Is Tapentadol an Opioid or a Non-opioid Analgesic?

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Yes—it is an opioid.

Several years ago, while attending a national conference, I listened as a well-known pharmacist spoke about the devastation caused by prescription opioids in the United States. During his talk, he stated that if a member of his own family ever required pain treatment, he would never allow them to receive opioids. Instead, he said, they would be given Tylenol, Toradol, and tapentadol. I was taken aback that a respected clinical pharmacologist appeared to regard tapentadol as something other than an opioid. He is not alone in this view.

In discussions about the risks associated with opioid therapy, tapentadol is frequently presented as a “non-opioid” alternative. This misconception is encountered repeatedly among students, colleagues, and even in articles published in highly regarded medical journals. Cheap Tapentadol is now approved for use in more than 100 countries and is among the most widely prescribed opioid analgesics worldwide. In the United States, prescriptions for tapentadol more than doubled between 2007 and 2015, making it one of the most commonly prescribed opioids.

This trend raises an important question: are clinicians—particularly in primary care and among non-physician prescribers—more willing to prescribe tapentadol during the so-called opioid epidemic because they do not perceive it as an opioid? If so, this assumption is problematic. Data on postoperative opioid use indicate that tapentadol is at least as likely as other opioids to be continued long term, a commonly used surrogate marker for abuse and overdose risk. Supporting this concern, data from the Drug Abuse Warning Network show a 250% increase in emergency department visits related to misuse or abuse of tapentadol online between 2005 and 2025.

This article examines the pharmacology of tapentadol, with particular attention to clarifying its opioid and non-opioid mechanisms of action.

Regulatory Ambiguity

The compound 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol was first synthesized by Grünenthal in Germany in 1962 and later marketed as tapentadol in 1977. In the United States, the FDA approved tapentadol in 1995 as a prescription-only medication that was initially not classified as a controlled substance. Both immediate-release and extended-release oral formulations are currently available.

In 2014, tapentadol was reclassified as a Schedule IV controlled substance, acknowledging its potential for abuse, although it remains outside Schedule II, where most opioid analgesics are placed. As a result, tapentadol is now included in all state prescription drug monitoring programs (PDMPs) across the country.

Prodrug Pharmacology

Tapentadol differs from many other opioids in that it functions as a prodrug. The parent compound itself has very low affinity for the μ-opioid receptor (MOR). It is marketed as a racemic mixture of (+) and (–) enantiomers, with the (+) enantiomer demonstrating approximately 20-fold greater MOR affinity than the (–) form, though still several thousand times weaker than morphine.

In contrast, the primary active metabolite, O-desmethyl-tapentadol (M1), exhibits MOR affinity only about tenfold lower than that of morphine and is believed to account for the majority of the drug’s opioid analgesic effects. Thus, it is not the parent compound but its metabolite that is primarily responsible for tapentadol’s opioid activity.

This pharmacologic profile closely parallels that of codeine, another well-established prodrug metabolized to morphine, whose opioid classification is not in question. Similarly, the clinical effects of tapentadol are strongly influenced by pharmacogenetic variability in the cytochrome P-450 2D6 (CYP2D6) enzyme, which is responsible for its conversion to the M1 metabolite. Individuals with reduced CYP2D6 activity—so-called poor metabolizers—including approximately 20% of African Americans, 10% of Caucasians, and 2% of Asians, may experience little to no opioid effect from tapentadol.

Non-opioid Analgesic Mechanisms

Tapentadol’s monoaminergic activity—specifically its inhibition of norepinephrine (NE) reuptake, with minimal effects on serotonin (5-HT)—has been widely discussed in the literature. This mechanism contributes meaningfully to its analgesic profile and distinguishes it from traditional pure μ-opioid receptor (MOR) agonists.

Similar to its opioid activity, tapentadol demonstrates stereoselective pharmacologic properties. Differences between its enantiomers are reflected not only in MOR affinity but also in monoaminergic effects. One enantiomer exhibits greater opioid receptor activity, while the other more effectively inhibits NE reuptake. Increases in synaptic NE are well known to activate endogenous descending inhibitory pain pathways and are largely responsible for the analgesic effects observed with serotonin–norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). By contrast, the analgesic role of increased central nervous system serotonin remains more controversial.

As a result, a portion of tapentadol’s analgesic efficacy is mediated through enhanced synaptic NE signaling and subsequent activation of α₂-adrenergic receptors, a mechanism that operates independently of MOR activation. This dual mechanism—opioid receptor agonism combined with norepinephrine reuptake inhibition—accounts for tapentadol’s classification as a dual-action analgesic rather than a purely opioid medication.

Side Effect Profile

Given its multimodal mechanism of action, it was initially hypothesized that tapentadol would reduce overall opioid requirements and, consequently, the incidence of opioid-related adverse effects when compared with conventional opioids. Early preclinical studies supported this assumption, reporting lower levels of drug reinforcement and less respiratory depression in animal models.

Nevertheless, like other opioids, tapentadol’s adverse effect profile remains clinically significant. Although it is not a classic opioid prodrug, interindividual variability in metabolism and receptor sensitivity still influences both therapeutic and adverse outcomes. Tapentadol is capable of producing opioid-related side effects, including respiratory depression—particularly when combined with other central nervous system depressants—as well as opioid use disorder.

Common opioid-like adverse effects associated with tapentadol online include constipation, sedation, and pruritus, though these may occur at somewhat lower frequencies than with some traditional opioids. In contrast, nausea appears to be relatively common and remains a frequent reason for discontinuation. As with other agents acting on opioid pathways, tolerance can develop with repeated use, and both physical dependence and withdrawal have been documented.

Importantly, withdrawal from tapentadol may reflect not only opioid discontinuation but also abrupt cessation of its monoaminergic effects, producing symptoms that resemble those seen with norepinephrine reuptake inhibitors. This dual withdrawal profile further underscores the need to recognize tapentadol as a pharmacologically complex opioid analgesic rather than a benign non-opioid alternative.

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Table 1. Common Opioid and SSRI-Like Withdrawal Symptoms Associated with Abrupt Tapentadol Discontinuation

Opioid Withdrawal Symptoms

  • Abdominal cramping

  • Agitation

  • Anxiety

  • Depression

  • Gooseflesh

  • Hyperkinesia

  • Insomnia

SSRI-Like Withdrawal Symptoms

  • Lacrimation

  • Myoclonus

  • Nausea

  • Paresthesia

  • Rhinorrhea

  • Sweating

  • Tremors

Neuropsychiatric Symptoms

  • Confusion

  • Delusions

  • Hallucinations

  • Panic attacks

  • Paranoia

  • Restless leg syndrome

  • Unusual sensory phenomena

In addition to classic opioid-related adverse effects, tapentadol is associated with several side effects that are not typically characteristic of opioids. These include headache, dizziness, dyspepsia, and flushing, effects that are likely related to its monoaminergic activity, particularly increased central norepinephrine and serotonin signaling.

Of greater clinical concern, however, are the potentially serious non-opioid adverse effects of seizures and serotonin (5-HT) syndrome, as their underlying mechanisms may not be immediately apparent to prescribers.

Seizures associated with tapentadol occur more frequently in patients with a prior seizure disorder or in those taking concomitant medications that lower the seizure threshold. This risk is especially pronounced with drugs that enhance serotonergic activity, such as selective serotonin reuptake inhibitors and other serotonergic psychotropic agents. These interactions implicate elevated serotonin levels as a contributing factor and may help explain why seizure incidence with tapentadol appears lower than that historically reported with tramadol.

Conversely, the observation that seizure risk increases when tapentadol is co-administered with CYP2D6 inhibitors suggests that the parent compound—or its non-opioid metabolites—may play a direct role. This mechanism also offers a plausible explanation for the heightened seizure risk observed in patients with renal impairment, given the predominantly renal elimination of tapentadol and its metabolites.

Interestingly, naloxone administration has been reported to increase seizure activity in patients exposed to tapentadol, a finding that supports the hypothesis that μ-opioid receptor activation may exert a protective effect by raising the seizure threshold.

Serotonin Syndrome

As with seizure risk, elevated serotonin levels underlie tapentadol’s most dangerous non-opioid adverse effect: serotonin syndrome. This condition remains a clinical diagnosis, as no definitive laboratory test exists. It may present with the classic triad of neuromuscular hyperactivity, autonomic instability, and altered mental status, though milder and less specific manifestations—such as diaphoresis, tremor, and hyperreflexia—are far more common.

Despite its often subtle presentation, clinicians must maintain a high index of suspicion, as severe serotonin syndrome can lead to life-threatening complications, including rhabdomyolysis, acute renal failure, disseminated intravascular coagulation, acute respiratory distress syndrome, and death.

Serotonin syndrome constitutes a medical emergency and requires prompt intervention, including supplemental oxygen, active cooling, intravenous fluid resuscitation, continuous cardiac monitoring, and administration of the serotonin antagonist cyproheptadine.

Is Tapentadol an Opioid or a Non-opioid Analgesic? Yes.

Table 2. Severity, Signs, and Symptoms of Serotonin (5-HT) Syndrome

Mild

  • Diaphoresis

  • Tremor

  • Diarrhea

  • Irritability

  • Sleep disturbances

  • Tachycardia

  • Hyperreflexia

Moderate

  • Agitation

  • Hypervigilance

  • Hyperthermia (<41°C)

  • Tachycardia

  • Hypertension

  • Myoclonus (inducible clonus and ocular clonus)

Severe

  • Delirium

  • Hyperthermia (>41°C)

  • Severe hypertension

  • Severe tachycardia

  • Peripheral hypertonicity

  • Trismus

  • Truncal rigidity

  • Spontaneous clonus

High-dose tapentadol exposure—typically two to three times the recommended maximum daily dose—is occasionally sufficient to precipitate serotonin syndrome. However, as with seizure risk, serotonin syndrome far more commonly arises from drug–drug interactions involving other serotonergic agents rather than from tapentadol monotherapy. Antidepressants, antiemetics, and medications used for headache disorders have all been reported to trigger serotonin syndrome when combined with therapeutic doses of tapentadol. These interactions are particularly relevant given the frequent co-prescribing of antidepressants for chronic pain and the common occurrence of nausea and headache during tapentadol therapy.

Table 3. Medications Known to Precipitate Serotonin (5-HT) Syndrome When Combined with Tapentadol

Antiarrhythmic agents

  • Quinidine

Antibiotics

  • Linezolid

Antiemetics (controversial)

  • Setrons (e.g., ondansetron)

  • Metoclopramide

Antimigraine agents

  • Ergot alkaloids

  • Triptans (e.g., sumatriptan; controversial)

Antiretrovirals

  • Ritonavir

Appetite suppressants

  • Sibutramine

Cold and allergy medications

  • Dextromethorphan

  • Chlorpheniramine

Herbal supplements

  • St. John’s wort (Hypericum perforatum)

  • Yohimbe

  • Ginseng

  • L-tryptophan

Illicit substances

  • MDMA (ecstasy)

  • Amphetamines

  • Cocaine

Opioid analgesics

  • Fentanyl

  • Methadone
    (morphine and oxycodone remain controversial)

Psychotropic medications

  • MAO inhibitors

  • Tricyclic antidepressants

  • SSRIs

  • SNRIs

  • Nefazodone

  • Maprotiline

  • Amphetamines

  • Second-generation antipsychotics

  • Bupropion

  • Divalproex

  • Carbamazepine

Patients at increased risk for nonadherence—including those with a history of substance abuse or prior overdose—have been shown to have a higher incidence of tapentadol-associated seizures. Similarly, individuals most likely to misuse tapentadol often have a prior history of substance use disorder, chronic pain, or occupational access to controlled medications, including healthcare professionals. A review of physician health programs reported that tapentadol ranked among the most frequently misused prescription drugs, surpassing even fentanyl and oxycodone in reported cases during the study period.

Sounds Like Toradol — But Isn’t

It is therefore concerning to encounter surgical patients with extensive histories of alcohol or drug abuse who are maintained on tapentadol for chronic pain. This practice is unlikely to stem from simple name confusion with the nonsteroidal anti-inflammatory drug ketorolac (Toradol). Rather, it reflects a broader misunderstanding of tapentadol’s pharmacology.

Unlike ketorolac, tapentadol is an opioid analgesic with a complex pharmacokinetic and pharmacodynamic profile capable of producing both opioid and non-opioid adverse effects that may be clinically dangerous and diagnostically challenging. Although the FDA approved tapentadol for the treatment of moderate to severe pain, similar to other opioids, its analgesic efficacy has been the subject of ongoing debate. The World Health Organization places tapentadol on Step 2 of its three-step analgesic ladder, below most traditional opioids.

Evidence from a network meta-analysis evaluating morphine-sparing effects of purported “non-opioid” analgesics in the postoperative setting demonstrated that tapentadol reduced morphine consumption to a degree comparable to acetaminophen but less effectively than NSAIDs or α₂-adrenergic receptor agonists. Moreover, unlike acetaminophen, the addition of tapentadol to morphine therapy did not confer a meaningful improvement in analgesia.

These findings should weigh heavily in prescribers’ risk–benefit assessments, particularly given the more favorable safety profiles of truly non-opioid analgesics such as acetaminophen and NSAIDs for the majority of patients.

Yes you can buy tapentadol online but Tapentadol is a prescription opioid analgesic.