Difference between revisions of "NSAIDs and Running"

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{{DISPLAYTITLE: NSAIDs (Ibuprofen, Acetaminophen/Paracetamol) for runners, impairs healing and interferes with hydration}}
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{{DISPLAYTITLE: NSAIDs (Ibuprofen, Naproxen, Aspirin) and Acetaminophen/Paracetamol for runners, impairs healing and interferes with hydration}}
 
[[File:Extra Strength Tylenol and Tylenol PM.jpg|right|thumb|200px|Acetaminophen (brand names Tylenol, aspirin-free Anacin, Excedrin, and numerous cold medicines)]]
 
[[File:Extra Strength Tylenol and Tylenol PM.jpg|right|thumb|200px|Acetaminophen (brand names Tylenol, aspirin-free Anacin, Excedrin, and numerous cold medicines)]]
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NSAIDs are Non-Steroidal Anti-Inflammatory Drugs, the most common are Ibuprofen (Advil, Motrin), Acetaminophen/Paracetamol (Tylenol, aspirin-free Anacin, Excedrin, and numerous cold medicines) and Aspirin. They work by inhibiting a particular enzyme ([http://en.wikipedia.org/wiki/Cyclooxygenase Cyclooxygenase]) which reduces pain, fever and inflammation. NSAIDs are generally bad for runners, impairing healing, masking symptoms, interfering with hydration and in extreme situations can be life threatening. Ibuprofen use is so common among runners that it is sometimes called "Vitamin I"<ref name="VitaminI"/>.
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NSAIDs are generally unhelpful for runners, masking the symptoms while impairing healing, interfering with hydration and can be life threatening. Risks include kidney failure, heart attacks, strokes, intestinal damage, and liver failure. The most common NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) are Ibuprofen (Advil, Motrin), Naproxen (Aleve, Naprosyn), and Aspirin. They work by inhibiting a particular enzyme ([http://en.wikipedia.org/wiki/Cyclooxygenase Cyclooxygenase]) which reduces pain, fever and inflammation. Ibuprofen use is so common among runners that it is sometimes called "Vitamin I"<ref name="VitaminI"/>. This article also covers Acetaminophen (also called Paracetamol), though it's not technically an NSAID.  
 
==NSAIDs and Healing==
 
==NSAIDs and Healing==
 
The inflammation response of our bodies is a key part of the healing process. Using NSAIDs to reduce the inflammation has been shown to impair healing in different tissue types:
 
The inflammation response of our bodies is a key part of the healing process. Using NSAIDs to reduce the inflammation has been shown to impair healing in different tissue types:
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* '''Muscles'''. <ref name="MuscleTrappe"/>. A 2001 study showed that Ibuprofen and Acetaminiaphen reduce [[Muscle|muscle]] growth after eccentric exercise. Another study<ref name="muscle"/> on muscle damage and NSAIDs showed impaired recovery in the early stages of healing. There was some increased [[Protein]] synthesis with NSAIDs in latter stages of healing, but the muscles were still weaker 28 days after injury. Other studies<ref name="muscle2"/><ref name="muscle3"/> have shown that four days after injury, NSAIDs resulted in very little muscle regeneration compared with no drugs.
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* '''Muscles'''. <ref name="MuscleTrappe"/>. A 2001 study showed that Ibuprofen and Acetaminophen reduce [[Muscle|muscle]] growth after eccentric exercise. Another study<ref name="muscle"/> on muscle damage and NSAIDs showed impaired recovery in the early stages of healing. There was some increased [[Protein]] synthesis with NSAIDs in latter stages of healing, but the muscles were still weaker 28 days after injury. Other studies<ref name="muscle2"/><ref name="muscle3"/> have shown that four days after injury, NSAIDs resulted in very little muscle regeneration compared with no drugs.
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* '''Tendons'''. A primate study<ref name="TendonPrimates"/> showed "a marked decrease in the breaking strength of tendons at four and six weeks in the ibuprofen-treated animals". Another animal study<ref name="TendonCOX2"/> showed treated tendons were 32% weaker than their untested counterparts.  
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* '''Tendons'''. A primate study<ref name="TendonPrimates"/> showed "a marked decrease in the breaking strength of tendons at four and six weeks in the ibuprofen-treated animals". Another animal study<ref name="TendonCOX2"/> showed treated tendons were 32% weaker than their untested counterparts.
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* '''Bone-Tendon Junctions'''. An animal study<ref name="tendon"/> of rotator cuff injuries shows that NSAID usage resulted in injuries that did not heal, and those that did heal were weaker than those without NSAID. To quote from the study "Given that NSAID administration was discontinued after 14 days yet affected load-to-failure eight weeks following repair, it appears that inhibition of the early events in the inflammatory cascade has a lasting negative effect on tendon-to-bone healing," Dr. Rodeo said.  
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* '''Bone-Tendon Junctions'''. An animal study<ref name="tendon"/> of rotator cuff injuries shows that NSAID usage resulted in injuries that did not heal, and those that did heal were weaker than those without NSAID. To quote from the study "Given that NSAID administration was discontinued after 14 days yet affected load-to-failure eight weeks following repair, it appears that inhibition of the early events in the inflammatory cascade has a lasting negative effect on tendon-to-bone healing," Dr. Rodeo said.
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* '''Cartilage. ''' NSAIDs have been shown<ref name="CartilageRabbit"/> to impair the healing of bone and cartilage in rabbits.  
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* '''Cartilage. ''' NSAIDs have been shown<ref name="CartilageRabbit"/> to impair the healing of bone and cartilage in rabbits.
 
* '''Bone fractures.''' Tests on rats shows that a NSAID (Celecoxib) in the early stages of bone healing impaired healing, producing a weaker repair.<ref name="bone"/> A study <ref name="BoneLaurence "/> in 2004 declared " Nonsteroidal anti-inflammatory drugs continue to be prescribed as analgesics for patients with healing fractures even though these drugs diminish bone formation, healing, and remodeling".
 
* '''Bone fractures.''' Tests on rats shows that a NSAID (Celecoxib) in the early stages of bone healing impaired healing, producing a weaker repair.<ref name="bone"/> A study <ref name="BoneLaurence "/> in 2004 declared " Nonsteroidal anti-inflammatory drugs continue to be prescribed as analgesics for patients with healing fractures even though these drugs diminish bone formation, healing, and remodeling".
 
===Counterpoint===
 
===Counterpoint===
 
While there is extensive experimental evidence for NSAIDs impairing healing, there are also some studies that show no change with NSAID use, and a few that indicated improved healing. For instance, one study<ref name="LigamentImprovement"/> showed that using an NSAID for 6 days after injury resulted in a 42% increased ligament strength at day 14, though there was no change by day 21. Another study<ref name="LigamentUninjuredImprovement"/> showed that an NSAID did not change ligament healing, but did improve the strength of the uninjured ligaments. However, my reading indicates that the preponderance of evidence shows NSAIDs impair healing.  
 
While there is extensive experimental evidence for NSAIDs impairing healing, there are also some studies that show no change with NSAID use, and a few that indicated improved healing. For instance, one study<ref name="LigamentImprovement"/> showed that using an NSAID for 6 days after injury resulted in a 42% increased ligament strength at day 14, though there was no change by day 21. Another study<ref name="LigamentUninjuredImprovement"/> showed that an NSAID did not change ligament healing, but did improve the strength of the uninjured ligaments. However, my reading indicates that the preponderance of evidence shows NSAIDs impair healing.  
 
===Ice, Inflammation and Healing===
 
===Ice, Inflammation and Healing===
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If NSAIDs are bad for healing, should we treat with ice? So far I have found no definitive studies, but ice has a differenct mechanism of action from NSAIDs. By cooling the tissues, ice temporarily reduces inflammation, thereby flushing the wound. It does not directly impact any of the body's enzymes or other processes. If applied for a longer period of time, ice will produce a periodic increase in blood supply that creates a further flushing effect. I have found that ice can produce dramatic improvements in healing speed. See [[Cryotherapy - Ice for Healing]] for more details.
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If NSAIDs are bad for healing, should we treat with ice? So far I have found no definitive studies, but ice has a different mechanism of action from NSAIDs. By cooling the tissues, ice temporarily reduces swelling, thereby flushing the wound. If applied for a longer period of time, ice will produce a periodic increase in blood supply that creates a further flushing effect. I have found that ice can produce dramatic improvements in healing speed. See [[Cryotherapy - Ice for Healing]] for more details. There is no evidence that ice reduces any of the inflammation processes.
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=NSAIDs and Acute kidney failure=
 
=NSAIDs and Acute kidney failure=
 
Kidney failure while running is extremely rare, and seems to require multiple factors to come together. Looking at the [http://en.wikipedia.org/wiki/Comrades_Marathon Comrades Marathon], a 90 Km/56 Mile ultramarathon in South Africa, there have only been 19 cases of kidney failure between 1969 and 1986, it even though thousands of people participate each year<ref name="rhabdo1"/>. The following are considered factors in acute kidney failure related to running.
 
Kidney failure while running is extremely rare, and seems to require multiple factors to come together. Looking at the [http://en.wikipedia.org/wiki/Comrades_Marathon Comrades Marathon], a 90 Km/56 Mile ultramarathon in South Africa, there have only been 19 cases of kidney failure between 1969 and 1986, it even though thousands of people participate each year<ref name="rhabdo1"/>. The following are considered factors in acute kidney failure related to running.
 
* '''Dehydration'''. Exercise reduces blood flow to the kidneys and dehydration makes this worse.
 
* '''Dehydration'''. Exercise reduces blood flow to the kidneys and dehydration makes this worse.
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* '''NSAIDs'''. NSAIDs also reduce blood flow to the kidneys<ref name="coxibs"/>. NSAIDs reduce prostaglandin production, and prostaglandins are vital to maintaining blood flow to the kidneys. While NSAIDs are considered safe drugs, NSAIDs are associated with a relatively high incidence of adverse drug reactions involving the kidneys. Generally NSAID side effects are restricted to individuals with predisposition to kidney problems, so extra care should be taken if you have a history of kidney problems. However, athletes push their bodies to extremes, so what applies to the general population may not be valid for runners. One runner was told<ref name="Anecdote"/> by doctors that 2400mg Ibuprofen in an ultramarathon was a contributing factor to his kidney failure.  
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* '''NSAIDs'''. NSAIDs also reduce blood flow to the kidneys<ref name="coxibs"/>. NSAIDs reduce prostaglandin production, and prostaglandins are vital to maintaining blood flow to the kidneys. While NSAIDs are considered safe drugs, NSAIDs are associated with a relatively high incidence of adverse drug reactions involving the kidneys. Generally, NSAID side effects are restricted to individuals with predisposition to kidney problems, so extra care should be taken if you have a history of kidney problems. However, athletes push their bodies to extremes, so what applies to the general population may not be valid for runners. One runner was told<ref name="Anecdote"/> by doctors that 2400mg Ibuprofen in an ultramarathon was a contributing factor to his kidney failure.
 
* '''Rhabdomyolysis'''. All strenuous exercise causes some muscle damage, but this is generally resolved without a problem. However large amounts of a [[Protein]] called myoglobin from damaged muscle can cause a condition called [http://en.wikipedia.org/wiki/Rhabdomyolysis rhabdomyolysis] (AKA 'rhabdo'). While serious rhabdomyolysis is rare, it is worth understanding one key symptom, which is low volume, dark urine, often likened to 'coca-cola'. The other symptoms include severe, incapacitating muscle pain and elevated levels of creatine kinase (CK) in the blood (which requires a specialist test). Some individuals<ref name="rhabdoGenes"/> have a genetic condition that makes rhabdomyolysis possible after relatively moderate exercise. Rhabdomyolysis is also more likely after eccentric exercise, such as [[Downhill Running]].
 
* '''Rhabdomyolysis'''. All strenuous exercise causes some muscle damage, but this is generally resolved without a problem. However large amounts of a [[Protein]] called myoglobin from damaged muscle can cause a condition called [http://en.wikipedia.org/wiki/Rhabdomyolysis rhabdomyolysis] (AKA 'rhabdo'). While serious rhabdomyolysis is rare, it is worth understanding one key symptom, which is low volume, dark urine, often likened to 'coca-cola'. The other symptoms include severe, incapacitating muscle pain and elevated levels of creatine kinase (CK) in the blood (which requires a specialist test). Some individuals<ref name="rhabdoGenes"/> have a genetic condition that makes rhabdomyolysis possible after relatively moderate exercise. Rhabdomyolysis is also more likely after eccentric exercise, such as [[Downhill Running]].
 
* '''Sickness'''. A viral or bacterial infection is often a factor in exercise related kidney failure.
 
* '''Sickness'''. A viral or bacterial infection is often a factor in exercise related kidney failure.
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=NSAIDs and Hyponatremia=
 
=NSAIDs and Hyponatremia=
 
The kidneys are responsible for removing excess fluid from the blood as well as excreting or withholding sodium. If kidney function is compromised, then this can result in [[Hyponatremia]], which can be fatal. Some studies<ref name="hypo"/><ref name="hypo2"/><ref name="siadh"/> have shown a correlation between NSAID use in races and [[Hyponatremia]], but others<ref name="nohypo"/><ref name="Dumke-2007"/> have not. Using NSAIDs when hydration is a concern increases the risk of problems occuring.  
 
The kidneys are responsible for removing excess fluid from the blood as well as excreting or withholding sodium. If kidney function is compromised, then this can result in [[Hyponatremia]], which can be fatal. Some studies<ref name="hypo"/><ref name="hypo2"/><ref name="siadh"/> have shown a correlation between NSAID use in races and [[Hyponatremia]], but others<ref name="nohypo"/><ref name="Dumke-2007"/> have not. Using NSAIDs when hydration is a concern increases the risk of problems occuring.  
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=NSAIDs and Sickness=
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=NSAIDs causing Heart Attacks or Strokes=
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The U.S. Food and Drug Administration (FDA) warnings that non-aspirin NSAIDs increase the risk of a heart attack or stroke<ref name="www.fda.gov"/>. The risk appears to be related to ongoing usage rather than single doses, with the risk increasing in the first weeks of usage and the risk may increase with prolonged usage. The increased risk is dose dependent (taking more has a greater risk), and the includes those without heart disease or risk factors for heart disease. Not surprisingly, those already with a higher risk of heart disease or stroke have a proportionately higher risk with NSAID usage.
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=NSAIDs and Infection=
 
Because a bacterial or viral infection puts more stress on the body, including the kidneys, taking NSAIDs and continuing to run increases your risk of complications. If the sickness is too bad to run without NSAIDs, you probably shouldn't run.  
 
Because a bacterial or viral infection puts more stress on the body, including the kidneys, taking NSAIDs and continuing to run increases your risk of complications. If the sickness is too bad to run without NSAIDs, you probably shouldn't run.  
 
=NSAIDs for Pain Reduction=
 
=NSAIDs for Pain Reduction=
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[[Delayed Onset Muscle Soreness]] (DOMS) generally occurs between 24 and 72 hours after unusual or severe exercise, such as racing a marathon or [[Downhill Running]]. The use of NSAIDs to prevent or treat DOMS has been widely researched, with somewhat mixed results. Even scholarly reviews of the research have differing conclusions<ref name="Cheung-2003"/> <ref name="Smith-1992"/> <ref name="Baldwin Lanier-2003"/><ref name="Howatson-2008"/>. My conclusions based on the available research are:
 
[[Delayed Onset Muscle Soreness]] (DOMS) generally occurs between 24 and 72 hours after unusual or severe exercise, such as racing a marathon or [[Downhill Running]]. The use of NSAIDs to prevent or treat DOMS has been widely researched, with somewhat mixed results. Even scholarly reviews of the research have differing conclusions<ref name="Cheung-2003"/> <ref name="Smith-1992"/> <ref name="Baldwin Lanier-2003"/><ref name="Howatson-2008"/>. My conclusions based on the available research are:
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* The most common NSAIDs (Ibuprofen, Acetaminophen (Paracetamol), and Aspirin) are unlikely to help with DOMS.  
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* The most common NSAIDs (Ibuprofen, Acetaminophen (Paracetamol), and Aspirin) are unlikely to help with DOMS.
 
* There is some evidence that Naproxen may be more effective than the common NSAIDs. There is not enough evidence to reach a conclusion on Diclofenac, Codeine, Rofecoxib, Ketoprofen, or Bromelain.
 
* There is some evidence that Naproxen may be more effective than the common NSAIDs. There is not enough evidence to reach a conclusion on Diclofenac, Codeine, Rofecoxib, Ketoprofen, or Bromelain.
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* If an NSAID is taken for DOMS, it should probably be taken immediately after the damaging exercise rather than waiting until the soreness develops.  
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* If an NSAID is taken for DOMS, it should probably be taken immediately after the damaging exercise rather than waiting until the soreness develops.
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* It seems likely that taking an NSAID for DOMS will reduce the muscular growth that would normally occur as part of the recovery.  
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* It seems likely that taking an NSAID for DOMS will reduce the muscular growth that would normally occur as part of the recovery.
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** In one study, rabbits treated with flurbiprofen after DOMS inducing exercise regained more strength after 3-7 days, but between days 7 and 28 days the treated rabbits became weaker while the controls became stronger<ref name="Mishra-1995"/>. This is only one study, and on animals, but it is rather troubling as none of the human studies look at the results over this time period.  
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** In one study, rabbits treated with flurbiprofen after DOMS inducing exercise regained more strength after 3-7 days, but between days 7 and 28 days the treated rabbits became weaker while the controls became stronger<ref name="Mishra-1995"/>. This is only one study, and on animals, but it is rather troubling as none of the human studies look at the results over this time period.
 
==A Summary of the Research on NSAIDs and DOMS==
 
==A Summary of the Research on NSAIDs and DOMS==
 
The table below summarizes the research I located on the effect of NSAIDs on DOMS in humans. I've only considered the primary DOMS markers of soreness (pain) and weakness, rather than including things like blood enzymes. For each NSAID I've shown how many studies show an improvement and how many studies show no effect.  
 
The table below summarizes the research I located on the effect of NSAIDs on DOMS in humans. I've only considered the primary DOMS markers of soreness (pain) and weakness, rather than including things like blood enzymes. For each NSAID I've shown how many studies show an improvement and how many studies show no effect.  
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{| class="wikitable"
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{| class="wikitable"  
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!NSAID!!Soreness!!Weakness
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! NSAID
 +
! Soreness
 +
! Weakness
 
|-
 
|-
−
|Ibuprofen
+
| Ibuprofen
−
|2xImproved<ref name="Hasson-1993"/><ref name="pmid12580656"/>
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| 2xImproved<ref name="Hasson-1993"/><ref name="pmid12580656"/>
 
7xNo Effect<ref name="Grossman-1995"/><ref name="Pizza-1999"/><ref name="RahnamaRahmani-Nia2005"/> <ref name="KrentzQuest2008"/><ref name="Arendt-NielsenWeidner2007"/><ref name="Donnelly-1990"/><ref name="Stone-2002"/>  
 
7xNo Effect<ref name="Grossman-1995"/><ref name="Pizza-1999"/><ref name="RahnamaRahmani-Nia2005"/> <ref name="KrentzQuest2008"/><ref name="Arendt-NielsenWeidner2007"/><ref name="Donnelly-1990"/><ref name="Stone-2002"/>  
−
|1xMaybe<ref name="Hasson-1993"/>
+
| 1xMaybe<ref name="Hasson-1993"/>
 
8xNo Effect<ref name="Grossman-1995"/><ref name="Pizza-1999"/><ref name="RahnamaRahmani-Nia2005"/> <ref name="KrentzQuest2008"/><ref name="Arendt-NielsenWeidner2007"/><ref name="Donnelly-1990"/><ref name="pmid12580656"/><ref name="Stone-2002"/>  
 
8xNo Effect<ref name="Grossman-1995"/><ref name="Pizza-1999"/><ref name="RahnamaRahmani-Nia2005"/> <ref name="KrentzQuest2008"/><ref name="Arendt-NielsenWeidner2007"/><ref name="Donnelly-1990"/><ref name="pmid12580656"/><ref name="Stone-2002"/>  
 
|-
 
|-
−
|Ibuprofen Gel
+
| Ibuprofen Gel
−
|1xNo Effect<ref name="HyldahlKeadle2010"/>
+
| 1xNo Effect<ref name="HyldahlKeadle2010"/>
−
|
+
|  
 
|-
 
|-
−
|Acetaminophen (Paracetamol)
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| Acetaminophen (Paracetamol)
−
|2xNo Effect<ref name="Barlas-2000"/><ref name="SmithGeorge1995"/>
+
| 2xNo Effect<ref name="Barlas-2000"/><ref name="SmithGeorge1995"/>
−
|
+
|  
 
|-
 
|-
−
|Aspirin
+
| Aspirin
−
|2xImproved<ref name="Riasata-2010"/><ref name="Francis-1987"/>
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| 2xImproved<ref name="Riasata-2010"/><ref name="Francis-1987"/>
 
2xNo Effect<ref name="Barlas-2000"/><ref name="SmithGeorge1995"/>
 
2xNo Effect<ref name="Barlas-2000"/><ref name="SmithGeorge1995"/>
−
|2xNo Effect<ref name="Riasata-2010"/><ref name="Francis-1987"/>
+
| 2xNo Effect<ref name="Riasata-2010"/><ref name="Francis-1987"/>
 
|-
 
|-
−
|Naproxen   
+
| Naproxen   
−
|4xImproved<ref name="Dudley-1997"/><ref name="Baldwin-2001"/><ref name="Lecomte-1998"/><ref name="journals.ut.ac.ir"/>
+
| 4xImproved<ref name="Dudley-1997"/><ref name="Baldwin-2001"/><ref name="Lecomte-1998"/><ref name="journals.ut.ac.ir"/>
 
1xNo Effect<ref name="Bourgeois-1999"/>
 
1xNo Effect<ref name="Bourgeois-1999"/>
−
|3xImproved<ref name="Dudley-1997"/><ref name="Baldwin-2001"/><ref name="Lecomte-1998"/>
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| 3xImproved<ref name="Dudley-1997"/><ref name="Baldwin-2001"/><ref name="Lecomte-1998"/>
 
1xNo Effect<ref name="Bourgeois-1999"/>
 
1xNo Effect<ref name="Bourgeois-1999"/>
 
|-
 
|-
−
|Diclofenac   
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| Diclofenac   
−
|Possible slight reduction<ref name="DonnellyMcCormick1988"/>
+
| Possible slight reduction<ref name="DonnellyMcCormick1988"/>
−
|
+
|  
 
|-
 
|-
−
|Codeine
+
| Codeine
−
|1xNo Effect<ref name="Barlas-2000"/>  
+
| 1xNo Effect<ref name="Barlas-2000"/>  
−
|
+
|  
 
|-
 
|-
−
|Rofecoxib  
+
| Rofecoxib  
−
|1xNo Effect<ref name="LoramMitchell2005"/>  
+
| 1xNo Effect<ref name="LoramMitchell2005"/>  
−
|
+
|  
 
|-
 
|-
−
|Ketoprofen  
+
| Ketoprofen  
−
|1xImproved<ref name="Sayers-2001"/>
+
| 1xImproved<ref name="Sayers-2001"/>
−
|1xImproved<ref name="Sayers-2001"/>
+
| 1xImproved<ref name="Sayers-2001"/>
 
|-
 
|-
−
|Bromelain  
+
| Bromelain  
−
|1xNo Effect<ref name="Stone-2002"/>
+
| 1xNo Effect<ref name="Stone-2002"/>
−
|
+
|  
 
|}
 
|}
−
 
 
=NSAIDs and Intestinal Damage=
 
=NSAIDs and Intestinal Damage=
 
As little as one hour of intense cycling can result in indications of small intestinal damage<ref name="van Wijck-2011"/>. This is believed to be due to the redirection of blood away from the digestive system and towards the active muscles. These markers are significantly higher if 400mg ibuprofen (the standard single adult dose) is taken before the exercise<ref name="VAN Wijck-2012"/>. The marker used is Plasma Intestinal Fatty Acid Binding [[Protein]] which is an early marker of intestinal necrosis<ref name="Vermeulen Windsant-2012"/>.
 
As little as one hour of intense cycling can result in indications of small intestinal damage<ref name="van Wijck-2011"/>. This is believed to be due to the redirection of blood away from the digestive system and towards the active muscles. These markers are significantly higher if 400mg ibuprofen (the standard single adult dose) is taken before the exercise<ref name="VAN Wijck-2012"/>. The marker used is Plasma Intestinal Fatty Acid Binding [[Protein]] which is an early marker of intestinal necrosis<ref name="Vermeulen Windsant-2012"/>.
 
[[File:Ibuprofen and GI damage.jpg|none|thumb|500px|The level of a marker of intestinal damage during and after 60 minutes of cycling at 70% [[VO2max|V̇O<sub>2</sub>max]].]]
 
[[File:Ibuprofen and GI damage.jpg|none|thumb|500px|The level of a marker of intestinal damage during and after 60 minutes of cycling at 70% [[VO2max|V̇O<sub>2</sub>max]].]]
−
=NSAIDs and wound healing=
+
=NSAIDs and Wound Healing=
 
''Main article: [[Popping Blisters]]''
 
''Main article: [[Popping Blisters]]''
  
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=NSAIDs and Racing=
 
=NSAIDs and Racing=
 
Taking NSAIDs in ultramarathon events can improve performance by reducing pain and acute inflammation, but doing so represents a significant risk. There is some evidence<ref name="wser1"/> <ref name="wser2"/> that many runners taking NSAIDs have the same level of pain and greater damage markers compared with non-users. This may be because the runners push themselves to a similar level of pain, with the NSAIDs allowing them to do more damage.  
 
Taking NSAIDs in ultramarathon events can improve performance by reducing pain and acute inflammation, but doing so represents a significant risk. There is some evidence<ref name="wser1"/> <ref name="wser2"/> that many runners taking NSAIDs have the same level of pain and greater damage markers compared with non-users. This may be because the runners push themselves to a similar level of pain, with the NSAIDs allowing them to do more damage.  
−
* It seems likely that NSAIDs will increase the risk of injury rather than reducing it, as the symptoms of damage will be masked.  
+
* It seems likely that NSAIDs will increase the risk of injury rather than reducing it, as the symptoms of damage will be masked.
−
* The most common NSAID for racing seems to be ibuprofen. I've not seen any evidence of the relative effectiveness of different NSAIDs on performance.  
+
* The most common NSAID for racing seems to be ibuprofen. I've not seen any evidence of the relative effectiveness of different NSAIDs on performance.
−
* It is better to take liquid ibuprofen than tablets or capsules. The tablets and capsules take longer to dissolve and if you have a digestive problem they may not be fully absorbed. You can chew the tablets, but this is unpleasant and ibuprofen can irritate your mouth and throat slightly, so the liquid form is best. It's obviously harder to transport, but you can fill an old film canister with a dose.  
+
* It is better to take liquid ibuprofen than tablets or capsules. The tablets and capsules take longer to dissolve and if you have a digestive problem they may not be fully absorbed. You can chew the tablets, but this is unpleasant and ibuprofen can irritate your mouth and throat slightly, so the liquid form is best. It's obviously harder to transport, but you can fill an old film canister with a dose.
 
* Before an ultramarathon race, you should think through under what circumstances you will consider using NSAIDs and what dosage. Make sure your crew knows that you're taking NSAIDs in case anything happens.
 
* Before an ultramarathon race, you should think through under what circumstances you will consider using NSAIDs and what dosage. Make sure your crew knows that you're taking NSAIDs in case anything happens.
 
* Extra care should be taken when NSAIDs are used in combination with dehydration, sickness or running the causes serious muscle damage.
 
* Extra care should be taken when NSAIDs are used in combination with dehydration, sickness or running the causes serious muscle damage.
−
* Taking NSAIDs in marathon or shorter races is probably ineffective as the level of damage seen is not as great as in ultramarathon events.  
+
* Taking NSAIDs in marathon or shorter races is probably ineffective as the level of damage seen is not as great as in ultramarathon events.
 
* If you need NSAIDs to start a race, you probably should not compete.
 
* If you need NSAIDs to start a race, you probably should not compete.
 
=Longer Term NSAID usage=
 
=Longer Term NSAID usage=
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=Acetaminophen Overdose Danger (AKA Paracetamol, Tylenol)=
 
=Acetaminophen Overdose Danger (AKA Paracetamol, Tylenol)=
 
Acetaminophen does not have the same risk of ulcers, but it is linked to liver damage, especially in those who drink alcohol. Acetaminophen is the leading cause of acute liver failure<ref name="AcetaAcuteLiver"/><ref name="Staggered"/>. There are concerns<ref name="AcetaNormalDoseLiver"/> that even the standard dose can cause changes in liver function. Acetaminophen can cause delayed symptoms<ref name="Staggered"/>, with people seeking medical help up to 5 days after the overdose (20% < 12 hours, 35% 12-24 hours, 45% 24 hours+). Overdoses of Acetaminophen can be caused by taking slightly too much over several days, with the toxicity building up<ref name="Staggered"/>. This problem is again exacerbated by those taking alcohol with Acetaminophen<ref name="Staggered"/>. (One factor that increases the risk is that some common medications, such as cold remedies, include Acetaminophen. If people do not add in the dose of Acetaminophen from these other sources, it is easy to unwittingly exceed the safe dosage.)  
 
Acetaminophen does not have the same risk of ulcers, but it is linked to liver damage, especially in those who drink alcohol. Acetaminophen is the leading cause of acute liver failure<ref name="AcetaAcuteLiver"/><ref name="Staggered"/>. There are concerns<ref name="AcetaNormalDoseLiver"/> that even the standard dose can cause changes in liver function. Acetaminophen can cause delayed symptoms<ref name="Staggered"/>, with people seeking medical help up to 5 days after the overdose (20% < 12 hours, 35% 12-24 hours, 45% 24 hours+). Overdoses of Acetaminophen can be caused by taking slightly too much over several days, with the toxicity building up<ref name="Staggered"/>. This problem is again exacerbated by those taking alcohol with Acetaminophen<ref name="Staggered"/>. (One factor that increases the risk is that some common medications, such as cold remedies, include Acetaminophen. If people do not add in the dose of Acetaminophen from these other sources, it is easy to unwittingly exceed the safe dosage.)  
−
=Tangent - Is Acetaminophen really an NSAID?=
+
=Is Acetaminophen an NSAID?=
−
There are differing opinions around the classification of Acetaminophen as an NSAID with some resources<ref name="NotAnNsaid"/> stating it is not an NSAID. While Acetaminophen has limited anti-inflammatory properties, it shares the same mechanism of action with most NSAIDs of inhibiting the COX enzyme and the inhibition of prostaglandin synthesis. It is therefore reasonable and useful to classify Acetaminophen as an NSAID.  
+
Acetaminophen (also called paracetamol) is generally not classified as an NSAID<ref name="NotAnNsaid"/>. While Acetaminophen has limited anti-inflammatory properties, it shares the same mechanism of action with most NSAIDs of inhibiting the COX enzyme and the inhibition of prostaglandin synthesis<ref name="Graham-2005"/><ref name="BottingAyoub2005"/><ref name="ToussaintYang2010"/><ref name="Anderson2008"/>. Therefore, this article includes Acetaminophen in with NSAIDs.  
 
=References=
 
=References=
 
<references>
 
<references>
Line 173: Line 175:
 
<ref name="StadelmannDigenis1998">Wayne K. Stadelmann, Alexander G. Digenis, Gordon R. Tobin, Impediments to wound healing, The American Journal of Surgery, volume 176, issue 2, 1998, pages 39S–47S, ISSN [http://www.worldcat.org/issn/00029610 00029610], doi [http://dx.doi.org/10.1016/S0002-9610(98)00184-6 10.1016/S0002-9610(98)00184-6]</ref>
 
<ref name="StadelmannDigenis1998">Wayne K. Stadelmann, Alexander G. Digenis, Gordon R. Tobin, Impediments to wound healing, The American Journal of Surgery, volume 176, issue 2, 1998, pages 39S–47S, ISSN [http://www.worldcat.org/issn/00029610 00029610], doi [http://dx.doi.org/10.1016/S0002-9610(98)00184-6 10.1016/S0002-9610(98)00184-6]</ref>
 
<ref name="GuoDiPietro2010">S. Guo, L. A. DiPietro, Factors Affecting Wound Healing, Journal of Dental Research, volume 89, issue 3, 2010, pages 219–229, ISSN [http://www.worldcat.org/issn/0022-0345 0022-0345], doi [http://dx.doi.org/10.1177/0022034509359125 10.1177/0022034509359125]</ref>
 
<ref name="GuoDiPietro2010">S. Guo, L. A. DiPietro, Factors Affecting Wound Healing, Journal of Dental Research, volume 89, issue 3, 2010, pages 219–229, ISSN [http://www.worldcat.org/issn/0022-0345 0022-0345], doi [http://dx.doi.org/10.1177/0022034509359125 10.1177/0022034509359125]</ref>
 +
<ref name="Graham-2005">GG. Graham, KF. Scott, Mechanism of action of paracetamol., Am J Ther, volume 12, issue 1, pages 46-55, PMID [http://www.ncbi.nlm.nih.gov/pubmed/15662292 15662292]</ref>
 +
<ref name="Anderson2008">Brian J. Anderson, Paracetamol (Acetaminophen): mechanisms of action, Pediatric Anesthesia, volume 18, issue 10, 2008, pages 915–921, ISSN [http://www.worldcat.org/issn/11555645 11555645], doi [http://dx.doi.org/10.1111/j.1460-9592.2008.02764.x 10.1111/j.1460-9592.2008.02764.x]</ref>
 +
<ref name="BottingAyoub2005">Regina Botting, Samir S. Ayoub, COX-3 and the mechanism of action of paracetamol/acetaminophen, Prostaglandins, Leukotrienes and Essential Fatty Acids, volume 72, issue 2, 2005, pages 85–87, ISSN [http://www.worldcat.org/issn/09523278 09523278], doi [http://dx.doi.org/10.1016/j.plefa.2004.10.005 10.1016/j.plefa.2004.10.005]</ref>
 +
<ref name="ToussaintYang2010">K. Toussaint, X. C. Yang, M. A. Zielinski, K. L. Reigle, S. D. Sacavage, S. Nagar, R. B. Raffa, What do we (not) know about how paracetamol (acetaminophen) works?, Journal of Clinical Pharmacy and Therapeutics, volume 35, issue 6, 2010, pages 617–638, ISSN [http://www.worldcat.org/issn/02694727 02694727], doi [http://dx.doi.org/10.1111/j.1365-2710.2009.01143.x 10.1111/j.1365-2710.2009.01143.x]</ref>
 +
<ref name="www.fda.gov">FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes, http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm, Accessed on 25 January 2016</ref>
 
</references>
 
</references>
 +
[[Category:Training]]
 +
[[Category:Injury]]
 +
[[Category:Science]]

Revision as of 16:52, 25 January 2016

Acetaminophen (brand names Tylenol, aspirin-free Anacin, Excedrin, and numerous cold medicines)

NSAIDs are generally unhelpful for runners, masking the symptoms while impairing healing, interfering with hydration and can be life threatening. Risks include kidney failure, heart attacks, strokes, intestinal damage, and liver failure. The most common NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) are Ibuprofen (Advil, Motrin), Naproxen (Aleve, Naprosyn), and Aspirin. They work by inhibiting a particular enzyme (Cyclooxygenase) which reduces pain, fever and inflammation. Ibuprofen use is so common among runners that it is sometimes called "Vitamin I"[1]. This article also covers Acetaminophen (also called Paracetamol), though it's not technically an NSAID.

1 NSAIDs and Healing

The inflammation response of our bodies is a key part of the healing process. Using NSAIDs to reduce the inflammation has been shown to impair healing in different tissue types:

  • Muscles. [2]. A 2001 study showed that Ibuprofen and Acetaminophen reduce muscle growth after eccentric exercise. Another study[3] on muscle damage and NSAIDs showed impaired recovery in the early stages of healing. There was some increased Protein synthesis with NSAIDs in latter stages of healing, but the muscles were still weaker 28 days after injury. Other studies[4][5] have shown that four days after injury, NSAIDs resulted in very little muscle regeneration compared with no drugs.
  • Tendons. A primate study[6] showed "a marked decrease in the breaking strength of tendons at four and six weeks in the ibuprofen-treated animals". Another animal study[7] showed treated tendons were 32% weaker than their untested counterparts.
  • Bone-Tendon Junctions. An animal study[8] of rotator cuff injuries shows that NSAID usage resulted in injuries that did not heal, and those that did heal were weaker than those without NSAID. To quote from the study "Given that NSAID administration was discontinued after 14 days yet affected load-to-failure eight weeks following repair, it appears that inhibition of the early events in the inflammatory cascade has a lasting negative effect on tendon-to-bone healing," Dr. Rodeo said.
  • Cartilage. NSAIDs have been shown[9] to impair the healing of bone and cartilage in rabbits.
  • Bone fractures. Tests on rats shows that a NSAID (Celecoxib) in the early stages of bone healing impaired healing, producing a weaker repair.[10] A study [11] in 2004 declared " Nonsteroidal anti-inflammatory drugs continue to be prescribed as analgesics for patients with healing fractures even though these drugs diminish bone formation, healing, and remodeling".

1.1 Counterpoint

While there is extensive experimental evidence for NSAIDs impairing healing, there are also some studies that show no change with NSAID use, and a few that indicated improved healing. For instance, one study[12] showed that using an NSAID for 6 days after injury resulted in a 42% increased ligament strength at day 14, though there was no change by day 21. Another study[13] showed that an NSAID did not change ligament healing, but did improve the strength of the uninjured ligaments. However, my reading indicates that the preponderance of evidence shows NSAIDs impair healing.

1.2 Ice, Inflammation and Healing

If NSAIDs are bad for healing, should we treat with ice? So far I have found no definitive studies, but ice has a different mechanism of action from NSAIDs. By cooling the tissues, ice temporarily reduces swelling, thereby flushing the wound. If applied for a longer period of time, ice will produce a periodic increase in blood supply that creates a further flushing effect. I have found that ice can produce dramatic improvements in healing speed. See Cryotherapy - Ice for Healing for more details. There is no evidence that ice reduces any of the inflammation processes.

2 NSAIDs and Acute kidney failure

Kidney failure while running is extremely rare, and seems to require multiple factors to come together. Looking at the Comrades Marathon, a 90 Km/56 Mile ultramarathon in South Africa, there have only been 19 cases of kidney failure between 1969 and 1986, it even though thousands of people participate each year[14]. The following are considered factors in acute kidney failure related to running.

  • Dehydration. Exercise reduces blood flow to the kidneys and dehydration makes this worse.
  • NSAIDs. NSAIDs also reduce blood flow to the kidneys[15]. NSAIDs reduce prostaglandin production, and prostaglandins are vital to maintaining blood flow to the kidneys. While NSAIDs are considered safe drugs, NSAIDs are associated with a relatively high incidence of adverse drug reactions involving the kidneys. Generally, NSAID side effects are restricted to individuals with predisposition to kidney problems, so extra care should be taken if you have a history of kidney problems. However, athletes push their bodies to extremes, so what applies to the general population may not be valid for runners. One runner was told[16] by doctors that 2400mg Ibuprofen in an ultramarathon was a contributing factor to his kidney failure.
  • Rhabdomyolysis. All strenuous exercise causes some muscle damage, but this is generally resolved without a problem. However large amounts of a Protein called myoglobin from damaged muscle can cause a condition called rhabdomyolysis (AKA 'rhabdo'). While serious rhabdomyolysis is rare, it is worth understanding one key symptom, which is low volume, dark urine, often likened to 'coca-cola'. The other symptoms include severe, incapacitating muscle pain and elevated levels of creatine kinase (CK) in the blood (which requires a specialist test). Some individuals[17] have a genetic condition that makes rhabdomyolysis possible after relatively moderate exercise. Rhabdomyolysis is also more likely after eccentric exercise, such as Downhill Running.
  • Sickness. A viral or bacterial infection is often a factor in exercise related kidney failure.

Looking at the analysis[15] of nine cases of continued kidney failure in Comrades Marathon, seven had taken NSAIDs, four may have had a viral or bacterial infection. The combination of dehydration, rhabdomyolysis, infection and NSAIDs are a perfect storm for the kidneys.

3 NSAIDs and Hyponatremia

The kidneys are responsible for removing excess fluid from the blood as well as excreting or withholding sodium. If kidney function is compromised, then this can result in Hyponatremia, which can be fatal. Some studies[18][19][20] have shown a correlation between NSAID use in races and Hyponatremia, but others[21][22] have not. Using NSAIDs when hydration is a concern increases the risk of problems occuring.

4 NSAIDs causing Heart Attacks or Strokes

The U.S. Food and Drug Administration (FDA) warnings that non-aspirin NSAIDs increase the risk of a heart attack or stroke[23]. The risk appears to be related to ongoing usage rather than single doses, with the risk increasing in the first weeks of usage and the risk may increase with prolonged usage. The increased risk is dose dependent (taking more has a greater risk), and the includes those without heart disease or risk factors for heart disease. Not surprisingly, those already with a higher risk of heart disease or stroke have a proportionately higher risk with NSAID usage.

5 NSAIDs and Infection

Because a bacterial or viral infection puts more stress on the body, including the kidneys, taking NSAIDs and continuing to run increases your risk of complications. If the sickness is too bad to run without NSAIDs, you probably shouldn't run.

6 NSAIDs for Pain Reduction

The primary purpose of NSAIDs is generally for reducing pain, and they are remarkably effective at achieving this. If you need a painkiller, acetaminophen is probably a better choice than ibuprofen, though be careful as it's easy to overdose on Acetaminophen (see below). Acetaminophen has limited anti-inflammatory properties, so it shouldn't impair healing as much as ibuprofen, but it is still good as a painkiller. Combining acetaminophen or other NSAIDs with Caffeine further improves their painkilling effectiveness. After a major race I can sometimes have so much leg pain that I can't sleep and a little acetaminophen can make all the difference. While the acetaminophen may impair healing somewhat I believe the trade-off in improved sleep is worthwhile. After all, the lack of sleep itself will impair healing, so it's a reasonable compromise.

7 NSAIDs and DOMS

Main article: Delayed Onset Muscle Soreness

Delayed Onset Muscle Soreness (DOMS) generally occurs between 24 and 72 hours after unusual or severe exercise, such as racing a marathon or Downhill Running. The use of NSAIDs to prevent or treat DOMS has been widely researched, with somewhat mixed results. Even scholarly reviews of the research have differing conclusions[24] [25] [26][27]. My conclusions based on the available research are:

  • The most common NSAIDs (Ibuprofen, Acetaminophen (Paracetamol), and Aspirin) are unlikely to help with DOMS.
  • There is some evidence that Naproxen may be more effective than the common NSAIDs. There is not enough evidence to reach a conclusion on Diclofenac, Codeine, Rofecoxib, Ketoprofen, or Bromelain.
  • If an NSAID is taken for DOMS, it should probably be taken immediately after the damaging exercise rather than waiting until the soreness develops.
  • It seems likely that taking an NSAID for DOMS will reduce the muscular growth that would normally occur as part of the recovery.
    • In one study, rabbits treated with flurbiprofen after DOMS inducing exercise regained more strength after 3-7 days, but between days 7 and 28 days the treated rabbits became weaker while the controls became stronger[28]. This is only one study, and on animals, but it is rather troubling as none of the human studies look at the results over this time period.

7.1 A Summary of the Research on NSAIDs and DOMS

The table below summarizes the research I located on the effect of NSAIDs on DOMS in humans. I've only considered the primary DOMS markers of soreness (pain) and weakness, rather than including things like blood enzymes. For each NSAID I've shown how many studies show an improvement and how many studies show no effect.

NSAID Soreness Weakness
Ibuprofen 2xImproved[29][30]

7xNo Effect[31][32][33] [34][35][36][37]

1xMaybe[29]

8xNo Effect[31][32][33] [34][35][36][30][37]

Ibuprofen Gel 1xNo Effect[38]
Acetaminophen (Paracetamol) 2xNo Effect[39][40]
Aspirin 2xImproved[41][42]

2xNo Effect[39][40]

2xNo Effect[41][42]
Naproxen 4xImproved[43][44][45][46]

1xNo Effect[47]

3xImproved[43][44][45]

1xNo Effect[47]

Diclofenac Possible slight reduction[48]
Codeine 1xNo Effect[39]
Rofecoxib 1xNo Effect[49]
Ketoprofen 1xImproved[50] 1xImproved[50]
Bromelain 1xNo Effect[37]

8 NSAIDs and Intestinal Damage

As little as one hour of intense cycling can result in indications of small intestinal damage[51]. This is believed to be due to the redirection of blood away from the digestive system and towards the active muscles. These markers are significantly higher if 400mg ibuprofen (the standard single adult dose) is taken before the exercise[52]. The marker used is Plasma Intestinal Fatty Acid Binding Protein which is an early marker of intestinal necrosis[53].

The level of a marker of intestinal damage during and after 60 minutes of cycling at 70% V̇O2max.

9 NSAIDs and Wound Healing

Main article: Popping Blisters

Ibuprofen, and possibly other NSAIDs, impair wound healing and should be avoided[54][55].

10 NSAIDs and Racing

Taking NSAIDs in ultramarathon events can improve performance by reducing pain and acute inflammation, but doing so represents a significant risk. There is some evidence[56] [57] that many runners taking NSAIDs have the same level of pain and greater damage markers compared with non-users. This may be because the runners push themselves to a similar level of pain, with the NSAIDs allowing them to do more damage.

  • It seems likely that NSAIDs will increase the risk of injury rather than reducing it, as the symptoms of damage will be masked.
  • The most common NSAID for racing seems to be ibuprofen. I've not seen any evidence of the relative effectiveness of different NSAIDs on performance.
  • It is better to take liquid ibuprofen than tablets or capsules. The tablets and capsules take longer to dissolve and if you have a digestive problem they may not be fully absorbed. You can chew the tablets, but this is unpleasant and ibuprofen can irritate your mouth and throat slightly, so the liquid form is best. It's obviously harder to transport, but you can fill an old film canister with a dose.
  • Before an ultramarathon race, you should think through under what circumstances you will consider using NSAIDs and what dosage. Make sure your crew knows that you're taking NSAIDs in case anything happens.
  • Extra care should be taken when NSAIDs are used in combination with dehydration, sickness or running the causes serious muscle damage.
  • Taking NSAIDs in marathon or shorter races is probably ineffective as the level of damage seen is not as great as in ultramarathon events.
  • If you need NSAIDs to start a race, you probably should not compete.

11 Longer Term NSAID usage

Using NSAIDs for longer periods of time can lead to serious health problems and can be fatal. I have a running friend who had a bleeding ulcer from using Ibuprofen, which is a known[58] side effect. The likelihood of a bleeding or perforated ulcer goes up with time, from 1% after 3-6 months, to 2-4% after 12 months. 35% of long term Ibuprofen users get an ulcer[59], which are grim odds.

12 Acetaminophen Overdose Danger (AKA Paracetamol, Tylenol)

Acetaminophen does not have the same risk of ulcers, but it is linked to liver damage, especially in those who drink alcohol. Acetaminophen is the leading cause of acute liver failure[60][61]. There are concerns[62] that even the standard dose can cause changes in liver function. Acetaminophen can cause delayed symptoms[61], with people seeking medical help up to 5 days after the overdose (20% < 12 hours, 35% 12-24 hours, 45% 24 hours+). Overdoses of Acetaminophen can be caused by taking slightly too much over several days, with the toxicity building up[61]. This problem is again exacerbated by those taking alcohol with Acetaminophen[61]. (One factor that increases the risk is that some common medications, such as cold remedies, include Acetaminophen. If people do not add in the dose of Acetaminophen from these other sources, it is easy to unwittingly exceed the safe dosage.)

13 Is Acetaminophen an NSAID?

Acetaminophen (also called paracetamol) is generally not classified as an NSAID[63]. While Acetaminophen has limited anti-inflammatory properties, it shares the same mechanism of action with most NSAIDs of inhibiting the COX enzyme and the inhibition of prostaglandin synthesis[64][65][66][67]. Therefore, this article includes Acetaminophen in with NSAIDs.

14 References

  1. ↑ Urban Dictionary: Vitamin I http://www.urbandictionary.com/define.php?term=Vitamin%20I
  2. ↑ Skeletal Muscle PGF2αand PGE2 in Response to Eccentric Resistance Exercise: Influence of Ibuprofen and Acetaminophen http://jcem.endojournals.org/content/86/10/5067.long
  3. ↑ An In Vitro Investigation Into the Effects of Repetitive Motion and Nonsteroidal Antiinflammatory Medication on Human Tendon Fibroblasts http://ajs.sagepub.com/content/23/1/119
  4. ↑ Cost-conscious prescribing of nonsteroidal anti-in... [Arch Intern Med. 1992] - PubMed result http://www.ncbi.nlm.nih.gov/pubmed/1417372
  5. ↑ Sports Injuries - NSAIDs: Why We Do Not Recommend Them http://www.caringmedical.com/sports_injury/nsaids.asp
  6. ↑ Oral ibuprofen: evaluation of its effect on peritendinous adhesions and the breaking strength of a tenorrhaphy. [J Hand Surg Am. 1986] - PubMed result http://www.ncbi.nlm.nih.gov/pubmed/3511134#
  7. ↑ A cyclooxygenase-2 inhibitor impairs ligament heal... [Am J Sports Med. 2001 Nov-Dec] - PubMed result http://www.ncbi.nlm.nih.gov/pubmed/11734496?dopt=Abstract&holding=npg
  8. ↑ NSAIDs Inhibit Tendon-to-Bone Healing in Rotator Cuff Repair http://www.shoulderdoc.co.uk/article.asp?article=295
  9. ↑ Effect of ibuprofen on the healing and remodeling of bone and articular cartilage in the rabbit temporomandibular joint http://www.joms.org/article/0278-2391%2892%2990276-6/abstract
  10. ↑ JBJS | Dose and Time-Dependent Effects of Cyclooxygenase-2 Inhibition on Fracture-Healing http://www.jbjs.org/article.aspx?Volume=89&page=500
  11. ↑ Effects of Nonsteroidal Anti-Inflammatory Drugs on Bone Formation and Soft-Tissue Healing -- Dahners and Mullis 12 (3): 139 -- Journal of the American Academy of Orthopaedic Surgeons http://www.jaaos.org/cgi/content/abstract/12/3/139
  12. ↑ The effect of a nonsteroidal antiinflammatory drug... [Am J Sports Med. 1988 Nov-Dec] - PubMed result http://www.ncbi.nlm.nih.gov/pubmed/3239621?dopt=Abstract&holding=npg
  13. ↑ The influence of a cyclooxygenase-1 inhibitor on i... [Am J Sports Med. 2003 Jul-Aug] - PubMed result http://www.ncbi.nlm.nih.gov/pubmed/12860547
  14. ↑ Exertional rhabdomyolysis and acute renal failure... [Sports Med. 2007] - PubMed - NCBI http://www.ncbi.nlm.nih.gov/pubmed/17465608
  15. ↑ 15.0 15.1 http://journals.lww.com/acsm-csmr/Abstract/2010/03000/Athletes,_NSAID,_Coxibs,_and_the_Gastrointestinal.11.aspx
  16. ↑ KIDNEY FAILURE AND ULTRAMARATHONING http://www.lehigh.edu/\~dmd1/kidney.html
  17. ↑ Recurrent rhabdomyolysis in a collegiat... [Med Sci Sports Exerc. 2006] - PubMed - NCBI http://www.ncbi.nlm.nih.gov/pubmed/16540825
  18. ↑ NSAID Use Increases the Risk of Developing Hyponatremia duri... : Medicine & Science in Sports & Exercise http://journals.lww.com/acsm-msse/Abstract/2006/04000/NSAID_Use_Increases_the_Risk_of_Developing.2.aspx
  19. ↑ http://journals.lww.com/cjsportsmed/Abstract/2007/01000/Exercise_Associated_Hyponatremia,_Renal_Function,.8.aspx
  20. ↑ http://www.sciencedirect.com/science/article/pii/S0002934307001672
  21. ↑ http://journals.lww.com/cjsportsmed/Abstract/2003/01000/The_Incidence,_Risk_Factors,_and_Clinical.8.aspx
  22. ↑ CL. Dumke, DC. Nieman, K. Oley, RH. Lind, Ibuprofen does not affect serum electrolyte concentrations after an ultradistance run., Br J Sports Med, volume 41, issue 8, pages 492-6; discussion 496, Aug 2007, doi 10.1136/bjsm.2006.033597, PMID 17331976
  23. ↑ FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes, http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm, Accessed on 25 January 2016
  24. ↑ K. Cheung, P. Hume, L. Maxwell, Delayed onset muscle soreness : treatment strategies and performance factors., Sports Med, volume 33, issue 2, pages 145-64, 2003, PMID 12617692
  25. ↑ Smith LL. Causes of delayed onset muscle soreness and the impact on athletic performance: a review. J Appl Sport Sci Res 1992; 6 (3): 135-41
  26. ↑ A. Baldwin Lanier, Use of nonsteroidal anti-inflammatory drugs following exercise-induced muscle injury., Sports Med, volume 33, issue 3, pages 177-85, 2003, PMID 12656639
  27. ↑ G. Howatson, KA. van Someren, The prevention and treatment of exercise-induced muscle damage., Sports Med, volume 38, issue 6, pages 483-503, 2008, PMID 18489195
  28. ↑ DK. Mishra, J. Fridén, MC. Schmitz, RL. Lieber, Anti-inflammatory medication after muscle injury. A treatment resulting in short-term improvement but subsequent loss of muscle function., J Bone Joint Surg Am, volume 77, issue 10, pages 1510-9, Oct 1995, PMID 7593059
  29. ↑ 29.0 29.1 SM. Hasson, JC. Daniels, JG. Divine, BR. Niebuhr, S. Richmond, PG. Stein, JH. Williams, Effect of ibuprofen use on muscle soreness, damage, and performance: a preliminary investigation., Med Sci Sports Exerc, volume 25, issue 1, pages 9-17, Jan 1993, PMID 8423760
  30. ↑ 30.0 30.1 Tokmakidis SP, Kokkinidis EA, Smilios I, Douda H, The effects of ibuprofen on delayed muscle soreness and muscular performance after eccentric exercise., J Strength Cond Res, 2003, volume 17, issue 1, pages 53-9, PMID 12580656
  31. ↑ 31.0 31.1 Effect of Ibuprofen Use on Delayed Onset Muscle Soreness of the Elbow Flexors http://journals.humankinetics.com/jsr-back-issues/jsrvolume4issue4november/effectofibuprofenuseondelayedonsetmusclesorenessoftheelbowflexors
  32. ↑ 32.0 32.1 FX. Pizza, D. Cavender, A. Stockard, H. Baylies, A. Beighle, Anti-inflammatory doses of ibuprofen: effect on neutrophils and exercise-induced muscle injury., Int J Sports Med, volume 20, issue 2, pages 98-102, Feb 1999, doi 10.1055/s-2007-971100, PMID 10190769
  33. ↑ 33.0 33.1 N Rahnama, F Rahmani-Nia, K Ebrahim, The isolated and combined effects of selected physical activity and ibuprofen on delayed-onset muscle soreness, Journal of Sports Sciences, volume 23, issue 8, 2005, pages 843–850, ISSN 0264-0414, doi 10.1080/02640410400021989
  34. ↑ 34.0 34.1 Joel R. Krentz, Braden Quest, Jonathan P. Farthing, Dale W. Quest, Philip D. Chilibeck, The effects of ibuprofen on muscle hypertrophy, strength, and soreness during resistance training, Applied Physiology, Nutrition, and Metabolism, volume 33, issue 3, 2008, pages 470–475, ISSN 1715-5312, doi 10.1139/H08-019
  35. ↑ 35.0 35.1 Lars Arendt-Nielsen, Morten Weidner, Dorte Bartholin, Allan Rosetzsky, A Double-Blind Randomized Placebo Controlled Parallel Group Study Evaluating the Effects of Ibuprofen and Glucosamine Sulfate on Exercise Induced Muscle Soreness, Journal Of Musculoskeletal Pain, volume 15, issue 1, 2007, pages 21–28, ISSN 1058-2452, doi 10.1300/J094v15n01_04
  36. ↑ 36.0 36.1 AE. Donnelly, RJ. Maughan, PH. Whiting, Effects of ibuprofen on exercise-induced muscle soreness and indices of muscle damage., Br J Sports Med, volume 24, issue 3, pages 191-5, Sep 1990, PMID 2078806
  37. ↑ 37.0 37.1 37.2 MB. Stone, MA. Merrick, CD. Ingersoll, JE. Edwards, Preliminary comparison of bromelain and Ibuprofen for delayed onset muscle soreness management., Clin J Sport Med, volume 12, issue 6, pages 373-8, Nov 2002, PMID 12466693
  38. ↑ Robert D. Hyldahl, Justin Keadle, Pierre A. Rouzier, Dennis Pearl, Priscilla M. Clarkson, Effects of Ibuprofen Topical Gel on Muscle Soreness, Medicine & Science in Sports & Exercise, volume 42, issue 3, 2010, pages 614–621, ISSN 0195-9131, doi 10.1249/MSS.0b013e3181b95db2
  39. ↑ 39.0 39.1 39.2 P. Barlas, JA. Craig, J. Robinson, DM. Walsh, GD. Baxter, JM. Allen, Managing delayed-onset muscle soreness: lack of effect of selected oral systemic analgesics., Arch Phys Med Rehabil, volume 81, issue 7, pages 966-72, Jul 2000, doi 10.1053/apmr.2000.6277, PMID 10896014
  40. ↑ 40.0 40.1 Lucille Smith, Robert George, Thomas Chenier, Michael McCammon, Joseph Houmard, Richard Israel, R. A. Hoppmann, Susan Smith, Do over-the-counter analgesics reduce delayed onset muscle soreness and serum creatine kinase values?, Research in Sports Medicine, volume 6, issue 2, 1995, pages 81–88, ISSN 1543-8627, doi 10.1080/15438629509512039
  41. ↑ 41.0 41.1 Riasati et al.: Aspirin and delayed onset muscle soreness ASPIRIN MAY BE AN EFFECTIVE TREATMENT FOR EXERCISE- INDUCED MUSCLE SORENESS | ResearchGate http://www.researchgate.net/publication/228091056_Riasati_et_al._Aspirin_and_delayed_onset_muscle_soreness_ASPIRIN_MAY_BE_AN_EFFECTIVE_TREATMENT_FOR_EXERCISE-_INDUCED_MUSCLE_SORENESS
  42. ↑ 42.0 42.1 KT. Francis, T. Hoobler, Effects of aspirin on delayed muscle soreness., J Sports Med Phys Fitness, volume 27, issue 3, pages 333-7, Sep 1987, PMID 3431117
  43. ↑ 43.0 43.1 GA. Dudley, J. Czerkawski, A. Meinrod, G. Gillis, A. Baldwin, M. Scarpone, Efficacy of naproxen sodium for exercise-induced dysfunction muscle injury and soreness., Clin J Sport Med, volume 7, issue 1, pages 3-10, Jan 1997, PMID 9117523
  44. ↑ 44.0 44.1 AC. Baldwin, SW. Stevenson, GA. Dudley, Nonsteroidal anti-inflammatory therapy after eccentric exercise in healthy older individuals., J Gerontol A Biol Sci Med Sci, volume 56, issue 8, pages M510-3, Aug 2001, PMID 11487604
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  46. ↑ The Effect of Taking Naproxen Drug on the Level of Perceived Pain and Changes of CPK Serum after Eccentric Exercise - Harakat Volume: 37, Issue:, Accessed on 3 January 2013
  47. ↑ 47.0 47.1 J. Bourgeois, D. MacDougall, J. MacDonald, M. Tarnopolsky, Naproxen does not alter indices of muscle damage in resistance-exercise trained men., Med Sci Sports Exerc, volume 31, issue 1, pages 4-9, Jan 1999, PMID 9927002
  48. ↑ A E Donnelly, K McCormick, R J Maughan, P H Whiting, P M Clarkson, Effects of a non-steroidal anti-inflammatory drug on delayed onset muscle soreness and indices of damage., British Journal of Sports Medicine, volume 22, issue 1, 1988, pages 35–38, ISSN 0306-3674, doi 10.1136/bjsm.22.1.35
  49. ↑ L.C. Loram, D. Mitchell, A. Fuller, Rofecoxib and tramadol do not attenuate delayed-onset muscle soreness or ischaemic pain in human volunteers, Canadian Journal of Physiology and Pharmacology, volume 83, issue 12, 2005, pages 1137–1145, ISSN 0008-4212, doi 10.1139/y05-113
  50. ↑ 50.0 50.1 SP. Sayers, CA. Knight, PM. Clarkson, EH. Van Wegen, G. Kamen, Effect of ketoprofen on muscle function and sEMG activity after eccentric exercise., Med Sci Sports Exerc, volume 33, issue 5, pages 702-10, May 2001, PMID 11323536
  51. ↑ K. van Wijck, K. Lenaerts, LJ. van Loon, WH. Peters, WA. Buurman, CH. Dejong, Exercise-induced splanchnic hypoperfusion results in gut dysfunction in healthy men., PLoS One, volume 6, issue 7, pages e22366, 2011, doi 10.1371/journal.pone.0022366, PMID 21811592
  52. ↑ K. VAN Wijck, K. Lenaerts, AA. VAN Bijnen, B. Boonen, LJ. VAN Loon, CH. Dejong, WA. Buurman, Aggravation of exercise-induced intestinal injury by Ibuprofen in athletes., Med Sci Sports Exerc, volume 44, issue 12, pages 2257-62, Dec 2012, doi 10.1249/MSS.0b013e318265dd3d, PMID 22776871
  53. ↑ IC. Vermeulen Windsant, FA. Hellenthal, JP. Derikx, MH. Prins, WA. Buurman, MJ. Jacobs, GW. Schurink, Circulating intestinal fatty acid-binding protein as an early marker of intestinal necrosis after aortic surgery: a prospective observational cohort study., Ann Surg, volume 255, issue 4, pages 796-803, Apr 2012, doi 10.1097/SLA.0b013e31824b1e16, PMID 22367448
  54. ↑ Wayne K. Stadelmann, Alexander G. Digenis, Gordon R. Tobin, Impediments to wound healing, The American Journal of Surgery, volume 176, issue 2, 1998, pages 39S–47S, ISSN 00029610, doi 10.1016/S0002-9610(98)00184-6
  55. ↑ S. Guo, L. A. DiPietro, Factors Affecting Wound Healing, Journal of Dental Research, volume 89, issue 3, 2010, pages 219–229, ISSN 0022-0345, doi 10.1177/0022034509359125
  56. ↑ Ibuprofen use during extreme exercise: ... [Med Sci Sports Exerc. 2007] - PubMed - NCBI http://www.ncbi.nlm.nih.gov/pubmed/17596774
  57. ↑ Ibuprofen use, endotoxemia, inflammation, ... [Brain Behav Immun. 2006] - PubMed - NCBI http://www.ncbi.nlm.nih.gov/pubmed/16554145
  58. ↑ Ibuprofen Official FDA information, side effects and uses. http://www.drugs.com/pro/ibuprofen.html
  59. ↑ Ibuprofen/Famotidine Reduces Gastric Ulcer Incidence http://www.medscape.com/viewarticle/732432
  60. ↑ Acetaminophen-induced acute liver failure: Results of a United States multicenter, prospective study - Larson - 2005 - Hepatology - Wiley Online Library http://onlinelibrary.wiley.com/doi/10.1002/hep.20948/pdf
  61. ↑ 61.0 61.1 61.2 61.3 Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2011.04067.x/full
  62. ↑ FDA May Restrict Acetaminophen http://www.webmd.com/pain-management/news/20090701/fda-may-restrict-acetaminophen
  63. ↑ ACETAMINOPHEN (PARACETAMOL) http://www.chemicalland21.com/lifescience/phar/ACETAMINOPHEN.htm
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  65. ↑ Regina Botting, Samir S. Ayoub, COX-3 and the mechanism of action of paracetamol/acetaminophen, Prostaglandins, Leukotrienes and Essential Fatty Acids, volume 72, issue 2, 2005, pages 85–87, ISSN 09523278, doi 10.1016/j.plefa.2004.10.005
  66. ↑ K. Toussaint, X. C. Yang, M. A. Zielinski, K. L. Reigle, S. D. Sacavage, S. Nagar, R. B. Raffa, What do we (not) know about how paracetamol (acetaminophen) works?, Journal of Clinical Pharmacy and Therapeutics, volume 35, issue 6, 2010, pages 617–638, ISSN 02694727, doi 10.1111/j.1365-2710.2009.01143.x
  67. ↑ Brian J. Anderson, Paracetamol (Acetaminophen): mechanisms of action, Pediatric Anesthesia, volume 18, issue 10, 2008, pages 915–921, ISSN 11555645, doi 10.1111/j.1460-9592.2008.02764.x
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