Tapentadol

Summary

Tapentadol, frequently marketed under Nucynta, is a synthetic opioid analgesic that shares structural similarities with tramadol. Tapentadol exerts its effects through a dual mechanism of action, functioning as both a μ-opioid receptor agonist and a norepinephrine reuptake inhibitor. It is employed for the treatment of moderate to severe pain. Users often describe the subjective effects of tapentadol as akin to those of tramadol. Notably, attempting to insufflate tapentadol may result in severe discomfort for many individuals.

Identifiers

IUPAC name
CAS Number	175591-23-8 HCl: 175591-09-0
PubChem CID	9838022
IUPHAR/BPS	7477
DrugBank	DB06204
ChemSpider	8013742
UNII	H8A007M585HCl: 71204KII53
KEGG	D06007
ChEMBL	ChEMBL1201776
CompTox Dashboard (EPA)	DTXSID30170003
ECHA InfoCard	100.131.247
Chemical and physical data
Formula	C14H23NO
Molar mass	221.344 g·mol−1

Chemistry

Tapentadol, known chemically as 3-((1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl) phenol hydrochloride, is a non-racemic compound. Its molecular formula is C14H23NO.HCl. Initially synthesized in the United States, it was introduced to the market by Ortho-McNeil-Janssen Pharmaceuticals under the trade name Nucynta.
In terms of chemical structure, tapentadol bears a resemblance to both tramadol and dextropropoxyphene. Notably, tapentadol possesses a single cyclic ring, unlike tramadol, which features two. Its empirical formula is C14H23NO, with a molar mass of 221.339 grams per mole. The complete IUPAC name for tapentadol is 3-[(2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl]phenol.

Pharmacology

Opioids exert their effects by binding to and activating the μ-opioid receptor. This interaction occurs because opioids structurally resemble endogenous endorphins in the body, which also engage with the μ-opioid receptor system. The structural similarity between opioids and these natural endorphins leads to the desired effects of euphoria, pain relief, and anxiety reduction. Endorphins are pivotal in reducing pain, inducing drowsiness, and generating pleasurable sensations. Their release can be triggered by various stimuli, such as pain, strenuous exercise, orgasm, or heightened excitement.
As for tapentadol, it exhibits an oral bioavailability of approximately 32%. The metabolism of tapentadol takes place in the liver through the Cytochrome P450 system, and it is subsequently excreted via the kidneys in urine and, to a lesser extent, in faeces. Notably, tapentadol diverges from most opioids because it acts as a norepinephrine reuptake inhibitor and possesses modal serotonergic effects.
Tapentadol is an orally administered synthetic benzenoid that acts as an agonist for the mu-opioid receptor (MOR) while concurrently inhibiting noradrenaline reuptake. This dual mechanism of action contributes to its potential anti-nociceptive properties. Upon oral ingestion, tapentadol binds to the MOR, enhancing MOR-mediated signalling, mitigating the perception of pain, and resulting in analgesia. Additionally, it inhibits the reuptake of noradrenaline, leading to increased noradrenaline levels (NA). This, in turn, activates inhibitory alpha-2 receptors and produces an analgesic effect.
Regarding elimination, tapentadol and its metabolites are primarily excreted via the kidneys, accounting for approximately 99% of excretion. Conjugated forms comprise the majority, with roughly 70% (containing 55% O-glucuronide and 15% sulfate of tapentadol) being excreted in this manner. A mere 3% of the drug is excreted in urine in its unchanged form.

Subjective effects

Disclaimer: The effects outlined below are based on the Subjective Effect Index (SEI), a collection of anecdotal user reports and individual analyses contributed by PsychonautWiki contributors. As such, they should be approached with a measure of caution.

It is important to note that these effects may not necessarily manifest consistently or predictably. However, higher doses are more likely to evoke a broader range of products. Additionally, higher doses carry an increased risk of adverse effects, which may include addiction, severe harm, or even fatality ☠.

Physical:

• Pain Relief: Tapentadol is known for its general pain-relieving properties.
• Physical Euphoria: While the physical euphoria induced by this substance is significant, it tends to be less intense than morphine or diacetylmorphine (heroin). It is characterized by intense feelings of physical comfort, warmth, love, and bliss.
• Itchiness
• Respiratory Depression: At lower to moderate doses, this effect may mildly slow down breathing without causing noticeable impairment. However, higher doses and overdoses can lead to significant respiratory depression, resulting in shortness of breath, irregular breathing patterns, semi-consciousness, or unconsciousness. Severe overdoses may lead to a coma or death without prompt medical intervention.
• Constipation
• Cough Suppression
• Difficulty Urinating
• Nausea
• Sedation
• Double Vision
• Pupil Constriction
• Decreased Libido
• Appetite Suppression
• Dizziness: Tapentadol tends to induce dizziness faster than other opioids.
• Orgasm Suppression
• Dry Mouth

Cognitive:

• Anxiety Suppression
• Cognitive Euphoria: Tapentadol’s mental euphoria is generally less intense than morphine or heroin.
• Dream Potentiation
• Increased Music Appreciation
• Focus Enhancement: This effect is noticeable at lower doses but diminishes as the dose increases and the soothing and euphoric effects become more prominent.
• Motivation Enhancement
• Sleepiness: At higher doses, users may experience significant drowsiness, potentially leading to drifting in and out of consciousness or experiencing “nodding.”
• Thought Acceleration
• Irritability

Visual:

• Visual Effects: Tapentadol exhibits more pronounced visual effects compared to other opioids of its class, which intensify progressively with dosage.
• Suppressions:
  • Double Vision
  • Visual Acuity Suppression
• Hallucinatory States:
  • Internal Hallucination: Tapentadol’s internal hallucinations are notably more solid than those induced by psychedelics and lack the typical visual geometric patterns. They usually manifest as hypnagogic scenarios and are observable at various doses, potentially causing difficulty in falling asleep. These hallucinations can be described as believably lucid, stylistically fixed, autonomously controllable, and consistent in new experiences and memory replays in content.

Toxicity

Tapentadol exhibits a relatively low toxicity in its dosage. However, like all opioids, it can manifest varying long-term effects, including reduced libido, apathy, and memory impairment. When combined with depressants like alcohol or benzodiazepines, it can potentially be life-threatening, and its list of dangerous interactions is more extensive compared to other opioids. Furthermore, Tapentadol is known to lower the seizure threshold, making it unsuitable for use during benzodiazepine withdrawals due to the risk of seizures.

It is strongly advisable to implement harm-reduction practices when using this substance.

Tolerance and Addiction Potential

As with other opioids, chronic use of Tapentadol can be considered moderately addictive, carrying a high risk of abuse and the potential for users to develop psychological dependence. Those addicted may experience cravings and withdrawal symptoms if they abruptly cease consumption.

Tolerance to various effects of Tapentadol develops with prolonged and repeated use, with some products, such as constipation, developing tolerance particularly slowly. This necessitates users to escalate their doses to achieve the same effects. Reducing tolerance to half typically takes about 3 – 7 days, with a return to baseline taking approximately 1 – 2 weeks without further consumption. Importantly, Tapentadol engenders cross-tolerance with all other opioids, diminishing the effects of other opioids following its use.

Dangerous Interactions

Warning: Combining psychoactive substances, even those considered safe when used individually, can become dangerous and potentially life-threatening when mixed with certain other substances. The following list highlights some known perilous interactions (though it may not cover all possibilities).

It is imperative to conduct independent research (e.g., via search engines medical databases) to ascertain the safety of combining two or more substances. Some of the interactions mentioned are sourced from TripSit.

• Alcohol: When combined with Tapentadol, both substances enhance each other’s ataxia and sedative effects, potentially resulting in unexpected loss of consciousness at high doses. This combination may also lead to memory blackouts.
• Amphetamines: Stimulants increase respiration rate, permitting higher doses of opioids than would typically be safe. However, if the stimulant wears off before the opioid, it may lead to respiratory arrest.
• Benzodiazepines: The central nervous system and respiratory-depressant effects of benzodiazepines can additively or synergistically potentiate those of Tapentadol, rapidly inducing unconsciousness. During unconsciousness, vomit aspiration is risky, and memory blackouts are common.
• Cocaine: Stimulants like cocaine boost respiration rates, allowing for higher opioid doses. However, if the stimulant effects wear off first, opioid overdose and respiratory arrest become more likely.
• DXM (Dextromethorphan): Generally considered toxic when combined with opioids, DXM can lead to CNS depression, breathing difficulties, heart problems, and liver toxicity. Additionally, it can reduce opioid tolerance, increasing the risk of overdose.
• GHB/GBL: These substances intensely and unpredictably potentiate each other, quickly leading to unconsciousness. During this state, there’s a risk of vomit aspiration if proper precautions aren’t taken.
• Ketamine: Combining ketamine with Tapentadol poses risks of vomiting and unconsciousness. If the user loses consciousness under the influence of these substances, there’s a severe risk of vomit aspiration if they are not placed in the recovery position.
• MAOIs (Monoamine Oxidase Inhibitors): Combining MAOIs with certain opioids can lead to severe adverse reactions. There are two types of interactions: excitatory and depressive. Symptoms may include agitation, headache, sweating, hyperpyrexia, flushing, tremors, seizures, and coma. Death has occurred in some cases.
• MXE: While it can potentiate opioid effects, it also increases the risk of respiratory depression and organ toxicity.
• Nitrous: Both substances enhance each other’s ataxia and sedation, potentially causing sudden loss of consciousness at high doses. During unconsciousness, vomit aspiration is a concern, and memory blackouts are common.
• PCP: PCP may reduce opioid tolerance, heightening the risk of overdose.
• Tramadol: Combining Tapentadol with tramadol increases the risk of seizures, as both substances can induce seizures individually. Furthermore, central nervous system and respiratory-depressant effects may be synergistically present.
• Grapefruit: Although not psychoactive, grapefruit can affect the metabolism of certain opioids, leading to prolonged drug effects and potential toxicity with repeated doses. This interaction is particularly relevant for tramadol, oxycodone, and fentanyl, primarily metabolized by the enzyme CYP3A4 inhibited by grapefruit juice. Methadone may also be affected, while CYP2D6 metabolizes codeine and hydrocodone.

Serotonin Syndrome Risk

Combining Tapentadol with certain substances can elevate serotonin levels dangerously, potentially leading to serotonin syndrome, which necessitates immediate medical attention and can be fatal if left untreated. These substances include:

• MAOIs: Such as banisteriopsis caapi, Syrian rue, phenelzine, selegiline, and moclobemide.
• Serotonin Releasers: MDMA, 4-FA, methamphetamine, methylone, and αMT.
• SSRIs: Such as citalopram and sertraline.
• SNRIs: Such as tramadol and venlafaxine.
• 5-HTP.

Legal status

Germany: In Germany, Tapentadol is classified as a controlled substance listed in Anlage III of the BtMG. It can only be prescribed through a narcotic prescription form.

Switzerland: Switzerland designates Tapentadol as a controlled substance explicitly mentioned in Verzeichnis A. Medicinal use of this substance is allowed.

United Kingdom: In the United Kingdom, Tapentadol is categorized as a Class A, Schedule 2 drug.

United States: Tapentadol is classified as a Schedule II Controlled Substance in the United States.

FAQ

1. What is Tapentadol?

• Tapentadol is a medication used to manage moderate to severe pain. It belongs to the class of drugs known as opioids and is available in both immediate-release and extended-release formulations.

2. How does Tapentadol work?

• Tapentadol binds to specific receptors in the brain and spinal cord, altering how your body perceives and responds to pain signals. It also affects the levels of certain neurotransmitters.

3. What conditions is Tapentadol prescribed for?

• Tapentadol is typically prescribed for conditions involving severe pain, such as post-surgery pain, chronic pain due to injury, nerve pain (neuropathic pain), and certain musculoskeletal conditions.

4. Is Tapentadol safe to use?

• Tapentadol can be safe and effective when used as prescribed by a healthcare professional. However, it carries potential risks and side effects, including the risk of addiction, respiratory depression, and other adverse reactions. It should only be used under medical supervision.

5. What are the common side effects of Tapentadol?

• Common side effects of Tapentadol may include dizziness, nausea, vomiting, constipation, headache, and drowsiness. It’s essential to discuss potential side effects with your healthcare provider.

6. Is Tapentadol addictive?

• Yes, like other opioids, Tapentadol has the potential for addiction and dependence. It’s crucial to use it only as directed by a healthcare professional and to be aware of the signs of opioid dependence.

7. How should I take Tapentadol?

• Follow your doctor’s instructions carefully. Tapentadol is usually taken by mouth with or without food. The dosage and frequency will depend on your condition and pain level.

8. Can I drink alcohol while taking Tapentadol?

• It is not recommended to consume alcohol while taking Tapentadol, as it can increase the risk of side effects and may be dangerous.

9. Can I drive or operate machinery while using Tapentadol?

• Tapentadol may cause dizziness and drowsiness, so it’s important to avoid activities that require mental alertness until you know how it affects you. It’s best to consult your healthcare provider regarding your ability to drive or operate machinery while taking Tapentadol.

10. Can I stop taking Tapentadol abruptly?

• It’s essential to follow your doctor’s guidance when discontinuing Tapentadol. Abruptly stopping the medication can lead to withdrawal symptoms. Your healthcare provider will typically taper your dose gradually to minimize withdrawal effects.

11. Is Tapentadol available without a prescription?

• No, Tapentadol is a prescription medication unavailable over the counter. It should only be used under the supervision of a licensed healthcare provider.

12. Are there any drug interactions with Tapentadol?

• Yes, Tapentadol can interact with other medications. It’s crucial to inform your doctor about all your prescriptions, supplements, and herbs to avoid potentially harmful interactions.

13. What should I do if I suspect an overdose of Tapentadol?

• If you suspect an overdose, seek immediate medical attention or contact a poison control centre. Overdosing on Tapentadol can be life-threatening.

14. Can pregnant or breastfeeding individuals use Tapentadol?

• Tapentadol should only be used during pregnancy or breastfeeding under the guidance of a healthcare provider. It may pose risks to the developing fetus or nursing infant.

15. Is Tapentadol available in generic form?

• Yes, generic versions of Tapentadol are available. These typically contain the same active ingredient but may have different inactive ingredients.

Always consult your healthcare provider or pharmacist for specific information and guidance related to your use of Tapentadol.

References

1. Tapentadol Hydrochloride: A Novel Analgesic – This study, published in the “Saudi Journal of Anaesthesia,” explores the properties and applications of Tapentadol hydrochloride as an analgesic. It provides valuable insights into its pharmacological effects and uses. Source
2. PubChem, Tapentadol – Tapentadol’s chemical properties and information can be found on PubChem, providing comprehensive data for those interested in its chemical composition and characteristics. Source
3. Role of Tapentadol Immediate Release in Pain Management – This article from the “Pharmacy and Therapeutics” journal discusses the role of Tapentadol Immediate Release (Nucynta) in managing moderate-to-severe pain, shedding light on its effectiveness and applications. Source
4. Tapentadol – Additional information on Tapentadol can be found on PubChem, providing users with detailed insights into its molecular structure and properties. Source
5. Opioid Toxidrome Following Grapefruit Juice Consumption – This study published in the “Journal of Addiction Medicine” explores the potential consequences of consuming grapefruit juice in the context of methadone maintenance and its impact on the opioid toxidrome. Source
6. Monoamine Oxidase Inhibitors, Opioid Analgesics, and Serotonin Toxicity – In this article from the “British Journal of Anaesthesia,” the potential interactions and risks associated with combining monoamine oxidase inhibitors, opioid analgesics, and serotonin are discussed in detail. Source
7. Anlage III BtMG – This is the official reference to Tapentadol’s status in Germany, where it is listed under Anlage III of the BtMG, indicating its controlled substance status. Source
8. Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien – This is the Swiss Federal Chancellery’s official document detailing the controlled status of Tapentadol in Switzerland. Source
9. List of Most Commonly Encountered Drugs Controlled Under Misuse of Drugs Legislation – This list provides an overview of commonly encountered drugs controlled under drug misuse legislation, including information on their legal status. Source
10. DEA Controlled Substances – The U.S. Drug Enforcement Administration (DEA) provides a comprehensive list of controlled substances, including Tapentadol, under Schedule II, with detailed information on its classification and regulations. Source