Tapentadol

Limits on what this shows

• Null findings: Single doses at therapeutic exposure left testosterone at or above placebo (Study 1) or minimally changed (Study 2) [4]. The authors state the data are not intended as a basis for clinical decisions [4]. Testosterone and LH values in Study 2 stayed within normal ranges (per the journal page summary).
• At-risk subgroups: Men on prolonged opioid therapy (the Study 3 population was male osteoarthritis patients on multi-week dosing). Women and non-osteoarthritis populations were not covered in the text read.

Direction

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

Regulatory status

Present as a class-worded warning. Both tapentadol labels state that cases of androgen deficiency have occurred with prolonged opioid use, with possible reduced libido or erectile dysfunction [1][2].

Population evidence

Eichenbaum 2015 [4], three randomized, double-blind, placebo-controlled studies with tapentadol in the cohort. Study 1 (single dose, healthy volunteers), testosterone 6 hours after dosing: placebo 8.6, tapentadol IR 43 mg 8.8, 86 mg 9.3, morphine IR 30 mg 5.4 nmol/L. Study 2 (single-dose escalation, healthy volunteers): no or minimal testosterone change at therapeutic IR doses (75 to 100 mg); a modest fall at supratherapeutic doses with values staying within the normal range. Study 3 (multiple dose, osteoarthritis patients, males), change from baseline: tapentadol ER 100 mg -1.9, 200 mg -2.1, oxycodone CR 20 mg -2.7, placebo -0.3 nmol/L. Sample sizes and significance tests were not in the abstract text read.

Mechanism

Opioid effect on the sex-hormone axis, with testosterone, LH and FSH measured [4]. The authors' proposal that tapentadol's norepinephrine reuptake inhibition lessens the effect is stated by them as a hypothesis needing further testing [4]; it is not demonstrated.

Counter-evidence held on record

Counter-evidence and confounding Only one Tier A publication supports this entry, read as an abstract through summarizing tools. Study 3 had a placebo arm, so confounding by pain or indication is handled by design, but baseline testosterone, group sizes and p values were not seen. Sponsor and author affiliations were not captured; these trials belong to the tapentadol development program, so sponsor involvement should be presumed. The decline is smaller than the oxycodone decline, so the entry does not support the idea that tapentadol is hormone-neutral (see Fails verification). 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 serotonin syndrome in the 22 studies of the systematic review [19]; post-marketing data did not confirm the risk [18]. Searches for monoamine stores or tryptophan depletion under tapentadol: the IR label has no tryptophan text [1]; the PubMed query "tapentadol tryptophan" was refused (HTTP 429) twice and not completed.
• At-risk subgroups: People taking other serotonergic drugs (the label list above), overdose settings, and renal or hepatic impairment where exposure rises [1][2].

Direction

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

Regulatory status

Both labels carry the warning. Listed serotonergic drugs include SSRIs, SNRIs, tricyclics, triptans, mirtazapine, trazodone, tramadol, certain muscle relaxants (cyclobenzaprine, metaxalone) and MAO inhibitors [1][2]. The IR label text was searched for St. John's wort, herbal, supplement and tryptophan and none was found (per summarizer) [1]. The labels describe the mechanism as mu-opioid agonism plus norepinephrine reuptake inhibition [2].

Population evidence

Post-marketing review [18] (spontaneous reports in context of trial data): the data "did not confirm the theoretical risk of serotonin syndrome". PubMed listing for tapentadol and serotonin syndrome [19] (listing summaries only, not opened): a systematic review of 22 studies found none reporting serotonin syndrome (Gressler 2017, PMID 29336654); one case report of probable serotonin syndrome after overdose with duloxetine and amitriptyline also taken (PMID 27303080); a toxicity systematic review concluding it is unlikely (PMID 30079795); and a comparative review judging tapentadol less likely than tramadol to cause serotonergic effects (PMID 34196947).

Mechanism

Norepinephrine reuptake inhibition is stated by the label [2]. A mechanistic review listing says tapentadol inhibits serotonin transporters in vitro (PMID 29916050, listing only [19]). A serotonergic supplement stacked on tapentadol is a theoretical, not demonstrated, hazard: no source read names a supplement case.

Counter-evidence held on record

Counter-evidence and confounding The case report involved two other serotonergic drugs and an overdose, so attribution to tapentadol is uncertain. Reports and reviews are mostly manufacturer-linked or listing summaries; independence was not assessed. The supplement part of this entry (St. John's wort, 5-HTP, SAMe, tryptophan) 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, and it runs from the substance to the drug effect. 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 hyponatremia signal in any tapentadol record retrieved [20]; absent from both labels [1][2].
• At-risk subgroups: Unknown for tapentadol. For tramadol, older adults and people on other serotonergic or hyponatremia-inducing drugs [13][14]; transfer to tapentadol is unproven.

Direction

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

Cohort test (Hard Rule 6)

Tapentadol was NOT in the cohort of any hyponatremia source opened. Fournier [13] studied tramadol versus codeine; the case report [14] concerned tramadol plus desvenlafaxine. Tier C, CLASS EXTRAPOLATION, capped at yellow.

Regulatory status

Hyponatremia, SIADH and sodium were searched in the IR label and the ER label text and not found [1][2] (per summarizers).

Population evidence

Tapentadol itself: PubMed "tapentadol hyponatremia" returned one 2009 drug-review record (PMID 19748880, listing only); "tapentadol AND (sodium OR SIADH OR hyponatraemia)" returned 10 records, none reporting a sodium disturbance [20]; the post-marketing review [18] does not address it. Class data: Fournier 2015 [13], 332,880 UK patients, tramadol versus codeine, hospitalization for hyponatremia 4.6 versus 1.9 per 10,000 person-months, adjusted HR 2.05 (95% CI 1.08 to 3.86). Case report [14]: serum sodium 137, then 127 mmol/L 7 days after tramadol started with desvenlafaxine, 133 mmol/L 5 days after stopping.

Mechanism

SIADH is named for tramadol in the case report [14]. Whether tapentadol's norepinephrine reuptake inhibition or opioid action influences ADH release was not established by any source opened.

Counter-evidence held on record

Counter-evidence and confounding Tramadol and tapentadol differ in serotonergic activity [19], so the tramadol signal may not transfer. The tramadol cohort used an active comparator (codeine), not non-use, and the case report had a co-prescribed antidepressant that can itself cause hyponatremia [14]. 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: None sought beyond the above.
• At-risk subgroups: People on opioids for more than one month, per the label wording [1][2].

Direction

HORMONE SUPPRESSION (adrenal). Not a nutrient depletion.

Cohort test (Hard Rule 6)

The label wording is class-level ("with opioid use"). No tapentadol cohort study was retrieved, so this is labeled CLASS EXTRAPOLATION and capped at yellow, although the sentence sits in tapentadol's own regulatory label.

Regulatory status

Present in both labels: cases reported with opioid use, more often after more than one month; presentation includes nausea, vomiting, anorexia, fatigue, weakness, dizziness and hypotension; management is physiologic corticosteroid replacement and opioid tapering [1][2].

Population evidence

None tapentadol-specific retrieved. A dedicated PubMed query for tapentadol and adrenal function was not completed.

Mechanism

Not stated in the label text read.

Counter-evidence held on record

Counter-evidence and confounding The symptoms are nonspecific and overlap with opioid adverse effects and the underlying pain condition. Prevalence in tapentadol users is unknown from the sources read. 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: Only the oxycodone group was reported as significantly decreased; tapentadol figures were close to placebo, though significance versus placebo was not reported in the text read [12]. The title states better gastrointestinal tolerability than oxycodone.
• At-risk subgroups: Patients on higher or longer dosing and those with obstruction risk, per the label [2].

Direction

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

Regulatory status

IR label table: constipation 8% with tapentadol versus 3% with placebo [1]. ER label: 17% in low back pain and osteoarthritis trials and 13% in diabetic neuropathy trials (comparator rates not captured) [2]. The ER label says propulsive colonic waves are decreased and tone raised to the point of spasm, and contraindicates use in known or suspected gastrointestinal obstruction including paralytic ileus [2]. IR label nausea 30% versus 13% and vomiting 18% versus 4% with placebo [1], a possible intake effect (mechanism class H) that nobody measured.

Population evidence

Etropolski 2011 [12], randomized double-blind placebo-controlled trial, tapentadol IR 50 and 75 mg versus oxycodone IR 10 mg versus placebo: spontaneous bowel movements per week 9.0 (50 mg), 8.6 (75 mg), 6.7 (oxycodone, significantly decreased, P under 0.001) and 9.9 (placebo). Sample size not captured.

Mechanism

Opioid-receptor slowing of colonic propulsion, per the label [2].

Counter-evidence held on record

Counter-evidence and confounding Reduced fiber, fluid or food intake from nausea could contribute, and none of the sources measured nutrient intake or status. Constipation also complicates any gut microbiome interpretation (see that 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: No human homocysteine, B12 or folate measurement under tapentadol was found (see the ungraded B12 and folate entry).
• At-risk subgroups: None identified.

Direction

HIGHER homocysteine (marker) in animals. Not a B12, folate or B6 deficiency (Hard Rule 2): the vitamins themselves were not measured.

Regulatory status

Not mentioned in either label text read [1][2].

Population evidence

Cardoso 2023 [6], Wistar rats, 9 per group, 50 mg/kg intraperitoneal on 8 alternate days: tapentadol increased homocysteine (p under 0.05); tramadol decreased cysteine (conference abstract via publisher page). Soares-Cardoso 2024 [7], same dose protocol: serum cysteine, homocysteine, hydrogen peroxide and dopamine altered with either or both drugs; the direction for tapentadol was not captured in the abstract read. The PubMed query "tapentadol AND homocysteine" returned only [7] [21].

Mechanism

Not stated in the abstracts read.

Counter-evidence held on record

Counter-evidence and confounding Two reports from one laboratory using the same 50 mg/kg, 8-day protocol, probably the same animals (not confirmed). Homocysteine also rises with renal impairment, age and hypothyroidism, and the injected doses are not human equivalents. Framing caution A higher homocysteine in rats is not evidence that people on tapentadol are low in B12 or folate. Do not start B vitamins because of this entry. No dose or medication change without a prescriber or pharmacist.

Limits on what this shows

• Null findings: Higher, not lower, vitamin D in the opioid-dependent group [17].
• At-risk subgroups: None identified. Indication-linked low vitamin D in chronic pain populations is presumed (Hard Rule 6) and was not separately sourced in this review.

Direction

REVERSE (higher, not lower) in the class cohort, with unresolved confounding. Not a depletion.

Cohort test (Hard Rule 6)

Reece 2018 [17]: opioids taken were not named and "tapentadol is not mentioned". Tapentadol was NOT confirmed in the cohort. Tier C, CLASS EXTRAPOLATION, capped at yellow.

Regulatory status

Vitamin D not found in the IR label text [1]; not mentioned in the ER label text read [2].

Population evidence

Reece 2018 [17], Australian primary care, 1,168 opioid-dependent patients versus 415 general medical controls: vitamin D 70.35 versus 57.06 nmol/L (about 8.5% higher at median age after modeling); PTH not measured. Tapentadol searches: PubMed "tapentadol AND vitamin D" returned one record, a 2018 narrative review of nonopioid pain therapies that mentions transdermal vitamin D incidentally (PMID 29616344) [21].

Mechanism

None stated. The opioid-induced testosterone effect (see the androgen entry) is not shown by any source read to alter vitamin D.

Counter-evidence held on record

Counter-evidence and confounding Cross-sectional comparison of opioid-dependent patients, not people taking tapentadol for pain; sun exposure, body mass index, supplement use and drug-use level were unmeasured [17]. Confounding by indication and pain-related immobility are not excluded. Framing caution This is a reverse-direction, class-level 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 tapentadol, and no circulating consumer claim naming these vitamins for tapentadol was found. The rat homocysteine rise is graded separately as a functional marker and is not evidence about B12 or folate status. This is a disclosed absence of evidence, not a finding of safety. Indication-linked B12 insufficiency in a diabetic neuropathy population is presumed to be confounded by the underlying condition (Hard Rule 6) and was not sourced here.

What was searched

Labels: IR label text searched for vitamin, folate and B12, none found [1]; ER label analysis reports vitamin B12, folate, vitamin D, iron and copper not mentioned [2]. PubMed listings: "tapentadol vitamin B12 folate" (404 page); "tapentadol AND (cobalamin OR vitamin B12 OR folate OR folic acid)" (HTTP 429 on first attempt, not retried on the same URL); "tapentadol AND homocysteine" (one rat record [7], which measured homocysteine and cysteine, not B12 or folate). WebSearch "tapentadol homocysteine OR vitamin B12 OR folate OR vitamin D patients serum levels" returned unrelated B12 and dementia or psychiatric records, none involving tapentadol (titles only, not opened). The shared WebSearch budget was then exhausted. Papers opened and found not to measure B12 or folate: [5][6][7].

Channel outcomes

DailyMed search page and several PubMed listing pages returned HTTP 429; some phrasings returned 404 pages that cannot be told from empty results; PMC pages returned a bot-verification page; Europe PMC and direct PubMed or Crossref APIs are blocked by policy and were not used.

Genuine gap or tooling-limited

Mostly a genuine gap for direct B12 and folate measurement (labels silent, no records found across several phrasings), with a tooling-limited component: one directed PubMed phrasing returned an error page and a human case-control or diabetic-neuropathy cohort that reported B12 under tapentadol could be missed. Re-check with a working PubMed or Europe PMC channel.