Taissa Oliveira

Word Count: 2,626

Ibuprofen / Curcumin / Glucosamine

Ibuprofen was first synthesised in 1961 in the UK by Dr. Stewart Adams OBE (Halford,
Lordkipanidzé and Watson, 2012). Originally prescribed as an anti-rheumatic medication, it
gained approval in 1983 as the first over-the-counter (OTC) non-steroidal anti-
inflammatory drug (NSAID). It is used to treat moderate pain and fever and is now
available in over 80 countries worldwide (Rainsford, 2019). Ibuprofen is deemed safe for
both adults and children. In the UK, it is acknowledged as the safest traditional NSAID,
according to reports of spontaneous adverse drug reactions (Bushra and Aslam, 2010).

Pharmacokinetics

Absorption
Following oral administration, ibuprofen is quickly and fully absorbed in the stomach and
small intestine (Mazaleuskaya et al. 2015; Schettler et al. 2001), achieving peak plasma
concentrations within 1 to 2 hours (Mazaleuskaya et al. 2015). The absorption rate is
highest with liquid formulations (Adatia et al. 2012). While taking ibuprofen with food may
slow the absorption rate, it does not affect the overall extent of absorption (Bushra and
Aslam, 2010).

Distribution
Ibuprofen, which binds extensively to plasma proteins, particularly albumin, circulates
through the body in the bloodstream (Crofford, 2013). It can penetrate the central nervous
system and accumulate in peripheral areas where it delivers its analgesic and anti-
inflammatory effects (Mazaleuskaya et al. 2015).

Metabolism
Ibuprofen undergoes extensive metabolism in the liver, with virtually only a small amount
of the drug excreted unchanged in the urine (Drugbank online, 2024) and only minimal
amounts of metabolites and unabsorbed drug appearing in the stool (Rainsford, 2009).
The drug experiences enantiomeric inversion, a process that primarily occurs in the liver
but also to a lesser extent in the gut before systemic absorption (Mazaleuskaya et al.
2015; Shin et al. 2017).

Elimination
Complete removal from the body occurs approximately 24 hours after the final dose
(Rainsford, 2009), with no observed differences in elimination rates or half-lives between
adults and children (drugs.com, 2021). The main pathway for elimination is hepatic
oxidative metabolism via CYP enzymes, predominantly CYP2C9 (Mazaleuskaya et al.
2015), leading to the formation of inactive glucuronide-conjugate metabolites. These
metabolites are primarily excreted in the urine (Shin et al. 2017) and about 1% through bile
(Adatia et al. 2012).

Pharmacodynamics

Ibuprofen acts by non-selectively but reversibly inhibiting the cyclooxygenase enzymes

COX-1 and COX-2, effectively blocking the conversion of arachidonic acid to
prostaglandins, which are pivotal in mediating inflammation, pain, and fever (Ershad et al).
This inhibition results in the reduction of these symptoms, particularly effective in acute
inflammatory responses (Bushra and Aslam, 2010). Mazaleuskaya et al. (2015) further
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explains that ibuprofen's affinity for lower pH environments enables it to accumulate
preferentially at inflamed sites, such as the joints, where inflammation typically lowers pH
(Mazaleuskaya et al. 2015).
Ibuprofen significantly lowers PGE2 levels, a specific prostaglandin heavily involved in the
inflammation pathway, thereby substantiating its role in dampening inflammatory
processes (Mazaleuskaya et al. 2015). Additionally, Study 4 highlights that ibuprofen
maintains higher concentrations in synovial fluid than in plasma for prolonged periods,
suggesting that ibuprofen's unbound state in the joint fluid enhances its therapeutic
efficacy in treating joint-related conditions like osteoarthritis by ensuring sustained drug
presence at the site inflammation (Adatia et al. 2012).

Efficacy

A comprehensive analysis, involving sixteen systematic

reviews and four meta-analyses, consistently found
ibuprofen superior to paracetamol in treating
osteoarthritis. Direct comparisons in osteoarthritis
specifically favoured ibuprofen, showing more effective
pain relief. Additionally, indirect comparisons corroborated
ibuprofen's effectiveness over paracetamol in
osteoarthritis, despite one nonspecific finding in tension-
type headaches due to methodological issues (Moore et
al. 2014). A systematic review of six large randomised
control trials have rigorously evaluated ibuprofen for hip
and knee osteoarthritis, comparing it to other NSAIDs and
placebo. It significantly improves WOMAC scores,
showing 50-60% better outcomes than placebo (Adatia et
al. 2012). Comparisons with newer NSAIDs like coxibs
reveal similar benefits, though ibuprofen can cause
gastrointestinal issues in short-term use. Its long-term
advantages over coxibs diminish, but it maintains a lower
or similar cardiovascular risk (Adatia et al. 2012).
Instead of simply confirming Ibuprofen's effectiveness,
there is a need for more research to determine the most
effective dosages. A smaller study by Gallelli et al. (2012),
Ibuprofen Pathway involving 40 participants, explored daily doses between
Mazaleuskaya et al. 2015 800mg and 1800mg. This study suggested that higher
doses were more beneficial, but it had limitations,
including its small size, lack of double-blinding, and short
duration of only 7 days.
Side Effects and Drug Nutrient
Depletions

Ibuprofen, less irritating than aspirin or indomethacin, frequently causes gastric discomfort,
nausea, and vomiting (Bushra and Aslam, 2010). Drugs.com (2023) notes its potential to
significantly increase the risk of fatal cardiovascular events, especially in those with pre-
existing heart conditions, and serious gastrointestinal issues like bleeding, ulceration, and
perforation, even at therapeutic doses, particularly in older adults.
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Ershad et al. (2024) emphasise severe gastrointestinal complications from ibuprofen, such
as stomach ulcers and bleeding. Ibuprofen's role as a nonselective COX inhibitor disrupts
prostaglandin production, impairing stomach lining protection and leading to mucosal
damage ranging from minor haemorrhages to substantial erosions or ulcers (Perry et al.
2014; Ershad et al. 2024).

Additionally, Ershad et al. report the risk of acute kidney injury from regular use or
overdose of ibuprofen, typically reversible with medical intervention, and central nervous
system toxicity in extreme overdoses, with symptoms ranging from mild depression to
coma and seizures.

Long-term ibuprofen use may lead to nutrient depletion, particularly of iron, due to
gastrointestinal bleeding (Meshikhes, 2021) and potentially folic acid, as a competitive
inhibitor of folate metabolism enzymes (Baggott et al. 1992). The prevalence of these
nutrient depletions is under documented, with more focus often on immediate health risks
than long-term nutritional impacts.

Table 1: Side Effects - Ibuprofen (oral)

Common mild side effects Abdominal pain, belching, heartburn,
nausea, diarrhoea, constipation, shortness
of breath, indigestion, vomiting, weight
gain, cloudy urnine, skin rash, pale skin,
acid or sour stomach.
Specific side effects
Gastrointestinal GI haemorrhage, gastritis, dyspepsia,
peptic ulcer, perforation, hematemesis,
exacerbation of colitis and Crohn’s disease.
Cardiovascular Haemorrhage, hypertension, hypotension,
cardiac failure, tachycardia, arrhythmia,
palpitations, vasculitis, sinus bradycardia,
angina pectoris, thrombotic events.
Nervous System Headache, dizziness, cerebrovascular
accident, syncope, drowsiness,
parenthesis, tremors, convulsions, coma.
Renal Acute renal failure, renal insufficiency,
cystitis, creatinine clearance decreased,
glomerulitis, tubular necrosis,
nephrotoxicity.
Respiratory Bacterial pneumonia, cough, asthma,
bronchospasm, dyspnea, wheezing, apnea,
respiratory depression, rhinitis, epistaxis.
Hepatic Hepatitis, Jaundice, hepatorenal syndrome,
liver necrosis, liver failure, abdominal liver
function.
(Drugs.com, 2024)
Curcumin Mode of action
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Curcumin is polyphenol derived from turmeric plant (curcuma longa) (Alok at al. 2015).
Turmeric contains three principal curcuminoids: curcumin (CUR; 77%),
demethoxycurcumin (DMC; 17%), and bisdemethoxycurcumin (BMC; 3–6%) (Zhang and
Kitts, 2021).

Most of its benefits stem from its antioxidant and anti-inflammatory properties (Hewlings
and Kalman, 2017), but similar to ibuprofen, it has analgesic properties (Hewlings and
Kalman, 2017; Lyngstad, 2021) as well as antipyretic effects (Haider, 2013).

Curcumin modulates the inflammatory response similarly to ibuprofen by downregulating

the activity of cyclooxygenase (COX-2) (Sivani et al. 2022). Additionally, curcumin inhibits
the production of inflammatory cytokines such as interferon, interleukins, and tumor
necrosis factor, suppresses the inducible nitric oxide synthase enzymes, and prevents the
activation of NF-κB (Ross, 2016).
Curcumin effectively manages pain not only by downregulating the activity of
cyclooxygenase-2 (COX-2), which is similar to ibuprofen's target, but also by inhibiting the
activation of transient receptor potential vanilloid 1 (TRPV1). This action helps reduce pain
by blocking one of the key pathways that transmit pain signals (Yeon et al. 2010).
Additionally, curcumin inhibits several other inflammation-related enzymes and cytokines,
enhancing its pain-relieving properties (Alok et al. 2015).

Turmeric has a significantly lower bioavailability compared to Ibuprofen (Daily, Yang and
Park, 2016) due to its rapid metabolism and systemic elimination (Gupta et al. 2013) but
unlike ibuprofen, which can damage the intestinal mucosa, curcumin has been shown to
have a positive effect on the gut lining (Wang, Ghosh and Ghosh, 2017; Ershad et al.
(2024).

Curcumin Efficacy

Three studies assessed the efficacy and safety of turmeric and curcumin in treating
arthritis symptoms, particularly osteoarthritis.

The first study, a systematic review and meta-analysis, evaluated turmeric extracts and
curcumin as potential anti-inflammatory agents with minimal side effects. It reviewed 8–12
weeks of treatment with turmeric extracts (typically 1000 mg/day), finding improvements
comparable to ibuprofen. However, the study faced limitations like small sample sizes (45–
124 participants) and moderate quality, indicating a need for larger, high-quality trials
(Daily, Yang and Park, 2016). One author's affiliation with a turmeric supplement
manufacturer (Daily Manufacturing, Inc.) may pose a conflict of interest.

The second study, a meta-analysis involving 1258 participants with primary knee
osteoarthritis, analysed curcuminoids' effectiveness on pain using the visual analogue
scale (VAS) and Western Ontario and McMaster Universities Arthritis Index (WOMAC).
This study found curcuminoids more effective than comparators in reducing pain without
significant dose-related efficacy or adverse events differences. Curcumin resulted in fewer
adverse events compared to NSAIDs, though significance was reached in only one
comparative study (Hsiao et al. 2021). However, risks of bias like incomplete blinding and
outcome data might affect results reliability; publication bias was detected via Egger’s test.

The third study involved 1621 participants across 15 RCTs, comparing Curcuma longa
extract and curcumin with placebos and NSAIDs. It reported improved VAS and WOMAC
scores for pain, function, and stiffness with fewer adverse events compared to NSAIDs.
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The combination with NSAIDs did not increase adverse events, suggesting a potential
synergistic benefit. Despite adherence to PRISMA guidelines for a comprehensive review,
variability in dosage, treatment duration, and participant characteristics may introduce
heterogeneity in the meta-analysis results.

Nutrient Two - Glucosamine

Mode of Action

Glucosamine, identified as 2-amino-2-deoxy-D-glucose hydrochloride, is crucial for

synthesising articular cartilage (Jerosch, 2011). It is found in structures such as tendons,
ligaments, and synovial fluids, playing an essential role in maintaining joint health
(Gasparella et al. 2023). Its primary action involves serving as a substrate for
mucopolysaccharide synthesis, essential for joint health (Kirkham, S. G. and
Samarasinghe, R. K. 2009).

Glucosamine sulfate is theorised to support joint health by stimulating glycosaminoglycans

and type II collagen production in chondrocytes, key for cartilage strength and elasticity
(Williams, C. and Ampat, G. 2023). This process aids in repairing damaged joints and
developing new cartilage, providing symptomatic relief in osteoarthritis (OA) (Petersen et
al. 2010; Gouze et al. 2006). It also potentially reduces inflammatory cytokines and
catabolic enzyme activity, balancing structural protein turnover and degradation in OA
joints (Williams, C. and Ampat, G. 2023).

In vitro studies suggest glucosamine's anti-inflammatory effects, including NF-kB inhibition

and PGE2 level reduction, often targeted by drugs like Ibuprofen (Chiusaroli et al. 2011).

Glucosamine sulfate's pharmacokinetics reveal a half-life of about 15 hours, with

preferential accumulation in joint tissues, enhancing its OA effectiveness (Henrotin et al.
2012; Persiani, 2005).

Efficacy

An interesting aspect of glucosamine's impact on joint health is its effect on serum COMP
(Cartilage Oligomeric Matrix Protein) levels. COMP is a vital component of the cartilage
matrix, and elevated serum levels are indicative of joint damage. Studies have shown that
glucosamine supplementation can reduce these serum COMP levels, suggesting a
protective effect on cartilage integrity (Petersen et al. 2010).

Clinical studies comparing glucosamine to non-steroidal anti-inflammatory drugs (NSAIDs)

like Ibuprofen have yielded promising results. For example, a study by Lopez Vaz in 2008
involved a double-blind comparison over eight weeks, which demonstrated that although
Ibuprofen reduced pain more quickly initially, glucosamine sulfate resulted in a greater
overall reduction in pain by the end of the study. Additionally, a 12-week randomised
controlled trial (RCT) by Petersen et al. (2010) showed that glucosamine significantly
decreased serum COMP levels during joint-loading exercises, unlike Ibuprofen or placebo,
indicating a beneficial effect on cartilage under stress.

Beyond symptomatic relief, research suggests that glucosamine may also slow the
progression of osteoarthritis itself, offering a distinct advantage over NSAIDs, which
primarily address symptoms without altering the disease trajectory (Chiusaroli et al. 2011).
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Given its favourable risk-to-reward profile, glucosamine remains a valuable component of
OA treatment strategies, providing both immediate relief and long-term benefits to joint
health.

Application to practice: Drug- Nutrient interactions

Neither the Medscape Drug Reference Database (2024) nor Drugs.com (2023) list any
major interactions between Ibuprofen and turmeric/curcumin or glucosamine. However,
there is evidence suggesting that caution may be necessary when Ibuprofen is taken with
high doses of turmeric.

Ibuprofen and Turmeric

Sasaki et al. (2017) developed in vitro cells to evaluate the impact of health foods on P450
enzymes, discovering that curcumin inhibits by more than 50% CYP2C9, the enzyme
responsible for metabolising Ibuprofen (Bagher, 2023). Therefore, using high doses of
turmeric alongside Ibuprofen may require reducing the dosage of Ibuprofen to prevent
overloading the liver.

Additionally, turmeric could increase the risk of bleeding when used with medications that
affect platelet function or coagulation such as Ibuprofen. In vitro date indicates that
curcumin may inhibit factors that activate platelets and reduce their clustering (Drugs.com,
2023).

Turmeric supports digestion and increases stomach acid, which could interfere with the
use of high-dose Ibuprofen but also offers protective properties for the gut lining, possibly
reducing the negative effects of Ibuprofen on the intestinal mucosa (Lopresti, 2018). These
effects mainly occur with very high doses of both turmeric and Ibuprofen, indicating that
careful dosage management is recommended rather than completely avoiding their
simultaneous use, especially considering the potential benefits and the risks associated
with long-term high-dose Ibuprofen use (Gupte et al. 2019). With the development of more
effective and bioavailable curcumin supplements, a transitional approach to their use may
be preferable to long-term concurrent administration (El-Saadony et al. 2022).

Ibuprofen and Glucosamine

In treatment protocols for osteoarthritis, NSAIDs and glucosamine are often primary
therapeutic agents (Petersen, 2010). Researchers at Temple University have discovered
that combining glucosamine with ibuprofen enhances pain relief, potentially allowing for
lower dosages and fewer side effects (Journal of Pharmacology and Experimental
Therapeutics, November 2003). This synergy could improve patient compliance and
efficacy in pain management without increasing side effects. While glucosamine alone
does not block pain, when used with ibuprofen, the combination shows a significant
synergistic effect, offering enhanced pain management. The study suggests that with
further clinical trials, this combination could provide effective pain relief with reduced risks
associated with high doses of NSAIDs (Tallarida, Cowan and Raffa 2023). The article does
not extensively discuss the mechanisms through which glucosamine might enhance the
efficacy of ibuprofen, which could be crucial for understanding and optimising the drug
combination. Furthermore, since the study was conducted on mice, the generalisability to
humans is uncertain until human clinical trials are conducted. Differences in metabolism,
side effects, and dosages between mice and humans can significantly alter the efficacy
and safety profile of the drug combination.
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Turmeric and Glucosamine

Due to the synergistic properties of turmeric and glucosamine, which are beneficial for joint
pain relief and cartilage health, there has been a marked increase in the number of
commercial brands offering formulations that combine these two compounds. The efficacy
of turmeric, primarily due to its anti-inflammatory compound curcumin (Ross, 2016), in
conjunction with glucosamine, known for its role in the synthesis and repair of cartilage
(Jerosch, 2011), creates a complementary mechanism that enhances their overall
effectiveness in treating joint-related ailments.
A double-blinded, randomised controlled study compared the effectiveness of a dietary
supplement combination of curcumagalactomannosides (CGM) (400 mg) and glucosamine
hydrochloride (GLN) (500 mg) with a standard combination of chondroitin sulfate (CHN)
(415 mg) and GLN (500 mg) in alleviating symptoms of osteoarthritis. Eighty participants
were divided into two groups, with one receiving CGM-GLN and the other CHN-GLN, twice
daily for 84 days. The effectiveness was assessed using a treadmill test, visual analogue
scale, Karnofsky Performance Scale, and the Western Ontario and McMaster Universities
Osteoarthritis Index. Results showed CGM-GLN significantly outperformed CHN-GLN in
reducing pain, stiffness, and improving physical function, nearly doubling the efficacy by
the study's end. Additionally, CGM-GLN significantly reduced levels of inflammatory
markers like IL-1β, IL-6, and sVCAM, demonstrating an enhanced anti-inflammatory effect
(Khanna, A. et al. 2020).
The study demonstrates a solid experimental design typical of clinical pharmacology
research, but its conclusions must be considered preliminary due to limitations in sample
size and study duration. Further larger-scale, multi-center studies would be valuable to
confirm these findings and assess long-term outcomes and safety.
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