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Introduction: Tramadol is an opioid drug that, unlike classic opioids, also modulates the monoaminergic system by inhibiting noradrenergic and serotoninergic reuptake. For this reason, tramadol is considered an atypical opioid. These special pharmacological characteristics have made tramadol one of the most commonly prescribed analgesic drugs to treat moderate to severe pain. Areas covered: The aim of this review is to provide a historical description of the biochemistry, pharmacokinetics and particularly, the mechanisms of action of tramadol. In addition, a summary is offered of the analgesic effects of tramadol in a variety of animal models of acute and chronic pain. Finally, clinical studies that demonstrate the efficacy and safety of tramadol in the treatment of pain are also assessed. Expert opinion: The discovery that tramadol combines opioid and monoaminergic effects represented a milestone in the evolution of pain treatment. Given its ‘mild effect’ on opioid receptors, tramadol induces fewer side effects than classic opioids. Tramadol produces satisfactory analgesia against various types of pain and it is currently approved for the treatment of moderate to severe pain. Thus, the combination of monoamine and opioid mechanisms opens new avenues for the design of innovative analgesics.
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Expert Opinion on Drug Discovery
ISSN: 1746-0441 (Print) 1746-045X (Online) Journal homepage: http://www.tandfonline.com/loi/iedc20
Discovery and development of tramadol for the
treatment of pain
Lidia Bravo, Juan Antonio Mico & Esther Berrocoso
To cite this article: Lidia Bravo, Juan Antonio Mico & Esther Berrocoso (2017) Discovery and
development of tramadol for the treatment of pain, Expert Opinion on Drug Discovery, 12:12,
1281-1291, DOI: 10.1080/17460441.2017.1377697
To link to this article: http://dx.doi.org/10.1080/17460441.2017.1377697
Published online: 17 Sep 2017.
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DRUG DISCOVERY CASE HISTORY
Discovery and development of tramadol for the treatment of pain
Lidia Bravo
a,b,d
, Juan Antonio Mico
b,c,d
and Esther Berrocoso
a,b,d
a
Neuropsychopharmacology and Psychobiology Research Group, Psychobiology Area, Department of Psychology, University of Cadiz, Puerto Real
(Cadiz), Spain;
b
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain;
c
Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cadiz, Cadiz, Spain;
d
Instituto de
Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz, Spain
ABSTRACT
Introduction: Tramadol is an opioid drug that, unlike classic opioids, also modulates the monoaminer-
gic system by inhibiting noradrenergic and serotoninergic reuptake. For this reason, tramadol is
considered an atypical opioid. These special pharmacological characteristics have made tramadol one
of the most commonly prescribed analgesic drugs to treat moderate to severe pain.
Areas covered: The aim of this review is to provide a historical description of the biochemistry,
pharmacokinetics and particularly, the mechanisms of action of tramadol. In addition, a summary is
offered of the analgesic effects of tramadol in a variety of animal models of acute and chronic pain.
Finally, clinical studies that demonstrate the efficacy and safety of tramadol in the treatment of pain are
also assessed.
Expert opinion: The discovery that tramadol combines opioid and monoaminergic effects represented
a milestone in the evolution of pain treatment. Given its mild effecton opioid receptors, tramadol
induces fewer side effects than classic opioids. Tramadol produces satisfactory analgesia against various
types of pain and it is currently approved for the treatment of moderate to severe pain. Thus, the
combination of monoamine and opioid mechanisms opens new avenues for the design of innovative
analgesics.
ARTICLE HISTORY
Received 22 May 2017
Accepted 6 September 2017
KEYWORDS
Tramadol; pain;
monoamines; opioid;
analgesia
1. Introduction
Tramadol is an opioid drug with pharmacodynamics charac-
teristics distinct to those of the more classic opioids, which has
led to it being considered as the first member of the atypical
opioidsgroup. Unlike other opioids, tramadol can modulate
the monoaminergic system by inhibiting noradrenaline (NA)
and serotonin (5HT) reuptake at presynaptic terminals [1,2].
Although NA and 5HT have long been considered to be
involved in nociceptive regulation, tramadol was the first
analgesic drug with pharmacological activity based on its
combined opioid and monoaminergic effects. These particular
pharmacological characteristics and this unique mechanism of
action have since made tramadol a commonly prescribed
analgesic drug.
Since its discovery in 1962, in vitro and in vivo studies have
shown the strong analgesic efficacy of tramadol, as confirmed
in controlled clinical trials. Tramadol was initially approved for
medical use in Germany in 1977, although it was not approved
by the Food and Drugs Administration (FDA) until 1995. The
efficacy and safety of tramadol in treating moderate to severe
pain has since been demonstrated in extensive clinical studies,
including post-operative, cancer-related, and inflammatory
pain [35]. Moreover, preclinical and clinical studies indicate
tramadol may be effective in situations where the monoami-
nergic and opioid system might be involved, such as chronic
pain, depression, or obsessive-compulsive disorder [610].
Interestingly, tramadol has been seen to be effective in the
relief of neuropathic pain, a type of pain where classical
opioids use is limited by the side effects associated with
their long-term treatment. Furthermore, tramadol may have
other advantages over opioids, including less withdrawal reac-
tions and less respiratory depression than conventional
opioids at equivalent doses. In addition, potent synergy was
recently reported when using tramadol in combination with
paracetamol or dexketoprofen [11,12]. This makes it even
more interesting to investigate how the activity of tramadol
complements that of these other analgesic drugs.
Despite the years that have passed since its discovery, the
mechanism of action of tramadol remains a matter of intense
research. Some of its effects are well known, such as the
inhibition of NA and 5HT reuptake and the activation of µ-
opioid receptors. However, other effects of tramadol are no
less important and they include the possible inhibition of M1
and M3 muscarinic receptors, or the opening of K
+
channels.
Thus, the main focus of this review will be on the neuronal
activity of tramadol and on its influence against both acute
and chronic pain.
The principal objective is to describe the mechanisms of
action through which tramadol has been shown to produce its
analgesic effects and that has instigated research into other
such innovative analgesics. Finally, a reflection on the clinical
CONTACT Esther Berrocoso esther.berrocoso@uca.es Department of Psychology, University of Cadiz, Campus Universitario Rio San Pedro s/n, 11510 Puerto
Real (Cadiz), Spain
EXPERT OPINION ON DRUG DISCOVERY, 2017
VOL. 12, NO. 12, 12811291
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studies validating the efficacy of tramadol has been included,
as well as a consideration of the future perspectives for its
analgesic use.
2. Biochemistry and pharmacokinetic properties
Tramadol ((+)-cis-2-[(dimethylamino) methyl]-1-(m-methoxy-
phenyl)cyclohexanol) (Figure 1)isanopioidanalgesicdrug
that exists as a racemic mixture of (+) and ()tramadol.
Both enantiomers contribute to its analgesic effect, albeit
through different mechanisms. In fact, (+)-tramadol has
greater affinity for µ-opioid receptor than ()-tramadol, and
it also inhibits 5HT uptake more strongly than ()-tramadol,
which more potently inhibits NA uptake [1,2]. Interestingly,
the first hepatic metabolite of tramadol described was
O-desmethyltramadol (M1), which possesses even greater
affinity for µ-opioid receptors than its parent compound,
being mainly responsible for the opioid-derived analgesic
effect [13](Table 1).
Tramadol is available in a wide range of pharmaceutical
formulations and it can be administered by various routes:
subcutaneous, intravenous, intramuscular, rectal, sublingual,
and oral delivery. After oral administration, tramadol is
rapidly absorbed and it reaches a peak serum concentration
after 2 h [13]. Indeed, its oral bioavailability is 70% following
a single dose due to its hepatic first metabolism. After
multiple oral administration, the bioavailability of tramadol
increases to 90100%probablyduetosaturationinphaseI
of hepatic metabolism [15]. Tramadol is distributed rapidly
around the body, with about 20% apparently bound to
plasma proteins, and after a single oral dose of 100 mg
the half-life of tramadol is 5.1 h, while that of the M1
metabolite is 9 h [15].
Tramadol is metabolized to O-desmethyltramado l (M1)
by the cytochrome isoenzyme P50 CYP2D6. However,
CYP2D6 genes are very polymorphic. Thus, according to
the CYP2D6 genotypes, the plasma levels of tramadol can
result reduced or increased and consequently, patients
may respond differently to tramadol [16]. Other enzymes
(P450 CYP2B6 and CYP3A4) catalyze the production of
N-desmethyltramadol (M2), an inactive metabolite (Phase
I: Figure 2). These compounds are subsequently metabo-
lized to the secondary metabolites N-didesmethyltramadol
(M3), N,N,O-tridesmethyltramadol (M4), and N,O-dides-
methyltramadol (M5, Phase II: Figure 2), which are then
inactivated by the addition of sulfate and glucuronic acid,
andexcretedintheurine[17,18].
The excretion of tramadol occurs almost exclusively via
the kidney, as initial studies of tramadol using radioactive
isotopes showed that at least 90% of the radiolabel is
excreted in the urine, with only residual activity recovered
in the feces. Moreover, around 1030% of this tramadol is
excreted as the unmetabolized drug, while 60% is excreted
as a metabolite [19].
3. Pharmacodynamics
3.1. Effect of tramadol on the opioid system
Since the first preclinical studies, it was thought that tramadol-
induced antinociception was mediated exclusively via the opioid
system [20,21]. However, it was soon noted that tramadol does
not produce the classic side effects associated to opioids, such as
constipation, respiratory depression, or sedation [22,23], sug-
gesting that it might not act exclusively on the opioid system.
In fact, in vitro studies performed on rat pontine slices
demonstrated that tramadol has a low affinity for opioid
receptors. Specifically, tramadol has a modest affinity for µ-
opioid receptors (K
i
= 2.1 µM), as well as a weak affinity for
δ-andκ-opioidreceptors(K
i
= 57.6 µM and 42.7 µM,
respectively), representing a 10-fold and 6000-fold weaker
affinity than codeine and morphine, respectively [2].
Interestingly, the affinity for µ-opioid receptors differs
between the enantiomers of tramadol, with (+)-tramadol
Article highlights
Tramadol is an efficacious and safe drug to treat moderate to severe
pain.
Tramadol is an atypical opioidthat combines the activation of µ-
opioid receptors with the inhibition of noradrenaline and serotonin
reuptake.
Its first hepatic metabolite, O-desmethyltramadol (M1), has higher
affinity for µ-opioid receptors than the parental tramadol.
Given its mild action on opioid receptors, this compound has fewer
side effects than classic opioids: weaker respiratory depression, con-
stipation, tolerance and dependence.
The analgesic efficacy of tramadol has been proven extensively in
animal models of both acute and chronic pain.
Figure 1. Chemical structure of tramadol
Table 1. In vitro binding affinities of tramadol, M1, M5 and morphine for opioid
receptors and the inhibition of monoamines uptake.
Opioid receptors Monoamines
µ- δ-κ- NA 5HT
Tramadol 2.1 57.6 42.7 0.79 0.99
(+)-Tramadol 1.3 62.0 54.0 2.51 0.53
()-Tramadol 24.8 213.0 54.0 0.43 2.35
O-desmethyltramadol (M1) 0.0054
a
--- -
N, O-didesmethyltramadol
(M5)
0.1
a
--- -
Morphine 0.00034 0.092 0.57 Inactive Inactive
Ki: affinity constants expressed in µM; NA: noradrenaline, 5HT: serotonin.
a
Affinity for cloned human µ-opioid receptor.
Data obtained from [1,2,14].
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binding more strongly to the µ-opioid receptor (K
i
=1.3µM)
than ()-tramadol (K
i
=24.M)[1]. Given the modest
affinity of tramadol and its enantiomers for µ-opioid recep-
tors, the affinity of the racemic mix, the enantiomers, and its
main metabolite (M1) was studied by ectopically expressing
cloned human µ-, δ-, and κ-opioidreceptorsinneuroblas-
toma cells. Accordingly, M1 shows greater affinity for µ-
opioid receptors than the parental compound
(K
i
= 0.0054 µM) [13]. In confirmatory studies, M5 displayed
high affinity for µ-opioid receptors (K
i
=0.M),albeitless
than M1, while the M2, M3, and M4 metabolites displayed
little or no affinity for these cloned human opioid receptors
[14]. Moreover, as the analgesic effect of tramadol is only
partially blocked by naloxone in different antinociceptive
tests [2], it would appear that tramadol also acts through
pathways that do not involve opioid receptors.
3.2. The effect of tramadol on the monoaminergic
system
3.2.1. Noradrenergic system
As a consequence of inhibiting NA reuptake, tramadol
enhances the NA released in vitro in both cortical rat brain
slices and spinal cord slices [24]. It was then shown that
tramadol inhibits transporter function in cultured adrenal
medullar cells [25]. Subsequently, a single effective dose of
tramadol (40 mg/kg, subcutaneously s.c.) was shown to
decrease [
3
H]-NA uptake by 73% in vivo, while chronic admin-
istration of increasing doses of tramadol reduce [
3
H]-NA
uptake by a further 35% [26]. As already mentioned, each
enantiomer is implicated distinctly in NA uptake and in vitro,
the ()-tramadol increases NA efflux by blocking NA uptake in
rat brain slices that contain the locus coeruleus (LC) [27].
The LC is the main noradrenergic nucleus in the brain,
playing a pivotal role in controlling the descending pain path-
ways by releasing NA to the spinal cord [28]. Many studies
have focused on how the LC mediates the increase in extra-
cellular NA induced by tramadol. Both tramadol enantiomers
and M1 inhibit the firing rate of the LC in rat pontine slices in
vitro [29], which is at least partially controlled by alpha2
adrenoceptors. Indeed, alpha2 adrenoceptor antagonists
appear to block the analgesic effects of tramadol in rodents
[2] and humans [30]. Significantly, acute administration of
tramadol induces alpha2-adrenoceptor downregulation in sev-
eral brain areas, an effect that is exacerbated by chronic
tramadol administration [31]. Similarly, electrophysiological
studies in anesthetized animals confirmed that tramadol has
an inhibitory effect of LC neurons through alpha2
Figure 2. Schematic representation of human tramadol metabolism pathway
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adrenoceptors [32]. Overall, these data suggest that the nora-
drenergic system is involved in the analgesia induced by
tramadol and specifically that inhibits NA transporters indir-
ectly by a mechanism that involves alpha2 adrenoceptors.
3.2.2. Serotonergic system
Tramadol augments extracellular 5HT by inhibiting the 5HT
transporter, and in the rat frontal cortex in vitro, the (+)-enan-
tiomer blocks 5HT uptake more selectively than the (-)-enan-
tiomer [24]. Administering a single effective dose of tramadol
to rats in vivo (31 mg/kg, s.c.) inhibits cortical synaptosome
uptake of 5HT by 63%, while increasing the doses of tramadol
through chronic administration reduces 5HT uptake by a
further 41% [33]. In addition, chronic tramadol administration
reduces the cortical 5HT
2A
receptors in rats [34] and indeed,
the implication of the different 5HT receptor subtypes on the
efficacy of tramadol has been studied in several pain condi-
tions. Thus, 5HT
1A
receptors contribute to the analgesic effect
of tramadol in acute [35] and neuropathic pain [36], while
5HT
2A
contributes to relief from inflammatory pain [37,38].
Interestingly, blockade of 5HT
7
receptors reduces the antino-
ciceptive effect of tramadol and M1 in an animal model of
post-operative pain [39].
Notably, the inhibition of NA and 5HT uptake by tramadol
is similar to the mechanism of action of some antidepressants.
In fact, the extracellular increase of both NA and 5HT in brain
structures like the hippocampus has been compared to that
produced by the antidepressants duloxetine, venlafaxine, and
clomipramine [40]. Indeed, the binding of tramadol to beta-
adrenoceptors and 5HT
2A
receptors is similar to that of classic
antidepressants [34]. Accordingly, preclinical studies have
demonstrated the antidepressant effect of tramadol in predic-
tive antidepressant tests [8,4143].
3.3. Effect of tramadol on the cholinergic system
While tramadol has been characterized by its action on µ-
opioid receptors and the inhibition of monoamine reuptake,
other sites of action have also been studied to fully under-
stand its neuronal effects. Tramadol suppresses the activity of
M1 and M3 muscarinic receptors, while its main metabolite
(M1) only inhibits M1 receptor function when evaluated by
whole-cell voltage clamp in Xenopus oocytes expressing the
cloned muscarinic receptors [44,45]. In terms of nicotinic
receptors, tramadol inhibits α7 more strongly than α3β4
receptors in adrenal chromaffin cells [45]. Indeed, both the
muscarinic and nicotinic antagonists (atropine and hexam-
ethonium, respectively) specifically inhibit [14C]-tramadol
binding by about 15% in cultured bovine adrenal medulla
cells [25]. Therefore, muscarinic and nicotinic receptors are
possible sites of action of tramadol, which could explain the
proposed anticholinergic effects of this drug. In this regard,
acute and chronic administration of tramadol apparently
impairs spatial memory in rats evaluated in the object recog-
nition test [46]. In clinical settings, the side effects of dry
mouth and constipation associated to tramadol could be con-
sidered anticholinergic effects mediated by M3 receptors [47].
Finally, it should be noted that tramadol is considered to be a
safe drug in relation to cognitive performance in humans [48].
3.4. Effect of tramadol on ion channels
Many ion channels are targets of anesthetics and analgesic
drugs, such as the voltage-dependent K
+
ion channels that
participate in the antinociceptive effects of drugs widely used
in clinical practice (e.g. morphine and diclofenac) [49,50].
Intracerebroventricular administration of at least two K
+
chan-
nels blockers (4-amynopiridine [4-AP] and tetraethylammo-
nium [TEA]) dampens the antinociceptive effect of tramadol
in mice [43]. Moreover, in vitro tramadol produces an inhibi-
tory effect on delayed rectifier K
+
currents in a neuronal cell
line expressing a subtype of K
+
channels (NG108-15) [51],
potentially delaying the repolarization of neurons after an
action potential. These effects are consistent with the fact
that tramadol induces long-term anesthesia after epidural
administration and indeed, the inhibition of delayed rectifier
K
+
currents was proposed as a mechanism by which tramadol
might induce less analgesic tolerance [52].
In terms of other ion channels, tramadol has an inhibitory
effect on muscarinic acetylcholine receptors [45] and on
NMDA receptors, although not on glycine and GABA-A recep-
tors [53]. This latter data is consistent with the weak hypnotic
effects of tramadol in clinical practice. The effects of tramadol
on the transient receptor potential vanilloid-1 (TRPV1) recep-
tor that integrates physical and chemical stimuli at peripheral
nociceptor terminals remain unclear. TRPV1 was first proposed
as a possible target for tramadol in 2008 when a heterologous
expression system was used with single-cell calcium imaging
as readout [54]. While tramadol induces a transient increase in
intracellular [Ca
2+
], mimicking the classic TRPV1 agonist, cap-
saicin, tramadol, and M1 were shown to inhibit TRPA1 (tran-
sient receptor potential ankyrin-1) but not TRPV1 activity [55].
Such discrepancies might reflect the different cell lines in
which TRPV1 was expressed, such that further studies should
be performed to clarify the action of tramadol on TRPV1.
4. Preclinical studies on tramadol
4.1. Acute pain models
Initial studies on models of acute pain indicated that intrathe-
cal administration of tramadol to rats suppresses the pain tail-
flick response. This effect is reversed by opioid antagonist [56].
Thus, tramadol-induced antinociception appears to be exclu-
sively mediated by spinal opioid mechanisms. However, local
tramadol administration in the periaqueductal grey (PAG) pro-
longs the tail-flick latency, and it reduces evoked Aδand C
fiber activity. As the PAG activates descending pain inhibition,
tramadol may produce antinociception via spinal and suprasp-
inal pathways [57]. Later studies confirmed this concept, as
tramadol administered by different routes (subcutaneously,
orally, and intraperitoneally) resulted in antinociception in
the abdominal constriction, hot plate, and tail-flick tests [2]
(Table 2). Moreover, this was the first preclinical data demon-
strating that unlike morphine or codeine, tramadol antinoci-
ception is only partially antagonized by naloxone, suggesting
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the involvement of opioid and non-opioid mechanisms in its
analgesic activity. Such findings were consistent with clinical
studies demonstrating that yohimbine (an alpha2-adrenocep-
tor antagonist) reduced the analgesic effects of tramadol in
healthy volunteers [30], suggesting that its mechanism of
action in part involves non-opioid-driven effects.
Subsequently, the analgesic effect of tramadol in the hot
plate (mice) and plantar test (rats) was shown to be enhanced
by co-administration of pindolol, a 5HT1A blocker [41].
Moreover, in the hot plate and the tail-flick test the analgesic
effect of tramadol in µ-opioid receptor knockout (KO) mice
was mainly mediated by µ-opioid and alpha2-adrenoceptor
activation [58]. Alternatively, K
+
channel blockade and the
inhibition of nitric oxide synthase also reduce the antinocicep-
tive effect of tramadol in mice in the hot plate test [43],
suggesting other possible sites of action for tramadol.
4.2. Chronic pain models
4.2.1. Inflammatory pain
The efficacy of tramadol in animal models of chronic pain was
initially reported in monoarthritic rats (Table 3). In this model
of inflammatory pain, acute tramadol administration produces
a dose-dependent analgesic effect [59]. In turn, chronic admin-
istration of tramadol is effective for 810 days after treatment
in this model, an effect correlated with an increase in 5HT
2A
receptor-positive cells in the nucleus of raphe magnus, ven-
trolateral periaqueductal gray, and spinal dorsal horn [38]. In
addition, intraperitoneal and intraarticular administration of
tramadol also seems to provide analgesic relief from periph-
eral edema [60,61], an effect associated with a decrease in
prostaglandin (PGE
2
) in peripheral exudates [71]. Elsewhere,
intraplantar administration of a selective A1 receptor antago-
nist blocks the effect of tramadol in the formalin test, indicat-
ing a possible role for adenosine receptors in the local
analgesia induced by tramadol [62]. Hence, tramadol seems
to be effective in relieving the central and peripheral conse-
quences of inflammatory pain. In addition, tramadol dampens
pain-related behavior in the second phase of the formalin test,
without affecting the first phase [37]. This effect was reversed
by the 5HT
2
receptor antagonist ketanserin but not by nalox-
one, and as fluoxetine enhances the analgesic effect of low
doses of tramadol in the formalin test, the serotonergic system
seems to be implicated in this phenomenon.
4.2.2. Neuropathic pain
Tramadol appears to be effective in several models of neu-
ropathic pain that mimic clinical scenarios (Table 3). Acute
and chronic administration of tramadol relieves thermal
hypersensitivity in a rat model involving chronic constriction
injury (CCI) of the sciatic nerve (6 days post-surgery) [63]. A
similar effect was also reported after acute administration of
tramadol, evident as a decrease in paw lifts in the cold plate
test 7 days after CCI surgery [36]. Since this analgesic effect
is enhanced by blocking 5HT
1A
receptors, the combination
of tramadol and 5HT
1A
antagonists could be suitable to
alleviate neuropathic pain. Dose-dependent effects of acute
treatments have been reported in long-term neuropathic
rats when sensorial hypersensitivity is most severe (15
Table 2. Analgesic effect of tramadol in preclinical models of acute pain.
Test Response Effective Dose Animal Comments Bibliography
Radiant heat tail-flick test tail-flick latency 26 nM i.t. SD rats Efficacy: nortilidine = tramadol
= nefopam > codeine > tilidine
[56]
Radiant heat tail-flick test tail-flick latency 100 µg, intra-PAG SD rats Depression of Aδand C fiber-evoked activity [57]
Abdominal constriction writhe 1.9 mg/kg s.c. CD-1 mice Efficacy > codeine and < morphine [2]
Abdominal constriction writhe 5.4 mg/kg p.o. CD-1 mice Efficacy > codeine and < morphine
Abdominal constriction writhe 1.7 mg/kg p.o. SD rats Efficacy > codeine and ~ morphine
Hot plate (48ºC) PWL 21.4 mg/kg i.p. CD-1 mice Efficacy > codeine and < morphine
Hot plate (55ºC) PWL 33.1 mg/kg i.p. CD-1 mice Efficacy ~ codeine and < morphine
Hot plate (51ºC) PWL 19.5 mg/kg i.p. SD rats Efficacy ~ codeine
Tail flick tail-flick latency 22.8 mg/kg i.p. CD-1 mice Efficacy ~ codeine
Hot plate test PWL 20 and 40 mg/kg i.p. CD-1 mice Pindolol (2 mg/kg, s.c.) + tramadol (10mg/kg) = Tramadol 20mg/kg [35]
Plantar test PWL 40 and 80 mg/kg i.p. Wistar rats Pindolol (2 mg/kg, s.c.)+ tramadol (40mg/kg) = tramadol 80mg/kg
Hot plate test paw licking latency 20,40,50, and 60 mg/kg i.p. Swiss mice [43]
i.t: intrathecal; nM: nanomolar; PAG: periaqueductal grey; s.c: subcutaneously; p.o.: per os (oral administration); SD: Sprague Dawley; PWL: paw withdrawal latency.
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Table 3. Analgesic effect of tramadol in preclinical models of chronic pain.
Model Test Response Effective Dose Animal Comments Bibliography
Inflammatory
pain
Monoarthritic rats (CFA) Paw pressure test vocalization
after paw
pressure
0.1-1 mg/ Kg i.v. SD rats Efficacy: tramadol (1mg/kg)= nalbuphine (1 mg/kg)
=buprenorphine (3µg/kg)=morphine (1mg/kg)
[59]
Plantar test PWL 20mg/kg/day i.p. (10 days) SD rats Analgesic effect appears after 8 days of treatment [38]
Yeast-induced inflammation Paw pressure test force paw-
withdrawal
1.25, 2.50, 5.0 and 20 mg/Kg i.
p.
SD rats Tramadol was administered 15 min before yeast injection [60]
Plethysmometer edema
Knee joint inflammation Plantar test PWL 1mg/kg i.a. Wistar rats Analgesic effect was obtained before (15 min) and after (30 min)
inflammation induction
[61]
Plethysmometer edema
Formalin test Recording of pain
behavior
flinching
behaviour
35 mg/Kg i.p. C57Bl6 mice Analgesic effect was observed mainly in the second phase [62]
Recording of pain
behavior
nociceptive
response
2 and 4 mg/ Kg i.p. SD rats Analgesic effect obtained in the second phase [37]
Neuropathic
pain
Chronic constriction
injury
Plantar test PWL 10,20 and 30 mg/Kg s.c. SD rats PWLs were measured 30, 60, 90, 120, 150 and 180 min after
treatment
[63]
40mg/kg/day minipumps (7
days)
Tramadol effect was evaluated 6 days after surgery and analgesic
effect appears 2 days after minipumps infusion
Cold plate test paw lift 22 mg/ Kg i.p. SD rats Analgesic effect was evaluated 7 days after surgery (15 min
intervals from 0 to 60 min)
[36]
Paw pressure test vocalization
after paw
pressure
2.5, 5 and 10 mg/ Kg i.p. Wistar rats Analgesic effect was evaluated after 15-21 days of surgery [64]
Elevated plus
maze
time open arms 10 mg/ Kg i.p. Wistar Han
rats
Tramadol was administered 30 min before each test [65]
Forced swimming
test
immobility
Cold plate test paw lift 4.64 mg/Kg i.v SD rats Analgesic potency ratio (ED50 tramadol/ED50 morphine): 2.3 in
CCI, 1.2 in SNL and 7.8 for nociceptive pain models.
[66]
Spinal Nerve
Ligation
von Frey test PWL 10 mg/ Kg i.v SD rats
Diabetic
neuropathy (STZ
injection)
von Frey test PWL 4.4 mg/ Kg i.v. SD rats Analgesic effect was evaluated 4 weeks after STZ injection [67]
Plus mialgia Partial sciatic nerve
ligation
von Frey test PWL 10 and 30mg/ Kg i.p. and p.o. SD rats Analgesic effect was evaluated 7 days after surgery [68]
Reserpine-induced
fibromialgia
von Frey test PWL 10 and 30mg/ Kg p.o. Analgesic effect was evaluated 5 days after last reserpine
administration (14 days)
Visceral
model of
pain
Ureteral calculosis (stone
implantation)
Recording
spontaneous
behavior
ureteral crises 1.25, 2.5 and 5 mg/ Kg i.p.
(twice a day, 4 days)
SD rats Analgesic effect was evaluated 4 days after treatment and stone
implantation
[69]
Pinching oblique
musculature
muscle
hyperalgesia
Endometriosis plus ureteral
calculosis
Recording
spontaneous
behavior
ureteral crises 0.625, 1.25, 2.5 and 5 mg/ Kg i.
p. (twice a day, 5 days)
SD rats Tramadol was administered 1418th day postendometriosis as
preventive treatment
[70]
i.v: intravenous; i.p: intraperiotenal; s.c: subcutaneously; p.o.: per os (oral administration); i.a: intraarticular; STZ: streptozotocin; SD: Sprague Dawley; PWL: paw withdrawal latency.
1286 L. BRAVO ET AL.
Downloaded by [Universidad De Cadiz] at 01:25 10 November 2017
21 days post-surgery) [64]. Moreover, tramadol has also
shown better efficacy compared to opioids (morphine) in
neuropathic pain models [66]. Interestingly, acute tramadol
treatment also relieves mechanical hypersensitivity in a rat
model of diabetic neuropathy, conjunction with NA release
in the LC [67]. This effect is similar to that of clomipramine, a
tricyclic antidepressant that is a first-line drug used in
patients suffering neuropathic pain. In addition, acute
administration of tramadol is effective in a rat model of
myalgia [68] and chronic tramadol treatment suppresses
the anxiety-like behavior associated with chronic pain in
CCI rats 25 days after surgery [65]. These findings demon-
strate that tramadol has beneficial effects in the treatment
of chronic neuropathic pain. Finally, robust synergistic anti-
hypersensitivity is evident in neuropathic rats after combin-
ing tramadol with paracetamol [72,73], a combination
commonly used in clinical practice.
4.2.3. Visceral pain
In chronic visceral pain models, such as in a rat model of
ureteral calculosis, semi-chronic tramadol therapy is effective
in relieving visceral pain [69](Table 3). Moreover, it protects
against the phenomenon of viscero-visceral hyperalgesiain a
rat model of ureteral calculosis plus endometriosis [70]. Hence,
tramadol might be an interesting option for the relief of
chronic visceral pain.
4.3. Studies of tolerance and withdrawal syndrome
The side effects associated with the chronic use of tramadol to
treat pain have been evaluated and compared with those
associated with classic opioid drugs. Chronic tramadol admin-
istration does not appear to induce tolerance in a rat model of
neuropathic pain [59,63]. Moreover, when tolerance and phy-
sical dependence are compared between tramadol and mor-
phine in a mouse model of pain that involves acetic acid
administration (0.6%, i.p.), tolerance only develops with mor-
phine (as reflected in a reduction of the ED
50
by 7084%) [74].
In addition, when evaluated by intraperitoneal administration
of naloxone (jumps, piloerection, seizure, diarrhea, and urina-
tion), withdrawal syndrome is significantly more pronounced
in mice treated with morphine than in those that receive
tramadol. These results are consistent with the low tolerance
and dependence associated with tramadol in clinical trials
[20,75]. Hence, tramadol may offer advantages over classic
opioids like morphine or buprenorphine in the treatment of
chronic pain.
Early self-administration studies in rhesus monkeys suggest
that tramadol produces a less intense reinforcing effect than
codeine or pentatozine [76]. More recently, tramadol was
shown to induce conditioned place preference (CPP) in rats.
Interestingly, this CPP is associated with an increase of dopa-
mine in the nucleus accumbens but unlike morphine, trama-
dol does not induce classic behavioral sensitization [77,78].
Although little misuse and abuse have been observed with
tramadol in clinical studies [79], preclinical studies suggest
that tramadol administration should be monitored in drug-
experienced opioid users.
5. From preclinical studies to the clinical use of
tramadol
The evaluation of the analgesic effect of tramadol in humans
has benefited from preclinical data. Clinical trials first reported
that tramadols efficacy is similar to that of the analgesics
available on the market at that time (acetylsalicylic acid, phe-
nacetin, codeine and phentobarbital) [80]. A particularly rele-
vant study was an open multi-center trial with a total of 840
patients suffering acute pain of diverse origin [81]. This study
reported efficacy in more than 80% of the patients after
intramuscular, intravenous, and rectal administration, with no
serious adverse effects. In the 1990s, the efficacy of tramadol
was compared to that of morphine [82], pentatozine [83], and
ketorolac [84], mainly relieving acute pain in post-operative
situations.
After a range of clinical studies reporting that tramadol is
well tolerated in acute pain patients, this compound was
included in controlled clinical trials to study its efficacy in
relieving different conditions of chronic pain. Thus, there are
reports of the effectiveness of tramadol in cancer [3,85], and
chronic non-cancer pain like osteoarthritis [86], low back pain
[87], diabetic neuropathy [88], and polyneuropathy [89]. These
studies have led to tramadol being commonly prescribed to
relieve acute and cancer pain today. More recently, its effec-
tiveness is being potentiated by combining it with paraceta-
mol and dexketoprofen [11,12]), and it is thought to be a good
candidate to reduce intra- and post-anesthetic shivering
[90,91].
6. Conclusion
In the present review, we describe the discovery of tramadol as
an atypical opioidanalgesic drug. Each enantiomer of tramadol
and its main metabolite (M1) have different affinities for opioid
receptors and distinct preferences to inhibit NA and 5HT uptake.
As well as its classic mechanism of action, other effects of trama-
dol may be driven by inhibiting the M1 and M3 muscarinic
receptors, NMDA receptors, and by opening K
+
channels, the
latter influencing the hyperpolarization of neurons. Extensive
preclinical studies have shown tramadol to be effective against
both acute and chronic pain (inflammatory, neuropathic, and
visceral), its chronic administration associated with weak depen-
dence, tolerance, and signs of abuse. Interestingly, the influence
of tramadol on the monoaminergic system is comparable to that
of antidepressant drugs and several preclinical studies have
demonstrated its antidepressant-like activity. Many clinical trials
have confirmed the analgesic efficacy of tramadol when treating
acute and chronic pain, accompanied by a reasonable safety
profile. However, the FDA has to date only approved its medical
use for moderate to severe pain. Nevertheless, more recent
formulations indicate a high efficacy whentramadol is combined
with paracetamol or dexketoprofen.
7. Expert opinion
The discovery of tramadol by Grünenthal in Germany in 1962,
acting via opioid and monoaminergic mechanisms, represents
a pharmacological milestone and it was initially approved as a
EXPERT OPINION ON DRUG DISCOVERY 1287
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drug for medical use in 1977. This compound was introduced
into the US market in 1995, and it was approved in the United
Kingdom in 1997. Since then, it has become used more and
more frequently in many countries.
Market introduction of tramadol produced a significant
change in clinical practice, and it represented an evolutionary
advance in the therapeutic treatment of pain. Until its discov-
ery, two large groups of analgesics were available: the NSAIDs
that inhibit cyclooxygenase and the opioids that act on opioid
receptors. The involvement of the monoaminergic system in
endogenous nociceptive modulation was discovered long ago,
yet with the exception of antidepressants, a drug capable of
taking advantage of this system to induce analgesia was not
available. In addition to its main activities, other effects of
tramadol were later discovered, although it is still not clear
precisely how these are related to its analgesic activity.
Tramadol is now a widely used analgesic that has under-
gone many clinical trials and it is included in nearly all clinical
guidelines for the treatment of moderate to severe pain.
Currently, tramadol is positioned on the second step of the
WHO analgesic scale and there are several galenic formula-
tions. Although tramadol is an opioid and these drugs have a
potent addictive capacity over prolonged treatments, this
drug offers a reasonable safety profile. Obviously, tramadol is
not free from some of the typical undesirable effects of
opioids but it is still a more manageable drug when used in
primary care. This compound is associated with more inci-
dences of nausea than other drugs like oxycodone and mor-
phine [92,93], yet it produces less respiratory depression than
morphine, oxycodone, or pethidine [8,9496]. Moreover, tra-
madol does not produce the classic signs of opioid withdrawal
[75], with nausea considered to be the most frequent undesir-
able side effect. Due to its monoaminergic mechanism, parti-
cularly its pro-serotonergic action, the effects of combining
tramadol with antidepressants that inhibit serotonin reuptake
are likely to be complex, and serotonergic syndrome may
possibly be induced.
Tramadol is effective in relieving different types of chronic
pain, including neuropathic pain [85,88,89]. For a long time,
opioids have provided limited benefits in the treatment of
neuropathic pain, yet tramadol has a similar mechanism of
action to tricyclic antidepressants (NA and 5HT reuptake inhi-
bitor), drugs commonly used for this particular type of pain.
Therefore, the combined opioid/monoaminergicapproach
may represent a new strategy to relieve chronic neuropathic
pain, which should be investigated more thoroughly through
controlled trials to study the efficacy and tolerability of trama-
dol in this situation.
Indeed, the discovery of this joint activity of tramadol
opens new avenues for the development of future innova-
tive analgesics. While there is currently much research
aimed at avoiding opioid tolerance and addiction, the
relationship between opioids and the monoaminergic sys-
tem has received little attention to date despite the poten-
tial to benefit from such analgesic interactions. The mild
potential for tramadol abuse might be due to its relatively
low affinity for µ-opioid receptors and its joint effect on
the monoaminergic system. Moreover, the monoaminergic
system, particularly the noradrenergic system, is closely
related to opioid withdrawal syndrome [97]. Hence, it
seems to be possible to obtain effective and efficient
analgesia through a combined and complementary
mechanism of action, with tramadol providing information
to further drive research in this field.
According to the International Association for the Study
of Pain, pain is defined as an unpleasant sensory and emo-
tional experience associated with actual or potential tissue
damage, or described in terms of such damage.Therefore,
pain is not just a sensation but it is also an emotion. This
definition must be taken into account when future analge-
sics are developed. Tramadol has already highlighted that
benefits may be gained by taking advantage of synergies
between the opioid and monoaminergic systems. Both sys-
tems contribute to analgesia but the monoaminergic system
may also help improve the emotional response to pain
[28,98]. Hence, tramadol has been shown as we mentioned
antidepressant-like properties [8,41,43]. It should be noted
that antidepressants are combined with opiates in the treat-
ment of many types of pain. Therefore, pain research must
follow the avenues opened by tramadol and evaluate the
possibility of treating the sensory and emotional aspects of
pain together.
Tramadol is closely related in structure to the antidepres-
sant venlafaxine, which also inhibits NA and 5HT reuptake
[99]. Although few reports have evaluated tramadolseffi-
cacy in animal models of depression [100]somepredictive
tests have demonstrated antidepressant-like activity [8,94].
Thus, if tramadol shares antidepressant and analgesic activ-
ities, it might represent an alternative therapy for popula-
tions of chronic pain patients suffering depression.
However, to date tramadol has not been launched as an
antidepressant, and further preclinical and clinical research
must be performed along these lines.
Finally and what is most important today regarding the
discovery of tramadol is that it has placed the spotlight on
monoamines as possible new analgesic targets, particularly in
combination with opioid mechanisms. Moreover, given the
role of monoamines in regulating emotions, this might open
the door to developing future analgesics capable of treating
the different dimensions of pain.
Acknowledgments
This manuscript was language edited by Mark Sefton of BiomedRed S.L.
Madrid, Spain.
Funding
All the authors are supported by CIBERSAM (Centro de Investigación
Biomedica en Red de Salud Mental (G18), Spains Ministerio de
Economía y Competitividad (SAF2015-68647-R), the Instituto de
Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA),
Junta de Andalucía, Consejería de Economía y Conocimiento (CTS-510,
CTS-7748), the Fundación Española de Dolor (PI2015-FED-007) and the
University of Cádiz (PR2016-075).
1288 L. BRAVO ET AL.
Downloaded by [Universidad De Cadiz] at 01:25 10 November 2017
Declaration of Interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
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EXPERT OPINION ON DRUG DISCOVERY 1291
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... is an opioid drug that, unlike classic opioids, also modulates the monoaminergic system by inhibiting noradrenergic and serotoninergic reuptake (Bravo et al. 2017). For this reason, tramadol is considered an atypical opioid. ...
... For this reason, tramadol is considered an atypical opioid. These special pharmacological characteristics have made tramadol one of the most prescribed analgesic drugs to treat moderate to severe pain (Bravo et al. 2017). The main metabolite of tramadol, O-desmethyl tramadol (M1), acts on the µ-opioid receptor as a weak agonist and acts on serotonergic and noradrenergic nociception (Miotto et al. 2017). ...
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Individually, sleep deprivation and sub-chronic tramadol exposure have been reported to impair visual processes, however the underlying mechanisms of their combined effects are largely unknown. Thus, this study investigated the role of tramadol hydrochloride on lipid-immune activities in the ocular tissue and visual cortex of sleep-deprived periadolescent rats. Sixty female periadolescent Wistar rats were either sleep-deprived with or without tramadol treatment. Following euthanasia, brain and whole eye tissues were collected for biochemical and immunohistochemical assays. Results revealed impaired ocular tissue lipid profile following sleep deprivation (SD). Sleep deprivation also induced lipid peroxidation; upregulated apolipoprotein E (ApoE), and nuclear factor kappa B (NF-κB) 1 levels in the ocular tissue. Furthermore, chronic SD exposure triggered gliosis with marked increase in astrocyte and microglia counts in the visual cortex. However, treatment with tramadol restored ocular tissue lipid function markers, downregulated ocular tissue NF-κB levels, as well as ameliorated sleep deprivation-induced gliosis in the visual cortex. Taken together, this study demonstrates the role of tramadol in improving inflammatory processes and lipid homeostasis in the visual system by modulating ocular tissue ApoE and NF-κB signalling, and attenuating gliosis in the visual cortex of sleep-deprived rats.
... As a pain reducing agent is needed that does not influence the course of the infection, COXinhibitors were excluded in this study right from the beginning. Therefore, tramadol was chosen as pain reducing agent: Due to different receptor affinities, tramadol does not bear the same potential to interfere with inflammation and pain compared to the full (morphine) or partial µ-opioid (buprenorphine) receptor agonists which also contributes to less side effects for tramadol 17,29,30 . Finally, tramadol has also been used extensively in animal models for pain so that doses administered via the subcutaneous route assure rapid analgesia lasting for several hours 31,32 which was important for the neutropenic thigh infection model studied here. ...
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The neutropenic thigh infection model is one of the standard models in pharmacokinetic/ pharmacodynamic (PK/PD) characterization of novel antibacterials which are urgently needed due to the rise of antimicrobial resistance. The model enables to investigate PK/PD parameters crucial for translation of animal results towards humans. However, the neutropenic thigh infection model can result in moderate to severe discomfort of the animals, especially when high inocula are used. Tramadol has been proven to reduce pain effectively. This study investigates if tramadol influences the bacterial burden in the primary organ, the thighs, and organs affected by secondary seeding. Therefore, several strains of the ESKAPE pathogens, namely S. aureus, P. aeruginosa, K. pneumoniae, E. coli, A. baumannii and E. faecalis were examined. It was shown that tramadol did not influence the bacterial burden neither in thighs nor in organs affected by secondary seeding for the strains of E. faecalis, S. aureus, P. aeruginosa, K. pneumoniae and E.coli tested here, whereas secondary seeding seemed to be affected by tramadol for the tested strain of A. baumannii. Consequently, it was demonstrated that tramadol is an option to reduce discomfort in the untreated group for the strains of five out of the six tested ESKAPE pathogens and, thereby, contributes to the refinement of one of the standard PK/PD models.
... Currently, in clinical practice, the most commonly used opioid analgesics are pure µ-receptor agonists, such as sufentanil and norepinephrine, 5-hydroxytryptamine reuptake inhibitors, such as tramadol, and k-receptor agonists and μreceptor antagonists, such as dezocine. These three types of opioid analgesics have different mechanisms of action (Bravo et al., 2017;Ye et al., 2021). At present, the effects of daytime variations on the pharmaceutical effects of these three opioids remain unclear. ...
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Article
The role of daytime variation in the comprehensive pharmaceutical effects of commonly used opioid analgesics in clinical setting remains unclear. This study aimed to explore the differences in daytime variation among elective surgery patients who were scheduled to receive preemptive analgesia with equivalent doses of sufentanil, dezocine, and tramadol in the morning and afternoon. The analgesic effect was assessed by changes in the pressure pain threshold before and after intravenous administration of sufentanil, dezocine, and tramadol. Respiratory effects were evaluated using pulse oximetry, electrical impedance tomography, and arterial blood gas analysis. Other side effects, including nausea, sedation, and dizziness, were also recorded, and blood concentration was measured. The results showed that the analgesic effects of sufentanil, dezocine, and tramadol were significantly better in the morning than in afternoon. In the afternoon, sufentanil had a stronger sedative effect, whereas dezocine had a stronger inhibitory respiratory effect. The incidence of nausea was higher in the morning with tramadol. Additionally, significant differences in different side effects were observed among three opioids. Our results suggest that the clinical use of these three opioids necessitates the formulation of individualized treatment plans, accounting for different administration times, to achieve maximum analgesic effect with minimal side effects.
... Opioid category drugs, for example, morphine is a very potent analgesic drug, however, is used less because of its adverse effects of addiction, dependency, and constipation (Gholami et al., 2015, Subedi et al., 2019. Also, tramadol is used for the treatment of pain and has a potent analgesic effect (Bravo et al., 2017). The analgesic in uence of tramadol is ten times lesser than morphine nonetheless is preferred to be safe in comparison to morphine. ...
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The involvement of the opioidergic system on anxiolytic and anti-nociceptive responses induced by cholestasis was investigated in cholestatic and addicted mice. Elevated plus-maze and tail-flick devices were used to assess anxiety and pain levels, respectively. The data indicated that induction of cholestasis and injection of opioid drugs including morphine and tramadol enhanced %OAT and %OAE but naloxone reduced %OAT and %OAE in the sham-operated and bile duct ligated (BDL) mice. Induction of cholestasis and addiction to morphine and tramadol prolonged tail-flick latency which was reversed by naloxone. Co-administration of morphine and tramadol enhanced anxiolytic and analgesic effects in the sham-operated and BDL mice. It seems (i) cholestasis and addiction affect anxiety and pain behaviors, (ii) µ-opioid receptors play a key role in anxiolytic and analgesic effects induced by cholestasis, (iii) co-treatment with morphine and tramadol augmented the effectiveness of them for induction of anxiolytic and analgesic effects both in cholestatic and addicted mice.
... Second, tramadol has local anesthetic properties, possibly by blocking Kþ channels [17,25]. Finally, tramadol's monoaminergic actions include agonism at peripheral a2 receptors, suggesting a role in nerve blocks similar to that of clonidine [26,27]. ...
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Background Postoperative pain can have immediate and long-term consequences, including poor outcomes and prolonged hospitalization. It can also lead to chronic pain if not treated. Wound site infiltration with local anesthetic agents provides desirable analgesia for postoperative pain relief. The purpose of this study was to compare the analgesic effectiveness of local wound infiltration with a mixture of bupivacaine and tramadol (BT) versus bupivacaine alone (BA) for postoperative analgesia. Method A prospective cohort study design was employed on 120 patients who underwent elective lower abdominal surgery under general or spinal anesthesia and were selected by using a systematic random sampling technique. Patients were divided into two groups based on the anesthetist in charge of postoperative pain management. Patients who received BT at the end of surgery are called BT groups, and patients who received BA are called BA groups (control). Result The median (interquartile range) of pain severity score was significantly lower in the BT group as compared to the BA group with a p-value of 0.001. And, the median time to first analgesic request in the BT group was significantly longer as compared to patients in the BA group, with a p-value of 0.001. Conclusion Local wound infiltration with BT decreases the postoperative pain score, total analgesic consumption, and has a prolonged time to first analgesia request as compared to BA. Therefore, we recommend using a local wound infiltration with BT to be effective for postoperative analgesia in patients undergoing elective lower abdominal surgery under general or spinal anesthesia.
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Objective To review the current state of pharmaceutical treatment recommendations for the management of osteoarthritis. Method A narrative review was drafted to describe treatment guidelines, mechanism of action, pharmacokinetics, and toxicity for nine classes of pharmaceuticals: 1) oral nonsteroidal anti-inflammatory drugs (NSAIDs), 2) topical NSAIDs, 3) COX-2 inhibitors, 4) duloxetine, 5) intra-articular corticosteroids, 6) intra-articular hyaluronic acid, 7) acetaminophen (paracetamol), 8) tramadol, and 9) capsaicin. Results In general, oral and topical NSAIDs, including COX-2 inhibitors, are strongly recommended first-line treatments for osteoarthritis due to their ability to improve pain and function but are associated with increased risks in patients with certain comorbidities (e.g., heightened cardiovascular risks). Intra-articular corticosteroid injections are generally recommended for osteoarthritis management and have relatively minor adverse effects. Other treatments, such as capsaicin, tramadol, and acetaminophen, are more controversial, and many updated guidelines offer differing recommendations. Conclusion The pharmaceutical management of osteoarthritis is a constantly evolving field. Promising treatments are emerging, and medicines that were once considered conventional (e.g., acetaminophen) are gradually becoming less acceptable based on concerns with efficacy and safety. Clinicians need to consider the latest evidence and recommendations to make an informed decision with their patients about how to optimize treatment plans for patients with knee, hip, polyarticular, or hand osteoarthritis.
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Neuropathy is one among the known disorders corresponding diabetes. The biochemical mechanisms of this devastating neurodegenerative disorder of diabetic neuropathy (DN) have not yet clearly understood. DN is loss of function nerves beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. It leads to distressing and expensive clinical complications such as foot ulceration, leg amputation, and neuropathic pain. Despite countless promising therapeutic research efforts, effective drugs are still lacking for the treatment of DN. Therefore, current review emphasizes on complications and therapeutic strategies which could be effective in DN. Various search engines like Google Scholar, PubMed, SpringerLink, Medline and Science direct were used for accessing different articles of worldwide journals to harness the information of previous work done with our relevance. Databases like PDB and NCBI were used to understand molecular information of proteins and DNA in DN. In present review, we discussed causes, mechanisms that lead to promotion of DN and possible therapies of DN. The information provided in this review provide research gap to investigators to understand molecular mechanisms underlying DN and to attempt natural substances as possible effective therapy. Current review discusses significant research gaps for making an attempt to investigate a successful natural product and its molecular target for DN. We also accentuate the use of natural product instead of a synthetic drug for treatment of DN.
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The involvement of the opioidergic system on anxiolytic and antinociceptive responses induced by cholestasis was investigated in cholestatic and addicted mice. Elevated plus-maze and tail-flick devices were used to assess anxiety and pain levels, respectively. The data indicated that induction of cholestasis and injection of opioid drugs including morphine and tramadol enhanced %OAT and %OAE but naloxone reduced %OAT and %OAE in the sham-operated and bile duct ligation (BDL) mice. Induction of cholestasis and addiction to morphine and tramadol prolonged tail-flick latency, which was reversed by naloxone. Coadministration of morphine and tramadol enhanced anxiolytic and analgesic effects in the sham-operated and BDL mice. It seems (a) cholestasis and addiction affect anxiety and pain behaviors, (b) μ-opioid receptors play a key role in anxiolytic and analgesic effects induced by cholestasis, and (c) cotreatment with morphine and tramadol augmented the effectiveness of them for induction of anxiolytic and analgesic effects both in cholestatic and addicted mice.
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IntroductionThe utilization and misuse of prescription and controlled medications are expanding globally. However, the kind of substance abused may contrast from one country to another, but few drugs expand their horizons due to misused capabilities, expansion of the darknet, and increase in the Internet Connecting World. One of them is tramadol, a widely misused drug worldwide, which enforcement agencies recently noticed. In treating moderate to severe pain, a racemic combination of tramadol is employed. The non-medical utilization of narcotic drugs, i.e., tramadol, is a quick arising general medical issue prompting expanding calls for planning alterations to existing policies, reconnaissance, research, and wellbeing advancement measures. Tramadol addicts typically have a history of substance usage, and studies show that the number of tramadol abusers is increasing, particularly in some Middle Eastern Nations.Method This review article finds the trends of analytical methods toward identification in pharmaceutical preparation and toxicological samples such as hair, urine, blood, and saliva. In the last 20 years, various analytical tools such as UV–visible spectroscopy, HPTLC, HPLC, LC–MS, GC, GC–MS, NMR, Fluorescence Spectroscopy, Capillary Electrophoresis, Electrochemical sensors have been used for the identification of drugs in pharmaceutical preparation and toxicological samples. Forensic Scientists can only rely on quick and easy methods to perform.Result and discussionThis evaluation aims to give forensic scientists, pharmaceutical companies, and toxicologists the best solution for identifying tramadol acquired in the chemistry and toxicological divisions of various laboratories.
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Regional anaesthesia (spinal anaesthesia) is widely used as a safe anaesthetic technique for both elective and emergency operations. Shivering is known to be a frequent complication, reported in 40 to 70% of patients undergoing surgery under regional anaesthesia. Various methods are available for the control of shivering during anaesthesia. Here we have compared Tramadol, a synthetic opioid with Pethidine, the gold standard drug for the treatment of shivering, in the quest for more safe and efficacious drug. Forty patients of ASA 1 and 2 status posted for elective surgical procedures under neuraxial block were selected. Group P (n=20) received Pethidine 0.5mg/kg IV and group T (n=20) received tramadol 1.0 mg/kg IV. Both the drugs were found to be effective in reducing shivering. Nineteen patients in the Group T had control of shivering at end of 5 minutes but there were no patients who had control of shivering Group P (p < 0.0001) which is statistically significant. Tramadol reduced the occurrence of postanesthetic shivering more significantly than pethidine.
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Aims and objectives: The aim of this study was to evaluate the efficacy of intravenous tramadol in control of shivering in obstetric patients under spinal anaesthesia and to determine the minimal dose of tramadol that is effective. Patients and methods: This was a prospective, randomised, double-blind, cross-sectional study of 144 pregnant women at term who had an indication for caesarean section. The patients were randomly allocated into three groups at the occurrence of shivering. Group T0.5 received 0.5 mg/kg of tramadol (n = 47), Group T0.25 received 0.25 mg/kg tramadol (n = 47) and Group TNS received 0.05 ml/kg of normal saline (n = 46). Statistical analysis was performed using Statistical Package for Social Sciences version 17. Results: There were no significant differences between the groups with regard to age, weight and duration of surgery. There was a statistically significant difference in the time of cessation of shivering after the treatment for various groups (P = 0.000). A total of 80.1% responded to the treatment in Group T0.5, while for Group T0.25 and TNS, a total of 44.7% and 4.3%, respectively, responded. There were statistically significant differences in the recurrence rates of shivering among the groups (P = 0.000). Conclusion: Tramadol is effective in control of shivering during spinal anaesthesia in obstetric patients. Tramadol 0.5 mg/kg controlled shivering better than 0.25 mg/kg. Therefore, 0.5 mg/kg of tramadol can be used to manage shivering following caesarean section under spinal anaesthesia.
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The noradrenergic system is crucial for several activities in the body, including the modulation of pain. As the major producer of noradrenaline in the central nervous system, the Locus Coeruleus (LC) is a nucleus that has been studied in several pain conditions, mostly due to its strategic location. Indeed, apart from a well-known descending LC-spinal pathway that is important for pain control, an ascending pathway passing through this nucleus may be responsible for the noradrenergic inputs to higher centers of the pain processing, such as the limbic system and frontal cortices. Thus, the noradrenergic system appears to modulate different components of the pain experience and accordingly, its manipulation has distinct behavioral outcomes. The main goal of this review is to bring together the data available regarding the noradrenergic system in relation to pain, particularly focusing on the ascending and descending LC projections in different conditions. How such findings influence our understanding of these conditions is also discussed.
Article
Previous findings suggest that neuropathic pain induces characteristic changes in the noradrenergic system that may modify the sensorial and affective dimensions of pain. We raise the hypothesis that different drugs that manipulate the noradrenergic system can modify specific domains of pain. In the chronic constriction injury (CCI) model of neuropathic pain, the sensorial (von Frey and acetone tests) and the affective (place escape/avoidance paradigm) domains of pain were evaluated in rats 1 and 2 weeks after administering the noradrenergic neurotoxin [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] (DSP4, 50 mg/kg). In other animals, we evaluated the effect of enhancing noradrenergic tone in the 2 weeks after injury by administering the antidepressant desipramine (10 mg/kg/day, delivered by osmotic minipumps) during this period, a noradrenaline reuptake inhibitor. Moreover, the phosphorylation of the extracellular signal regulated kinases (p-ERK) in the anterior cingulate cortex (ACC) was also assessed. The ACC receives direct inputs from the main noradrenergic nucleus, the locus coeruleus, and ERK activation has been related with the expression of pain-related negative affect. These studies revealed that DSP4 almost depleted noradrenergic axons in the ACC and halved noradrenergic neurons in the locus coeruleus along with a decrease in the affective dimension and an increased of p-ERK in the ACC. However, it did not modify sensorial pain perception. By contrast, desipramine reduced pain hypersensitivity, while completely impeding the reduction of the affective pain dimension and without modifying the amount of p-ERK. Together results suggest that the noradrenergic system may regulate the sensorial and affective sphere of neuropathic pain independently.
Article
Tramadol hydrochloride, a synthetic opioid, acts via a multiple mechanism of action. Tramadol can potentially change the behavioral phenomena. The present study evaluates the effect of tramadol after single or multiple dose/s on the spatial memory of rat using object recognition task (ORT). Tramadol, 20 mg/kg, was injected intraperitoneally (i.p) as a single dose or once a day for 21 successive days considered as acute or chronic treatment respectively. After treatment, animals underwent two trials in the ORT. In the first trial (T1), animals encountered with two identical objects for exploration in a five-minute period. After 1 h, in the T2 trial, the animals were exposed to a familiar and a nonfamiliar object. The exploration times and frequency of the exploration for any objects were recorded. The results showed that tramadol decreased the exploration times for the nonfamiliar object in the T2 trial when administered either as a single dose (P<0.001) or as the multiple dose (P<0.05) compared to the respective control groups. Both acute and chronic tramadol administration eliminated the different frequency of exploration between the familiar and nonfamiliar objects. Our findings revealed that tramadol impaired memory when administered acutely or chronically. Single dose administration of tramadol showed more destructive effect than multiple doses of tramadol on the memory. The observed data can be explained by the inhibitory effects of tramadol on the wide range of neurotransmitters and receptors including muscarinic, N-methyl D-aspartate, AMPA as well as some second messenger like cAMP and cGMP or its stimulatory effect on the opioid, gama amino butyric acid, dopamine or serotonin in the brain.
Article
Tramadol, a weak opioid mu-receptor agonist, may have a favourable potency and side effect profile for intravenous patient-controlled analgesia (PCA). In a prospective, double-blind, randomized study involving 54 patients, tramadol was compared with oxycodone in PCA after maxillofacial surgery. All the patients were given diclofenac sodium 1 mg kg-1 intramuscularly and dexamethasone 8 mg twice a day. Post-operatively patients received tramadol or oxycodone by a PCA apparatus (lockout 5 min, tramadol 0.3 mg kg-1 bolus, oxycodone 0.03 mg kg-1 bolus). During the immediate recovery period, opioid was administered i.v. in a double-blind fashion, either tramadol 10 mg or oxycodone 1 mg increments until the pain control was judged to be satisfactory by the patient. Pain was assessed at rest and during activity (mouth opening) before and after loading, at 2 h after commencing the PCA, as well as at 21.00 and at 09.00 hours on the following morning. Side effects were recorded. The potency ratio of tramadol to oxycodone was found to be approximately 8:1. There was no significant difference between the groups in the VAS scores for pain. No respiratory depression was identified. Tramadol was found to provide adequate analgesia after maxillofacial surgery without risk of respiratory depression. However, the incidence of nausea was slightly greater in the tramadol group than in the oxycodone group (44% vs. 28%, NS).
Article
The transient receptor potential vanilloid 1 (TRPV1) and the transient receptor potential ankyrin 1 (TRPA1), which are expressed in sensory neurons, are polymodal nonselective cation channels that sense noxious stimuli. Recent reports showed that these channels play important roles in inflammatory, neuropathic, or cancer pain, suggesting that they may serve as attractive analgesic pharmacological targets. Tramadol is an effective analgesic that is widely used in clinical practice. Reportedly, tramadol and its metabolite (M1) bind to μ-opioid receptors and/or inhibit reuptake of monoamines in the central nervous system, resulting in the activation of the descending inhibitory system. However, the fundamental mechanisms of tramadol in pain control remain unclear. TRPV1 and TRPA1 may be targets of tramadol; however, they have not been studied extensively. We examined whether and how tramadol and M1 act on human embryonic kidney 293 (HEK293) cells expressing human TRPV1 (hTRPV1) or hTRPA1 by using a Ca imaging assay and whole-cell patch-clamp recording. Tramadol and M1 (0.01-10 μM) alone did not increase in intracellular Ca concentration ([Ca]i) in HEK293 cells expressing hTRPV1 or hTRPA1 compared with capsaicin (a TRPV1 agonist) or the allyl isothiocyanate (AITC, a TRPA1 agonist), respectively. Furthermore, in HEK293 cells expressing hTRPV1, pretreatment with tramadol or M1 for 5 minutes did not change the increase in [Ca]i induced by capsaicin. Conversely, pretreatment with tramadol (0.1-10 μM) and M1 (1-10 μM) significantly suppressed the AITC-induced [Ca]i increases in HEK293 cells expressing hTRPA1. In addition, the patch-clamp study showed that pretreatment with tramadol and M1 (10 μM) decreased the inward currents induced by AITC. These data indicate that tramadol and M1 selectively inhibit the function of hTRPA1, but not that of hTRPV1, and that hTRPA1 may play a role in the analgesic effects of these compounds.
Article
Although non-steroidal anti-inflammatory drugs and acetaminophen have no proven efficacy against neuropathic pain, they are frequently prescribed for neuropathic pain patients. We examined whether the combination of opioids (tramadol and morphine) with indomethacin or acetaminophen produce favorable effects on neuropathic pain and compared the efficacy for neuropathic pain with that for inflammatory pain. The carrageenan model was used as the inflammatory pain model while the tibial neuroma transposition (TNT) model was used as the neuropathic pain model. The tibial nerve is transected in the TNT model, with the tibial nerve stump then transpositioned to the lateral aspect of the hindlimb. Neuropathic pain (mechanical allodynia and neuroma pain) is observed after TNT injury. Drugs were administered orally. In the carrageenan model, all drugs produced anti-allodynic effects and all drug combinations, but not tramadol + indomethacin combination, produced synergistic anti-allodynic effects. In the TNT model, tramadol and morphine, but not acetaminophen and indomethacin, produced anti-neuropathic pain effects. In the combination, with the exception of morphine + acetaminophen combination, both acetaminophen and indomethacin reduced the 50 % effective dose (ED50) of tramadol and morphine as compared with the ED50s for the single drug study in the TNT model. The ED50s of tramadol and morphine in the carrageenan combination test were not statistically significantly different from the ED50s in the TNT model combination study. The combination of opioids with indomethacin or acetaminophen produced a synergistic analgesic effect both in inflammatory and neuropathic pain with some exceptions. The efficacy of these combinations for neuropathic pain was not different from that for inflammatory pain.
Article
Depression and anxiety are common comorbidities of neuropathic pain(NP). Pharmacological preclinical studies on NP have given abundant information on the effects of drugs on reflex measures of stimulus-evoked pain. However, few preclinical studies focus on relief of comorbidities evoked by NP. Tramadol is a weak μ-opioid receptor agonist which also inhibits the re-uptake of serotonin and norepinephrine. In this study, we investigated the effects of tramadol on nociceptive reflex, depression-associated and anxiety-related behaviors in a NP model in rats. We used chronic constriction injury(CCI) of the sciatic nerve as an animal model of neuropathic pain. We performed electronic von Frey tests to measure mechanical sensitivity, elevated plus maze tests(EPM) to record anxiety-related behaviors and forced swimming tests(FST) to evaluate depression-associated behaviors. In the electronic von Frey test, CCI rats showed a decrease of 82% of the paw withdrawal threshold(PWT) compared to sham (p<0.001). Tramadol increased the PWT by 336% in CCI rats (p<0.001) and by 16% in sham (p<0.05). On the EPM, CCI rats spent 45% less time than sham on the open arms of the maze (p<0.05). Tramadol increased the time spent on the open arms of CCI rats by 67% (p<0.05) and had no significant effect on sham. During the FST, CCI rats showed 28% longer immobility than sham (p<0.01). Tramadol reduced the immobility time in CCI rats by 22% (p<0.001), while having no effect on sham. Tramadol reversed the changes in mechanical sensitivity as well as anxiety-related and depression-associated behaviors that are caused by injury of the sciatic nerve with only minor effects in the absence of injury. These data suggest that tramadol relieves chronic pain and its indirect consequences and comorbidities, and that this study also is a model for pharmacological studies seeking to investigate the effect of drugs on the major disabling symptoms of NP.