Tapentadol, a novel analgesic: Review of recent trends in synthesis, related substances, analytical methods, pharmacodynamics and pharmacokinetics

Abstract

This write-up describes the comprehensive facts of tapentadol, on recent trends in syn-thesis, related substances, analytical methods, pharmacodynamics, pharmacokinetics, adverse effect and drug interaction. Chemically, tapentadol is 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpro-pyl] phenol hydrochloride. Tapentadol is a centrally-acting synthetic novel analgesic which acts as l-opioid receptor agonist as well as norepinephrine re-uptake inhibitor. Nausea and vomiting are common side effects and tapentadol glucuronide conjugate is a major metabolite excreted in urine. It is synthesized by three different schemes while nine related substances were reported. Tapentadol and its metabolites were determined in plasma matrix by chromatographic methods using spectro-fluorometric detection.

Full text

REVIEW PAPER
Tapentadol, a novel analgesic: Review of recent trends
in synthesis, related substances, analytical methods,
pharmacodynamics and pharmacokinetics
Deepti Jain
a
, Pawan Kumar Basniwal
a,b,
*
a
School of Pharmaceutical Sciences, Rajiv Gandhi Technological University, Bhopal 462 033, Madhya Pradesh, India
b
Lal Bahadur Shastri College of Pharmacy, Jaipur 302 004, Rajasthan, India
Received 20 February 2013; accepted 20 April 2013
KEYWORDS
Analysis;
Chemistry;
Pharmacodynamics;
Pharmacokinetics;
Tapentadol
Abstract This write-up describes the comprehensive facts of tapentadol, on recent trends in syn-
thesis, related substances, analytical methods, pharmacodynamics, pharmacokinetics, adverse effect
and drug interaction. Chemically, tapentadol is 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpro-
pyl] phenol hydrochloride. Tapentadol is a centrally-acting synthetic novel analgesic which acts as
l-opioid receptor agonist as well as norepinephrine re-uptake inhibitor. Nausea and vomiting are
common side effects and tapentadol glucuronide conjugate is a major metabolite excreted in urine.
It is synthesized by three different schemes while nine related substances were reported. Tapentadol
and its metabolites were determined in plasma matrix by chromatographic methods using spectro-
fluorometric detection.
ª 2013 Production and hosting by Elsevier B.V. on behalf of Faculty of Pharmacy, Cairo University.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2. Related substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
*
Corresponding author at: Lal Bahadur Shastri College of Phar-
macy, Jaipur 302 004, Rajasthan, India. Mobile: +91 9414788171.
E-mail addresses: deepti2515@yahoo.com (D. Jain), pawanbasniwal
@gmail.com (P.K. Basniwal).
Peer review under responsibility of Faculty of Pharmacy, Cairo
University.
Production and hosting by Elsevier
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Cairo University
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http://dx.doi.org/10.1016/j.bfopcu.2013.04.003
Please cite this article in press as: Jain D, Basniwal PK Tapentadol, a novel analgesic: Review of recent trends in synthesis, related
substances, analytical methods, pharmacodynamics and pharmacokinetics, Bulletin Facult Pharmacy Cairo Univ (2013), http://
dx.doi.org/10.1016/j.bfopcu.2013.04.003

3. Analytical methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3. Adverse effects and interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.4. Therapeutic uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Introduction
Pain is an unpleasant feeling often caused by intense or dam-
aging stimuli, which is not simply a biological response, but
a complex interaction that involves sensory, emotional and
behavioral factors.
1
Pain may be chronic or acute. Nociceptive
pain is caused by stimulation of peripheral nerve fibers which
respond only to stimuli approaching or exceeding harmful
intensity (nociceptors), and may be classified according to
mode of noxious stimulation; the most common categories
are as follows: thermal (heat or cold), mechanical (crushing,
tearing) and chemical (iodine in a cut, chili powder in the eyes).
Neuropathic pain is caused by damage or disease affecting any
part of the nervous system involved (somatosensory system)
2
Peripheral neuropathic pain is due to burning, tingling, electri-
cal, stabbing, pins and needles.
3
Current treatment options for pain consist of several thera-
peutic categories such as anticonvulsants, antidepressants, lo-
cal anesthetics, opioids and non-steroidal anti-inflammatory
drugs. Combinations of various mechanisms of action target-
ing pain transmission at different levels of pain communication
pathways may yield better efficacy. Most commonly used clin-
ical agents for analgesia through l-opioid receptor are 4,5b-
epoxymorphinans (morphine), morphinans (levorphanol),
phenylpiperidines (meperidine), 4-anilidopiperidines (fenta-
nyl), and acyclic analgesics (methadone).
4
These drugs are
associated with serious side effects, however, most notably
addiction liability and respiratory depression, which limit their
clinical usefulness. Therefore, there has been an intensive effort
to find new analgesics that retain the effectiveness of morphine
without or less potential side effects. The evaluation of a com-
bined mechanism of action, l-opioid receptor activation with
norepinephrine reuptake inhibition, has been undertaken to
improve the therapeutic usefulness of opioid analgesics.
Few years ago, tramadol (Fig. 1) was approved for treat-
ment of pain which is a synthetic 4-phenyl piperidine analogue
of codeine that produces analgesia in short- and long-term
pain states by synergistically combining weak l-opioid and
mono-aminergically (noradrenaline and serotonin) mediated
mechanisms.
5
In this sequence, tapentadol comes in picture
with improved dual mechanism for treatment of severe noci-
ceptive and neuropathic pain. Tapentadol combines l-opioid
receptor agonism and noradrenaline reuptake inhibition in
one molecule.
6
As tapentadol hydrochloride (TAP) is a promising novel
analgesic drug with dual mechanism and hitherto, as per
author literature preview there is no comprehensive report
on TAP. The aim of this write-up is to provide an ample review
on recent updates of TAP including recent trends in chemistry
(different synthetic schemes and related substances), analytical
methods, pharmacodynamics, pharmacokinetics, adverse ef-
fect and drug interactions.
2. Chemistry
Chemically, TAP is 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-
methylpropyl] phenol hydrochloride (Fig. 1). As TAP has
two chiral centers (1), it has four stereoisomers viz. RR, SS,
RS and SR forms and RR form of TAP is approved as anal-
gesic. The n-octanol: water partition coefficient log P value
of TAP is 2.87 and two pKa values are 9.34 and 10.45.
7–11
2.1. Synthesis
A ketone (2), 1-(3-(benzyloxy)phenyl)propan-1-one was trea-
ted (scheme 1, Fig. 2) with chloro-N,N-dimethyl-methanamine
(3) in acetonitrile and acetyl chloride at room temperature
(RT) and resulting amine (4) was collected by adding ether
and crystallizing the product. The amine (4) was crystallized
with L-()-dibenzoyl tartaric acid monohydrate (DBTA) in
ethanol at 6–8 C to give the desired enantiomer as a salt (5).
The free base of salt 5 was generated by reaction with aqueous
sodium hydroxide and then treated with ethyl magnesium bro-
mide (Grignard reagent) in tetrahydrofuran (THF) at 10 C
followed by stirring at RT overnight to give tertiary alcohol
(6). Tertiary alcohol was treated with trifluoroacetic anhydride
in 2-methyl THF at 40–45 C to give the corresponding trifluo-
romethyl ester which was then treated with 10% Pd/C (palla-
dium/carbon) and hydrogenated at 3 bar (pressure) with
ambient temperature. These hydrogenolytic conditions ef-
fected reductive cleavage of the trifluoromethyl ester and re-
moval of the benzyl protecting group with retention of
stereochemistry. Filtration of the catalyst followed by the addi-
tion of water and trimethyl-chlorosilane (TMSCl) to generate
Figure 1 Structure of tapentadol hydrochloride (1) and trama-
dol (1A).
2 D. Jain, P.K. Basniwal
Please cite this article in press as: Jain D, Basniwal PK Tapentadol, a novel analgesic: Review of recent trends in synthesis, related
substances, analytical methods, pharmacodynamics and pharmacokinetics, Bulletin Facult Pharmacy Cairo Univ (2013), http://
dx.doi.org/10.1016/j.bfopcu.2013.04.003

HCl in situ and allowing the product to crystallize out at 5–8%
gave the desired tapentadol hydrochloride (1).
12
Mannich reaction was applied to prepare side chain as 1-
(dimethylamino)-2-methylpentan-3-one (8) from pentan-3-
one (7), formaldehyde and dimethyl amine which were refluxed
(scheme 2, Fig. 2). It (8) was treated with 3-bromoanisole in
the presence of THF and magnesium to form alcohol deriva-
tive (9) which was refluxed with sulfuryl dichloride, followed
by treatment of zinc borohydride (ZnBH
4
) and triphenylphos-
phine (PPh
3
). The resulting intermediate (10) was refluxed with
hydrogen bromide and hydrochloride salt of tapentadol was
precipitated by methylene chloride in aqueous sodium bicar-
bonate and addition of water and trimethyl-cholorosilane
(TMSCl) with 2-butanone.
13
Tapentadol was synthesized enantioselectively by scheme 3
(Fig. 2). Benzoyl derivative of cinnamic acid (11) was activated
by oxalyl dichloride in the presence of methylene chloride and
protected by (R)-4-phenyl-2-oxazolidinone in the presence of
Figure 2 Different synthetic schemes for tapentadol hydrochloride.
Tapentadol, a novel analgesic 3
Please cite this article in press as: Jain D, Basniwal PK Tapentadol, a novel analgesic: Review of recent trends in synthesis, related
substances, analytical methods, pharmacodynamics and pharmacokinetics, Bulletin Facult Pharmacy Cairo Univ (2013), http://
dx.doi.org/10.1016/j.bfopcu.2013.04.003

triethyl amine (TEA) and methylene chloride at 0 C to form
cyclic amide (12). It was treated with an organocuprate pre-
pared from a CuBr-(CH
3
)
2
S (copper bromide – dimethyl sul-
fide) complex and ethylmagnesium bromide in THF at
20 C to form stereoselectively conjugate addition product
(13). The methylation reaction proceeded efficiently to get
intermediate (14) with excellent stereoslectivity. Conjugate
product was exposed to sodium hexamethyldisilazide (NaH-
MDS) at 78 C for 30 min followed by methyl iodide in
THF at 20 C for 4 h. Removal of the chiral auxiliary under
base hydrolysis conditions (LiOH/H
2
O
2
in H
2
O/THF) yielded
a, b-disubstituted acid (15). Treating 15 with oxalyl chloride
followed by dimethylamine hydrochloride in the presence of
TEA in CH
2
Cl
2
afforded the corresponding dimethylamide
(15). Subsequent reduction of amide 16 with LiAlH
4
in dry
THF gave o-benzyl-tapentadol (17). Finally, RR form of
tapentadol hydrochloride (1) was yielded by debenzylation of
17 under a hydrogen atmosphere followed by treatment of
hydrochloric acid.
14
2.2. Related substances
As structure-wise TAP is closely related to tramadol which is a
synthetic 4-phenylpiperidine analogue of codeine and centrally
acting analgesic with efficacy and potency ranging between
weak opioids and morphine.
15,16
In similar way, TAP has
two chiral centers and RR form is approved as analgesic.
Thus, stereoisomers of TAP, as related substances (Fig. 3)
come into picture viz. SS form (21), RS form (22) and SR form
(23).
20
Michal et al. have reported the enantioselective HPLC
determination of tapentadol above enantiomers using cellu-
lose-based chiral stationary phase in normal phase mode.
11
Deuterated TAP, tapentadol-d
5
(18) and tapentadol-d
6
(19)
were also used as internal standards for the determination of
TAP along with its metabolites and to study the pharmacoki-
netics of the drug
17–19
Tapentadol-N-oxide (20) and tapent-
adol-O-sulfate (27) were reported as process related
impurities but Kathirvel et al. have not established the struc-
ture of these impurities by different characterization tech-
niques.
21
Both N-desmethyltapentadol (27) and tapentadol-
O-sulfate (28) (Fig. 4) were reported as its metabolites as well
as process related impurities.
15–17
3
0
-O-Benzyl-(1R)-hydroxy
tapentadol (24) was also mentioned as a process related sub-
stance of TAP.
22
Figure 3 Tapentadol related substances – (18) tapentadol-d5-
hydrochloride, (19) tapentadol-d6 hydrochloride, (20) tapentadol-
N-oxide, (21) [S,S] tapentadol hydrochloride, (22) [R,S] tapentadol
hydrochloride, (23) [S,R] tapentadol hydrochloride, and (24) 3
0
-O-
benzyl-(1R)-hydroxy tapentadol.
Figure 4 Possible mechanism of action for tapentadol; where
(+) means agonistic action of mu-receptor and () means
inhibition of norepinephrine re-uptake (Reuse with the permission
of Elsevier Limited, The Boulevard, Langford Lane, Kidlington,
Oxford, OX5 1 GB,UK).
26
4 D. Jain, P.K. Basniwal
Please cite this article in press as: Jain D, Basniwal PK Tapentadol, a novel analgesic: Review of recent trends in synthesis, related
substances, analytical methods, pharmacodynamics and pharmacokinetics, Bulletin Facult Pharmacy Cairo Univ (2013), http://
dx.doi.org/10.1016/j.bfopcu.2013.04.003

3. Analytical methods
Very few analytical methods were reported for the determina-
tion of TAP. Dousa et al. have achieved better resolution for
all enantiomers on Chiralpak AD-H by using a mixture of hep-
tane–propan-2-ol–diethylamine (980:20:1). The detection was
carried out by fluorescence detector in a short analysis time.
11
TAP was determined in canine plasma by LC method, where
chromatographic separation was achieved on C18 column
(150 · 4.6 mm, 5 lm) at 25 C by gradient elution (acetonitrile
and 33 mM acetic acid) with spectrofluorimetric detection.
This validated method was applied to determine pharmacoki-
netic parameters in dog on oral administration of the drug,
where the LOD and LOQ were 0.3 ng/mL and 1.0 ng/mL,
respectively.
23
Pharmacokinetics of TAP was also reported in
dogs after oral and intravenous administration. Different types
of breeds (Greyhound, Staffordshire BT and mixed) for dog
(male and female) were used to determine terminal phase rate
constant, terminal half-life, time of peak, peak plasma concen-
tration, area under the plasma concentration–time curve
extrapolated to infinity, volume of distribution, clearance,
mean resident time and oral bioavailability.
24
TAP and its
metabolites (N-desmethyltapentadol-glucuronide, tapentadol-
glucuronide and N-desmethyltapentadol) were determined by
an ultra-performance liquid chromatographic (UPLC)
hyphenated with mass spectroscopy (MS); where UPLC col-
umn BEH Shield RP18 (2.1 · 50 mm · 1.7 l m) was coupled
with a tandem quadrupole detector operating in positive ESI
mode. Authentic nonhydrolyzed and hydrolyzed urine speci-
men were analyzed using tapentadol-d
5
as an internal standard
by multiple reaction monitoring (MRM) analysis.
17
An an-
other gradient LC method was reported to determine tapent-
adol and its metabolite N-desmethyltapentadol in urine and
oral fluid by using a mixture of ammonium formate (20 mM,
pH 6.4) and methanol on C18 (4.6 · 50 mm · 1.8 mm), which
was coupled to triple-quadrupole MS, operating in positive
electrospray ionization (ESI) mode. Methamphetamine-d
5
was used as an internal standard for linear regression line
and there was no interference shown from urine and oral fluid
specimens collected from drug-free individuals in the LC–MS–
MS analysis.
25
4. Pharmacology
4.1. Pharmacodynamics
The mu-receptors are present in periaqueductal gray region,
superficial dorsal horn of the spinal cord, and several layers
of cerebral cortex. Norepinephrine (noradrenaline) is involved
with descending modulation of pain (Fig 4).
1
Tapentadol is a
centrally-acting synthetic analgesic which acts as mu-opioid
receptor agonist as well as norepinephrine re-uptake inhibitor
(NRI).
2
It modifies sensory and affective aspects of pain
through mu-opioid agonistic action, inhibits the transmission
of pain at the spinal cord and affects the activity of pain per-
ception. It increases the level of norepinephrine in the brain by
inhibiting its re-absorption into nerve cells at the central ner-
vous system sites, which leads to analgesia (Fig. 4).
1,3,27
This
combination of complementary mechanisms of action addi-
tively or synergistically results in potent analgesic activity sim-
ilar to potent narcotic analgesics without their side effects.
The drugs which block the reuptake of norepinephrine and/
or serotonin are efficacious in the treatment of chronic painful
conditions and can enhance the analgesic effect of morphine.
Thus, TAP may have synergistic effect with morphine. It is less
potent in producing analgesia due to its poor ability in binding
to mu-opioid receptor. TAP was approved for treatment of
moderate to severe pain in adults, as it is effective against a
large spectrum of pain conditions, ranging from acute to
chronic pain.
4
4.2. Pharmacokinetics
TAP is 32% absorbed on oral administration.
3
Its pharmaco-
kinetics was not affected by gastric pH or gastrointestinal
motility and may be given with or without food.
5
It is widely
distributed throughout the body and no metabolic activation
is required for its action. TAP enantiomer (RR-form) readily
crosses the blood–brain barrier; a rapid onset of action after
administration.
3
Cmax and AUC values of tapentadol were in-
creased with dose of 50–150 mg and plasma protein binding is
about 20%.
6
The plasma half life is approximately 4 h after
oral administration
4
and peak effect is attained after 1 h while
duration of action is 4–6 h.
3
The drug undergoes extensive first pass hepatic metabolism
about 97%.
3
A small amount of TPA is metabolized by phase I
pathways while mainly metabolized via phase II pathways.
7
Hydroxylation and N-demethylation play a minor role in the
metabolic fate of TAP, which forms hydroxyl tapentadol
(29) and N-desmethyl tapentadol (25), respectively (Fig. 5).
Due to minor involvement of phase I metabolic pathways,
TAP has lower possibility of drug–drug interactions. Biotrans-
formation by metabolic enzymes results in deactivation of
TAP i.e., it has no active metabolites. Glucuronide conjugate
(27) as a major metabolite (55%) followed by
3
sulfate conju-
gate (15%) of dose is excreted in urine in a conjugated form
after oral administration. It is also metabolized to N-desmeth-
yl tapentadol (13%) by CYP2C9 and CYP2C19; and to hydro-
xy tapentadol (2%) by CYP2D6, which are further conjugated.
Thus, drug metabolism of TAP is less mediated by cytochrome
P450 system than conjugation phase. Only 3% of drug is ex-
creted as unchanged form of drug in urine. Both TAP and
its metabolites are excreted mainly (99%) through the
kidney.
7,28,31
Figure 5 Metabolism of tapentadol.
Tapentadol, a novel analgesic 5
Please cite this article in press as: Jain D, Basniwal PK Tapentadol, a novel analgesic: Review of recent trends in synthesis, related
substances, analytical methods, pharmacodynamics and pharmacokinetics, Bulletin Facult Pharmacy Cairo Univ (2013), http://
dx.doi.org/10.1016/j.bfopcu.2013.04.003

4.3. Adverse effects and interactions
The most common side effects of TAP are related to gastroin-
testinal tract (nausea and vomiting) and the nervous system
(dizziness, headache and somnolence).
4,29
Due to its mu-opioid
receptor agonism, gastrointestinal and central nervous system
related adverse effects may also exist (Table 1). Convulsion,
hypersensitivity and impaired gastric emptying were rarely
reported.
3
Due to overdose of TAP, symptoms of mu opioid
agonisms are precipitated. Therefore, treatment should be
focused on rescue from precipitated symptoms. Controlled
ventilation for patient should be of primary attention and
supportive measures (including oxygen and vasopressors)
should be used to manage circulatory shock and pulmonary
edema.
3
Probenecid may interact with the pharmacokinetics of
tapentadol; its metabolic interaction may be more prominent
than its secretion interaction. Table 2 shows the indicative list
of drug interaction of TAP.
4.4. Therapeutic uses
It is indicated in moderate to severe chronic pain and neuro-
pathic pain associated with diabetic peripheral neuropathy
(DPN) in adults. But it is not intended for use as an analgesic
for acute pain and mild pain which is not expected to persist
for an extended period of time. It is also not recommended
in postoperative pain unless the patient is already receiving
chronic opioid therapy prior to surgery.
30
5. Conclusion
The present work gives a quick comprehensive review on re-
cent trends of tapentadol as novel analgesic including its differ-
ent synthetic schemes, impurities and related substances,
analytical methods for different matrixes, pharmacodynamics,
pharmacokinetics, adverse effect and drug interactions. Thus,
tapentadol (R,R – form) is a novel opioid pain reliever for
moderate to severe acute pain with a dual mechanism of action
Table 1 Reported adverse effects of TAP.
8,32
Adverse drug reactions
Very common Nausea, vomiting, dizziness, somnolence, headache
Common Decreased appetite, anxiety, confessional state, hallucination, sleep disorders, abnormal dreams, tremor, flushing,
constipation, dyspepsia, dry mouth, pruritis, hyperhidrosis, rash, muscle spasms, asthenia, fatigue, feeling of body
temperature change
Uncommon Depressed mood, disorientation, agitation, nervousness, restlessness, euphoric mood, disturbance in attention, memory
impairment, presyncope, sedation, atexia, dysarthria, hypoaesthesia, paraesthesia, muscle contractions involuntary, visual
disturbance, heart rate increased, blood pressure decreased, respiratory depression, oxygen saturation decreased, dyspnoea,
abnormal discomfort, urticaria, sensation of heaviness, urinary hesitation, pollakiuria, drug withdrawal syndrome, edema,
feeling abnormal, feeling drunk, irritability, feeling of relaxation
Rare Hypersensitivity, thinking abnormal convulsion, depressed level of consciousness, coordination abnormal, heart rate
decreased, impaired gastric emptying
Table 2 Drug interactions of TAP.
Drug Interaction Ref.
General anesthetics CNS depression 4
Mu-opioid analgesics, phenothiazines, other tranquilizers,
sedatives, hypnotics or other CNS depressants (including
alcohol, opioids or illicit drugs)
CNS depression, respiratory depression, hypotension,
profound sedation, coma or death may result if these drugs
are taken in combination with TAP
3
Serotonergic drugs such as selective serotonin re-uptake
inhibitors (SSRI), serotonin–norepinephrine reuptake
inhibitors (SNRI), tricyclic antidepressants (TCA),
monoamine oxidase inhibitors I (MAOI) and triptans
Life-threatening serotonin syndrome (agitation,
hallucinations, coma); autonomic instability (tachycardia,
labile blood pressure, hyperthermia); neuromuscular
aberrations (hyperreflexia, incoordination);
gastrointestinal symptoms (nausea, vomiting, diarrhea)
3
Disease
In patients with paralytic ileus or in patients concurrently
using or within 14 days of using monoamine oxidase
inhibitors (MAOIs)
Significant respiratory depression, acute or severe
bronchial asthma
4
In elderly or debilitated patients and in those suffering
from conditions accompanied by hypoxia, hypercapnia, or
upper airway obstruction, in whom even moderate
therapeutic doses may significantly decrease pulmonary
ventilation.
Respiratory depression occurs more frequently. TAP
should be employed only under careful medical
supervision at the lowest effective dose in such patients.
3
Head injury and increased intracranial pressure Used with caution 4
In patients with pancreatic or biliary tract disease and
moderate hepatic impairment
Used with caution 4
6 D. Jain, P.K. Basniwal
Please cite this article in press as: Jain D, Basniwal PK Tapentadol, a novel analgesic: Review of recent trends in synthesis, related
substances, analytical methods, pharmacodynamics and pharmacokinetics, Bulletin Facult Pharmacy Cairo Univ (2013), http://
dx.doi.org/10.1016/j.bfopcu.2013.04.003

(mu-opioid receptor agonist and noradrenaline reuptake inhib-
itor) and it is also effective in managing pain associated with
osteoarthritis and low back pain.
Conflict of interest
There is no conflict of interest.
Acknowledgement
One of the authors, Pawan Kumar Basniwal, earnestly in-
debted to Science and Engineering Research Board (SERB),
DST, New Delhi, for the financial support to carry out related
work on this drug under Fast Track Scheme for Young
Scientists.
References
1. Mick G, Serpell A, Makin AH. Acute pain physiology and
pharmacological targets: the present and future. Acute pain
1998;3:31–7.
2. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO,
Griffin JW, et al. Neuropathic pain: redefinition and a grading
system for clinical and research purposes. Neurology
2008;70(18):1630–5.
3. Paice JA. Mechanisms and management of neuropathic pain in
cancer. J Support Oncol 2003;1(2):107–20.
4. Available from: <http://en.wikipedia.org/wiki/Pain> (accessed
26.12.12).
5. Cagnardi P, Villa R, Zonca A, Gallo M, Beccaglia M, Luvoni GC,
et al. Pharmacokinetics, intraoperative effect and postoperative
analgesia of tramadol in cats. Res Vet Sci 2011;90:503–9.
6. Babette K, Jean DV, Thomas MT, Thomas C. The antinociceptive
and antihyperalgesic effect of tapentadol is partially retained in
OPRM1 ((-opioid receptor) knockout mice. Neurosci Lett
2011;491:104–7.
7. Schneider J, Jahnel U, Linz K. Neutral effects of the novel
analgesic tapentadol on cardiac repolarization due to mixed ion
channel inhibitory activities. Drug Dev Res 2010;71:197–208.
8. Buynak R, Shapiro D, Okamoto A, Van HL, Rauschkolb C,
Steup A, et al. Expert Opin Pharmacol 2010;11:1787–804.
9. Riemsma R, Forbes C, Harker J, Worthy G, Misso K, Schafer M,
et al. Curr Med Res Opin 2011;27:1907–30.
10. Available from: <http://www.druglib.com/druginfo/nucynta/
description_pharmacology/> dated : 24.12.12.
11. Michal D, Petr L, Hana A, Zuzana B. Fundamental study of
enantioselective HPLC separation of tapentadol enantiomers
using cellulose-based chiral stationary phase in normal phase
mode. J Pharm Biomed Anal 2013;74:111–6.
12. Kevin KCL, Subas MS, Cristopher JO, Andrew CF, Jin L.
Synthetic approaches to the 2009 new drugs. Bioorg Med Chem
2011;19:1136–54.
13. Tschentke TM, Devry J, Terlinden R, Hennies HH, Lange C,
Strassburger W, et al. Tapentadol hydrochloride. Drugs Future
2006;31(12):1053–61.
14. Zhang Q, Li JF, Tian GH, Zhang RX, Sun J, Suo J, et al. A
practical and enantioselective synthesis of tapentadol. Tetrahe-
dron: Asymmetry 2012;23:577–82.
15. Giorgi M, Meizler A, Mills PC. Pharmacokinetics of the novel
atypical opioid tapentadol following oral and intravenous admin-
istration in dogs. Vet J 2012;194:309–13.
16. Ardakani YH, Rouini MR. Improved liquid chromatographic
method for the simultaneous determination of tramadol and its
three main metabolites in human plasma, urine and saliva. J
Pharm Biomed Anal 2007;44:1168–73.
17. Available from: http://www.cachesyn.com/com-
pound.php?cat_num=CSTT647 (accessed on 24.12.12).
18. Available from: http://www.tlcpharmachem.com/tlc_item.ph-
p?upc=T-647&li=&sub= accessed on 24.12.12.
19. Bourland JA, Collins AA, Chester SA, Ramachandran S, Backer
RC. Determination of tapentadol (Nucynta) and N-desmethylta-
pentadol in authentic urine specimens by ultra-performance liquid
chromatography–tandem mass spectrometry. J Anal Toxicol
2010;34:450–7.
20. Expert committee on drug dependence thirty-fifth meeting.
Tapentadol pre-review report, WHO, Hammamet, Tunisia, 4–8
June 2012.
21. Kathirvel S, Satyanarayana SV, Devalarao G. Application of the
validated stability indicating LC method for the simultaneous
estimation of tapentadol and its process related impurities in bulk
and its dosage form. J, Chemistry. 2013:1–8.
22. Available from: http://www.clearsynth.com/docs/COA-CS-T-
02519.pdf (assessed on 24.12.12).
23. Giorgia M, Meizler A, Mills PC. Quantification of tapentadol in
canine plasma by HPLC with spectrofluorimetric detection:
Development and validation of a new methodology. J Pharm
Biomed Anal 2012;67–68:148–53.
24. Giorgi M, Meizler A, Mills PC. Pharmacokinetics of the novel
atypical opioid tapentadol following oral and intravenous admin-
istration in dogs. Vet J 2011;90:503–9.
25. Coulter C, Taruc M, Tuyay J, Moore C. Determination of
tapentadol and its metabolite N-desmethyltapentadol in urine and
oral fluid using liquid chromatography with tandem mass spectral
detection. J Anal Toxicol 2010;34:458–63.
26. Steeds CE. The anatomy and physiology of pain. Surgery
2009;27(12):507–11.
27. Liu KKC, Sakya SM, O’Donnell CJ, Flick AC, Li J. Synthetic
approaches to the 2009 new drugs. Bioorg Med Chem
2011;19(3):1136–54.
28. Tayal G, Grewal A, Mittal R, Bhatia N. Tapentadol- a novel
analgesic. J Anaesth Clin Pharmacol 2009;25(4):463–6.
29. Tapentadol SujathaM. Kerala J Orthop 2012;25(2):119–22.
30. Available from: http://www.nucynta.com (accessed on
11.01.2013).
31. Australian Public Assessment Report for Tapentadol. Therapeutic
goods administration, Department of health and ageing, Austra-
lian government, Feb 2011.
32. Available from: http://www.imb.ie/images/uploaded/swedocu-
ments/LicenseSPC_PA1189-008-003_22122010094229.pdf (assessed
on 24.12.12).
Tapentadol, a novel analgesic 7
Please cite this article in press as: Jain D, Basniwal PK Tapentadol, a novel analgesic: Review of recent trends in synthesis, related
substances, analytical methods, pharmacodynamics and pharmacokinetics, Bulletin Facult Pharmacy Cairo Univ (2013), http://
dx.doi.org/10.1016/j.bfopcu.2013.04.003