Meperidine

Limits on what this shows

• Key negative or null findings: Kaiko [7]: renal dysfunction explained only part of the symptomatic group, so kidney function is not the sole determinant. Yilmaz and colleagues 2023 [18] (rat study, Tier B): short-term meperidine alone produced no seizure-like behavior; seizure severity rose with caffeine challenge after 7 days of dosing. Wong and Cheung 2020 [21] (62 randomized trials of single-course postoperative or labor pain): many trials were small or old and may have been underpowered to detect rare CNS toxicity, so absence of seizures in those trials is not reassurance.
• At-risk subgroups: People with renal or hepatic impairment, repeated or prolonged dosing, and older adults (label 8.5 recommends dose reduction and slow titration) [1]. Phenytoin raised normeperidine concentrations in healthy subjects, and ritonavir and acyclovir can raise normeperidine levels, per the label interaction text [2][3]. Rodman and Maxwell 1994 [9] (single sickle cell patient on a PCA pump, normal creatinine) show that normal renal function does not exclude the event.
• Counter-evidence and confounders: Case reports are confounded by co-medication (promethazine in [9]), underlying disease and absent EEG; the human series [7][8] are observational and had no unexposed group. The paper [9] relays literature plasma thresholds (about 0.46 to 0.81 microgram/mL for twitching to seizures in cancer patients), but those thresholds were not verified in a primary source here.

Regulatory status

Meperidine tablets and oral solution label (Hikma, DailyMed) section 5.16: meperidine may increase the risk of seizure in patients with or without a seizure disorder, and prolonged use may raise that risk through accumulation of normeperidine [1]. Sections 8.6 and 8.7: meperidine and/or normeperidine can accumulate in hepatic and renal impairment, with elevated levels linked to central nervous system excitatory effects [1]. Section 12.3 (Demerol label mirror): normeperidine is the only bioactive metabolite, average half-life 20.6 hours [2]; injection label: meperidine half-life 2 to 5 hours, normeperidine 15 to 30 hours [3]. All read through summarizing fetch tools.

Population evidence, this drug in cohort

Kaiko and colleagues 1983 [7] (Ann Neurol; abstract reconstructed from OpenAlex, read through a summarizing fetch tool): 67 patients given meperidine for postoperative or chronic pain, plasma meperidine and normeperidine tracked. In 48 patients with excitatory effects ranging from nervousness to seizures, the effects tracked normeperidine accumulation; impaired kidney function was found in only 14 of the symptomatic patients. A second study of 47 patients (29 on other narcotics) linked repeated meperidine dosing to mood changes. The record gave no concentration values. Szeto and colleagues 1977 [8] (Ann Intern Med; OpenAlex abstract, patient total not stated in the record): one hour after a dose, normeperidine was 0.13 to 0.36 microgram/mL in renal-failure patients versus 0.05 to 0.28 in cancer patients, the normeperidine-to-meperidine ratio was consistently higher in renal failure, and two patients on multiple doses showed CNS excitation with high normeperidine and very high ratios. Both are Tier A for the metabolite and the neurologic outcome; neither measured a nutrient.

Mechanism

Named: N-demethylation of meperidine to normeperidine by CYP3A4 and CYP2B6, renal excretion of both compounds, and a metabolite half-life several times longer than the parent [2][3]. Shochet and Murray 1988 [10] (review abstract via the publisher record) argue that normeperidine, not meperidine, causes the excitatory toxicity and that its proconvulsant effect may by itself explain the symptoms.

Boundary stated for the orange grade

Repeated or prolonged dosing, and renal or hepatic impairment; the graded effect is a neurologic outcome of a metabolite, not a nutrient state. It stays orange rather than red because red requires a nutrient directly measured (here the measured analyte is the drug's own metabolite) and because the human series are small, observational and abstract-level in this review.

Counter-evidence held on record

Framing caution for the consumer surface This is a drug-safety signal about the medicine's own metabolite, not a nutrient deficiency. No vitamin, mineral or supplement prevents or treats it, and none is implied. Dose, duration and kidney function are prescriber and pharmacist decisions.

Limits on what this shows

• Key negative or null findings: No meperidine hyponatremia case series or cohort was located. Three labor water-intoxication case reports opened (Saudi Med J 2014, J Med Case Rep 2008, Infant 2008) mention oxytocin or IV fluid and do not mention meperidine or pethidine; they are excluded [42].
• At-risk subgroups: Patients on diuretics (label) [1][3]; renal insufficiency, eclampsia, septic shock and postoperative anuria (authors' cautions) [13].
• Counter-evidence and confounders: Surgery, pain, nausea, IV fluids, oxytocin, thiazides and SSRIs alter sodium independently. The 1965 study measures urine flow, not blood sodium.

Regulatory status

Label section 7: "Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone" [1][3]. No hyponatremia or SIADH wording was found in the label text read; the summarizer's absence report is not proof of absence [1][2][3].

Population evidence, this drug in cohort

Vorherr and Huter 1965, Klin Wochenschr [13] (German; abstract-level summary of the Springer page, no abstract in OpenAlex, number of subjects not stated): Dolantin (meperidine) dose-dependently inhibited water diuresis in humans and rats, and absolute ion excretion fell dose-dependently. Onset and time course resembled vasopressin, a circulatory cause was not supported in rats, smooth-muscle relaxation of the urinary tract was ruled out, and a renal or pituitary-renal (vasopressin) mechanism remained open. The authors advised care in septic shock, eclampsia, renal insufficiency and postoperative anuria. Tier A for the functional water-handling outcome with meperidine in the cohort; serum sodium was not reported in the text read.

CLASS EXTRAPOLATION: cohort test

Beukhof and colleagues 2007, Clin Endocrinol [14] (matched case-control, 50 patients with hospital-acquired hyponatraemia versus 69 normonatraemic controls; summary read on a repository page): opioids were independently associated with hyponatraemia, OR 2.9 (95% CI 1.1 to 7.8), alongside insulin (OR 10.5) and antibiotics (OR 4.5); mean serum sodium in cases fell from 141 to 130 mmol/L. The page says only "opioids"; whether meperidine was among them is NOT confirmed, so this is Tier C for meperidine and cannot raise the grade.

Mechanism

Named in the label: opioid-induced ADH release [1][3]. Human antidiuresis with a vasopressin-like profile [13]; plasma ADH was not measured in the text read.

Why not orange

Orange needs the nutrient-level deficit shown in a Tier A source with this drug. Here the human data are a functional urine-flow effect from an old abstract-level record with unknown sample size. See the near-orange note in the report.

Counter-evidence held on record

Framing caution for the consumer surface A possible retention or dilution risk, not a sodium shortage. Salt loading or sodium supplements would be the hazard. Any sodium concern is a clinician decision.

Limits on what this shows

• Key negative or null findings: No meperidine-specific testosterone, LH or SHBG measurement was located in any channel that opened. Searches for pethidine users and testosterone could not be run once the shared web search budget ran out.
• At-risk subgroups: Men on continuous long-term opioid therapy in general; not defined for meperidine, which is rarely used long term (label and reviews steer it to short courses) [1][21].
• Counter-evidence and confounders: Chronic pain, obesity, age and co-medication lower testosterone independently. The class cohort [15] compares drugs with each other, not with non-use.

Regulatory status

Label section 6: "Cases of androgen deficiency have occurred with use of opioids for an extended period of time" [1]. Section 12.2 (Demerol label mirror): opioids inhibit ACTH, cortisol and luteinizing hormone secretion, and prolonged use "may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency" [2]. Section 8.3: extended opioid use may reduce fertility in females and males [1].

CLASS EXTRAPOLATION: cohort test

Rubinstein and Carpenter 2016, Pain Med [15] (1,159 men on a single opioid for at least 90 days, hydrocodone referent; fentanyl OR 25.7, 95% CI 2.82 to 234.97; methadone OR 7.33; oxycodone OR 3.15): the abstract (reconstructed from OpenAlex) names fentanyl, methadone, oxycodone and hydrocodone only; meperidine is NOT in the abstract and group sizes were not given, so Tier C for meperidine. Fraser and colleagues 2009 [20] (cross-sectional, 12 men and 14 premenopausal women on oral opioids for at least a year; hypogonadism 75% in men): opioids not named on the page read; Tier C. A University of Birmingham review of opioid endocrinopathies [19] used "pethidine" and "meperidine" as search terms for cortisol, testosterone and prolactin, yet the text read lists pethidine only in a drug-class list and reports no pethidine endocrine finding.

Mechanism

Named in the label: opioid inhibition of LH and the hypothalamic-pituitary-gonadal axis [2]. No meperidine hormone assay study was found.

Counter-evidence held on record

Framing caution for the consumer surface A hormone effect of extended opioid therapy listed on the label, not a nutrient deficiency. No vitamin, mineral or testosterone product is implied; testing and treatment belong with a clinician.

Limits on what this shows

• Key negative or null findings: Yilmaz and colleagues 2023, Medicina [18] (66 male Wistar rats; page read through a summarizing fetch tool): short-term meperidine did not change serum cortisol, while meperidine twice daily for 7 days raised cortisol (opposite to suppression); metyrapone blocked the rise. Tier B, animal. Taken together, human data show no clear suppression in acute use, a lower labor stress peak confounded by pain relief, and no chronic human cortisol data.
• At-risk subgroups: Patients on more than one month of continuous opioid therapy (label wording) [1]. Label symptoms are non-specific.
• Counter-evidence and confounders: Pain, labor and surgical stress drive cortisol independently of any drug; glucocorticoid co-treatment and illness alter it too.

Regulatory status

Label section 5.12: "Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use" [1]. Section 12.2: opioids inhibit ACTH and cortisol secretion in humans [2].

Population evidence, this drug in cohort

Oyama and colleagues 1969, Can Anaesth Soc J [17] (30 surgical patients, plasma free cortisol; page read through a summarizing fetch tool): intramuscular meperidine 2 mg/kg one hour before induction did not prevent adrenocortical stimulation by emotional stress; 30 minutes of meperidine-supplemented nitrous oxide anaesthesia did not stimulate adrenocortical activity, and that regimen did not block stimulation during and after surgery. Onur and colleagues 1989, Arch Gynecol Obstet [16] (30 healthy multiparous women in three groups: oxytocin induction only, oxytocin plus intramuscular meperidine, untreated controls; abstract on a repository page): cortisol peaked at delivery in all groups, and the peak was significantly lower in the meperidine group than in the oxytocin-only and control groups; the dose unit was garbled in the text read and group sizes were not given. Tier A for meperidine in the cohort, but acute stress settings.

Mechanism

Named in the label: opioid inhibition of ACTH and cortisol release [2]. Not demonstrated for meperidine in the studies opened.

Counter-evidence held on record

Framing caution for the consumer surface A hormone-axis monitoring point, not a nutrient finding. Fatigue and low appetite are non-specific and should be evaluated by a clinician. No supplement is implied.

Limits on what this shows

• Key negative or null findings: No source opened tested a supplement (tryptophan, 5-HTP, SAMe, St John's wort) or a dietary item with meperidine. The nutrient angle is therefore not evidenced.
• Counter-evidence and confounders: Meperidine serotonin syndrome reports are mostly polypharmacy; causality in single cases is disputed [11].

Regulatory status

Injection label: section 4 contraindicates concomitant MAOI use or use within the last 14 days; section 5.6 (fatal interaction with MAOIs): "Do not use Meperidine Hydrochloride Injection in patients taking MAOIs or within 14 days of stopping such treatment"; section 5.8: serotonin syndrome reported with serotonergic drugs, discontinue if suspected [3]. Tablet and oral solution label sections 5.8 and 5.10 say serotonin syndrome may occur within the recommended dosage range [1]. The tablet label text as relayed also ties the MAOI reaction to pre-existing hyperphenylalaninemia; that wording came through the summarizer and was not verified, and no nutrient conclusion is drawn from it [1].

Population evidence, this drug in cohort

Guo and colleagues 2009, Br J Anaesth [11] (single case; abstract and reader comments only because the full text is paywalled): a patient with clomipramine-induced serotonin syndrome five years earlier developed serotonin syndrome after one dose of meperidine; reader comments dispute whether the episode met criteria. Tier B, case report.

CLASS EXTRAPOLATION: cohort test

Truedson and colleagues 2021, Eur Psychiatry [12] (systematic case review of 299 published serotonin syndrome cases from 2004 to 2014): MAOIs were involved in 40% of 118 severe cases versus 13% of non-severe cases, OR 4.3 (95% CI 2.4 to 7.5). The abstract does not say which non-MAOI drugs were combined with MAOIs and does not name meperidine, so it is Tier C and supports only the general severity signal for MAOI combinations.

Mechanism

Named in the label: serotonergic toxicity with MAOIs and other serotonergic drugs [1][3]. Wikipedia's pethidine page links normeperidine neurotoxicity to serotonergic effects, which is a reference-page statement and is not used for grading [6].

Why not orange

The orange tier needs a Tier A source showing a real, bounded effect in a cohort that included this drug. The label contraindication is regulatory text rather than measured population evidence, and the cohort-level source [12] does not name meperidine. Primary meperidine-MAOI case series would be needed.

Counter-evidence held on record

Framing caution for the consumer surface A medication-safety interaction, not a deficiency. Medication and supplement lists should be reviewed by a prescriber or pharmacist; nothing here recommends adding or avoiding any nutrient.

Limits on what this shows

• Key negative or null findings: No 25-hydroxyvitamin D measurement in meperidine users was found. The one opioid-dependent cohort with controls [24] found higher, not lower, vitamin D.
• Counter-evidence and confounders: Confounding by indication is presumed (Hard Rule 6): chronic pain, immobility, obesity, age and sun exposure alter vitamin D independent of any drug; sun exposure and supplement use were not recorded in [24].

Regulatory status

No vitamin D wording in the label text read [1][2][3].

CLASS EXTRAPOLATION: cohort test

Frontiers in Nutrition 2024 [23] (NHANES 2001 to 2018, 1,856 long-term prescription opioid users, defined as narcotic analgesic use of at least 90 days; 67.2% below 75 nmol/L and 32.4% below 50 nmol/L): the text names no individual opioid, meperidine is not mentioned, and there is no opioid-free comparison group; Tier C. Reece and Hulse 2018, BMJ Open [24] (retrospective record review in an Australian clinic, 1,168 opioid-dependent patients versus 415 controls, dependence inferred from hepatitis C testing): 25-hydroxyvitamin D was higher in opioid-dependent patients, 70.35 versus 57.06 nmol/L, and levels below 50 nmol/L were less frequent (27.48% versus 45.3%, OR 0.46, 95% CI 0.36 to 0.58); the opioids are described as illicit, heroin is a keyword and meperidine is not named; Tier C.

Direction check (Hard Rule 4)

The 2021 Science Advances study [25] (abstract reconstructed from OpenAlex): vitamin D deficiency is more common in opioid use disorder and, in mice, deficient vitamin D signaling amplified opioid responses; the direction runs from vitamin D to opioid response and no individual opioid is named.

Mechanism

Absent for meperidine. No absorption, catabolism or renal mechanism was found.

Counter-evidence held on record

Framing caution for the consumer surface Vitamin D insufficiency in opioid-treated populations is not evidence that meperidine causes it, and one cohort found the opposite. Any testing decision belongs with a clinician.

Limits on what this shows

• Key negative or null findings: Meperidine is usually given in short courses, so long-term bowel data are scarce; none was found.
• Counter-evidence and confounders: Diet, dehydration, immobility, surgery and co-medication drive constipation independently.

Regulatory status

Tablet and oral solution label section 6 lists "Dry mouth, constipation, biliary tract spasm" under gastrointestinal reactions; section 7 states anticholinergic drugs "may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus"; section 5.15 warns of sphincter of Oddi spasm and serum amylase rises [1]. Section 12.2: meperidine causes "a reduction in motility associated with an increase in smooth muscle tone" [2]. A consumer drug page lists severe constipation (Tier D, context only) [38].

Population evidence, this drug in cohort

No meperidine-specific constipation incidence, comparison with another opioid, or bowel-function trial was retrieved. Wong and Cheung 2020 [21] (narrative review of 62 randomized trials of meperidine for postoperative or labor pain; abstract on a repository page) report more sedation and respiratory depression versus comparators; the abstract does not state constipation findings.

Mechanism

Named: mu-opioid receptor reduction of gut motility and increased smooth muscle tone [2].

Counter-evidence held on record

Framing caution for the consumer surface A bowel effect to manage with the prescriber, not a sign of a nutrient shortage. No fiber, magnesium or other supplement recommendation is made.

Limits on what this shows

• Key negative or null findings: No pharmacokinetic study of meperidine with grapefruit juice was located.
• Counter-evidence and confounders: Interaction magnitude is unknown; Tier D page is a generic statement.

Regulatory status

Label section 5.7 and section 7: CYP3A4 inhibitors (macrolides, azole antifungals, protease inhibitors such as ritonavir) may increase meperidine plasma concentrations and prolong opioid adverse reactions; stopping a CYP3A4 inducer (rifampin, carbamazepine, phenytoin) may also increase concentrations [1][3]. Grapefruit juice was not named in the label text read.

Population evidence, this drug in cohort

None. The grapefruit statement comes only from a Drugs.com consumer food-interaction page (Tier D, never supports a claim) [39].

Mechanism

Meperidine is converted to normeperidine mainly by CYP3A4 and CYP2B6 [2][3]. Whether grapefruit changes meperidine exposure was not tested in any source opened; because CYP2B6 also contributes, that single-enzyme effect is uncertain (inference, not a source statement).

Counter-evidence held on record

Framing caution for the consumer surface A food-and-drug timing question for a prescriber or pharmacist. No separation interval was established in the text read, and no supplement is implied.

Why no ungraded entry

The dual condition in Step 7 (no Tier B or C evidence and no circulating claim) was not met for any entry. The weakest yellow entries are oxygen delivery (label and review pharmacology only, no hemoglobin data), the grapefruit entry (Tier D page plus label enzyme text), the androgen axis (label statement only) and the seven class extrapolations (vitamin D, gut microbiome, mitochondrial burden, oxidative stress, ATP, and the animal parts of copper and iron), where no meperidine-specific data were opened.

Channels tried

DailyMed SPL search listing and the Hikma tablet and oral solution label page (opened; section 12 not returned); Drugs.com mirrors of the Demerol and meperidine injection labels (opened at several offsets); Drugs.com consumer monograph and food-interaction pages; WHO ATC page; Wikipedia pethidine and MPTP pages; single-record OpenAlex lookups by PMID or DOI (worked for about ten records); Springer, Frontiers, Nature, De Gruyter, BMJ Open, Oxford Academic, Cambridge, Thieme, JABFM, a repository PDF, repository pages (Selcuk, Erasmus, HKU, Birmingham) and one PubMed Central page (PMC10608679) worked; web search worked for roughly two dozen queries (pethidine or meperidine with testosterone, hyponatremia, SIADH, antidiuretic, cortisol, oxidative stress, mitochondria, gut microbiota, vitamin D, copper, zinc, iron, methemoglobinemia, hemoglobin, constipation, normeperidine, serotonin syndrome, MPTP) and then reported its shared budget exhausted on two further queries (testosterone in pethidine users; vasopressin and serum sodium in pethidine studies); PubMed listing pages (429, told not to refetch), a Springer article (429, told not to refetch), the OpenAlex works search endpoint (429), a Europe PMC query (429, told not to refetch), NCBI Bookshelf (bot page), most other PubMed Central pages (bot page), PubMed record pages (bot page), a Turkish university repository (bot page) and a university library page (bot page) could not be read. Crossref bibliographic searches worked for four queries (meperidine or pethidine with testosterone, hyponatremia or antidiuretic hormone, oxidative stress or mitochondria, addiction hormones or minerals) and returned only reference-book chapters and unrelated papers, plus one Iranian buprenorphine-withdrawal note that reports no hormone or mineral data; a fifth Crossref query and a Europe PMC query returned 429 with a request not to refetch; Semantic Scholar was not queried.

Gap type

Partly tooling-limited. Searches for meperidine or pethidine with testosterone, LH, serum sodium, plasma ADH, microbiome, oxidative markers, mitochondrial function, hemoglobin and iron stores returned no meperidine-specific human study in the channels that opened, but PubMed itself could not be queried. These should be re-run when PubMed and Europe PMC are reachable.