Levels below 20 ng/mL represent a deficiency. 

NSAID Alternative No. 5: Optimise Your Omega 3 Levels


Many people are also deficient in the omega 3 fatty acids, known as EPA and DHA. These are found in oily fish or grass-fed meats. Taking a high-quality fish oil or krill oil supplement can play an essential role in reducing inflammation since these fats are required to produce anti-inflammatory prostaglandins in your body. 

Numerous studies have shown that Omega 3 Fatty Acids have an anti-inflammatory effect that is comparable to NSAIDs (19). Other studies have shown that taking fish oil for 3 months can significantly alleviate pain from inflammatory bowel disease, dysmenorrhea (painful periods), and inflammatory arthritic conditions like rheumatoid arthritis. (20)

To top it off omega-3 fatty acids have been clinically proven to regulate inflammation, enhance brain function and mood as well support a healthy cardiovascular system. 

However, it is crucial to take high-quality fish oil. Not all oils are created equal, and many on the market are unstable, rancid or riddled with heavy metal toxins. My favourite brand is Nordic Oil because it has been tested to be pure and stable and contains the correct ratios of EPA to DHA omega 3 fats. 

Krill oil is another good option, and in some ways maybe even better since it contains naturally high levels of the carotenoid Astaxanthin which has been shown to have potent antioxidant effects. 

Gamma Linolenic Acid (GLA) derived from Borage oil, or Blackcurrant Seed oil is a beneficial omega 6 fat that is often lacking in modern human diets and has also been linked strongly with an anti-inflammatory effect. (21) We use these fats alongside Omega 3 fish oils and certain vitamins and minerals as part of a comprehensive anti-inflammatory strategy for our patients at SpineCentral. 

One last factor to take into account on the topic of fats is avoiding the bad ones. Transfats from fried foods, crisps, margarine and processed foods are highly inflammatory in their nature. If you eat these foods, you will very likely experience an inflammatory response. The worst part about transfers is that they have a half-life of 50 days, which means that half of the bad fat you ate in those fish and chips will still be in your system, wreaking inflammatory havoc, a full 50 days from now.  It is very wise to avoid transfats, like the plague completely. 

The final fats to avoid are the unhealthy omega 6 fats which are far too abundant in the modern diet. Oils that contain unhealthy omega 6 fats include sunflower, safflower, rapeseed, vegetable and corn oil. It is smart to avoid these and cook instead with coconut oil or avocado oil. It is a good idea not to cook with Olive oil with because it becomes unstable at high temperatures. Although it is perfectly ok to use it abundantly as a condiment. 

NSAID Alternative No. 6: Activated Turmeric Paste


This is my current favourite natural anti-inflammatory strategy, quite simply because it works. You can learn how to make this powerful concoction at home, here. 

Many studies are showing the impressive anti-inflammatory actions of curcumin, the active component of turmeric. Adding in turmeric powder to your smoothies may help, but activating it first to increase the bioavailability of the curcumin can make it many times more effective. 

NSAID Alternative No. 7: Advanced Biostructural Correction


Structural correction is your secret weapon when it comes to healing your current body pains and injuries as well as preventing future injuries in sports and life. 

Human bodies are incredibly robust and able to self-heal quickly when they are in proper alignment. When they are out of alignment joints, become tight, twisted and surrounding muscles can become tight and weak. This is a recipe for pain, injury, inflammation and incomplete healing. 

 The challenge comes with finding an approach to structural health that is able to consistently and predictably restore ideal alignment and movement to your bones and joints. 

Advanced Biostructural Correction is the current state of the art when it comes to rebuilding healthy pain-free and upright bodies. 

If you have chronic injuries that just do not heal, or come back with regularity. If your posture is off and you know that you are out of balance and if you are suffering from backaches and pains on an ongoing basis then improving your biomechanics with ABC chiropractic could be the one factor that allows you to get to a pain-free, injury-free life. 

In my experience, structural health is the most overlooked area of health care. Many people are just unaware of how important it is to look after posture and alignment as part of an overall strategy for health and performance. 

Summary

Ibuprofen and other NSAIDs are used far too often in modern medicine and as over the counter remedies. They are far from risk-free and even taking one tablet may set into effect a damaging effect to your gut lining and kidneys. 

When used in the short term, and when you are younger, the risks may be negligible for some, but when taken on a more frequent basis and above the age 50 then you may be taking some significant risks with your health. 

Lastly, using these NSAIDs as a pain prevention strategy in sports seems to be counterproductive, especially with endurance athletes, since they may harm kidney, gut, joint and soft tissue health in the process, not only degrading your health but also prolonging your recovery after the event. 

There are much safer alternatives available. Begin by getting the basics in place, starting with reduced sugar and low carbohydrate diet, taking adequate amounts of healthy omega 3 fatty acids from fish or krill oil, taking healthy omega 6 fats like Borage oil, reducing your stress and adding collagen powder, bone broth and turmeric to your diet.

Ensuring that your body structure is well aligned and that your muscles are balanced and strong is crucial to regaining and maintaining a pain-free healthy body. ABC Chiropractic can be very valuable for rebuilding your body back to pain-free, injury-free status. 

When you implement these methods, you will bounce back a lot faster from the stress and strains of sports and life. You will be much happier during intense workouts and heal more quickly after injuries, surgeries or extreme events like marathons, spartan races or Ironman triathlons. 

Faster recovery translates into more days spent training and being productive in sports and life. It also translates to a longer-lived, happier and healthier life. There is a lot to be said of the peace of mind that comes from knowing that your body is able to repair itself well and bounce back well from the grind of life. 

Resilience is the key to higher performance now and better health in the future. 

Do you have any questions, comments or feedback about anything I’ve said in this article?, or your own natural alternatives to NSAIDs? If so I’d love to hear from you place your comments in the box below, and I promise to reply!

References

1. https://www.nhs.uk/news/medication/almost-half-of-all-adults-take-prescription-drugs/

2. https://www.google.co.uk/amp/s/www.independent.co.uk/life-style/health-and-families/health-news/373-thats-the-average-number-of-painkillers-we-each-take-in-a-year-is-it-too-many-516127.html%3Famp

3. https://www.ncbi.nlm.nih.gov/m/pubmed/3304754/?i=1&from=Fromm%20D%5BAuthor%5D

4. https://www.bmj.com/content/354/bmj.i4857

5. https://www.ncbi.nlm.nih.gov/pubmed/18661874

6. https://www.ncbi.nlm.nih.gov/pubmed/16210573

7. https://www.ncbi.nlm.nih.gov/pubmed/3728782

8. https://www.ncbi.nlm.nih.gov/pubmed/22776871

9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1478782/

10. https://www.ncbi.nlm.nih.gov/pubmed/16195036

11. https://www.ncbi.nlm.nih.gov/m/pubmed/17596774/?i=2&from=McAnulty%

12. https://emj.bmj.com/content/early/2017/06/28/emermed-2016-

13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC175811/

14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138772/

15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815746/

16. https://www.jurology.com/article/S0022-5347%2810%2905203-1/abstract

17. https://www.ncbi.nlm.nih.gov/pubmed/22500661

18. http://www.scielo.br/pdf/rbgg/v19n1/1809-9823-rbgg-19-01-00153.pdf

19. https://www.ncbi.nlm.nih.gov/pubmed/16531187

20. https://www.ncbi.nlm.nih.gov/pubmed/17335973

21. https://www.ncbi.nlm.nih.gov/pubmed/17168669