Tapentadol, brand names Nucynta among others, is a centrally acting
opioid
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...
analgesic
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
of the benzenoid class with a dual mode of action as an
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
of the
μ-opioid receptor
The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical Π...
and as a
norepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epineph ...
(NRI).
[ Analgesia occurs within 32 minutes of oral administration, and lasts for 4–6 hours.]
It is similar to tramadol
Tramadol, sold under the brand name Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an h ...
in its dual mechanism of action; namely, its ability to activate the mu opioid receptor and inhibit the reuptake of norepinephrine.[ Unlike tramadol, it has only weak effects on the reuptake of serotonin and is a significantly more potent opioid with no known active metabolites.] Tapentadol is not a pro-drug
A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
and therefore does not rely on metabolism to produce its therapeutic effects; this makes it a useful moderate-potency analgesic option for patients who do not respond adequately to more commonly used opioids due to genetic disposition (poor metabolizers of CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
and CYP2D6
Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.
CYP2D ...
), as well as providing a more consistent dosage-response range among the patient population.
The potency
Potency may refer to:
* Potency (pharmacology), a measure of the activity of a drug in a biological system
* Virility
* Cell potency, a measure of the differentiation potential of stem cells
* In homeopathic dilutions, potency is a measure of how ...
of tapentadol is somewhere between that of tramadol and morphine
Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a analgesic, pain medication, and is also commonly used recreational drug, recreationally, or to make ...
, with an analgesic efficacy comparable to that of oxycodone
Oxycodone, sold under various brand names such as Roxicodone and OxyContin (which is the extended release form), is a strong, semi-synthetic opioid used medically for treatment of moderate to severe pain. It is highly addictive and a commonly ...
despite a lower incidence of side effects.[ It is generally regarded as a moderately strong opioid.
Tapentadol was approved by the US ]FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
in November 2008, by the TGA of Australia in December 2010 and by the MHRA of the UK in February 2011. In India, Central Drug Standard Control Organisation (CDSCO) approved tapentadol immediate-release (IR) preparations (50, 75 and 100 mg) for moderate to severe acute pain and extended-release (ER) preparations (50,100,150 and 200 mg) for severe acute pain in April 2011 and December 2013 respectively.
Medical use
Tapentadol is used for the treatment of moderate to severe pain for both acute (following injury, surgery, etc.) and chronic musculoskeletal pain
Musculoskeletal disorders (MSDs) are injuries or pain in the human musculoskeletal system, including the joints, ligaments, muscles, nerves, tendons, and structures that support limbs, neck and back. MSDs can arise from a sudden exertion (e.g., ...
. It is also specifically indicated for controlling the pain of diabetic neuropathy
Diabetic neuropathy is various types of nerve damage associated with diabetes mellitus. Symptoms depend on the site of nerve damage and can include motor changes such as weakness; sensory symptoms such as numbness, tingling, or pain; or autonomic c ...
when around-the-clock opioid medication is required. Extended-release formulations of tapentadol are not indicated for use in the management of acute pain.
Tapentadol is Pregnancy Category C. There are no adequate and well-controlled studies of tapentadol in pregnant women, and tapentadol is not recommended for use in women during and immediately prior to labor and delivery.[Nucynta Label]
, last updated October 2013. Main FDA index page is her
to check for updates.
There are no adequate and well-controlled studies of tapentadol in children.[
]
Contraindications
Tapentadol is contraindicated in people with epilepsy or who are otherwise prone to seizures. It raises intracranial pressure so should not be used in people with head injuries, brain tumors, or other conditions which increase intracranial pressure. It increases the risk of respiratory depression so should not be used in people with asthma. As with other mu-opioid agonists, tapentadol may cause spasms of the sphincter of Oddi
The sphincter of Oddi (also hepatopancreatic sphincter or Glisson's sphincter), abbreviated as SO, is a muscular valve that in some animals, including humans, controls the flow of digestive juices (bile and pancreatic juice) out of the pancreas t ...
, and is therefore discouraged for use in patients with biliary tract
The biliary tract, (biliary tree or biliary system) refers to the liver, gallbladder and bile ducts, and how they work together to make, store and secrete bile. Bile consists of water, electrolytes, bile acids, cholesterol, phospholipids and co ...
disease such as both acute and chronic pancreatitis
Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic pancr ...
. People who are rapid or ultra rapid metabolizers for the CYP2C9
Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...
, CYP2C19
Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some pr ...
, and CYP2D6 enzymes may not respond adequately to tapentadol therapy. Due to reduced clearance, tapentadol should be administered with caution to people with moderate liver disease and not at all in people with severe liver disease.[
]
Adverse effects
The most commonly reported side effects of tapentadol therapy in clinical trials were nausea, vomiting, dizziness, sleepiness, itchiness, dry mouth, headache, and fatigue.[
According to the World Health Organization there is little evidence to judge the abuse potential of tapentadol.] Although early pre-clinical animal trials suggested that tapentadol has a reduced abuse liability compared to other opioid analgesics[ the US DEA placed tapentadol into Schedule II, the same category as stronger opioids more commonly used recreationally, such as morphine, oxycodone, and ]fentanyl
Fentanyl, also spelled fentanil, is a very potent synthetic opioid used as a pain medication. Together with other drugs, fentanyl is used for anesthesia. It is also used illicitly as a recreational drug, sometimes mixed with heroin, cocaine ...
.[
Tapentadol has been demonstrated to reduce the seizure threshold in patients. Tapentadol should be used cautiously in patients with a history of seizures, and in patients who are also taking one or more other drugs which have also been demonstrated to reduce the seizure threshold. Patients at high risk include those using other serotogenic and adrenergic medications, as well as patients with head trauma, metabolic disorders, and those in alcohol and/or drug withdrawals.]
Tapentadol has been demonstrated to potentially produce hypotension
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dias ...
(low blood pressure), and should be used with caution in patients with low blood pressure, and patients who are taking one or more other medications which are also known to reduce blood pressure
Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...
.
Interactions
Combination with SSRI
Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.
SSRIs increase the extracellul ...
s/ SNRIs, SRAs, serotonin receptor agonist
A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin (5-hydroxytryptamine; 5-HT), a neurotransmitter and hormone and the endogenous ligand of the ...
s may lead to potentially lethal serotonin syndrome
Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain serotonergic medications or drugs. The degree of symptoms can range from mild to severe, including a potentiality of death. Symptoms in mild cases include high ...
. Combination with MAOIs may also result in an adrenergic storm
An adrenergic storm is a sudden and dramatic increase in serum levels of the catecholamines adrenaline and noradrenaline (also known as epinephrine and norepinephrine respectively), with a less significant increase in dopamine transmission. It ...
. Use of tapentadol with alcohol or other sedatives such as benzodiazepines
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, i ...
, barbiturates
Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as ...
, nonbenzodiazepines
Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep problem ...
, phenothiazines
Phenothiazine, abbreviated PTZ, is an organic compound that has the formula S(C6H4)2NH and is related to the thiazine-class of heterocyclic compounds. Derivatives of phenothiazine are highly bioactive and have widespread use and rich history. Th ...
, and other opiates may result in increased impairment, sedation, respiratory depression, and death.[ Tapentadol is partially metabolized by the hepatic enzymes CYP2C9, CYP2C19, and CYP2D6 so it innately has interactions with drugs that enhance or repress the activity/expression of one or more of these enzymes, as well as with substrates of these enzymes (due to competition for the enzyme); some enzyme mediators/substrates require dosing adjustments to one or both medications.][
The combination of tapentadol and ]alcohol
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of sev ...
may result in increased plasma concentrations of tapentadol and produce respiratory depression to a degree greater than the sum of the two drugs when administered separately; patients should be cautioned against alcohol consumption when taking tapentadol as the combination may be fatal.
Tapentadol should be used with caution in patients who are taking one or more anticholinergic
Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system.
These agents inhibit the parasympathetic nervous system ...
drugs, as this combination may result in urine retention (which can result in serious renal damage and is considered a medical emergency).
Pharmacology
Tapentadol is an agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
of the μ-opioid receptor
The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical Π...
and a norepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epineph ...
(NRI).[ Analgesia occurs within 32 minutes after oral administration, and lasts for 4–6 hours.][ It is 18 times less potent than morphine in terms of binding to human mu-opioid receptors in ]in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
research on human tissue
In biology, tissue is a biological organizational level between cells and a complete organ. A tissue is an ensemble of similar cells and their extracellular matrix from the same origin that together carry out a specific function. Organs are ...
. In vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
, only 32% of an oral dose of tapentadol will survive first pass metabolism
The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the system ...
and proceed to the bloodstream
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
to produce its effects on the central
Central is an adjective usually referring to being in the center of some place or (mathematical) object.
Central may also refer to:
Directions and generalised locations
* Central Africa, a region in the centre of Africa continent, also known as ...
and peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...
s of the patient.[
It is similar to ]tramadol
Tramadol, sold under the brand name Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an h ...
in its dual mechanism of action but unlike tramadol, it has much weaker effects on the reuptake of serotonin and is a significantly more potent opioid with no known active metabolites.[
Commercial preparations contain only the (R,R) ]stereoisomer
In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...
, which is the weakest isomer in terms of opioid activity.[ The free base conversion ratio for salts includes 0.86 for the hydrochloride.
The peak plasma concentration (]Cmax
CMAX is a bus rapid transit (BRT) service in Central Ohio, operated by the Central Ohio Transit Authority (COTA). The line begins in Downtown Columbus, traveling northeast to Westerville. CMAX is Central Ohio's first bus rapid transit line; it ...
; amount of active drug in the bloodstream) when taken after eating is increased by 8% and 18% for tapentadol IR and ER preparations, respectively. This difference is not clinically significant, and tapentadol may be administered orally with or without food as circumstances allow, and the patient will generally not notice any change in the efficacy and/or duration of analgesic effects if the drug is not consistently administered in fasting or fed states (patients will receive the same benefits from their dose regardless of what and when they last ate). The plasma concentration of tapentadol differs to a relevant degree based on the administered dose, with the highest tested dose (250 mg) resulting in a higher Cmax than would be expected via the dose-proportionate plasma concentration expectations. Increased doses of tapentadol should be anticipated to be slightly stronger than predicted by linear functions of the previous dose-response relation.
History
Tapentadol was invented at the German pharmaceutical company Grünenthal
Grünenthal is a pharmaceutical company headquartered in Aachen in Germany. It was founded in 1946 as Chemie Grünenthal and has been continuously family-owned. The company was the first to introduce penicillin into the German market in the ...
in the late 1980s led by Helmut Buschmann; the team started by analyzing the chemistry and activity of tramadol
Tramadol, sold under the brand name Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an h ...
, which had been invented at the same company in 1962.[Helmut Buschmann. Tapentadol – From Morphine and Tramadol to the Discovery of Tapentadol. Chapter 12 in Analogue-based Drug Discovery III, First Edition. Edited by Janos Fischer, C. Robin Ganellin, and David P. Rotella. Wiley-VCH Verlag GmbH & Co. KGaA. 2013. ] Tramadol has several enantiomers, and each forms metabolites after processing in the liver. These tramadol variants have varying activities at the μ-opioid receptor
The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical Π...
, the norepinephrine transporter
The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene.
NET is a monoamine transporter and is responsible for the sodium- ...
, and the serotonin transporter
The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein tha ...
, and differing half-lives, with the metabolites having the best activity. Using tramadol as a starting point, the team aimed to discover a single molecule that minimized the serotonin activity, had strong μ-opioid receptor agonism and strong norepinephrine reuptake inhibition, and would not require metabolism to be active; the result was tapentadol.[
In 2003 Grünenthal partnered with two ]Johnson & Johnson
Johnson & Johnson (J&J) is an American multinational corporation founded in 1886 that develops medical devices, pharmaceuticals, and consumer packaged goods. Its common stock is a component of the Dow Jones Industrial Average and the company i ...
subsidiaries, Johnson & Johnson Pharmaceutical Research and Development and Ortho-McNeil Pharmaceutical
The company was formed from the merger of Ortho Pharmaceutical and McNeil Pharmaceutical in 1993. Both of these pharmaceutical companies are pioneers and leaders in areas such as pain management, acid reflux disease, and infectious diseases. Or ...
to develop and market tapentadol; Johnson & Johnson had exclusive rights to sell the drug in the US, Canada, and Japan while Grünenthal retained rights elsewhere.[Dan Froicu and Raymond S Sinatra. Tapentadol. Chapter 31 in The Essence of Analgesia and Analgesics, Eds. Raymond S. Sinatra, Jonathan S. Jahr, J. Michael Watkins-Pitchford. Cambridge University Press, 2010. ] In 2008 tapentadol received FDA approval; in 2009 it was classified by DEA as a Schedule II drug, and entered the US market.[ Tapentadol was reported to be the "first new molecular entity of oral centrally acting analgesics" class approved in the United States in more than 25 years.]
In 2010 Grünenthal granted Johnson & Johnson the right to market tapentadol in about 80 additional countries. Later that year, tapentadol was approved in Europe. In 2011, ''Nucynta ER'', an extended release formulation of tapentadol, was released in the United States for management of moderate to severe chronic pain and received FDA approval the following year for the treatment of neuropathic pain associated with diabetic peripheral neuropathy.
After annual sales of $166 million, in January 2015, Johnson & Johnson sold its rights to market tapentadol in the US to Depomed
Assertio Therapeutics, Inc. (formerly Depomed, Inc.) is an American specialty pharmaceutical company. It mainly markets products for treatment in neurology, pain and diseases of the central nervous system. Depomed was founded in 1995 and is headqu ...
for $1 billion.[Staff, The Pharma Letter. January 16, 201]
Depomed pays over $1 billion for US rights to Janssen’s Nucynta franchise
The drug was manufactured at a plant located on the island of Puerto Rico
Puerto Rico (; abbreviated PR; tnq, Boriken, ''Borinquen''), officially the Commonwealth of Puerto Rico ( es, link=yes, Estado Libre Asociado de Puerto Rico, lit=Free Associated State of Puerto Rico), is a Caribbean island and Unincorporated ...
that was hit by Hurricane Maria
Hurricane Maria was a deadly Saffir–Simpson scale#Category 5, Category 5 Tropical cyclone, hurricane that devastated the northeastern Caribbean in September 2017, particularly Dominica, Saint Croix, and Puerto Rico. It is regarded as the wo ...
in 2017 causing a major shortage in the drug's availability. In January 2018 Depomed sold off the manufacturing of the drug and licensed it to Collegium Pharmaceutical for $10 million up front with an annual royalty payment of a minimum $135 million for the next 4 years. This combination of events has caused additional short supply of the drug leaving patients who depend on it to seek alternative treatments.
Abuse and controls
There have been calls for Tapentadol to be only marketed in countries where appropriate controls exist, but after performing a critical review, the United Nations Expert Committee on Drug Dependence in 2014 advised that tapentadol ''not'' be placed under international control but remain under surveillance.
Since 2009 the drug has been categorized in the US as a Schedule II narcotic with ACSCN Administrative Controlled Substances Code Number (ACSCN) is a number assigned to drugs listed on the schedules created by the US Controlled Substances Act (CSA). The ACSCN is defined in 21 CFR § 1308.03(a).
Each chemical/drug on one of the schedu ...
9780; in 2014 it was allocated a 17,500 kilogram aggregate manufacturing quota.
In 2010, Australia made tapentadol an S8 controlled drug.
The following year, tapentadol was classified as a Class A controlled drug in the United Kingdom, and was also placed under national control in Cyprus, Estonia, Finland, Greece, Latvia and Spain.
More recently, Canada made the opioid a Schedule I controlled drug.
In India (except the state of Punjab), multiple brands of Tapentadol remain available over the counter. Recent reports have suggested increasing Tapentadol abuse and dependence in India, where users have improvised injections with 50 and 100 mg tablets. Furthermore, a large number of listings for Tapentadol sourced from India can be found internationally on illicit marketplaces on the dark web
The dark web is the World Wide Web content that exists on ''darknets'': overlay networks that use the Internet but require specific software, configurations, or authorization to access. Through the dark web, private computer networks can communi ...
. There have been several reports of Tapentadol from Indian pharmacies being smuggled to the US, the EU and Bangladesh where they are sold on the black market.
References
{{Opioid receptor modulators
Mu-opioid receptor agonists
Phenols
Serotonin–norepinephrine reuptake inhibitors
Johnson & Johnson brands