Levorphanol

Limits on what this shows

• Null findings: Levorphanol had no effect on plasma LH in pro-oestrous rats (listing summary) [31]. The levorphanol trials opened [7][8] did not report hormones in the abstracts read.
• At-risk subgroups: Men on prolonged, higher-dose opioid therapy, and long-acting rather than short-acting opioids, in the class data [9][10]. Levorphanol is a long-acting opioid by half-life [1][6], which is an inference, not a measurement.

Direction

HORMONE SUPPRESSION (lower testosterone). Not a depletion of any dietary nutrient; no vitamin or mineral was measured in any source.

Cohort test (Hard Rule 6)

Levorphanol was NOT named in any human hormone cohort or meta-analysis opened: the de Vries 2020 meta-analysis [9] (the summarizing fetch tool found no mention of levorphanol; methadone was the most frequent opioid, then morphine), Rubinstein and Carpenter 2017 [10] (fentanyl, methadone, oxycodone and hydrocodone) and Rajagopal 2003 [11] (opioid not named in the abstract). Tier C, CLASS EXTRAPOLATION, capped at yellow, although the sentence sits in levorphanol's own label.

Regulatory status

Clinical Pharmacology, effects on the endocrine system: opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency, which in the Virtus label may manifest as low libido, impotence and erectile dysfunction; Postmarketing: cases of androgen deficiency have occurred with use of opioids for an extended period of time [1][2]. The wording is opioid-class wording.

Population evidence

de Vries 2020 [9]: systematic review and meta-analysis, hypogonadism prevalence 63% (95% CI 55% to 70%), 15 studies, 3,250 patients, 99.5% male; 13 studies used methadone and 12 morphine; testosterone in one cited cohort 172.1, 188.5 and 265.8 ng/dL in high, intermediate and low-dose users versus 449.1 ng/dL in controls (as reported through the summarizer). Rubinstein and Carpenter 2017 [10]: retrospective cohort of 1,159 men on a stable single opioid, odds of androgen deficiency versus hydrocodone: fentanyl 25.7 (95% CI 2.82 to 234.97), methadone 7.33 (3.29 to 16.33), oxycodone 3.15 (1.87 to 5.33), and 1.18 per 10 mg dose increment (1.09 to 1.28). Rajagopal 2003 [11]: 20 male cancer survivors on at least 200 mg morphine-equivalent daily for at least a year, median testosterone 140 ng/dL (normal 241 to 827) with low-normal FSH and LH and no compensatory rise. Levorphanol-specific (Tier B, all via PubMed listing summaries read by a fetch tool; abstracts not independently opened): levorphanol testosterone returned one record, a study of 20 opiates on human placental aromatase (CYP19), summarized as levorphanol raising estriol formation to 124 to 160% of control with no effect on estradiol formation [25]; in pro-oestrous rats levorphanol lowered hypothalamic noradrenaline and serotonin but had no effect on plasma LH (1989) [31]; in male rats levorphanol enhanced the naloxone-induced rise in serum LH in morphine-pretreated animals (1983) [31]. No levorphanol testosterone measurement in any species was found: the query levorphanol AND (hypogonadism OR androgen OR libido OR endocrine) returned 17 records, 10 displayed, none on testosterone or human hypogonadism [27].

Mechanism

Central suppression of the gonadal axis by opioids (low testosterone with non-elevated FSH and LH in [11]); stated as a class effect in the label [1][2]. Whether levorphanol, with its long half-life and accumulating glucuronide [1][6], differs from other long-acting opioids is untested in anything opened.

Counter-evidence held on record

Counter-evidence and confounding The class cohorts are mostly methadone and morphine users, often with cancer, pain syndromes, illness or intrathecal delivery; obesity, age, diabetes and pain itself lower testosterone, and the Rubinstein cohort found large differences among opioids, so a pooled class estimate cannot be assigned to levorphanol. All reads were abstracts or summarized pages; no full text. Framing caution This is a hormone effect to raise with a prescriber if low libido, erectile dysfunction, low mood or fatigue develop on long-term therapy. It is not a vitamin or mineral deficiency, and no supplement is implied. No dose or medication change without a prescriber or pharmacist.

Limits on what this shows

• Null findings: No levorphanol study measured a cortisol deficit or an insufficiency state; clonidine, not levorphanol, was the variable that moved cortisol in [29].
• At-risk subgroups: People on opioids for more than one month, per the label wording [1][2]; intrathecal and oral opioid users in the meta-analysis [9].

Direction

HORMONE SUPPRESSION (adrenal) is the label and meta-analysis direction (class). The levorphanol-specific rodent direction is ACUTE STIMULATION of ACTH and corticosterone. Not a nutrient depletion.

Cohort test (Hard Rule 6)

The label wording is class-level ('with opioid use'). Levorphanol was not named in the meta-analysis opened [9]: Tier C, CLASS EXTRAPOLATION for the suppression claim, capped at yellow. Levorphanol WAS in the rat, mouse and small human studies below [28][29][30], but none measured chronic suppression or an insufficiency state, so they do not raise the grade.

Regulatory status

Warnings: 'Cases of adrenal insufficiency have been reported with opioid use, more often following greater than 1 month of use'; the Virtus label adds that corticosteroid treatment and weaning off the opioid may be needed [1][2].

Population evidence

de Vries 2020 [9]: hypocortisolism prevalence 15% (95% CI 6% to 28%), 5 studies, 205 patients (57.5% male); insulin tolerance test subgroup 24% (95% CI 16% to 33%), 2 studies, 97 patients. The text read did not link opioid types to these five studies. Levorphanol-specific: Pechnick and Poland 2004 [28], male Sprague-Dawley rats: levorphanol increased plasma ACTH and corticosterone and naloxone (2 mg/kg) blocked the increase, whereas dextrorphan and dextromethorphan raised both without naloxone sensitivity (dose, route and numbers not in the abstract text read). Gibson 1979 [30], mice: levorphanol 20 mg/kg prevented the rise in plasma corticosteroids caused by one minute of ether stress (no baseline values or sample size in the abstract). Listing summaries only [27]: levorphanol stimulated plasma corticosterone in rats with tolerance developing (1982), and acute levorphanol elevated corticosterone in rats (1979). Human: Rosen 1996 [29], seven heroin-dependent participants stabilized on levorphanol (dose not stated) given a naloxone challenge with placebo or clonidine pretreatment over 4 days: clonidine significantly attenuated plasma cortisol (P under 0.05) and naloxone produced a dose-dependent ACTH response; baseline cortisol and any deficit were not reported.

Mechanism

Not stated in the label text read; opioid suppression of the hypothalamic-pituitary-adrenal axis is the class concept.

Counter-evidence held on record

Counter-evidence and confounding Symptoms are nonspecific (fatigue, nausea, dizziness, hypotension) and overlap with opioid adverse effects and the underlying illness. Five small studies pooled with wide intervals; the 15% estimate came from heterogeneous opioids and settings. The levorphanol rodent studies measured acute pharmacology of single doses, the human study had seven participants who were opioid dependent and in a withdrawal challenge, and all were read as abstracts. Framing caution This is a hormone-axis safety signal for a prescriber to evaluate, not a nutrient finding. No supplement is implied, and no dose or medication change should be made without a prescriber or pharmacist.

Limits on what this shows

• Null findings: No effect of levorphanol on sodium excretion in the isolated kidney [12]; no hyponatremia text in either label; no human case found.
• At-risk subgroups: Not defined for levorphanol. Older adults and people on diuretics or other sodium-lowering drugs are the usual hyponatremia risk groups in general pharmacology, but no levorphanol source was opened to support that here.

Direction

EXCESS/RETENTION of free water with a possible dilutional fall in serum sodium (SIADH-type). Not a dietary sodium deficiency; adding salt is not the remedy (Hard Rule 5).

Cohort test (Hard Rule 6)

No human hyponatremia source with levorphanol exists in what was opened. The class mechanism rests on the label sentence [1][2]; no opioid hyponatremia cohort was opened, so no class cohort is cited. Capped at yellow.

Regulatory status

Drug Interactions, diuretics: 'Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone' [1][2]. Hyponatremia, SIADH and sodium disturbance were searched in both label texts and not found (per summarizers).

Population evidence

Levorphanol-specific, Tier B: Ellis and Adam 1991 [12], isolated perfused rat kidney: dextrorphan and dextromethorphan reduced sodium excretion; 'levorphanol, levomethorphan, the kappa agonist ketocyclazocine and a range of other opiates had no effect on sodium excretion' (abstract paraphrased by a fetch tool; the levorphanol concentration was not stated in the record read). Huidobro and Huidobro 1981 [13] studied central effects of morphine, levorphanol and (-)-methadone on urine volume and electrolytes in rats per the title and indexing terms; its abstract could not be retrieved, so no result is reported here. A PubMed query for levorphanol with sodium, hyponatremia, SIADH and vasopressin terms returned 43 records (23 displayed), none reporting hyponatremia in people [27]; a 1975 guinea pig organ culture study found levorphanol did not alter vasopressin synthesis (listing summary only).

Mechanism

Opioid-induced antidiuretic hormone release is the label's stated mechanism for the diuretic interaction [1][2]. The isolated kidney result argues against a direct renal tubular sodium effect of levorphanol, but it does not test central ADH release.

Counter-evidence held on record

Counter-evidence and confounding An ex vivo rat kidney is not a human with intact central ADH control; the levorphanol null is an abstract-level paraphrase. Nausea, vomiting, pain and co-medications are competing explanations for any low sodium seen in practice. Framing caution This is a retention (dilutional) concept, not a depletion. Extra sodium or salt would be a hazard, not a remedy. Report confusion, nausea, headache or unsteadiness to a prescriber. No dose or supplement change without a prescriber or pharmacist.

Limits on what this shows

• Null findings: No serotonin syndrome case with levorphanol was found in the sources opened; searches were limited (see Sources).
• At-risk subgroups: People taking other serotonergic drugs or MAO inhibitors, per the label list [1][2].

Direction

INTERACTION (pharmacodynamic, drug on drug). Not a depletion, and not a supplement deficiency.

Regulatory status

Both labels: concomitant use with serotonergic drugs has resulted in serotonin syndrome; the listed classes include MAO inhibitors (also linezolid and intravenous methylene blue per the Virtus summary); the label advises discontinuing if serotonin syndrome is suspected [1][2]. The NMDA and SNRI pharmacology statements were absent from the Sun label text read [1].

Population evidence

None opened for serotonin syndrome with levorphanol. Pharmacology: a review abstract states levorphanol is an NMDA receptor antagonist and that evidence suggests it may inhibit norepinephrine and serotonin reuptake, 'suggested, not established' [5]; a later review states it 'also blocks the reuptake of serotonin (5-HT) and norepinephrine (NE)' and is 'a strong NMDA receptor antagonist' [6]. Rowbotham 2003 [7] (81 patients, randomized, high versus low strength levorphanol) is the only trial opened; its abstract reports analgesia and side effects, not serotonin syndrome.

Mechanism

Reuptake inhibition and NMDA antagonism are stated by reviews [5][6], not by the Sun label. A serotonergic supplement stacked on levorphanol is a theoretical hazard: no source read names a supplement case or lists a supplement.

Counter-evidence held on record

Counter-evidence and confounding The SNRI claim is a literature assertion; one abstract hedges it as suggested rather than established [5]. The supplement part of this entry is extrapolation from the label's drug list and was not tested by any source read. Framing caution This is a drug-interaction hazard, not a nutrient depletion. Do not start or stop any serotonergic medicine or supplement without a prescriber or pharmacist. No dose is implied.

Limits on what this shows

• Null findings: No levorphanol-specific human constipation rate was retrieved; intrathecal levorphanol did not markedly slow transit in rats (listing summary) [27]. Reddy 2023 reported symptom improvement after rotation from other opioids [8], which is an uncontrolled comparison.
• At-risk subgroups: Patients on higher doses [7] and with obstruction risk, per general opioid labeling; not separately sourced for levorphanol.

Direction

NEUTRAL for nutrients. A clinical outcome of opioid pharmacology (Hard Rule 2); no nutrient was measured.

Regulatory status

Adverse Reactions describe the type and incidence of side effects in about 1,400 patients as those expected of an opioid analgesic, listing constipation, nausea, vomiting, dyspepsia and biliary tract spasm without percentages; patients are advised of the potential for severe constipation [1][2].

Population evidence

Reddy 2023 [8], prospective open-label rotation of 40 cancer outpatients (MEDD 60 to 300 mg) to levorphanol at 10:1: 33 of 40 (82.5%) successful rotations, with improvement in ESAS and opioid side-effect scores; the abstract gives no constipation count. Rowbotham 2003 [7], 81 patients, 8-week double-blind high (0.75 mg) versus low (0.15 mg) strength capsules: higher doses produced more side effects, most dropouts were due to opioid side effects, no constipation figure in the abstract. A review on levorphanol versus methadone did not discuss constipation [6]. Levorphanol-specific animal records from the PubMed query levorphanol AND (constipation OR gastrointestinal transit OR bowel function), 8 records, listing summaries only [27]: levorphanol slowed charcoal-meal transit in mice and that slowing was not reversed by a putative delta antagonist (1982); levorphanol-induced constipation was measured alongside antinociception, hypothermia and activity in mice (1982, no abstract); intrathecal levorphanol at 10 to 50 times analgesic doses had no marked effect on transit in rats (1983). A 2017 Cochrane overview of opioids for chronic non-cancer pain found constipation significantly more frequent with opioids than placebo, with levorphanol only in the pooled set and no agent-specific result.

Mechanism

Opioid-receptor slowing of gut transit (class mechanism; the Sun label text read states it only as an expected effect).

Counter-evidence held on record

Counter-evidence and confounding Reduced food, fluid or fiber intake and immobility can contribute, and none of the sources measured nutrient intake or status. Constipation also confounds the gut microbiome entry. Framing caution Constipation is a drug effect to report to a prescriber or pharmacist, not a sign of a nutrient shortage. No supplement or dose change is implied.

Limits on what this shows

• Null findings: Higher, not lower, vitamin D in opioid-dependent patients [14].
• At-risk subgroups: None identified for levorphanol. Indication-linked low vitamin D in chronic pain populations is presumed (Hard Rule 6) and was not separately sourced.

Direction

REVERSE (higher) in one class cohort [14] and CONFLICTING (more deficiency in opioid use disorder; deficiency amplifying opioid response in mice, nutrient acting on drug effect) in another [15]. Not a depletion by levorphanol.

Cohort test (Hard Rule 6)

Reece and Hulse [14]: opioids not named in the body text read; levorphanol not mentioned. Kemeny 2021 [15]: opioid use disorder patients and mice given exogenous opioids; levorphanol not mentioned in the abstract. Levorphanol was NOT confirmed in either cohort. Tier C, CLASS EXTRAPOLATION, capped at yellow.

Regulatory status

Vitamin D is absent from both label texts read [1][2].

Population evidence

Reece and Hulse 2018 [14], single Australian outpatient clinic, retrospective record review: 1,168 opioid-dependent patients (72.5% men) versus 415 general medical controls; observed 25-hydroxyvitamin D 70.35 versus 57.06 nmol/L (p under 0.0001); modelled at median age 62.71 versus 57.81 nmol/L (difference 4.90 nmol/L, about 8.5%); values under 50 nmol/L in 27.48% versus 45.3% (OR 0.46); PTH not measured; sun exposure, body mass index and supplement use unavailable. Kemeny 2021 [15] (abstract via OpenAlex): higher rates of vitamin D deficiency in people with opioid use disorder and an inverse dose-dependent link between vitamin D levels and self-reported opioid use; in mice vitamin D deficiency amplified responses to exogenous opioids and normalized when vitamin D signaling was restored; sample sizes not in the abstract. PubMed query levorphanol AND (folate OR cobalamin OR homocysteine OR vitamin D) returned one irrelevant 1978 cat spinal cord record [27]; a plain levorphanol vitamin query was refused (HTTP 429).

Mechanism

None shown for a levorphanol or opioid effect on vitamin D metabolism. The testosterone effect (see Androgen axis) is not shown to alter vitamin D by any source read.

Counter-evidence held on record

Counter-evidence and confounding [14] and [15] disagree on direction, both are opioid use disorder populations rather than people taking levorphanol for pain, and sun exposure, body mass index, supplement use and illicit drug use are unmeasured or unresolved. Confounding by indication and immobility are not excluded. Framing caution This is a class-level, direction-conflicting association, not a depletion. No vitamin D supplement decision should be made from this entry. No dose or medication change without a prescriber or pharmacist.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C source measures or supports depletion of B12 or folate by levorphanol, and no circulating consumer claim naming these vitamins for levorphanol was found. Indication-linked B12 insufficiency in chronic pain or neuropathic pain populations is presumed to be confounded by the underlying condition (Hard Rule 6) and was not sourced. This is a disclosed absence of evidence, not a finding of safety.

What was searched

Labels: Sun and Virtus label texts searched for vitamin, B12, folate and related terms; only generic Medication Guide wording on vitamins and herbal supplements and the excipient magnesium stearate were found [1][2]. Papers opened and found not to report B12 or folate: Rowbotham 2003 [7], Reddy 2023 [8], Prommer 2007 [5], Haider 2020 [6]. PubMed listings: levorphanol AND (folate OR cobalamin OR homocysteine OR vitamin D) returned 1 record, a 1978 cat spinal cord neurophysiology study unrelated to vitamins; levorphanol (857 records, first 18 displayed, none about vitamins or minerals), levorphanol with sodium terms (43 records, none about vitamins), levorphanol with cortisol terms (7 records), levorphanol with prolactin, LH, gonadotropin, gonadal or estradiol terms (7 records) and levorphanol AND mitochondria (7 records) were read and none concerned B12, folate or homocysteine [27]; a plain levorphanol vitamin query was refused (HTTP 429) and not completed. Drugs.com food interactions page lists alcohol only [26]; the Antidote Research levorphanol page returned a 404. WebSearch was run for levorphanol nutrient depletion and returned only generic depletion charts with no levorphanol content (titles only, not opened), after which the shared budget was exhausted.

Channel outcomes

DailyMed search listing worked once; the Hikma label page, many PubMed phrasings and Crossref and OpenAlex search queries returned HTTP 429 (a minority of PubMed phrasings succeeded after long pauses); PubMed single-record lookups worked intermittently; Europe PMC and direct PubMed or Crossref API access by curl are blocked by policy and were not used.

Genuine gap or tooling-limited

Mostly a genuine gap: the labels are silent, four levorphanol papers opened do not touch B12 or folate, and the targeted levorphanol PubMed query for folate, cobalamin and homocysteine returned no relevant record. A tooling-limited component remains: only 18 of 857 levorphanol records were displayed, one plain vitamin query was rate limited, PubMed 404 pages cannot be told from empty results, and no non-PubMed index (Europe PMC) was available, so a small human or animal study reporting B12, folate or homocysteine under levorphanol could be missed. Re-check with a working PubMed or Europe PMC channel.