Biomedicine & Pharmacotherapy 111 (2019) 443–451

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

An overview of tramadol and its usage in pain management and future T

perspective
⁎
Muna Subedi, Shalini Bajaj, Maushmi S. Kumar, Mayur YC
Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’S NMIMS, V.L. Mehta Road, Vile Parle West, Mumbai, 400056, India

A R T I C LE I N FO A B S T R A C T

Keywords: Patients with chronic non-malignant pain report impairment of physical and social life along with psychological
Analgesic state affecting their overall quality of life. The purpose of managing pain is to reduce the trauma and improve the
μ-opioid receptor patient comfort with better quality of life. Tramadol is a centrally acting weak μ-opioid receptor analgesic and is
Noradrenalin a racemic mixture of (+)-tramadol and (−)-tramadol enantiomers. Tramadol is used worldwide and is listed in
Serotonin
many medical guidelines for pain management. The (+)-tramadol has greater affinity for μ-opioid receptor and
Tramadol
provides additional prevention of 5- hydroxy tryptamine reuptake, while the (-)-tramadol is a successful nora-
drenaline reuptake inhibitor and intensifies its release by activating the auto receptor. Tramadol is prescribed to
relieve moderate to severe pain management in patients. Tramadol does not show much serious adverse effects
without any dependency potential in therapeutic doses as seen in other opioids, like morphine. Tramadol me-
tabolite M1 also has μ-opioid receptor agonist activity, but it faces poor blood brain barrier permeability. In this
review, we report the complete updated status of Tramadol along with its chemistry, synthesis, pharmacology,
medicinal uses, adverse effects and its combinations available in the market. We have also covered Tramadol
patents so that a complete overview provides a broader perspective for future designing of its derivatives and
increase their potential use for pain management in terminal cancer patients.

1. Introduction
Pain is an unpleasant sensation occurring majorly due to tissue
damage, influenced by thinking, outlook, behaviour, community fac-
tors, and responsible for causing emotional and psychological dis-
comfort too. It is classified into three types: (i) Nociceptive pain (pro-
duced by tissue injury) (ii) Neuropathic pain (due to nerve injury) (iii)
Neuroplastic pain (due to musculoskeletal disease like inflammatory
pain) [1]. Various pharmacological approaches have been used for its
treatment with drugs such as paracetamol, NSAID category drugs, anti-
depressants, anti-cytokines and opioids. Tramadol is used for the
treatment of pain and possess potent analgesic activity [2,3].
Opioid drugs comes under the alkaloid class of compounds obtained
from “Papaver somniferum L" and are considered in narcotic category
which acts on the central nervous system to relieve the pain [4]. Con-
stant use and misuse of opioids causes serious health problems [5,6].
Opioid analgesics act on the brain through binding with opioidal re-
ceptor present in brain, spinal cord and others parts of the body and
reduces the pain sensation. Afghanistan accounts for the world’s largest
opium poppy cultivation [7]; opioid drugs such as morphine, codeine,
fentanyl, hydrocodone, meperidine, methadone, oxycodone etc. though
differ chemically but act by interacting with the primary target re-
cognised as μ opioid receptor (MOR). Opium addicts suffering from
opioid withdrawal symptoms are usually managed with tramadol in the
initial stage [8].
Tramadol is 2-(dimethyl amino)-methyl)-1-(3ʹ-methoxyphenyl) cy-
clohexanolhydrochloride. It is 4-phenyl-piperidine analogue of opioid
drug codeine. It was discovered and synthesized in 1962 for the first
time by German company (Grunenthal GmbH) for the treatment of pain
while being introduced in the market by the name ‘Tramadol’ in 1977.
In US it was made available after 1995 [9]. Now it is available under
trade name ULTRAM®, and is a racemic mixture of the (R, R) - and (S, S)
- enantiomers and mostly available in hydrochloride salt form [10].
Opioid category drugs such as morphine is a very potent analgesic, but
is used less due to its adverse effects of respiratory depression, addic-
tion, dependency, and constipation. The analgesic potency of tramadol
is found to be ten times lesser than morphine but is preferred being safe
than the later. Tramadol is considered safe, as it does not cause re-
spiratory depression and addiction when compared to other opioid
analgesics [11]. Additionally, tramadol when administered by par-
enteral route has less abuse potential. It produces analgesic action by
exhibiting agonistic activity to MOR and central GABA catecholamine

⁎
Corresponding author.
E-mail addresses: mayuryc@rediffmail.com, mayur.yergeri@nmims.edu (M. YC).

https://doi.org/10.1016/j.biopha.2018.12.085
Received 16 October 2018; Received in revised form 6 December 2018; Accepted 19 December 2018
0753-3322/ © 2018 Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
M. Subedi et al. Biomedicine & Pharmacotherapy 111 (2019) 443–451

Table 1
Patents Filed and Granted on Tramadol.
Publication No. Title Assignee Publication Date Ref.

WO1993004675 A1 Composition comprising a tramadol material and Mcneilab, Inc. 1991, 6 Sep [13]
acetaminophen and its use
US6254887B1 Controlled release tramadol Euroceltique SA 1993, 5 Oct [14]
US5723668A Method of separating the racemate of tramadol Grunenthal GmbH 1996, 19 Jan [15]
WO1999036390 A1 Purification of tramadol Macfarlan Smith Limited 1998, 14 Jan [16]
WO2002026694A1 O-substituted 6-methyl-tramadol derivatives Grünenthal GmbH 2000, 29 Sep [17]
EP1397126B9 Use of tramadol for delaying ejaculation DMI BioSciences Inc 2001, 16 Mar [18]
US20030171440A1 Tramadol analogs and uses thereof Sunovion Pharmaceuticals Inc 2001, 30 Nov [19]
US6399829 B1 Synthesis and purification of (r*,r*)-2-[(dimethylamino) Mallinckrodt LLC 1998, 22 May [20]
methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride
US 6,469,213 B1 Tramadol, salts thereof and process for their preparation Russinsky Ltd 1997, 15 Jul [21]
US6254887B1 Controlled release tramadol Euroceltique SA 1993, 10 May [22]
EP 0,996,613 B1 Pure cis-tramadol hydrochloride production Russinsky Ltd 1997, 15 Jul [23]
EP 1,346,978 A1 Process for preparing tramadol hydrochloride and/or tramadol Jubilant Organosys Ltd 2002, 21 Mar [24]
monohydrate
WO2003078380 A2 Process for preparing tramadol hydrochloride and/or tramadol Jubilant Organosys Ltd 2002, 20 Mar [25]
momohydrate
EP2022778A1 A crystalline form of (R,R)-tramadol-(S)-naproxene salt Laboratorios del Dr Esteve SA 2007, 7 Aug [26]
US6436438B1 Tramadol multiple unit formulations Asta Medica AG 1996, 25 July [27]
US7030276B2 Process for the preparation of 2-{(dimethylamino) methyl]-1-(3- Grunenthal GmbH 2002, 9 Aug [28]
methoxy-phenyl) cyclohexanol.
US 7,470,816 B2 Tramadol recovery process Ipca Laboratories 2005, 14 Nov [29]
245583 A controlled release tablet containing topiramate, Tramadol Cilag Ag 2011, 28 Jan [30]
hydrochloride and xanthan gum
US7988998 B2 Sustained-release tramadol formulations with 24-hour efficacy Labopharm (Barbados) Ltd. Labopharm IncPaladin Labs 2002, 25 Oct [31]
Europe Ltd
WO 2,014,154,747 A1 Extraction of tramadol from Nauclea latifolia smith Institut National De La Sante Et De La Recherche Medicale 2013, 26 Mar [32]
(Inserm) Universite Joseph Fourier - Grenoble 1
IP 263257 Process for isolation of active tramadol hydrochloride Wanbury Limited 2014, 17 Oct [33]
WO2015044952A3 Tramadol hydrochloride and paracetamol orally disintegrating Athena Drug Delivery Solutions Pvt Ltd. 2013, 30 Sep [34]
composition and process for preparing the same

and serotonergic receptors. It also has receptor binding antitussive

property [12]. We have enlisted important patents since 1991 for the
drug tramadol and the same is summarized in Table 1 [13–34]. Tra-
madol is mainly used in the treatment of muscle pain, joint pain and
wound pain. Its use is not recommended for children below 16 years.
Patients with medical history of drug addiction, alcoholism, seizure,
epilepsy, head injury and metabolic disorders have more possibility of
seizures when treated with tramadol. Its use is not practiced in patients
with kidney disease, liver disease, stomach disorder, mental illness,
depression and suicidal ideation as it can worsen the patient’s condi-
tion. Its usage is restricted in pregnant women as well as breast feeding
mothers as it may cause birth defects and harm the foetus and to the
nursing babies. Tramadol is rated as Category C in the pregnancy risk Fig. 1. Isomer of Tramadol.
drug by American Food and Drug Administration. Due to these effects,
physician should avoid prescribing tramadol to pregnant women and 3. Sources of tramadol
nursing mothers [35].
3.1. Natural source

2. Chemistry of tramadol The biosynthesis of tramadol is a hypothetic pathway, since the

Tramadol is 4-phenyl-piperidine analogue (2-(dimethylamino-
methyl)-1-(3-methoxyphenyl) cyclohexanol) of codeine. Commercially
available tramadol is a combination of dextro (+) and levo (-) en-
antiomer (Fig. 1). Tramadol hydrochloride is actively soluble in water
and ethanol. Di-methylaminomethyl group of tramadol is methylated
ring nitrogen of codeine and morphine which are essential for binding
to MOR. It is metabolized by de-methylation of nitrogen, oxygen and
conjugation reactions [36]. Tramadol follows the Lipinski rule of five
which are: molecular weight- 263.19, hydrogen bond donor-1, hy-
drogen bond acceptor-2, molar refractivity-1.55 and partition coeffi-
cient-2.88.
natural origin of tramadol is still a matter of debate. However, the
occurrence of tramadol in Nauclea latifolia was recently detected by
Boumendjel et al. [37]. Tramadol is found to be present (< 0.00002%
w/w) in roots and bark of Nauclea latifolia [38]. Extraction of tramadol
was done and characterized by high performance liquid chromato-
graphy (HPLC) (Fig. 2) and its analgesic property was tested by in vivo
assay using mice model.
L-lysine, L-arginine, L-tyrosine, L-phenylalanine and L-tryptophan
amino acid are the biosynthetic precursors of Tramadol [39]. A bio-
synthetic pathway has been also proposed by the authors by 13C posi-
tion-specific isotope analysis. Biosynthetic pathway of tramadol is
showed in Scheme 1; it starts from amino acid L-phenylalanine and L-
lysine. Aldolization of 3′-methoxyacetophenone with N, N-dimethyl-5-
aminopentanal gives intermediate 1 (7-(dimethyl amino)-3-hydroxy-1-
(3-methoxyphenyl) heptan-1-one). Then intermediate 1 is reduced into

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M. Subedi et al. Biomedicine & Pharmacotherapy 111 (2019) 443–451

Fig. 2. Extraction process of Tramadol.

amino ketone (2) and is further oxidized to iminium 3. Finally, tra-

madol is obtained by cyclization of 3 followed by reduction

3.2. Chemical synthesis of tramadol

Tramadol synthesis through the chemical reaction is easy and eco-

nomical, its chemical synthetic pathway is showed in Scheme 2. Cy-
clohexanone is used as a starting material, compound 2 and 3 are ob-
tained by the reaction of cyclohexanone with dimethylamine
hydrochloride and n-methyl-1-phenylmethanamide. These compounds
2 and 3 react with (3-methoxyphenyl) lithium in the presence of ethyl
ether and HCl to produce Tramadol [40–42].

4. Mechanism of action (MOA) Scheme 2. Synthetic scheme of Tramadol HCl.

Tramadol shows very good analgesic activity by its action on central

enantiomer inhibits noradrenalin reuptake (Fig. 3) [43–45].
nervous system. The racemic mixture of (+) dextro and (-) levo en-
Opioid receptors are G-protein coupled receptor and are of four
antiomer of tramadol has synergistic analgesic effect. It acts by various
types. The most commonly used opioids analgesic act on μ opioid re-
pathways such as a weak MOR agonist or as a serotonin and nor-
ceptor. The (+) Dextro enantiomer of Tramadol showed Mu (μ) opioid
epinephrine reuptake inhibitors for the nociception. O-desmethyl tra-
receptor agonistic activity and enhance the activation of central dopa-
madol metabolite (M1) of tramadol also shows analgesic action by
mine.
acting as weak MOR agonist. The (+) enantiomer of tramadol acts as a
MOR agonist and by inhibition of the reuptake of serotonin, whereas (-)

Scheme 1. Biosynthesis of tramadol HCl.

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M. Subedi et al.
Fig. 3. Schematic representation of MOA of Tramadol.
5. Pharmacokinetics (ADME) of tramadol
When tramadol is used in racemic form for oral administration it
gets completely absorbed in the intestine and shows bioavailability of
about 75% for 100 mg tramadol. Tissue distribution of tramadol is
about 2.6–2.9 L/kg body weight. After administration in healthy adults,
tramadol and its metabolite M1 reaches the plasma after two to three
hours. Tramadol is metabolized in liver by O and N-demethylation and
by conjugation reactions to form glucuronides and sulfates. The O-
desmethyltramadol (M1) is catalysed by CYP2D6 enzymes and N-de-
methyltramadol (M2) catalysed by CYP2B6 and CYP3A4 [47]. The M1
metabolite of tramadol is more potent and has 200 times more affinity
compared to dextro form of tramadol. The elimination half-life for M1
metabolite is around nine hours, lesser to tramadol half-life of six hours.
The hepatic metabolites of tramadol being polar in nature are excreted
from the kidneys. About 30% dose of tramadol is excreted through
urine in unchanged form and 60% is excreted in the form of metabo-
lites. The plasma half-lives of tramadol and M1 metabolite are 6.3 and
7.4 h respectively [48]. Lethal dose (LD50) is about 300–350 mg/kg
(oral, rat) [49,50].
6. Molecular modelling of tramadol
Shen et al. (2015) have reported the design and synthesis of N-
phenyl alkyl substituted tramadol derivatives. They also reported the
docking study for all the synthesized compounds and compared their
binding residues with morphine at MOR [46]. Molecular modeling
study revealed that tramadol metabolite M1 and morphine bind with
similar residue ASP147 of MOR. Both have similar pharmacophore
features and alignment as shown in Figs. 4 and 5. Substitution of the
nitrogen atom of M1 metabolite and morphine showed similar binding
with Trp293 and Tyr326 residues. The N-phenyl ethyl tramadol have 8
Fig. 4. A. Docking of M1 metabolite of Tramadol; B. Docking of Morphine on μ opioid receptor.
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Biomedicine & Pharmacotherapy 111 (2019) 443–451
Fig. 5. Alignment of M1 metabolite of tramadol (red color) and morphine (blue
color) (For interpretation of the references to colour in this figure legend, the
reader is referred to the web version of this article).
times less activity compared to tramadol, but have similar activity to
M1 metabolite of tramadol [51].
6.1. Structure activity relationship of tramadol
Shen et al. (2015) revealed that the substitution of phenyl group on
nitrogen of tramadol was important for analgesic activity [46]. Affinity
towards MOR will decrease with the increasing length of linker (no. of
methyl between nitrogen and phenyl). Phenolic hydroxyl group has
high MOR agonistic activity compared to methoxy group substitution
(Fig. 6).
7. Precautions to be taken before taking tramadol
Tramadol is used in the treatment for managing different types of
pain as listed in Table 2. The WHO has developed a three-step "ladder"
for cancer pain relief in adults (Fig. 7) Strong opioids are given to pa-
tients with severe pain. It is mentioned as a step-2 analgesic in the WHO
guidelines for cancer pain relief. It has more efficient pain relief com-
pared to morphine. However various precautions are to be taken while
prescribing tramadol. It should not be given to children below age of
sixteen years and Ultram ER should be only given to patients older than
18 years. It is not prescribed to children who have undergone tonsils or
adenoids surgery [70–72]. Tramadol should not be prescribed to the
patients having the conditions such as- sensitivity to tramadol, asthma
or breathing problems, stomach or intestinal blockage, person taking
-alcohol, sedatives, tranquilizers, or narcotic medications; person with
14 days history of using isocarboxazid, linezolid, methylene blue in-
jection, phenelzine, rasagiline, selegiline, or tranylcypromine (MAO
inhibitors); liver or kidney disease, mental illness or suicide attempt,
during pregnancy, breast-feeding and expecting mothers, addiction to
drug or alcohol, person with metabolic disorders, person taking
M. Subedi et al. Biomedicine & Pharmacotherapy 111 (2019) 443–451

Fig. 6. SAR of tramadol derivatives substituted with N-phenyl alkyl Substitution.

antibiotics, antifungal, anti-HIV medication to treat blood pressure and

any heart disease, person with epilepsy history etc.

8. Various combinations of tramadol with paracetamol

To relieve moderate to severe pain, tramadol is often prescribed in

combination with non-opioid analgesics like paracetamol. Fixed-dose
combination of tramadol and paracetamol gives rapid onset and long
duration of action and multimodal analgesic effects. Patients with
moderate to severe acute pain and chronic pain are given- tramadol
(37.5 mg) + paracetamol (325 mg). In dental pain, it relieves pain over
an 8-hour period than the drug alone. In postoperative dental pain the
combinations give same analgesic effect to hydrocodone/paracetamol
10/650 mg over an 8-hour period compared to tramadol (37.5 mg) +
paracetamol (325 mg). In osteoarthritis flare pain: one or two tramadol Fig. 7. Steps for cancer pain treatment.
(37.5 mg) + paracetamol (325 mg), four times daily for five days is
usually prescribed. In chronic back pain- tramadol (37.5 mg) + para- during treatment period [76].
cetamol(325 mg), maximum 10 tablets or capsules per day for 4 weeks
is usually prescribed [73,74].
10. Tramadol-drug interactions

9. Tramadol in pharmaceutical market
Tramadol is available in the market under the brand names- Ultram,
Tramadol hydrochloride ER, ConZip and Ultram ER. The generic tra-
madol is manufactured by 108 different pharmaceutical companies
with about 164 brands available in the market. Tramadol available in
the market is usually combined with paracetamol. Tramadol formula-
tions are available in the form of tablet, capsule, syrup, cream, gel,
ointment, and injection [75]. When taken orally tramadol is used at a
dose of 50–100 mg every 4–6 hrs with or without food. Maximum dose
of tramadol is 400 mg/day; intravenous and intramuscular tramadol is
used in severe pain with a dose 50–100 mg every 4–6 hrs. Excess dose of
tramadol should be avoided and should strictly refrain alcohol use
Drug interactions are one of the leading causes of accidental poi-
soning deaths all over the world [77]. Adverse drug interactions are
mainly due to overdose and abrupt combination of medicines which
can interact with each other. Before taking tramadol, care should be
taken to avoid harmful drug interactions. Tramadol mainly interacts
with the drugs such as MAO inhibitors, antidepressants, tegretol, blood
thinners, digoxin, ketoconazole, rifampin, erythromycin, quinidine and
medications that cause drowsiness. It has been shown to interact with
761 drugs; it causes major drug interactions with 446 drugs, moderate
drug interactions with 311 drugs and minor drug interactions with 4
drugs.
Tramadol should not be taken with alcohol, street drugs, sedatives,
narcotic pain relievers, antidepressants, anti-anxiety medications and

Table 2
Use of Tramadol in different types of pain.
Types of Pain Uses Reference

Osteoarthritic pain Tramadol Contramid® OAD (once in a day) in woman shows high potency and is used both as immediate as well as [52,53]
extended-release components.
Endodontic or Dental pain Tramadol is used for pain management in root canal and dental pulpectomy [54,55]
Chronic cancer pain It is given orally in combination with other non-opioid and shows good relief from pain in cancer patients [56–60]
Acute myocardial infarction Tramadol in combination with acetaminophen is given in the pain of myocardial infarction. The combination has [61]
similar action to beta blockers and nitrates.
Postoperative pain Pain caused by caesarean operation and lumbar disc surgery are treated using tramadol. [62,63].
Postoperative shivering in lower abdominal Tramadol is very effective compared to clonidine in controlling post spinal shivering. [64]
surgery
Acute renal pain In ureteral calculi, tramadol shows very good therapeutic effect. In acute renal colic, intravenous tramadol with [65,66].
diclofenac sodium shows superior pain relief compared to buscopan and diclofenac.
Neuropathic pain Tramadol effectively relieves the neuropathic pain when compared to placebos. [67]
Brugada syndrome Tramadol is very effective in managing Brugada syndrome. This syndrome has irregular heart activity with risk of [68]
death due to cardiac arrest. It is a genetic disorder due to mutation in gene encoding human cardiac sodium channels.
Morphine allergy Tramadol is also given to patients who are allergic to Morphine. [69]

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M. Subedi et al.
Table 3
Clinical features of Serotonin Syndrome.
S.N. Features
1. Neuromuscular changes
2. Autonomous nervous system changes (ANS)
3. Mental status changes
should be avoided for the treatment of mental illness, bipolar disorder
and schizophrenia. The IM injection of tramadol during anaesthesia
decreases the gastric acid secretion [78].
10.1. Tramadol interaction with food
Tramadol interacts with alcohol and increases the CNS side effects
like dizziness, sleepiness, lack of concentration, thinking and judgment
behaviour. Due to this effect of tramadol, driving and operation of
machine should be avoided while using tramadol.
10.2. Tramadol effects on different disorders/diseases
10.2.1. Seizure disorders
Tramadol overdose increases the risk of seizures, thus caution must
be taken during usage of tramadol in patients with history of seizure
and other neurologic abnormalities (head trauma, brain damage or CNS
tumor). In tramadol overdose, naloxone administration may also in-
crease the risk of seizures [79].
10.2.2. Acute alcohol intoxication
Tramadol is also contraindicated in patients with acute alcohol in-
toxication showing depression. Sometimes respiratory depression and
death may occur. Naloxone is used as antidote in respiratory depression
caused by Tramadol [80,81].
10.2.3. Liver disease
Tramadol and its metabolite M1 elimination time increases in pa-
tients with advanced liver cirrhosis. Care should be taken during use of
tramadol in patients with impaired liver function. The suggested dosage
of tramadol for patients with liver cirrhosis is 50 mg every 12 hrs [82].
10.2.4. Renal dysfunction
In patients with weak renal function the excretion rate of both
Tramadol and its M1 metabolite is decreased. In that case the dosing
interval will increase to 12 h and in patient with creatinine clearance
below 30 mL/min, 200 mg dose is given per day [83].
10.2.5. Acute abdominal conditions
In patients with acute abdominal conditions the use of tramadol is
complicated.
10.2.6. Intracranial pressure
Tramadol use may cause meiosis by increasing the intracranial
pressure, so caution must be taken during use of tramadol in patients
with head injury and high intracranial pressure.
10.2.7. Respiratory depression
When tramadol is used in high doses with anaesthetic medications
or alcohol it may lead to respiratory depression. Respiratory depression
caused by tramadol is comparatively low with morphine. Tramadol
may also cause dyspnoea (increasing airway resistance).
10.2.8. Suicidal tendency
When tramadol is administered to a patient with emotional dis-
turbances it can lead to suicidal ideation also with history of misuse of
tranquilizers, alcohol and other CNS-active drugs may lead to death.
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Signs/symptoms
Shivering, clonus, hyperreflexia, inflexibility
Diaphoresis, increase body temperature, tachycardia
Disturbance, perplexity
The use of this drug should avoided in patients with suicidal or addicts
[84,85].
11. Contraindications, overdose, physical dependence and
withdrawal symptoms of tramadol
Tramadol should not be prescribed to the patients with deficiency of
CYP2D6 enzymes as it decreases the tramadol metabolism to the more
potent metabolite M1 [86]. It should be avoided in patients with history
of tramadol and other opioids hypersensitivity. Overdose causes head-
ache, dizziness, drowsiness, breathing problem, low heart rate, weak-
ness, freezing and damp skin, coma and even death [87]. Long-time use
of the drug may cause physical dependency [88]. It also causes addic-
tion; consequently stopping and reducing the dose may precipitate
withdrawal symptoms [89–91]. Naloxone is used as an antagonist
which reverses the toxic effect of tramadol overdose but may enhance
the chance of convulsions in the patient [92].
12. Adverse effects of tramadol
Long-term continuous use of tramadol produces various harmful
adverse effects to the body [93,94].
12.1. Serotonin syndrome
When patients are co-administered tramadol along with serotonin
receptor inhibitors ex: fluoxetine and paroxetine, it leads to serotonin
syndrome [95–97]. Fluoxetine and paroxetine inhibits the metabolism
of tramadol and increases the plasma concentration of the drug. Some
clinical features of serotonin syndrome are listed in Table 3. Treatment
of serotonin syndrome includes hospitalization with agitation and sei-
zure treatment by benzodiazepines. Hydration is maintained by giving
intravenous fluids (IVF). The drug responsible for the cause of serotonin
syndrome is discontinued in severe cases and cyproheptadine (Peri-
actin) is given to inhibit serotonin production [98,99].
12.2. Seizures
When tramadol is used with antidepressant drugs the chances of
seizures increase. Therefore, tramadol should not be prescribed to the
patients who are taking antidepressant drugs and have seizures history
[100].
13. Respiratory depression
The chance of respiratory depression by tramadol is less compared
to morphine. Respiratory depression occurs in few cases, and it is
mainly due to tramadol being used with anaesthetics, alcohol and other
sedative drugs [101].
13.1. Hyperalgesia
In hyperalgesia, patients become more sensitive to pain receptor.
Hyperalgesia is seen in patients who use tramadol on a long term basis
[102].
M. Subedi et al.
13.2. Central nervous system [103,104]
Long-time usage of tramadol produces various common psychiatric
effects such as CNS stimulation, anxiety, euphoria, nervousness, sleep
disorder, insomnia, depression, agitation, apathy and depersonaliza-
tion, emotional liability and in very rare cases produces hallucinations,
nightmares, dependency and withdrawal syndrome.
13.3. Gastrointestinal
The various gastrointestinal disturbances seen due to the usage of
tramadol are nausea, constipation, vomiting, dyspepsia, dry mouth,
diarrhoea, abdominal pain, flatulence, sore throat, gastroenteritis viral,
toothache, appendicitis and pancreatitis [103].
13.4. Nervous system
The effects seen due to the usage of tramadol on the nervous system
are dizziness, somnolence, headache, confusion, coordination dis-
turbance, tremor, paraesthesia, hypoesthesia, migraine, sedation, syn-
cope, disturbance in attention, epileptic form of seizures [103].
13.5. Dermatologic
In rare cases, Tramadol causes Stevens-Johnson syndrome and hair
disorder. Pruritus, sweating, rash, dermatitis, cellulitis, piloerection,
clamminess, urticaria and toxic epidermal necrolysis are common skin
disorder [103].
13.6. Genitourinary
In genital system, tramadol causes menopausal symptoms and ur-
inary tract infection. In some cases, it may cause difficulty in micturi-
tion, haematuria, dysuria, cystitis and sexual function abnormality
[103].
13.7. Cardiovascular (CVS)
On the cardiovascular system tramadol causes vasodilatation,
myocardial infarction, postural hypotension and chest pain and in very
rare cases it causes tachycardia and bradycardia.
13.8. Metabolic
Tramadol causes some metabolic disorders such as anorexia, de-
creased weight, increased blood glucose, gout and in rare case it causes
anorexia [103].
13.9. Endocrine
Tramadol causes improper secretion of antidiuretic hormone
leading to water retention [103].
13.10. Ocular
On eye, tramadol causes meiosis, visual disturbance and blurred
vision. Lacrimation disorder is very uncommon adverse effect caused by
tramadol [103].
13.11. Renal
Blood urea nitrogen level is increased [103].
13.12. Musculoskeletal
In 1–10 % cases Tramadol causes hypertonia, arthralgia, back pain,
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Biomedicine & Pharmacotherapy 111 (2019) 443–451
limb pain, neck pain, muscle cramps, muscle spasms, joint stiffness,
muscle twitching, myalgia and aggravated osteoarthritis [103].
13.13. Others
In some cases, tramadol may cause tinnitus, vertigo and ear infec-
tions [104].
14. Spectral analysis of tramadol
In pharmaceutical preparations tramadol is identified by spectro-
photometric, spectrofluorimetric and ultra-performance liquid chro-
matography (UPLC) methods. In spectrophotometric and spectro-
fluorimetric methods- tramadol is condensed with anhydrides mixture
of malonic and acetic acids for about 25–40 min s at 60 °C temp.
Colored condensation product of tramadol is obtained, which is sub-
jected to spectrophotometric and spectrofluorimetric determination at
434 nm. For spectrophotometric assay Beer's law is obeyed from 0.5 to
2.5 μg/ml for tramadol. The linearity range for spectrofluorimetric
method is 0.25 to 1.25 μg/ml. In UPLC, the tramadol curve is plotted
between the mean peak area and concentration of tramadol which
produces linear plot for 0.5–300 μg/mL concentration. Potassium di-
hydrogen phosphate: acetonitrile (1:1) is used as mobile phase and
concentration is measured at 226 nm using UV detector [105].
15. Conclusions
Tramadol is an atypical synthetic analgesic which has tremendous
use in acute pain, dental pain, labor pain, chronic pain, cancer pain
mostly due to its dual mechanism of action. Tramadol can interact with
other drugs that share the same metabolic pathway and utilizes same
enzymes, thus use of tramadol should be carefully monitored in the
patients to avoid its misuse and associated adverse effects. However,
tramadol have many side effects and thus the tramadol should be
chosen carefully to treat the patients outlining the risk to benefits ratio
and the patients must be monitored carefully for any possible side ef-
fects. To avoid adverse effects newer drugs are needed and we propose
tramadol based derivatives for future and this review will give better
insights to design them with lesser side effects and potent therapeutic
activity with minimum side effects.
Declarations of interest
None.
Acknowledgments
The authors gratefully acknowledge SPP SPTM-School of Pharmacy
and Technology Management, SVKM’S NMIMS, Mumbai for providing
facility to carry out the work.
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