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NSAIDs (Ibuprofen, Naproxen, Aspirin) and Acetaminophen/Paracetamol for runners, impairs healing and interferes with hydration

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Revision as of 12:40, 22 December 2016 by User:Fellrnr (User talk:Fellrnr | contribs)

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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], with one study finding about 60% of runners using NSAIDs during training[2]. This is unsurprising given the estimates of injury rates in runners varying between 20% and 80%[3]. This article also covers Acetaminophen (also called Paracetamol), though it's not technically an NSAID.

Contents

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[4]. A 2001 study showed that Ibuprofen and Acetaminophen reduce muscle growth after eccentric exercise. Another study[5] 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[6][7] have shown that four days after injury, NSAIDs resulted in very little muscle regeneration compared with no drugs.
  • Tendons. A primate study[8] showed "a marked decrease in the breaking strength of tendons at four and six weeks in the ibuprofen-treated animals". Another animal study[9] showed treated tendons were 32% weaker than their untested counterparts. A study of older adults showed a weakening of tendons with acetaminophen (but not ibuprofen) use[10].
  • Bone-Tendon Junctions. An animal study[11] 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[12] 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.[13] A study [14] 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[15] 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[16] 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 Turmeric as an NSAID

Turmeric rhizome and powder (By Simon A. Eugster - Own work, CC BY-SA 3.0).

Turmeric is an anti-inflammatory[17][18] that is often considered an alternative to more common NSAIDs. Like other NSAIDs, Turmeric is an effective pain reliever (analgesic)[19][20][21][22] and it may be effective in treating Delayed Onset Muscle Soreness[23][24][25][26][27][28]. Studies of Turmeric and turmeric derivatives as treatments for osteoarthritis[29][30], rheumatoid arthritis[31], and cancer[32][33][34] show potentially promising results. However, there are concerns that most of the human studies on Turmeric are of poor quality and should be treated with caution[35].

2.1 Turmeric Safety

Turmeric has been medicinally used for 1000s of years[36] and even in large doses turmeric shows low acute toxicity[37][32][31][38] with only a few studies finding nausea and diarrhea[37] or abdominal pain[30]. However, there are concerns that many studies on Turmeric are in vitro (isolated tissues) at dose levels that are hard to replicate in humans[39]. Doses as high as 12g of curcumin produce negligible levels in the blood[40]. At therapeutic levels there is evidence that Turmeric (curcumin) may be carcinogenic[41][42][43][44][45][46][47][48][49], though it can exhibit both anticancer and carcinogenic properties[50]. Curcumin can inhibit liver function, including the drug-metabolizing P450 enzymes[51][52][53][54][55]. (This could cause problematic drug interactions.) Turmeric may bind to iron, resulting in iron deficiency[56][57], though it has been suggested that some of the benefits of Turmeric are from this iron binding[58]. It should be remembered that other common constituents of normal diet have shown to be toxic when used as dietary supplements[59]

2.2 Turmeric Doses

It's been estimated people in India consuming high culinary intakes of Turmeric obtain about 150mg/day of curcumin[60], and average intake is probably 60-100mg/day[61]. However, must studies use much higher levels, and culinary levels (~2g/day) Turmeric is probably ineffective as an NSAID[62]. Turmeric has poor bioavailability[63][64] due to poor absorption and rapid metabolism[64]. The curcumin level in Turmeric powder can vary dramatically, with one study finding levels between 0.6 and 3.1% dry weight, a more than five-fold variation[65]. This makes it hard to use the raw powder, as the actual dose could vary enormously and a high dose of curcumin such as 8g would potentially require the consumption of 1.3Kg/2.8 pounds of Turmeric powder. It's been shown that 3.6 g curcumin produces effective levels in the digestive system, but negligible levels outside the gut[66], and even 12g of curcumin produce negligible levels in the blood[40]. This is compounded by the rapid removal, with concentrations of curcumin typically peak 1-2 hours after consumption and declining within 12 hours[32][19]. At this point, it's hard to define a dose of Turmeric or curcumin beyond saying that it's safe at culinary levels (~2g/day of Turmeric powder).

2.3 Turmeric Enhancers

The levels of Turmeric can be enhanced by taking it with piperine, a constituent of black pepper. One study that gave subjects 2g of curcumin found extremely low levels in the blood, but adding 20mg of piperine boosted blood levels by 2000%[67]. Another animal study using intravenous administration found piperine enhanced the effectiveness of curcumin[68]. However, an animal study found that low levels (20 mg/kg) of piperine did not enhance the effectiveness of curcumin, and higher levels (40 mg/kg) actually negated the curcumin benefits[69]. Piperine increases the absorption of curcumin[70] and reduces the metabolism of curcumin by the liver[67][55]. However, the reduced metabolism is because like curcumin, piperine is a powerful inhibitor of liver function[71][72][73]. Personally, I am cautious about boosting the levels of curcumin by impairing the liver. There are also versions of curcumin with improved bioavailability are being developed such as Flexofytol[74] or Meriva[24]. However, it should be noted that the bulk of the current research does not use enhancers, so caution may be appropriate.

2.4 Turmeric as a selective COX-2 Inhibitor

Digestive problems, a common side effect of NSAIDs, are believed to be because most NSAIDs inhibit both COX-1 and COX-2 enzymes[75]. COX-2 is predominantly responsible for inflammation where COX-1 helps maintain the digestive system[76]. Selectively inhibiting just COX-2 may have the benefits of NSAIDS without the digestive issues[77][78][76]. Studies have found that Turmeric is a COX-2 inhibitor[79][80][81][82][83], and turmeric preferentially inhibits COX-2 over COX-1[84]. Turmeric has ~36% COX-1 inhibition and ~77% COX-2 inhibition, while aspirin, ibuprofen and naproxen had 41-52% COX-1 inhibition and ~30-40% COX-2 inhibition[84]. Diferuloylmethane (Curcumin) is the main active ingredient in turmeric[63][85], though it also includes monodemethoxycurcumin (curcumin II) and bisdemethoxycurcumin (curcumin III)[84].

3 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[86]. 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[87]. 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[88] 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[89] 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[87] 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.

4 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[90][91][92] have shown a correlation between NSAID use in races and Hyponatremia, but others[93][94] have not. Using NSAIDs when hydration is a concern increases the risk of problems occuring.

5 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[95]. 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.

6 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.

7 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.

8 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[96] [97] [98][99]. 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.
  • There is also some evidence that Turmeric may help with DOMS.
  • 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[100]. 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.

8.1 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[101][102]

7xNo Effect[103][104][105] [106][107][108][109]

 1xMaybe[101]

8xNo Effect[103][104][105] [106][107][108][102][109]

Ibuprofen Gel 1xNo Effect[110]
Acetaminophen (Paracetamol) 2xNo Effect[111][112]
Aspirin 2xImproved[113][114]

2xNo Effect[111][112]

 2xNo Effect[113][114]
Naproxen 4xImproved[115][116][117][118]

1xNo Effect[119]

 3xImproved[115][116][117]

1xNo Effect[119]

Diclofenac Possible slight reduction[120]
Codeine 1xNo Effect[111]
Rofecoxib 1xNo Effect[121]
Ketoprofen 1xImproved[122] 1xImproved[122]
Bromelain 1xNo Effect[109]
Turmeric 2xImproved[23][24]

2xNo Effect[25][26]

 2xImproved[26][27]

9 NSAIDs and Intestinal Damage

As little as one hour of intense cycling can result in indications of small intestinal damage[123]. 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[124]. The marker used is Plasma Intestinal Fatty Acid Binding Protein which is an early marker of intestinal necrosis[125].

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

10 NSAIDs and Wound Healing

Main article: Popping Blisters

Ibuprofen, and possibly other NSAIDs, impair wound healing and should be avoided[126][127].

11 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[128] [129] 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.

12 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[130] 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[131], which are grim odds.

13 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[132][133]. There are concerns[134] that even the standard dose can cause changes in liver function. Acetaminophen can cause delayed symptoms[133], 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[133]. This problem is again exacerbated by those taking alcohol with Acetaminophen[133]. (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.)

14 Is Acetaminophen an NSAID?

Acetaminophen (also called paracetamol) is generally not classified as an NSAID[135]. 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[136][137][138][139]. Therefore, this article includes Acetaminophen in with NSAIDs.

15 References

  1. ↑ Urban Dictionary: Vitamin I http://www.urbandictionary.com/define.php?term=Vitamin%20I
  2. ↑ Jeremy D Joslin, Jarem B Lloyd, Timur Kotlyar, Susan M Wojcik, NSAID and other analgesic use by endurance runners during training, competition and recovery, South African Journal of Sports Medicine, volume 25, issue 4, 2013, pages 101, ISSN 2078-516X, doi 10.7196/sajsm.495
  3. ↑ RN. van Gent, D. Siem, M. van Middelkoop, AG. van Os, SM. Bierma-Zeinstra, BW. Koes, Incidence and determinants of lower extremity running injuries in long distance runners: a systematic review., Br J Sports Med, volume 41, issue 8, pages 469-80; discussion 480, Aug 2007, doi 10.1136/bjsm.2006.033548, PMID 17473005
  4. ↑ Skeletal Muscle PGF2αand PGE2 in Response to Eccentric Resistance Exercise: Influence of Ibuprofen and Acetaminophen http://jcem.endojournals.org/content/86/10/5067.long
  5. ↑ 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
  6. ↑ Cost-conscious prescribing of nonsteroidal anti-in... [Arch Intern Med. 1992] - PubMed result http://www.ncbi.nlm.nih.gov/pubmed/1417372
  7. ↑ Sports Injuries - NSAIDs: Why We Do Not Recommend Them http://www.caringmedical.com/sports_injury/nsaids.asp
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  9. ↑ 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
  10. ↑ C. C. Carroll, J. M. Dickinson, J. K. LeMoine, J. M. Haus, E. M. Weinheimer, C. J. Hollon, P. Aagaard, S. P. Magnusson, T. A. Trappe, Influence of acetaminophen and ibuprofen on in vivo patellar tendon adaptations to knee extensor resistance exercise in older adults, Journal of Applied Physiology, volume 111, issue 2, 2011, pages 508–515, ISSN 8750-7587, doi 10.1152/japplphysiol.01348.2010
  11. ↑ NSAIDs Inhibit Tendon-to-Bone Healing in Rotator Cuff Repair http://www.shoulderdoc.co.uk/article.asp?article=295
  12. ↑ 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
  13. ↑ JBJS | Dose and Time-Dependent Effects of Cyclooxygenase-2 Inhibition on Fracture-Healing http://www.jbjs.org/article.aspx?Volume=89&page=500
  14. ↑ 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
  15. ↑ 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
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  20. ↑ Y. Panahi, AR. Rahimnia, M. Sharafi, G. Alishiri, A. Saburi, A. Sahebkar, Curcuminoid treatment for knee osteoarthritis: a randomized double-blind placebo-controlled trial., Phytother Res, volume 28, issue 11, pages 1625-31, Nov 2014, doi 10.1002/ptr.5174, PMID 24853120
  21. ↑ V. Kuptniratsaikul, S. Thanakhumtorn, P. Chinswangwatanakul, L. Wattanamongkonsil, V. Thamlikitkul, Efficacy and safety of Curcuma domestica extracts in patients with knee osteoarthritis., J Altern Complement Med, volume 15, issue 8, pages 891-7, Aug 2009, doi 10.1089/acm.2008.0186, PMID 19678780
  22. ↑ X. Zhu, Q. Li, R. Chang, D. Yang, Z. Song, Q. Guo, C. Huang, Curcumin alleviates neuropathic pain by inhibiting p300/CBP histone acetyltransferase activity-regulated expression of BDNF and cox-2 in a rat model., PLoS One, volume 9, issue 3, pages e91303, 2014, doi 10.1371/journal.pone.0091303, PMID 24603592
  23. ↑ 23.0 23.1 LM. Nicol, DS. Rowlands, R. Fazakerly, J. Kellett, Curcumin supplementation likely attenuates delayed onset muscle soreness (DOMS)., Eur J Appl Physiol, volume 115, issue 8, pages 1769-77, Aug 2015, doi 10.1007/s00421-015-3152-6, PMID 25795285
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  25. ↑ 25.0 25.1 Brian K. McFarlin, Adam S. Venable, Andrea L. Henning, Jill N. Best Sampson, Kathryn Pennel, Jakob L. Vingren, David W. Hill, Reduced Inflammatory and Muscle Damage Biomarkers following Oral Supplementation with Bioavailable Curcumin, BBA Clinical, 2016, ISSN 22146474, doi 10.1016/j.bbacli.2016.02.003
  26. ↑ 26.0 26.1 26.2 Yoko Tanabe, Seiji Maeda, Nobuhiko Akazawa, Asako Zempo-Miyaki, Youngju Choi, Song-Gyu Ra, Atsushi Imaizumi, Yoshihiko Otsuka, Kazunori Nosaka, Attenuation of indirect markers of eccentric exercise-induced muscle damage by curcumin, European Journal of Applied Physiology, volume 115, issue 9, 2015, pages 1949–1957, ISSN 1439-6319, doi 10.1007/s00421-015-3170-4
  27. ↑ 27.0 27.1 JM. Davis, EA. Murphy, MD. Carmichael, MR. Zielinski, CM. Groschwitz, AS. Brown, JD. Gangemi, A. Ghaffar, EP. Mayer, Curcumin effects on inflammation and performance recovery following eccentric exercise-induced muscle damage., Am J Physiol Regul Integr Comp Physiol, volume 292, issue 6, pages R2168-73, Jun 2007, doi 10.1152/ajpregu.00858.2006, PMID 17332159
  28. ↑ N. Kawanishi, K. Kato, M. Takahashi, T. Mizokami, Y. Otsuka, A. Imaizumi, D. Shiva, H. Yano, K. Suzuki, Curcumin attenuates oxidative stress following downhill running-induced muscle damage., Biochem Biophys Res Commun, volume 441, issue 3, pages 573-8, Nov 2013, doi 10.1016/j.bbrc.2013.10.119, PMID 24184481
  29. ↑ Y. Henrotin, M. Gharbi, Y. Dierckxsens, F. Priem, M. Marty, L. Seidel, A. Albert, E. Heuse, V. Bonnet, Decrease of a specific biomarker of collagen degradation in osteoarthritis, Coll2-1, by treatment with highly bioavailable curcumin during an exploratory clinical trial., BMC Complement Altern Med, volume 14, pages 159, 2014, doi 10.1186/1472-6882-14-159, PMID 24886572
  30. ↑ 30.0 30.1 V. Kuptniratsaikul, P. Dajpratham, W. Taechaarpornkul, M. Buntragulpoontawee, P. Lukkanapichonchut, C. Chootip, J. Saengsuwan, K. Tantayakom, S. Laongpech, Efficacy and safety of Curcuma domestica extracts compared with ibuprofen in patients with knee osteoarthritis: a multicenter study., Clin Interv Aging, volume 9, pages 451-8, 2014, doi 10.2147/CIA.S58535, PMID 24672232
  31. ↑ 31.0 31.1 B. Chandran, A. Goel, A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis., Phytother Res, volume 26, issue 11, pages 1719-25, Nov 2012, doi 10.1002/ptr.4639, PMID 22407780
  32. ↑ 32.0 32.1 32.2 AL. Cheng, CH. Hsu, JK. Lin, MM. Hsu, YF. Ho, TS. Shen, JY. Ko, JT. Lin, BR. Lin, Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions., Anticancer Res, volume 21, issue 4B, pages 2895-900, PMID 11712783
  33. ↑ S. Rao, C. Dinkar, L. K. Vaishnav, P. Rao, M. P. Rai, R. Fayad, M. S. Baliga, The Indian Spice Turmeric Delays and Mitigates Radiation-Induced Oral Mucositis in Patients Undergoing Treatment for Head and Neck Cancer: An Investigational Study, Integrative Cancer Therapies, volume 13, issue 3, 2013, pages 201–210, ISSN 1534-7354, doi 10.1177/1534735413503549
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  132. ↑ 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
  133. ↑ 133.0 133.1 133.2 133.3 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
  134. ↑ FDA May Restrict Acetaminophen http://www.webmd.com/pain-management/news/20090701/fda-may-restrict-acetaminophen
  135. ↑ ACETAMINOPHEN (PARACETAMOL) http://www.chemicalland21.com/lifescience/phar/ACETAMINOPHEN.htm
  136. ↑ GG. Graham, KF. Scott, Mechanism of action of paracetamol., Am J Ther, volume 12, issue 1, pages 46-55, PMID 15662292
  137. ↑ 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
  138. ↑ 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
  139. ↑ 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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