Meloxicam, classified as a nonsteroidal anti-inflammatory drug (NSAID), serves as a therapeutic intervention for osteoarthritis and rheumatoid arthritis in adults, along with juvenile rheumatoid arthritis in the pediatric population. It effectively alleviates diverse forms of pain emanating from musculoskeletal ailments, osteoarthritis, and rheumatoid arthritis. [1] Benefiting from an extended half-life surpassing that of many other NSAIDs, meloxicam presents itself as a favorable choice for individuals seeking the convenience of once-daily dosing. The versatility of meloxicam is reflected in its availability across oral, transdermal, and intravenous formulations. Distinguished as a selective COX-2 inhibitor, it is purportedly positioned to diminish the likelihood of adverse effects on the gastrointestinal tract. Nonetheless, it is crucial to note that this aspect remains a contentious topic, generating ongoing debates and discussions. [2,3]
1.1 Chemical Taxonomy
Classification: This compound falls within the category of organic compounds referred to as benzothiazines. These compounds are characterized by the presence of a benzene ring fused to a thiazine ring, which consists of a six-membered structure comprising four carbon atoms, one nitrogen atom, and one sulfur atom.
Kingdom: Organic compounds
Super Class: Organoheterocyclic compounds
Class: Benzothiazines
Substituents: 2,5-disubstituted 1,3-thiazole / Alpha-amino acid or derivatives / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Benzothiazine / Carbonyl group / Carboxamide group / Carboxylic acid derivative
Molecular Framework: Aromatic heteropolycyclic compounds
External Descriptors: monocarboxylic acid amide, 1,3-thiazole, benzothiazine
Molecular Weight
Average: 351.401
Monoisotopic: 351.034747299
Chemical Formula: C14H13N3O4S2
1.2 Indications
Meloxicam finds its clinical indication in the symptomatic management of arthritis and osteoarthritis. Furthermore, it serves as a treatment option for both the pauciarticular and polyarticular manifestations of Juvenile Rheumatoid Arthritis (JRA) in patients aged 2 years and older. [4] Meloxicam is occasionally employed for off-label purposes, encompassing the alleviation of dental or post-surgical pain. Beyond its established indications, meloxicam has garnered attention through investigations into its potential for managing neuropathic pain. [1] The combined administration of meloxicam and bupivacaine holds an indication for postsurgical analgesia among adult patients, extending for a period of up to 72 hours subsequent to surgical procedures involving the foot and ankle, small-to-medium open abdominal regions, as well as lower extremity total joint arthroplasty. [5]
1.3 Pharmacodynamics
Prostaglandins are bioactive compounds that play a significant role in promoting and mediating the inflammatory response within the body. [6] This medication additionally demonstrates a selective impact on COX-2, potentially mitigating the gastrointestinal effects that could arise from its use. [7]
In human studies, meloxicam has exhibited the capacity to lower the erythrocyte sedimentation rate (ESR) in individuals with rheumatoid arthritis. Moreover, it has demonstrated the ability to reduce not only ESR but also C-reactive protein (CRP) levels, alongside a decrease in aquaporin-1 expression. [1] In human subjects, meloxicam has exhibited the capability to diminish the erythrocyte sedimentation rate (ESR) among individuals with rheumatoid arthritis. Furthermore, it has displayed the potential to reduce both ESR and C-reactive protein (CRP) levels, along with a concurrent decrease in the expression of aquaporin-1.[4]
Due to its selective inhibition of COX-2, meloxicam is believed to induce comparatively lower gastrointestinal irritation in comparison to other NSAIDs. However, it's important to note that meloxicam still entails a potential risk of instigating gastric inflammation, bleeding, and ulceration. [3, 4]
1.4 Mechanism of Action
Meloxicam acts as an inhibitor of prostaglandin synthetase enzymes (both cylooxygenase 1 and 2), resulting in a reduction in the synthesis of prostaglandins. These molecules typically play a role in mediating the distressing symptoms associated with inflammation. [6] Prostaglandins have the capacity to sensitize neuronal pain receptors, and by impeding their synthesis, a cascade of analgesic and anti-inflammatory effects is induced. Meloxicam exhibits a preference for inhibiting COX-2, yet it also demonstrates certain activity against COX-1, resulting in a potential for gastrointestinal irritation. [1, 4]
1.5 Pharmacokinetics:
1.5.1 Absorption
In a specific pharmacokinetic investigation, the absolute bioavailability of oral capsules following a dose was determined to be 89%. The peak plasma concentration (Cmax) was achieved approximately 5 to 6 hours subsequent to the administration of a solitary dose, specifically following the first meal of the day. Notably, the Cmax exhibited a twofold increase when the drug was administered under fasting conditions. Remarkably, despite this observation, meloxicam retains the advantage of being suitable for ingestion without necessitating consideration of food intake, setting it apart from numerous other NSAIDs. [1,4]
Meloxicam, when formulated for instillation alongside bupivacaine, yielded diverse systemic outcomes subsequent to a single administration of varying strengths. In patients undergoing bunionectomy, an administration of 1.8 mg meloxicam led to a maximum plasma concentration (Cmax) of 26 ± 14 ng/mL, a median time to reach peak concentration (Tmax) of 18 hours, and an area under the concentration-time curve (AUC∞) of 2079 ± 1631 ng*h/mL.
Conversely, for a 9 mg dose administered during herniorrhaphy, the corresponding figures were 225 ± 96 ng/mL for Cmax, a Tmax of 54 hours, and the AUC∞ was not specified. Lastly, in the context of total knee arthroplasty, a 12 mg dose yielded values of 275 ± 134 ng/mL for Cmax, a Tmax of 36 hours, and a substantially higher AUC∞ of 25,673 ± 17,666 ng*h/mL. [5]
1.5.2 Volume of Distribution (Vd)
Meloxicam exhibits a volume of distribution within the range of 10 to 15 liters. Due to its substantial affinity for binding to albumin, it is anticipated to be distributed predominantly in highly perfused tissues, with notable emphasis on organs such as the liver and kidneys. [1] Following an oral dose, the concentrations of meloxicam in synovial fluid are estimated to reach approximately 40% to 50% of the concentrations observed in the plasma. [4] This medication is recognized to traverse the placental barrier in humans. [8]
1.5.3 Plasma Protein Binding (PPB)
Meloxicam is about 99.4% protein bound, primarily to albumin. [1, 4, 7]
1.5.4 Metabolism
Meloxicam undergoes nearly complete metabolic transformation. The primary enzyme accountable for the metabolism of meloxicam is CYP2C9, [1,9] with minor contributions from CYP3A4. [4] Meloxicam generates four prominent metabolites, each devoid of determined activity. Approximately 60% of the administered dose undergoes metabolism to produce 5'-carboxy meloxicam, facilitated by hepatic cytochrome enzymes, through the oxidation of an intermediate metabolite known as 5’-hydroxymethylmeloxicam. [9,10] It is plausible that two additional metabolites are generated through a process of peroxidation. [4,9]
Meloxicam → 5'-hydroxymethyl meloxicam → 5’-carboxy meloxicam
1.5.5 Route of Elimination
The principal route of elimination for meloxicam is through metabolic processes. Its resultant metabolites are subsequently eliminated via both renal and fecal routes. [7] A minute fraction, specifically less than <0.25%, of the administered dose is excreted unchanged in the urine. [4] Approximately 1.6% of the parent drug is eliminated through fecal excretion. [1]
1.5.6 Half-life (T1/2)
The half-life of meloxicam is approximately 20 hours. [7] Its duration of action notably surpasses that of numerous other NSAIDs. As a result, there is no requisite for the utilization of slow-release formulations when dosing meloxicam. [1].
When administered concurrently with bupivacaine for postsurgical analgesia, meloxicam displayed a median half-life ranging from 33 to 42 hours, contingent upon the specific dose and site of application. [5]
1.5.7 Clearance
Following oral administration, the total clearance of meloxicam ranges from 0.42 to 0.48 L/h. [1,7] As per the FDA label, the plasma clearance of meloxicam is documented within the range of 7 to 9 mL/min. Notably, adjustments in dosing are unnecessary for individuals with mild to moderate renal or hepatic impairment. However, it's important to acknowledge that the utilization of meloxicam among patients with severe renal or hepatic impairment remains unexamined. In alignment with the FDA prescribing information, it is advised against under such circumstances. [4]
1.5.8 Adverse Effects
The utilization of meloxicam carries the potential for gastrointestinal toxicity and bleeding, as well as the occurrence of headaches, rash, and the presence of very dark or black stool, which serves as an indication of intestinal bleeding. It's important to note that meloxicam exhibits a comparatively lower incidence of gastrointestinal side effects when compared to diclofenac, [14] and perhaps all other NSAIDs which are not COX-2 selective.
In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy. [15,16]
Cardiovascular: Similar to other NSAIDs, the utilization of meloxicam is linked to an elevated risk of cardiovascular events, including incidents such as heart attacks and strokes. [17] While meloxicam does inhibit the formation of thromboxane A, it seems to achieve this effect at levels that do not significantly interfere with platelet function. [18,19] In a comprehensive analysis that pooled data from various randomized, controlled studies spanning meloxicam therapy for a duration of up to 60 days, noteworthy findings emerged. Meloxicam showcased a statistically significant decrease in the occurrence of thromboembolic complications compared to the NSAID diclofenac, with rates of 0.2% and 0.8%, respectively. However, when juxtaposed with naproxen and piroxicam, meloxicam exhibited a comparable incidence of thromboembolic events. [20] Individuals with pre-existing conditions such as hypertension, elevated cholesterol levels, or diabetes are particularly vulnerable to experiencing cardiovascular side effects. Moreover, those with a family history of heart disease, heart attack, or stroke are advised to inform their attending physician, as the potential for severe cardiovascular side effects is noteworthy and warrants significant attention. [21]
Gastrointestinal: NSAIDs contribute to and escalate the likelihood of encountering severe gastrointestinal adverse events, encompassing issues like bleeding, ulceration, and perforation within the stomach or intestines, which can culminate in fatal outcomes. Elderly patients, in particular, face an elevated risk of experiencing these grave gastrointestinal events. [22]
1.5.9 Toxicity
The oral LD50 in rats is 98 mg/kg. [11] An overdose of meloxicam can manifest through various signs and symptoms, including shallow breathing, seizures, diminished urine output, gastrointestinal irritation, nausea, vomiting, gastrointestinal bleeding, as well as the presence of black, tarry stools. [12] In the event of an overdose, the recommended approach involves providing supportive treatment while also considering the removal of gastrointestinal contents. Notably, cholestyramine has demonstrated the capacity to augment the elimination of meloxicam and could be considered as a potential intervention. [11]
Specific populations (Geriatrics)
The utilization of meloxicam is cautioned against in individuals with peptic ulcer disease or an elevated risk of gastrointestinal bleeding. This pertains particularly to those aged 75 years and above, as well as those concurrently taking medications linked to an increased bleeding risk. It's worth noting that adverse events related to meloxicam have been observed to be contingent upon the dosage and duration of treatment. [13