Ketorolac

non-selective COX-1/COX-2 NSAID, Series 7

Also sold as Toradol.

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Findings for this medication

Research about this medication, graded for how strongly each finding can be attributed to it. Nothing here describes your own levels.

Ketorolac has no classical depletion machinery. It is not an enzyme inducer or inhibitor (the label states there is no evidence it induces or inhibits hepatic enzymes), about 92% of a dose is recovered in urine (about 60% unchanged, about 40% as hydroxylated and conjugated metabolites), and the label names no vitamin, mineral or other nutrient anywhere in the text read [1]. Use is capped by the label at 5 days combined across routes, which sharply limits the time available for any slow nutrient effect. Every real signal here is a toxicity of the drug's own pharmacology, not a dietary deficiency: gastrointestinal bleeding, platelet inhibition, and prostaglandin-dependent renal effects. Those are written as outcome or retention entries with direction stated, never as a nutrient to be replaced.

non-selective COX-1/COX-2 NSAID, Series 7 · ATC M01AB15 systemic, S01BC05 ophthalmic (WHO, via [2]) · also sold as Toradol and Sprix (nasal) and Acular (ophthalmic); many generics · reviewed 2026-10-07. This describes research about the medication. It does not say anything about your own levels or health.

How to read the evidence grades

These colours describe how strongly a finding can be attributed to the medication in the research. They are not a severity score and they say nothing about your own health.

Grades describe how strongly a finding can be attributed to Ketorolac in the research — not how common it is, how serious it would be, and not anything about you personally.

Red — Severe: Two or more independent Tier A sources, this drug in the cohort, the nutrient directly measured, consistent direction, clinically meaningful magnitude, a named mechanism, no substantial contradicting Tier A evidence.
Orange — Moderate: At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit.
Yellow — Low: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction.
Not graded — disclosed evidence gap: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result.Source definition: Not gradeable under the rules above because nothing has been measured. Published as a documented gap, never as reassurance that there is no effect.

What the research found

Platelet function and hemostasis: the drug's own reversible antiplatelet effect (mechanism clarification, not a nutrient)

Yellow — Low

See study details

Direction: ketorolac inhibits platelet aggregation and prolongs bleeding time by design of its COX-1 inhibition. This is a pharmacologic effect that explains the bleeding entries; no nutrient is involved and none is depleted.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow

Limits on what this shows

Null findings: Bleeding times mostly stayed in the normal range in healthy volunteers [6]. No increase in perioperative bleeding in the RCT meta-analysis (OR 1.1, 95% CI 0.61 to 2.06; 27 RCTs, 2,314 patients) [5].

Regulatory status

Label: NSAIDs "inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible." Contraindicated in suspected or confirmed cerebrovascular bleeding and hemorrhagic diathesis [1].

Population evidence

Spowart 1988 [6]: double-blind, placebo-controlled crossover in 12 healthy men; ketorolac alone and with low-dose heparin significantly prolonged bleeding time, inhibited platelet aggregation to arachidonic acid and collagen, and reduced platelet thromboxane production; almost all subjects stayed within the normal bleeding-time range (abstract via summarizing fetch). Singer 2003 [7]: 20 healthy volunteers, IM ketorolac, bleeding time rose from a mean 3 min 34 s to 5 min 20 s at 4 hours (about 50%).

Mechanism

Named: inhibition of platelet thromboxane production through COX-1 [1][6].

Counter-evidence held on record

Counter-evidence and confounding Under Hard Rule 2 a drug's intended pharmacologic effect is not a deficiency. It is listed because it is one of the requested angles and because it prevents the bleeding entries from being read as nutrient findings. Framing caution Not a nutrient entry and not a supplement prompt. Vitamin K, iron or other supplements are not indicated by this finding; bleeding risk questions go to the prescriber.

Potassium: retention risk (direction: excess), bounded to renal vulnerability, with a Tier A null cohort

Yellow — Low

See study details

The documented relationship is potassium retention and hyperkalemia in vulnerable patients, not depletion. Supplementation or salt substitutes would be the hazard, not the remedy.

Full detail and limits

Limits on what this shows

Null findings: Lafrance and Miller 2012 [10]: nested case-control in US Veterans Affairs patients, 18,326 moderate to severe hyperkalemia cases and 355,106 matched controls. Single NSAID use overall adjusted OR 1.03 (95% CI 0.98 to 1.08). Elevated risk for rofecoxib, celecoxib, diclofenac and indomethacin, but not for meloxicam, etodolac, piroxicam, sulindac, ibuprofen, naproxen or ketorolac. Ketorolac was in the cohort and its individual OR was not read (abstract via a PubMed listing summary). Dispensing data may under-represent short inpatient injectable exposure (my inference, not stated by the authors).
At-risk subgroups: Advanced renal impairment, volume depletion, patients dependent on prostaglandin-mediated renal perfusion, older adults [1][8].

Regulatory status

Hyperkalemia is listed as a rare adverse reaction ("Metabolic and Nutritional": hyperglycemia, hyperkalemia, hyponatremia). The renal warning describes reduced prostaglandin formation lowering renal blood flow; the label text read gave no stated potassium mechanism [1].

Population evidence

Pearce 1993 [8]: case series of 3 patients given injectable ketorolac who developed acute renal failure, hyperkalemia or both; two reversed on discontinuation; each had a pre-existing condition that depended on prostaglandin-mediated renal perfusion (abstract via an index record). Kim 2023 [11]: retrospective propensity-matched cohort (3,239 reviewed, 641 per group) after robot-assisted prostatectomy; AKI 31.5% with ketorolac-based PCA versus 22.6% with fentanyl PCA (OR 1.574, 95% CI 1.227 to 2.019); potassium was not reported. IJNRD 2017 [16]: 4 of 1,397 young adults (0.29%) had AKI after orthopedic day surgery, recovering in 3 to 6 weeks; potassium not reported. A narrative review [15] states that acute renal failure after ketorolac is usually reversible on stopping and does not discuss hyperkalemia.

Mechanism

Plausible through the renal prostaglandin pathway for the NSAID class; the label read does not name hyporeninemic hypoaldosteronism and no ketorolac mechanistic study of potassium handling was located.

Circulating claim

A consumer page cites a case of a 50-year-old man with high potassium after 8 days of ketorolac and advises avoiding potassium supplements and salt substitutes (case report, no citation) [29]. The direction matches this entry.

Counter-evidence held on record

Counter-evidence and confounding The Tier A cohort was null for ketorolac; cases are in renally vulnerable patients; AKI is itself an outcome and a competing explanation for hyperkalemia. Dispensing-based data may miss inpatient IV exposure. Framing caution This is an excess and retention risk. Do not increase potassium intake or add potassium supplements or salt substitutes on this basis; do the opposite, and defer to the prescriber when kidney function is reduced or other potassium-raising drugs (ACE inhibitors, ARBs) are in use.

Sodium and fluid: dilutional hyponatremia and fluid retention (direction: excess water), single case level

Yellow — Low

See study details

The signal is water retention through prostaglandin and ADH interplay, not a dietary sodium shortfall. It must never be read as advice to raise sodium or fluid intake.

Full detail and limits

Limits on what this shows

Null findings: None measured in ketorolac cohorts. The same case had competing contributors: pain, possible alcohol withdrawal, concurrent analgesics and COPD [9].
At-risk subgroups: Older adults, patients receiving IV fluids or other ADH-potentiating drugs, those with lung disease or hypovolemia.

Regulatory status

Hyponatremia is a rare adverse reaction; "fluid retention and edema have been observed in some patients treated with NSAIDs"; weight change is listed as a common reaction [1].

Population evidence

Case report [9]: 65-year-old man with COPD and hypertension given IV ketorolac 30 mg once or twice daily for 6 days; sodium 135 mmol/L to 122 on day 5 to 117 on day 6 with altered mental status; urine osmolality 517 mmol/kg; sodium returned to 130 to 140 mmol/L within 2 days of stopping ketorolac and fluid restriction. The authors call it the first reported SIADH case linked to ketorolac. No cohort or trial measuring sodium in ketorolac users was located.

Mechanism

Proposed by the case authors: renal prostaglandin inhibition removes the counterweight to ADH, potentiating antidiuresis [9]. Label notes fluid retention for the class [1].

Circulating claim

A consumer NSAID page says most NSAIDs "may deplete sodium" [30]. Direction is reversed for this mechanism; see Fails verification.

Counter-evidence held on record

Counter-evidence and confounding One case report with confounders; label frequency is rare. Framing caution This is dilutional (excess water) hyponatremia and fluid retention. Salt or sodium supplements are not the remedy and could be harmful with edema or hypertension; any fluid change belongs to the prescriber.

Folate: CLASS EXTRAPOLATION from in vitro enzyme inhibition; ketorolac was not in the cohort

Yellow — Low

See study details

Several NSAIDs competitively inhibit folate-dependent enzymes in vitro, but ketorolac was not among the drugs tested and no folate level was measured in ketorolac users.

Full detail and limits

Limits on what this shows

Null findings: None located in humans. Searches for NSAID and folate or homocysteine status returned unrelated papers (methotrexate and B12 in rheumatoid arthritis; a vitamin supplement epidemiology study) in which NSAIDs and ketorolac were not examined.

Regulatory status

No folate text in the label sections read. The label's methotrexate statement (NSAIDs "could enhance the toxicity of methotrexate") is a drug-on-drug interaction, not a folate depletion, and is not graded here [1].

Population evidence

None for ketorolac. Class source [17]: Biochemical Journal 1992 study, in vitro with human blood-cell systems; NSAIDs found to be competitive inhibitors (with respect to folate) of folate-dependent enzymes were sulphasalazine, sulindac, indomethacin, naproxen, salicylic acid, ibuprofen, piroxicam and mefenamic acid; aspirin, acetaminophen and antipyrine were weaker. Ketorolac was not tested. The summary states stronger antifolate activity tracked stronger anti-inflammatory activity (summarizing fetch of the full-text page).

Mechanism

Plausible but untested for ketorolac: competitive inhibition of folate-dependent enzymes. In vitro inhibition constants versus the 0.87 µg/mL human peak concentration [1] were not compared in the text read.

Class cohort test

CLASS EXTRAPOLATION. Cohort test: ketorolac absent from the cohort [17]. It is retained at yellow only because a real Tier C class study exists and the mechanism is at least plausible; it cannot rise above yellow and no human deficiency is implied.

Counter-evidence held on record

Counter-evidence and confounding In vitro enzyme inhibition does not establish a lowered circulating or tissue folate level. A 5-day course is unlikely to deplete stores even if inhibition occurs; this is reasoning, not a finding. Framing caution Not a deficiency claim for ketorolac. No folic acid supplement is recommended from this entry. Methotrexate co-use is a separate prescriber question.

The five body-system areas

Each finding is counted once, in a single area. Where a study is mentioned in a second area it is context only.

Mitochondrial Burden

Each finding below is counted once, in this area only.

Mitochondrial burden: in vitro and rodent signals at concentrations above clinical exposure

Yellow — Low

See study details

Ketorolac depolarized mitochondria and impaired mitochondrial function in several cell and isolated-organelle models, mostly at high concentrations; no human mitochondrial measurement was found.

Full detail and limits

Limits on what this shows

Null findings: Chavez 1993 [23]: ketorolac induced mitochondrial calcium release without affecting oxidative phosphorylation (listing snippet only; abstract not read). van Leeuwen [24]: ketorolac among eight NSAIDs in a yeast system, described in a listing snippet as relatively non-toxic (abstract not read). Zadori [28]: no mucosal damage at 1 and 3 mg/kg for 4 weeks in rats.
At-risk subgroups: Not defined. Hepatic or renal impairment raises exposure (longer half-life) but no mitochondrial subgroup data exist.

Regulatory status

No mitochondrial text in the label sections read [1].

Population evidence

Sodano 2021 [18]: human primary colonic epithelial cells exposed to ketorolac 1, 2.5 and 5 mM for 24 to 72 hours; JC-1 assay showed depolarization "three times higher than that in untreated cells"; a galactose conjugate (ketogal) did not. In mice, 5 days of oral ketorolac 10 mg/kg caused small intestine erosion and liver microvesicular steatosis. Browne 1999 [20]: the title states ketorolac, ibuprofen and flurbiprofen inhibit hepatic mitochondrial beta-oxidation and oxidative phosphorylation, stereoselectively, in isolated rat mitochondria (abstract not retrieved; a listing snippet said high concentrations, uncoupling). Lal 2009 [19]: ketorolac was one of five NSAIDs tested in rat liver mitochondria under tert-butyl hydroperoxide stress; the direction for ketorolac was not read. Kumar IUBMB Life [21]: ketorolac "depolarized mitochondrial membrane potential" and released cytochrome c with proteasome disturbance (metadata only; cell model and concentration not read).

Mechanism

Present in vitro: loss of membrane potential, permeability transition under oxidative stress, impaired beta-oxidation. Concentration context: the label's mean peak after a 10 mg oral dose is 0.87 µg/mL [1], roughly 3 to 4 µM by my arithmetic using about 255 g/mol for the free acid (molecular weight not retrieved from the label), so 1 to 5 mM in [18] is on the order of 300 to 1,500 times higher.

Counter-evidence held on record

Counter-evidence and confounding Concentrations far exceed clinical plasma levels, models are non-human or cultured cells, and the label limits use to 5 days. Direction varies across studies (null or non-toxic reports exist). Framing caution Mechanistic signal only; not evidence that ketorolac damages mitochondria in patients, and no antioxidant or mitochondrial supplement is recommended from it.

Oxidative Stress

Each finding below is counted once, in this area only.

Oxidative stress: mixed direction, raised in toxicity models and lowered in inflammation models

Yellow — Low

See study details

Ketorolac raised reactive oxygen species and lipid peroxidation in some models and lowered ROS and raised SOD in others; no human tissue redox measurement was opened.

Full detail and limits

Limits on what this shows

Null findings: None in humans opened. A PubMed listing for ketorolac and oxidative stress also listed rat gastric ulcer studies reporting raised oxidative stress, a canine ophthalmic study with higher MDA, and a human laparoscopic preemptive analgesia study reporting lower oxidative indicators; none of these were opened and none are relied on.
At-risk subgroups: Not defined.

Regulatory status

No antioxidant or oxidative stress text in the label sections read [1].

Population evidence

Raised: Sodano 2021 [18], ROS "remarkably high" in ketorolac-treated human colonic epithelial cells (1 to 5 mM). Galar-Martinez 2016 [27]: common carp exposed to 1 and 60 µg/L; increased lipid peroxidation, hydroperoxides and protein carbonyls in liver and brain, altered SOD, catalase and glutathione peroxidase activity, time and concentration dependent (environmental toxicology; relevance to human dosing is indirect). Lowered: Liu and Chen 2022 [25], IL-1 beta injured ATDC5 chondrocytes, ketorolac reduced ROS and NO and raised SOD activity (reconstructed abstract). Javdani 2023 [26], rat tibial bone defect with a chitosan hydrogel loaded with buprenorphine and ketorolac: oxidative stress parameters decreased, most in the ketorolac group, authors suggest an antioxidant property (local delivery, formulation confounded).

Mechanism

Raised-direction: mitochondrial depolarization and ROS leakage (shared with the mitochondrial entry). Lowered-direction: reduced COX-2 and inflammatory signaling in injured cells [25]. Neither shown in people.

Counter-evidence held on record

Counter-evidence and confounding The opposing directions are themselves the main counter-evidence. Models differ in tissue, concentration and disease state, and the fish study is an environmental exposure. Framing caution No antioxidant supplementation is implied. This is a research flag with unresolved direction, not a depletion of antioxidant nutrients.

Copper and Iron Balance

Copper and iron are assessed separately. Nothing here is counted twice.

Iron: blood-loss pathway through GI bleeding, bounded to long courses, older age and high dose

Yellow — Low

See study details

Direction: loss of blood (and therefore iron) through drug-induced GI bleeding, a toxicity of the drug's own COX inhibition. It is not an absorption or storage effect, and no source measured iron status in ketorolac users.

Full detail and limits

Limits on what this shows

Null findings: No retrieved study measured ferritin, transferrin saturation or iron-deficiency anemia in ketorolac users. A PubMed listing search ("ketorolac iron deficiency OR ferritin") returned only ferritin chemistry and unrelated papers in its first 10 results (listing summary only). Overall GI bleeding in the Strom cohort did not differ materially from opioids (4% versus 3.6%) [4]. A meta-analysis of 27 RCTs (2,314 patients) found postoperative bleeding with ketorolac OR 1.1 (95% CI 0.61 to 2.06) [5].
At-risk subgroups: Courses beyond 5 days, age 75 and over, high daily dose, prior ulcer or GI bleeding (a contraindication), concurrent aspirin or NSAIDs (a contraindication) [1][4].

Regulatory status

Boxed warning: ketorolac "can cause peptic ulcers, gastrointestinal bleeding and/or perforation"; contraindicated in active peptic ulcer disease or recent GI bleeding. The label says "the risk of clinically serious GI bleeding was dose-dependent" and that anemia in NSAID patients "may be due to fluid retention, occult or gross GI blood loss," advising hemoglobin or hematocrit checks if signs or symptoms appear. The label names no iron effect [1].

Population evidence

Castellsague 2012 [3]: systematic review and meta-analysis of observational studies (28 studies in the meta-analysis), ketorolac pooled RR for upper GI complications 11.50 (95% CI 5.56 to 23.78) versus non-use; only the abstract was read through a summarizing fetch. Strom 1996 [4], as described in a secondary pharmacy summary (primary article not opened): 10,272 ketorolac courses against 10,247 opioid courses in 35 hospitals; GI bleeding 4% versus 3.6% and clinically important bleeding 2.1% versus 1.9% overall; courses beyond 5 days OR 2.20 (all GI bleeding) and 2.72 (clinically important); increased risk at age 75 and over; 105 to 120 mg/day in patients over 65 doubled GI bleeding. Case report [14]: 70-year-old man given 30 mg IM twice daily, GI bleeding on postoperative day 4, hemoglobin 62 g/L.

Mechanism

Present: prostaglandin synthesis inhibition in gastric mucosa plus platelet inhibition (see platelet entry). Rodent data are dose dependent: no small intestinal mucosal damage at 1 and 3 mg/kg for 4 weeks, mild inflammation at 10 mg/kg [28]; erosion and vacuolation in mouse small intestine after 5 days at 10 mg/kg oral [18].

Circulating claim

Consumer pages state "NSAIDs cause gastrointestinal (GI) irritation, bleeding, and iron loss" (no reference given) [29] and "may deplete iron" [30]. Both are Tier D class statements. See Fails verification for the absorption or stores framing.

Counter-evidence held on record

Counter-evidence and confounding Why not orange: GI bleeding is an outcome and anemia is not iron deficiency (Hard Rule 2); iron was never measured; the allowed exposure is 5 days or less; and the largest hospital cohort showed no overall excess over opioids. Confounding by indication is presumed: surgical patients bleed for surgical reasons, and Strom compared against another analgesic, not non-use. Framing caution This is a bleeding-risk flag, not an iron-deficiency claim. Do not recommend iron supplementation from this entry. New anemia, black stools or vomiting blood during or after ketorolac calls for medical evaluation of bleeding.

Copper

Not graded — disclosed evidence gap

See study details

No evidence was found that ketorolac changes copper absorption, serum copper, ceruloplasmin or copper handling.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

Why no grade: Dual condition met: no Tier B or Tier C source on ketorolac and copper was opened to support even a yellow grade, and no circulating consumer claim about ketorolac and copper was found to rebut. This is a disclosed gap, not a finding of safety. Re-check PubMed with "ketorolac" plus copper, ceruloplasmin and trace elements when access is restored. Copper is kept separate from the iron entry under Hard Rule 7.

What was searched

Web search "ketorolac copper serum copper OR ceruloplasmin OR copper complex NSAID copper status": results were generic ceruloplasmin pages and a review of copper complexes of NSAIDs as drug candidates (coordination chemistry, not copper status in patients); none concerned ketorolac effects on copper status, and none were opened. A general web search for ketorolac nutrient depletion surfaced consumer pages naming iron, sodium, potassium, folate (sulindac), vitamin C (diflunisal) and B12 (aspirin), never copper. The label sections read named no copper effect [1].

Channel outcomes

PubMed listing "ketorolac copper": 429 rate limit (twice); PubMed listing "ketorolac ceruloplasmin serum copper": 429; OpenAlex search listing: 429; Crossref: 429; Europe PMC REST: 429. WebSearch was then exhausted (shared budget). DailyMed: zero results then 429. A genuine literature gap is likely, but the primary databases could not be searched for copper, so this is partly tooling-limited.

Gut Microbiome Risk

Each finding below is counted once, in this area only.

Gut microbiome risk: rat small intestinal dysbiosis after 4 weeks, human data absent

Yellow — Low

See study details

In rats, 4 weeks of oral ketorolac altered the small intestinal microbiota and bile acids without mucosal damage or slowed transit; no human microbiome study of ketorolac was found.

Full detail and limits

Limits on what this shows

Null findings: Diversity index unchanged; transit unchanged; no mucosal damage up to 3 mg/kg [28]. No human 16S or fecal microbiota data for ketorolac were located (web search for ketorolac with microbiome, 16S or dysbiosis returned only this rat study and aspirin or class-level papers; a class NSAID microbiome paper, PMC4754147, returned a bot-verification page and was not read).
At-risk subgroups: Not defined for humans.

Regulatory status

No microbiome text in the label sections read [1].

Population evidence

Zadori 2021 [28]: male Wistar rats, 10 per group, oral gavage 1, 3 and 10 mg/kg once daily for 4 weeks. At 3 mg/kg: loss of Firmicutes families (Paenibacillaceae, Clostridiales Family XIII, Christensenellaceae) and increased Enterobacteriaceae; Shannon diversity not significantly different. Conjugated bile acids fell, hyodeoxycholic acid rose, unconjugated-to-total ratio rose, total bile acids unchanged. Mucosal damage only at 10 mg/kg (mild inflammation, raised myeloperoxidase). GI transit unchanged.

Mechanism

Not identified. The authors excluded mucosal damage (at 3 mg/kg or less), direct antibacterial effect and delayed transit as explanations and said other unidentified factors may contribute [28].

Counter-evidence held on record

Counter-evidence and confounding Four weeks of dosing exceeds the label's 5-day cap, rodent-to-human translation is uncertain, and a small intestinal sample in rats is not a fecal human microbiome. Framing caution Not a finding about people. No probiotic or prebiotic recommendation follows from this entry.

Oxygen and ATP Output

Oxygen delivery and ATP production are assessed separately. Nothing here is counted twice.

Oxygen delivery/utilization: hemoglobin fall from bleeding, bounded to case-level and genotype-subgroup data (outcome, not a nutrient)

Yellow — Low

See study details

Direction: reduced hemoglobin (and so oxygen-carrying capacity) as a consequence of bleeding. This is a drug toxicity outcome. Ketorolac has no described mechanism that lowers oxygen utilization or tissue oxygenation directly.

Full detail and limits

Limits on what this shows

Null findings: Tabrizian 2019 [12]: 862 laparoscopic donor nephrectomy patients (469 given IV ketorolac 15 to 30 mg every 6 hours), concluded no association with increased postoperative bleeding or renal dysfunction (reconstructed abstract; carefully selected healthy donors, bleeding over 700 mL excluded). RCT meta-analysis OR 1.1 for postoperative bleeding [5]. A PubMed listing search for ketorolac with hemolytic anemia or methemoglobinemia returned only general methemoglobinemia reviews, none mentioning ketorolac (listing summary only). Listing snippets of two pediatric and one hysterectomy study reported no clinically significant hemoglobin change; those papers were not opened and are not relied on.
At-risk subgroups: Older adults, long or high-dose courses, CYP2C9 reduced-function carriers (single confounded study), anyone with prior GI bleeding.

Regulatory status

Label adverse reactions list, at rare frequency, "agranulocytosis, aplastic anemia, hemolytic anemia, lymphadenopathy, pancytopenia," and state that anemia is sometimes seen with NSAIDs. No methemoglobin text was found in the label sections read [1].

Population evidence

Muradian 2021 [13]: observational study, 107 patients after laparoscopic cholecystectomy given tramadol plus ketorolac; relative hemoglobin decrease greater in CYP2C9*2 and *3 carriers (reported differences 1.7, p=0.00268, and 2.2, p=0.000143, versus wild type; units not stated in the reconstructed abstract). No ketorolac-free comparison group and tramadol co-exposure, so it cannot isolate ketorolac. Case report [14]: hemoglobin 62 g/L after ketorolac-associated ulcer bleeding at above-recommended dosing.

Mechanism

Present for blood-loss anemia (see iron and platelet entries). For hemolysis, a label listing only; no mechanism or case series was located.

Counter-evidence held on record

Counter-evidence and confounding The hemoglobin signal in Muradian is confounded by surgery, hemodilution and tramadol, and no unexposed arm exists. The Tier A cohort and RCT data are null for bleeding in selected populations. Framing caution Hemoglobin loss here is a bleeding outcome. It is not an oxygen-delivery nutrient deficiency and does not call for iron or other supplements; it calls for assessing the bleeding source.

ATP production: possible impairment in vitro and rat gastric tissue, abstracts largely unread

Yellow — Low

See study details

Isolated-mitochondria and rat gastric studies point to impaired oxidative phosphorylation or pyruvate dehydrogenase function with ketorolac, but one study found no effect on oxidative phosphorylation, and nothing was measured in people.

Full detail and limits

Limits on what this shows

Null findings: Chavez 1993 [23] reported mitochondrial calcium release "without affecting oxidative phosphorylation" (listing snippet only; abstract not read). No human or in vivo systemic ATP measurement was located.
At-risk subgroups: Not defined.

Regulatory status

No energy-metabolism text in the label sections read [1].

Population evidence

Browne 1999 [20]: isolated rat hepatic mitochondria; per the title, ketorolac, ibuprofen and flurbiprofen inhibit beta-oxidation and oxidative phosphorylation stereoselectively (abstract not retrieved; a listing snippet said high concentrations, uncoupling). Majumder 2025 [22]: rat model of ketorolac-induced gastric ulcer with melatonin protection; a listing snippet said ketorolac disrupted mitochondrial pyruvate dehydrogenase, reducing ATP production and raising free radicals (OpenAlex record had no abstract; study not opened beyond that). Sodano 2021 [18] reported mitochondrial depolarization but did not report ATP or oxygen consumption.

Mechanism

Proposed: uncoupling or inhibition of oxidative phosphorylation, and PDH disruption. Shares its evidence with the mitochondrial entry (see Overlap map).

Counter-evidence held on record

Counter-evidence and confounding Conflicting in vitro results, supraclinical concentrations in the isolated-mitochondria work (per listing snippet), and the central source for the PDH and ATP claim is a listing summary, not a read abstract. Fatigue or "low energy" is not established by any of this. Framing caution Mechanistic flag only. No energy-support supplement is implied, and ATP effects must not be presented as a patient finding.

Claims checked and not supported

These circulate online for this medication. They are listed here only so they can be answered, never as findings, and they are not graded.

A claim with no supporting evidence is not necessarily disproven. Where evidence actually argues against a claim, that is stated below.

Iron depletion as an absorption or stores problem
Where it comes from: Consumer pages: "NSAIDs cause GI irritation, bleeding, and iron loss" (no reference) [29]; "Taking nonsteroidal anti-inflammatory drugs may deplete iron" [30].
Why it fails: Tier D, class-level, unreferenced. The label lists no iron interaction and no absorption mechanism, and ketorolac is limited to 5 days [1]. The real signal is blood loss through GI bleeding in bounded subgroups, filed as a yellow outcome entry. No study measured iron status in ketorolac users. The depletion framing fails; the bleeding finding is kept separately.
Sodium depletion needing more sodium
Where it comes from: Consumer NSAID page: most NSAIDs "may deplete sodium" (confusion, cramps) [30].
Why it fails: Direction is reversed for the one documented mechanism: ketorolac-associated hyponatremia is dilutional (SIADH-type water retention, urine osmolality 517 mmol/kg) [9][1]. Raising sodium intake is not the remedy. Tier D claim, no ketorolac-specific citation.
Vitamin B12, vitamin C and folate "depletion" read across from other NSAIDs
Where it comes from: Nutrient depletion chart rows naming aspirin (B12, vitamin C) [31]; a consumer page naming sulindac (folate) and diflunisal (vitamin C) [30].
Why it fails: These claims are about other drugs. Ketorolac is not named in the chart [31] or in the folate or vitamin C statements [30]. No ketorolac B12 or vitamin C source was found at any tier. The folate class-level enzyme paper [17] did not test ketorolac and is handled only as a yellow class extrapolation.

How the body handles this medication

Metabolism and enzymes: "Largely metabolized in the liver"; products are hydroxylated and conjugated forms of the parent drug. The label states there is no evidence in animal or human studies that ketorolac induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs. No CYP induction or inhibition is described.[1] label, clinical pharmacology and drug interactions (summarizing fetch)
Elimination: Principal route is renal: about 92% of a dose in urine, about 60% unchanged and about 40% as metabolites. Half-life is about 2.5 hours for the S-enantiomer and 5 hours for the R-enantiomer; mean half-life in renal impairment is 6 to 19 hours depending on severity; 99% plasma protein binding.[1]
Absorption: Label: "100% absorbed" after oral dosing; mean peak after a 10 mg tablet 0.87 +/- 0.22 µg/mL. A high-fat meal lowers the peak and delays time-to-peak by about 1 hour; antacids did not affect extent of absorption. No named absorption transporter appears in the text read.[1]
Renal handling of water and electrolytes: Label: reduced prostaglandin formation can decrease renal blood flow; volume depletion should be corrected before use; "fluid retention and edema" are noted for NSAIDs; hyperkalemia and hyponatremia are listed as rare reactions. Contraindicated in advanced renal impairment and in patients at risk for renal failure.[1] boxed warning, warnings, adverse reactions
Accumulation and limits: Combined duration across ketorolac routes must not exceed 5 days; tablets are continuation therapy after IV or IM dosing, and daily maximum is 40 mg in adults. Dose adjustment needed at 65 and over (half-life rises to about 7 hours). No significant PK difference in 7 patients with liver disease. Not indicated in pediatric patients; avoid at about 30 weeks gestation and later.[1] (tablet label only; injectable and nasal labels not read)
Documented interactions: Contraindicated with probenecid, pentoxifylline, aspirin and other NSAIDs. NSAIDs raise plasma lithium and may enhance methotrexate toxicity; they may blunt ACE inhibitor and ARB effects. Interaction direction is drug-on-drug; no food, mineral or antacid interaction of nutritional consequence is listed.[1]

What the research says is worth watching

General information from the medication label and the studies above. It is not personal medical advice, and any change belongs with your prescriber.

Clinical signs / labs
Bleeding and hemoglobin
The label advises hemoglobin or hematocrit checks when signs or symptoms of anemia or bleeding appear. Watch for black or bloody stools, vomiting blood, and new fatigue or pallor, especially beyond day 5, at age 75 or over, or at higher doses [1][4]. Ferritin and iron indices only if anemia is documented; the finding is a bleeding evaluation, not an iron supplement prompt.
Lab / volume status
Kidney function
Serum creatinine and volume status in older adults, dehydration, heart failure, cirrhosis or when ACE inhibitors, ARBs or diuretics are co-prescribed. Label contraindicates use in advanced renal impairment or risk of renal failure and advises correcting hypovolemia first [1].
Lab / retention
Serum potassium
Consider checking when kidney function is reduced or other potassium-raising drugs are present. Avoid adding potassium supplements or salt substitutes without a prescriber. This is a retention risk, not a depletion [1][8]; the large cohort was null for ketorolac [10].
Lab / symptoms
Serum sodium
Check sodium if confusion, headache, nausea or marked weight gain or edema appears during repeated IV or IM dosing in an older or hospitalized patient [9]. Fluid and sodium changes belong to the prescriber.
Timing and interactions
Food, antacids and contraindicated drugs
No nutrient separation interval is specified in the label. A high-fat meal lowers peak and delays absorption by about 1 hour; antacids did not alter extent of absorption. Never combine with aspirin or other NSAIDs, probenecid or pentoxifylline [1].
Special populations
Pregnancy, kidney, age, pediatrics
Avoid at about 30 weeks gestation and later and in labor and delivery. Half-life is 6 to 19 hours in renal impairment and longer in people 65 and over. Tablets are not indicated for pediatric patients. Injectable, nasal and ophthalmic labels were not read for population details [1].

Overlap map, to prevent double counting

Iron
Shares evidence with: Oxygen delivery/utilization; Platelet function
Note: One mechanism (COX inhibition causing mucosal injury plus platelet inhibition leading to GI bleeding) and the same bleeding sources: label boxed warning [1], Castellsague [3], Strom [4], the case report [14], and the RCT meta-analysis [5]. These are three views of one bleeding signal, not three independent findings.
Oxygen delivery/utilization
Shares evidence with: Iron
Note: Any hemoglobin fall is mediated by bleeding. Hemoglobin data (Muradian [13], Tabrizian [12], case report [14]) add perioperative confounding and are not counted as separate iron evidence.
Potassium
Shares evidence with: Sodium and fluid
Note: Same renal prostaglandin mechanism and the same label renal warning [1]; Pearce 1993 [8] and the AKI cohorts [11][16] bear on both as the renal context. The Lafrance cohort [10] bears only on potassium.
Mitochondrial burden
Shares evidence with: Oxidative stress; ATP production
Note: Sodano 2021 [18] supplies both the depolarization (mitochondrial) and ROS (oxidative) findings. Browne [20], Lal [19], Chavez [23] and Majumder [22] are shared between mitochondrial burden and ATP production. Count as one in vitro and rodent evidence cluster, not three confirmations.
Iron
Shares evidence with: Gut microbiome risk; Mitochondrial burden
Note: Rodent intestinal findings from Zadori [28] and Sodano mouse histology [18] appear in the iron entry (mucosal injury is dose dependent), the microbiome entry and the mitochondrial entry. They are separate rodent studies used for different statements.
Folate
Shares evidence with: None
Note: Rests only on the 1992 class enzyme paper [17], which did not test ketorolac. The label's methotrexate interaction is not counted.
Copper (ungraded)
Shares evidence with: None
Note: No evidence; no shared source.

All references used above

Ketorolac

Findings for this medication

What the research found

Platelet function and hemostasis: the drug's own reversible antiplatelet effect (mechanism clarification, not a nutrient)

Potassium: retention risk (direction: excess), bounded to renal vulnerability, with a Tier A null cohort

Sodium and fluid: dilutional hyponatremia and fluid retention (direction: excess water), single case level

Folate: CLASS EXTRAPOLATION from in vitro enzyme inhibition; ketorolac was not in the cohort

The five body-system areas

⚡Mitochondrial Burden

Mitochondrial burden: in vitro and rodent signals at concentrations above clinical exposure

💥Oxidative Stress

Oxidative stress: mixed direction, raised in toxicity models and lowered in inflammation models

⚖️Copper and Iron Balance

Iron: blood-loss pathway through GI bleeding, bounded to long courses, older age and high dose

Copper

🌿Gut Microbiome Risk

Gut microbiome risk: rat small intestinal dysbiosis after 4 weeks, human data absent

💨Oxygen and ATP Output

Oxygen delivery/utilization: hemoglobin fall from bleeding, bounded to case-level and genotype-subgroup data (outcome, not a nutrient)

ATP production: possible impairment in vitro and rat gastric tissue, abstracts largely unread

Claims checked and not supported

Iron depletion as an absorption or stores problem

Sodium depletion needing more sodium

Vitamin B12, vitamin C and folate "depletion" read across from other NSAIDs

How the body handles this medication

What the research says is worth watching

Overlap map, to prevent double counting

Mitochondrial Burden

Oxidative Stress

Copper and Iron Balance

Gut Microbiome Risk

Oxygen and ATP Output