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Tramadol synthesis and mechanism of action

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Tramadol synthesis and mechanism of
action
Hossam A. Shouip,

Tramadol (marketed as Ultram, and as generics) is an opioid pain

medication used to treat moderate to moderately severe pain. When taken as
an immediate-release oral formulation, the onset of pain relief usually occurs
within about an hour. It has two different mechanisms. First, it binds to the μ-
opioid receptor. Second, it inhibits the reuptake of serotonin and
norepinephrine.

Serious side effects may include: seizures, increased risk of suicide, serotonin
syndrome, decreased alertness, and drug addiction. Common side effects
include: constipation, itchiness and nausea, among others. A change in
dosage may be recommended in those with kidney or liver problems. Its use
is not recommended in women who are breast feeding. It is marketed as a
racemic mixture of both R- and S-stereoisomers. This is because the two
isomers complement each other's analgesic activity. It is often combined with
paracetamol as this is known to improve the efficacy of tramadol in relieving
pain. Tramadol is metabolised to O-desmethyltramadol, which is a more
potent opioid.

It was launched and marketed as Tramal by the German pharmaceutical

company Grünenthal GmbH in 1977 in West Germany, even though it would
take another 20 years for it to be launched in English-speaking countries such
as the UK, U.S., and Australia.

Medical uses:
Tramadol is used primarily to treat mild-severe pain, both acute and chronic.

Tramadol is recommended for the management of pain in fibromyalgia by the

European League Against Rheumatism. Its analgesic effects take about one
hour to come into effect and 2–4 hours to peak after oral administration with
an immediate-release formulation. On a dose-by-dose basis tramadol has
about one-tenth the potency of morphine and is approximately equally potent
when compared to pethidine and codeine.
For pain moderate in severity its effectiveness is equivalent to that of
morphine;; for severe pain it is less effective than morphine. These painkilling
effects peak at about 3 hours, post-oral
post administration and last for
approximately 6 hours. These analgesic effects
effects are only partially reversed by
naloxone,, hence indicating that its opioid action is unlikely the sole
contributing factor; tramadol's analgesic effects are also partially reversed by
α2 adrenergic receptor antagonists like yohimbine and the 5-HT3 receptor
antagonist, ondansetron. Pharmacologically, tramadol is similar to
levorphanol and tapentadol in that it not only binds to the mu opioid receptor,
but also inhibits the reuptake of serotonin
se and norepinephrine due to its action
on the noradrenergic and serotonergic systems, such as its "atypical" opioid
activity. Available dosage forms include capsules, tablets, including extended
release formulations and injections.

STRUCTURE:
Mechanism of action:

Tramadol acts as a μ-opioid receptor agonist, serotonin

releasing agent norepinephrine reuptake inhibitor, NMDA
receptor antagonist (IC50=16.5 μM), 5-HT2C receptor
antagonist (EC50=26 nM), (α7)5 nicotinic acetylcholine
receptor antagonist, TRPV1 receptor agonist, and M1 and
M3 muscarinic acetylcholine receptor antagonist.

Tramadol has inhibitory actions on the 5-HT2C receptor.

Antagonism of 5-HT2C could be partially responsible for
tramadol's reducing effect on depressive and obsessive-
compulsive symptoms in patients with pain and co-morbid
neurological illnesses. 5-HT2C blockade may also account
for its lowering of the seizure threshold, as 5-HT2C
knockout mice display significantly increased vulnerability
to epileptic seizures, sometimes resulting in spontaneous
death. However, the reduction of seizure threshold could
be attributed to tramadol's putative inhibition of GABAA
receptors at high doses. In addition, tramadol's major
active metabolite, O-desmethyltramadol, is a high-affinity
ligand of the δ- and κ-opioid receptors, and activity at the
former receptor could be involved in tramadol's ability to
provoke seizures in some individuals, as δ-opioid receptor
agonists are well known to induce seizures.
Synthesis and stereoisomerism:
stereoisomerism

The chemical synthesis of tramadol is described in the literature. Tramadol [2

[2-
(dimethylaminomethyl)-1-(3--methoxyphenyl)cyclohexanol]
methoxyphenyl)cyclohexanol] has two stereogenic
centers at the cyclohexane ring. Thus, 2-(dimethylaminomethyl)
(dimethylaminomethyl)-1-(3-
methoxyphenyl)cyclohexanol may exist in four different configurational forms:
  (1R,2R)-isomer
 (1S,2S)-isomer
 (1R,2S)-isomer
 (1S,2R)-isomer

The synthetic pathway leads to the racemate (1:1 mixture) of (1R,2R)-isomer and the
(1S,2S)-isomer as the main products. Minor amounts of the racemic mixture of the
(1R,2S)-isomer and the (1S,2R)-isomer are formed as well. The isolation of the
(1R,2R)-isomer and the (1S,2S)-isomer from the diastereomeric minor racemate
[(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of the
hydrochlorides. The drug tramadol is a racemate of the hydrochlorides of the (1R,2R)-
(+)- and the (1S,2S)-(–)-enantiomers. The resolution of the racemate [(1R,2R)-(+)-
isomer / (1S,2S)-(–)-isomer] was described employing (R)-(–)- or (S)-(+)-mandelic
acid. This process does not find industrial application, since tramadol is used as a
racemate, despite known different physiological effects of the (1R,2R)- and (1S,2S)-
isomers, because the racemate showed higher analgesic activity than either
enantiomer in animals and in humans.

Adverse effects:

The most common adverse effects of tramadol include

nausea, dizziness, dry mouth, indigestion, abdominal pain,
vertigo, vomiting, constipation, drowsiness and headache.
Compared to other opioids respiratory depression and
constipation is considered less of a problem with tramadol.
Methods of analysis:
analysis

1- Spectrophotometric and spectrofluorimetric

methods for analysis of tramadol, acebutolol and
dothiepin in pharmaceutical preparations.
Sensitive spectrophotometric and spectrofluorimetric methods are described for
the determination of tramadol, acebutolol and dothiepin (dosulepin
(dosulepin)
hydrochlorides. The two methods are based on the condensation of the cited
drugs with the mixed anhydrides of malonic and acetic acids at 60 degrees C for
25-40
40 min. The coloured condensation products are suitable for the
spectrophotometric and spectrofl
spectrofluorimetric determination at 329-333
333 and 431-
431
434 nm (excitation at 389 nm), respectively. For the spectrophotometric method,
Beer's law was obeyed from 0.5 to 2.5 microg ml(-1)
ml( 1) for tramadol, dothiepin and
5-25 microg ml(-1)
1) for acebutolol. Using the spectro
spectrofluorimetric
fluorimetric method linearity
ranged from 0.25 to 1.25 microg ml(-1)
ml( for tramadol, dothiepin and 1-55 microg
ml(-1)
1) for acebutolol. Mean percentage recoveries for the spectrophotometric
method were 99.68+/-1.00, 99.95+/-1.11 and 99.72+/-1.01 for tramadol, acebutolol
and dothiepin, respectively and for the spectrofluorimetric method, recoveries
were 99.5+/-0.844, 100.32+/-0.969 and 99.82+/-1.15 for the three drugs,
respectively. The optimum experimental parameters for the reaction has been
studied. The validity of the described procedures was assessed. Statistical
analysis of the results has been carried out revealing high accuracy and good
precision. The proposed methods were successfully applied for the determination
of the selected drugs in their pharmaceutical preparations with good recoveries.
The procedures were accurate, simple and suitable for quality control
application.

2- A Stability Indicating UPLC Method for the

Determination of Tramadol Hydrochloride:
Application to Pharmaceutical Analysis

The use of Ultra Performance Liquid Chromatography (UPLC), with a

rapid 5-minute

reversed phase isocratic separation on a 1.7
μm reversed-phase

packing material to provide rapid

high throughput’’ support for tramadol hydrochloride (TMH) is ‘‘

demonstrated. A simple, precise

and accurate stability-indicating isocratic UPLC method was developed

for the determination of

TMH in bulk drug and in its tablets. The method was developed using
Waters Aquity BEH C18
column (100
mm 2.1
mm, 1.7
μm) with mobile phase consisting of
a mixture of potassium

dihydrogen phosphate buffer of pH 2.8 and an equal volume of

acetonitrile (60
:
40
v/v). The eluted

compound was detected at 226
nm with a UV detector. The standard

curve of mean peak area

versus concentration showed an excellent linearity over a

concentration range 0.5–300
μg
mL−1

TMH with regression coefficient (r) value of 0.9999. The limit of

detection (S/N ) was 0.08
μg
mL−1 and the limit of quantification
(S/N

was 0.2
μg
mL−1. Forced degradation of the bulk (

sample was conducted an accordance with the ICH guidelines. Acidic,

,basic, hydrolytic, oxidative

thermal and photolytic degradation were used to assess the stability

.indicating power of the method

TMH was found to degrade significantly in acidic, basic and oxidative

stress conditions and stable

in thermal, hydrolytic and photolytic conditions

References:

Brayfield, A, ed. (13 December 2013). "Tramadol Hydrochloride". Martindale: The

Complete Drug Reference. Pharmaceutical Press. Retrieved 5 April 2014.

"Ultram, Ultram ER (tramadol) dosing, indications, interactions, adverse effects,

and more". Medscape Reference. WebMD. Retrieved 28 November 2013.

"PRODUCT INFORMATION Tramadol SANDOZ 50 mg capsules" (PDF). TGA

eBusiness Services. Sandoz Pty Ltd. 4 November 2011. Retrieved 6 April 2014.

"Tramadol Hydrochloride". The American Society of Health-System Pharmacists.

Retrieved Dec 1, 2014.

Katz WA (1996). "Pharmacology and clinical experience with tramadol in

osteoarthritis". Drugs. 52 Suppl 3: 39–47. doi:10.2165/00003495-199600523-00007.
PMID 8911798.

Now What? DEA Tosses Tramadol in Schedule IV, By Nadia Awad, MedPage
Today, Jul 10, 2014

Leppert, W (November–December 2009). "Tramadol as an analgesic for

mild to moderate cancer pain." (PDF). Pharmacological reports 61 (6): 978–
.92. doi:10.1016/s1734-1140(09)70159-8. PMID 20081232.

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