Biomedicine & Pharmacotherapy 70 (2015) 234–238

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Review

Tramadol hydrochloride: Pharmacokinetics, pharmacodynamics,

adverse side effects, co-administration of drugs and new drug delivery
systems
M. Vazzana a, T. Andreani b,c, J. Fangueiro d, C. Faggio a, C. Silva e, A. Santini f, M.L. Garcia g,h,
A.M. Silva b,c, E.B. Souto d,i,*
a
Department of Biological and Environmental Sciences, University of Messina, Viale Fernando Stagno d’ Alcontres, 31, 98166 S. Agata-Messina, Italy
b
Department of Biology and Environment, University of Trás-os Montes e Alto Douro, Quinta de Prados, P-5001-801, Vila Real, Portugal
c
Centre for Research and Technology of Agro-Environmental and Biological Sciences (CITAB, UTAD), Vila Real, Portugal
d
Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, Azinhaga de Santa Comba,
3000-548 Coimbra, Portugal
e
Center for Nanotechnology and Smart Materials, Rua Fernando Mesquita, 2785, 4760-034 Vila Nova de Famalicão, Portugal
f
Department of Pharmacy, University of Napoli ‘‘Federico II’’, Via D. Montesano 49, 80131 Napoli, Italy
g
Department of Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain
h
Institute of Nanoscience and Nanotechnology, University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain
i
Center for Neuroscience and Cell Biology & Institute for Biomedical Imaging and Life Sciences (CNC-IBILI), University of Coimbra, Pólo das Ciências da Saúde,
Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal

A R T I C L E I N F O A B S T R A C T

Article history: Tramadol hydrochloride (TrHC) is a synthetic analgesic drug exhibiting opioid and non-opioid
Received 10 January 2015 properties, acting mainly on the central nervous system. It has been mostly used to treat pain, although
Accepted 23 January 2015 its use to treat anxiety and depression has also been documented. These properties arise from the fact
that they inhibit serotonin (5-HT) reuptake augmenting 5-HT concentration on the synaptic cleft.
Keywords: Despite this, TrHC has also been described to have several side effects which are mainly due to its fast
Tramadol hydrochloride metabolization and excretion which in turn requires multiple doses per day. To surpass this limitation,
Solid lipid nanoparticles
new pharmaceutical formulations are being developed intending the protection, target and sustained
Polyacrylates
Drug delivery
delivery as well as a reduction on daily dose aiming a reduction on the side effects. In the present work
Pain relief we have revised the efficacy, safety, biological and adverse effects of TrHC, and the added value of
developing a novel drug delivery system for topical administration.
ß 2015 Elsevier Masson SAS. All rights reserved.

1. Introduction central nervous system (CNS). This drug is structurally related to

Tramadol hydrochloride (TrHC) is a synthetic analgesic drug
showing opioid and non-opioid properties, acting mainly on the
Abbreviations: 5-HT, serotonin; BBB, blood brain barrier; CNS, central nervous
system; FDA, Food and Drug Administration; GABA, gamma aminobutyric acid; M1,
O-desmethyltramadol; M2, N-desmethyltramadol; NA, noradrenaline; NE,
norepinephrine; NET, norepinephrine transporter; NMDA, N-methyl-D-aspartate;
NMDAR, N-methyl-D-aspartate receptor; NSAIDs, non-steroidal anti-inflammatory
drugs; P-gp, P-glicoprotein; SERT, serotonin (5-HT) transporters; TrHC, tramadol
hydrochloride.
* Corresponding author at: Department of Pharmaceutical Technology,
Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde,
Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal. Tel.: +351 239 488 400;
fax: +351 239 488 503.
E-mail address: ebsouto@ff.uc.pt (E.B. Souto).
codeine and morphine, but it is 6000-times less potent than
morphine and 10-times less potent than codeine [1–3]. It appeared
in the 1970s, but only approved by the Food and Drug Administra-
tion (FDA) in 1995 for the management, treatment and relief of
moderate to severe pain conditions [4–6]. The anti-nociceptive
effects are due to a double (opioid and non-opioid) mechanism of
action. In fact, TrHC acts on m-opioid and k-opioid receptors with
low affinity, exerting a weak agonist effect, and it affects monoamine
receptor systems by blocking norepinephrine (NE) and serotonin
(5-HT) reuptake, responsible for the inhibition of pain transmission
in the spinal cord [7,8]. TrHC is more advantageous than other
typical opioid agents for its unique pharmacological profile, since it
exhibits a lower incidence of side effects and abuse potential [8,9].
Table 1 summarizes the physicochemical properties of this drug.

http://dx.doi.org/10.1016/j.biopha.2015.01.022
0753-3322/ß 2015 Elsevier Masson SAS. All rights reserved.
 M. Vazzana et al. / Biomedicine & Pharmacotherapy 70 (2015) 234–238
Table 1
Technical details of tramadol hydrochloride.
Iupac name (1RS,2RS)-2-[(dimethylamino)methyl]-1-
(3-methoxyphenyl)cyclohexanol
hydrochloride (1:1)
Formula C16H26ClNO2 (Tramadol Hydrochloride);
C16H25NO2 (Tramadol)
Average molecular 299.84 g/mol (Tramadol Hydrochloride);
weight 263.4 g/mol (Tramadol, base)
Chemical class Phenylpropylamines
pKa 9.41
Solubility Water soluble
Category Narcotic analgesic opioid agonist for the
treatment of moderate to severe pain
Melting point 180–181 8C (TH)
UV–vis absorbance 271 nm
Plasma half-life 6h
Toxicity LD50 = 350 mg/kg (orally in mice)
CAS no. 22204-88-2
2. Pharmacokinetics and pharmacodynamics
TrHC is available in a variety of pharmaceutical formulations for
various routes e.g. sub-cutaneous, intra-muscular, intra-venous,
sub-lingual, and oral drug delivery. TrHC is rapidly and almost
completely absorbed after oral administration. The mean peak
plasma concentration occurs after 2 h and its bioavailability is
approximately 70% as a result of the first-pass metabolism in the
liver. About 20% of the drug is bound to plasma proteins and the
mean half-life is ca. 6 h [1,4,6]. TrHC is extensively metabolized in
the liver via cytochrome isoenzymes P450 2D6, and P450 2B6 and
P450 3A4, to O-desmethyltramadol (M1) and N-desmethyltrama-
dol (M2) respectively, being the main phase-1 metabolites. These
are further metabolized to three secondary metabolites, namely
N,N-didesmethyltramadol, N,N,O-tridesmethyltramadol and N,O-
desmethyltramadol. All metabolites are finally conjugated with
glucuronic acid and sulfate before excretion in urine [1,5,10].
The route of elimination almost totally involves the kidneys.
Approximately 30% of the dose is excreted in the urine as
unchanged drug, while 60% of the dose is excreted as metabolites.
The remaining drug is eliminated in the feces, therefore biliary
excretion is negligible [1,4,5].
TrHC exists as a racemic mixture with important differences in
binding, activity and targets associated with the two enantiomers
[3,11]. The (+) enantiomer has higher affinity to opioid receptors
and preferentially inhibits 5-HT uptake and enhances 5-HT release,
whereas the ( ) enantiomer inhibits NE reuptake. The synergistic
action of the two enantiomers is responsible for the analgesic effect
of TrHC [12,13]. Specifically, M1 metabolite is considered the most
pharmacologically active, being up to 6 times more potent than the
parent drug in producing analgesia, and 200 times more potent in
m-opioid binding [2,7,14].
TrHC exhibits anti-nociception in a range of preclinical pain
models, and the involvement of opioid, noradrenergic and
serotonergic mechanisms has been demonstrated. In addition to
well-recognized systemic actions, several studies reported anti-
nociception following spinal and local peripheral administration.
TrHC has reported to interact with additional cellular targets
(e.g. Na+ channels, N-methyl-D-aspartate (NMDA) receptors, and
transient potential vanilloid-1 receptors), contributing to anti-
nociceptive effects in particular when higher concentrations are
achieved from the local administration. Sawynok et al. confirmed
that local peripheral administration produces anti-nociception in
formalin test mice [13]. This local action also involves peripheral
adenosine A1 receptors, present on sensory neurons, widely
distributed throughout pain signaling pathways. Peripheral anti-
nociception following A1 receptor activation involves inhibition of
235
adenylate cyclase and cAMP production, interactions with the
nitric oxide/cyclic guanosine monophosphate signaling pathway,
and interactions with phospholipase C systems [13].
Given its monoaminergic properties, antidepressant and
anxiolytic-like effects have also been attributed to tramadol. The
drug has inhibitory effect via a2-adrenoceptors on Locus
Coeruleus, which regulates pain and anxiety, where the neuronal
activity is modified by opiate analgesics, antidepressant and
anxiolytics. The antidepressant effect is also modulated by 5-HT
system and, in particular, by 5-HT1A receptors [15]. This antide-
pressant activity has been confirmed in vivo [16].
TrHC was reported to decrease the binding of frontocortical
b-adrenoceptors, 5-HT2A receptors and a2-adrenoceptors, and to
increase the binding of a1-adrenoceptors and dopamine receptors,
therefore inducing changes in the central nervous system (CNS).
The drug has been applied for several psychiatric and anxiety-like
disorders [15,16]. The anti-depressant effect of TrHC has been
attributed to the noradrenergic (a2-adrenoceptors), dopaminergic
(D1/D2 receptors) and imidazoline (I1/I2 receptors) systems
[16]. In addition, anti-shivering and analgesic effects were also
attributed to TrHC, without undergoing severe sedation in post-
operative period [6,17].
Tramadol may also be clinically applied for the management of
premature ejaculation, the most common sexual disorder, affect-
ing 20–30% of adult men. Various studies evaluated and confirmed
the drug efficacy, safety, and tolerability when using small dosages
(25 and 50 mg) with minimal adverse side-effects [4,18]. This
effect has been attributed to the inhibition of neuronal reuptake of
5-HT and NE, enhancement of 5-HT efflux, anti-nociceptive effects
and inhibition of spinal somatosensory evoked potentials (a series
of waves that reflect sequential activation of neural structures
along the somatosensory pathways). As a result, peripheral
sensory nerves will depict some anesthetic-type effect [4].
Shah et al. demonstrated that TrHC inhibits KCl-induced
contractility of isolated human myometrium by stimulating b1-
adrenoceptors mediating tissue relaxation, at very high doses. It is
well-known TrHC inhibits NE reuptake by inhibiting NE transport-
er (NET). This carrier is present in various tissues of the body,
including the uterus. Therefore, the inhibition of NET in the
isolated myometrium may cause the increased levels of NE at the
neuroeffector junction, leading to stimulation of b1-adrenocep-
tors, resulting in inhibition of tissue contractility [19].
A pharmacokinetic study was carried out in male Sprague-
Dawley rats to evaluate the possible involvement of P-glycoprotein
(P-gp) in the brain distribution of TrHC [20], since the drug has
some features of being a P-gp substrate, i.e. the presence of planar
aromatic domains and tertiary amino groups. P-gp is a 170-kDa
energy-dependent integral membrane protein, product of multi-
drug resistance gene; it is also one of the most important members
of the ABC transporter superfamily consisting of several transpor-
ters with apparently different biological functions, having promi-
nent membrane transport activities in different tissues/cell types
(e.g. epithelial cells of gastrointestinal tract, canalicular cells of the
liver, placenta, kidney, and the blood brain barrier).
The highly extensive tissue localization of the drug, as well as
different influx/efflux roles and, more importantly, a wide
substrate specificity of different chemical and pharmacological
classes, lead to consider this transporter of strategic relevance for
pharmacokinetic studies. From some results, it is obvious that
TrHC unrestrictedly penetrates the brain parenchyma. Sheikho-
leslami et al. considering their results and those of previous
studies concluded that it seemed that the brain accumulation of
TrHC is not affected by P-gp inhibition implying that there may
be some other transport mechanisms involved in blood brain
barrier transport of the drug [20]. Recently, in vitro and in vivo
studies indicate the involvement of a proton-coupled organic
236 M. Vazzana et al. / Biomedicine & Pharmacotherapy 70 (2015) 234–238
cation antiporter in the transport of tramadol from blood to brain
[21].
TrHC was also suggested as an effective medication for pain also
in diabetic painful neuropathy. Lavasani et al. studied the
pharmacokinetic changes of the drug after in vivo intraperitoneal
administration in diabetic rat model showing that they accumulate
higher concentrations of TrHC and its metabolites M1 and M2,
comparing with the control group. Since diabetes is a condition
known to change the pattern of drug distribution in the body, and
any reduction in fat tissue, which usually happens during diabetic
state, may produce a reduction in volume of lipophilic drugs
distribution, such as TrHC. Considering the lipophilicity of TrHC
and the consequent distribution of fat tissue in diabetic individual,
this phenomenon may also explain its higher plasma concentra-
tion in diabetic rats. Furthermore, the higher production level of
a1-acid glycoprotein, an acute-phase serum protein which is
prominent in TrHC protein binding, in diabetic condition may
further cause in decrease of volume of distribution and increase in
plasma concentration of TrHC in diabetic rats [1].
3. Adverse side effects
Opioids are usually prescribed for chronic pain but their use is
frequently limited by their side effects. Whilst the long-term use of
opiates in patients with chronic pain and also for cancer pain gets
worse, evidence, based on a paucity of literature proving efficacy
for long-term use, suggests that opiates fail to fulfill any of the key
outcomes in terms of adequate pain relief, improved quality of life
or improvements in functional capacity [22,23]. Although para-
doxical, chronic opiate usage may lead to a pro-nociceptive state
inducing neuroplastic changes, that may enhance hyperalgesia and
give rise to tolerance [2,23].
Explanation for the hyperalgesia, as a consequence of the
neuro-adaptations to chronic opioid exposure, include the up-
regulation of cholecystokinin in the rostral ventromedial medulla
causing the activation of descending pain facilitation, increased
expression of dynorphin (endogenous ligand for some opioid
receptors), paradoxical activation of adenylate cyclase increasing
the levels of cAMP, paradoxical activation of several protein
kinases (including PKC), and subsequent paradoxical activation of
NMDA receptors system (which co-localize with opioid receptors)
appear to play an important role in hyperalgesia [24]. Also, the
increased level of dynorphin, resulting from ongoing stimulation of
m-opioid receptors, enhances the release of excitatory neuro-
transmitters, such as glutamate, aspartate and substance P from
primary afferents. In addition, the paradoxical activation of
adenilate cyclase also increases cAMP in locus ceruleus that
regulates the activity of the autonomic nervous system, and
appears to increase the intrinsic firing rate of their noradrenergic
neurons. These changes probably contribute to the withdrawal
symptoms mediated by an increased activity of the noradrenergic
system [2].
The most commonly reported adverse events upon therapeutic
use of TrHC include dizziness, followed by vomiting, nausea,
somnolence and constipation, often in sequence. However, TrHC
can be considered a preferable choice for pain relief with respect to
non-steroidal anti-inflammatory drugs (NSAIDs) since their long-
term use may lead to renal function deterioration and cause
gastrointestinal impairments, and with respect to other opioid
compounds for its low addiction rate and favorable safety profile
[25]. Nevertheless, TrHC has been reported as an adjuvant to
NSAIDs therapy in patient with osteoarthritis [2].
The inhibition of 5-HT and NE reuptake may account for
triggering two significant adverse events: seizures and serotonin
syndrome, particularly likely in patients receiving the drug in
overdose, or when co-administered with antidepressants or even
at the recommended dose in patients with history of epilepsy
[17,26,27].
Some authors hypothesized the mechanism of TrHC-induced
seizures. These are likely due to the inhibition of gamma amino-
butyric acid (GABA) pathways, specifically by exerting inhibition of
GABA receptors [14].
As previously reported, nausea and emesis are side effects
commonly observed in analgesic opioids. At clinical plasma
concentrations TrHC potently suppresses the human NET, whereas
it has only a slight effect on the human 5-HT3A receptor. This effect
is compatible with a possible mechanism for TrHC-induced early
emesis involving the serotonergic system. Human 5-HT3 receptors
are involved in the mediation of emesis. Serotonin transporters
(SERT) are membrane proteins responsible for the rapid reuptake,
into presynaptic nerve terminals, of released 5-HT. This transport-
er is not only located in 5-HT nerve endings, but also in platelets
and enterochromaffin cells. Thus, SERT is important both for the
modulation of the 5-HT concentration in the synaptic clefts and for
the control of 5-HT plasma concentration. Drugs that inhibit SERT,
such as the selective 5-HT reuptake inhibitors (e.g. antidepres-
sants), may lead to enhanced plasma and synaptic 5-HT
concentrations therefore stimulate 5-HT3 receptors. The serotonin
syndrome may result from the additional 5-HT increase lead by
TrHC, 5-HT3 receptors may be indirectly activated by TrHC because
the drug increases 5-HT concentrations [28].
Additionally, TrHC use is associated with dependence, albeit it
is generally considered safe at low dosage. Dopamine release in
various regions of CNS is responsible for this phenomenon.
Agonists of m-opioid receptors, such as TrHC, stimulate the release
of dopamine as well as inhibit GABA release, which in turn inhibits
dopamine release [14].
Adverse events are reported particularly from its abuse which
can result in intoxication. In this case, adverse effects can be apnea
and even death following co-ingestion of benzodiazepines,
barbiturates and/or drugs with serotonergic effects. There are
also few cases of respiratory depression described in the literature
[14].
Lota et al. reported a case of deep hyponatremia following a
TrHC overdose. Opioids are known to affect renal excretion of
water and sodium by means of various mechanisms with the result
of stimulation of ADH release and subsequent anti-diuretic effect
[29].
The effects of TrHC have been investigated in several animal
species such as mice, rats, rabbits, dogs, and also in horses as well
as in humans. Indeed, the drug is also used in veterinary medicine
[30]. Casella et al. found a significant increase of the maximum
degree and slope of equine platelet aggregation after addition of
TrHC in feeding condition. This could be explained by the fact that
the inhibition of NE system blocks the release of prostacyclin and
nitric oxide, both of which are known to be potent inhibitors of
platelet aggregation [3]. Cox et al. instead, reported short-term
agitation, tremors, tachycardia and muscle twitching that occurred
after rapid administration of TrHC in horses [30].
Bloor et al. overhauled the effects of TrHC during pregnancy,
labor, delivery and lactation. TrHC is classified as a category C drug
by the Australian Therapeutic Goods Administration Evaluation
Committee, i.e. drugs which have caused or may be suspected of
causing harmful effects (that may be reversible) on the human
fetus or neonate, without causing malformations. It would seem
that the most cautious approach is to avoid its use around the time
of conception and during the period of organogenesis, specifically
in the first trimester. There is currently no clear evidence of fetal or
neonatal harm, but increased fetal loss associated with typical
maternal doses taken during early pregnancy has been reported. If
chronic maternal TrHC use has occurred throughout pregnancy,
 M. Vazzana et al. / Biomedicine & Pharmacotherapy 70 (2015) 234–238
there is a risk of a neonatal withdrawal syndrome. The drug offers
limited analgesic effects during labor. During early lactation and
breastfeeding, it appears unlikely to cause harm to healthy term
infants. Unfortunately, there are no available data reporting this
statement [6].
4. Co-administration of drugs
In order to optimize pain control and minimize adverse effects,
opioids are combined with non-opioid analgesic drugs that act via
different mechanisms and provide an additive or synergistic effect
[27]. For instance, clonidine and other a2-adrenergic agonists are
commonly used for this purpose. Clonidine potentiates the anti-
nociceptive effects of TrHC, morphine and other opioids. It is
possible that 5-HT3, 5-HT2A and 5-HT1A receptors, as well as
glutamatergic and neurokinin-1 receptors are involved in TrHC
anti-nociception [9].
Combination of TrHC and acetaminophen provides rapid and
long-lasting analgesic effects resulting from the synergistic activity
of these two drugs in chronic low back pain treatment [31].
In another study, Aydin et al. showed that, when TrHC and
gabapentin are used in combination, in the acute neuropathic pain
models in mice, do not generate additive and synergistic effect at
regular doses [32]. Modi et al. worked on the combination of TrHC
and amlodipine, a calcium channel blocker, and concluded that the
interaction of the two drugs produces significant enhancement of
anti-nociceptive activity of TrHC [8]. Cialdai et al. reported that the
combination of dexketoprofen and tramadol, administered orally
or intra-articularly, produced anti-nociceptive effect at lower
doses than those necessary for each drug alone to induce
comparable effects in monosodium iodoacetate-induced osteoar-
thritis in rats [33]. Subedi et al. evaluated the effects of intrathecal
TrHC combined with local anesthetics for post-operative analgesia
following abdominal and perineal surgery. TrHC used as an adjunct
to bupivacaine for subarachnoid block for cesarean section,
showed a longer duration of analgesia with a reduced incidence
of shivering. Moreover, the authors reported drug safety also for
labor analgesia and for the pharmacokinetic profile in neonate
[34]. Pergolizzi et al. reported an example of fixed-dose combina-
tion analgesics based on TrHC and paracetamol, asserting that this
is the only where both the dual mechanism of action of TrHC and
the analgesic synergy between the two compounds have been
demonstrated in both preclinical studies (mouse model) and
human companion studies [27].
5. Newly developed drug delivery systems
Alongside the traditional dosage forms, including capsules and
tablets, new pharmaceutical technologies are known at present.
The benefits resulting from the use of innovative drug delivery
systems are related to day-long duration and less plasma variation
compared with conventional forms, leading to patient’s compli-
ance, therapeutic improvements and reduction of administration
frequency [25].
Due to fast metabolism in human body, the biological activity of
TrHC can be relatively short. Therefore, repeated administrations
are required in order to maintain the effective drug plasma
concentration. The consequence is an easiness of habit-forming as
side effect [35].
Sustained and controlled release formulations are particularly
advantageous since they are able to prolong the effective
therapeutic time by controlling drug blood concentration
[36]. To modulate drug release, the most commonly used methods
is to include it in a matrix system [37]. In this regard, lipid-based
delivery systems are considered the most advantageous in terms of
237
controlled drug release and targeting, due to different available
route of administration, small sizes, enhancement of therapeutic
effect, reduction of toxicity and side effects, improvement of
pharmaceuticals performance and biodistribution/bioavailability,
and last but not least patient compliance. Nevertheless, formula-
tion of TrHC in lipid-based delivery systems is totally unknown in
scientific literature. What it is possible to report are other
strategies of delivery for TrHC.
Subramanian et al. have introduced chitosan-graft-poly
(2-hydroxyethyl methacrylate-co-itaconic acid) as a drug carrier
for oral delivery of TrHC with controlled release [38]. Chen et al.
have developed a composite montmorillonite-based as a potential
controlled TrHC release system, by intercalation of TrHC into
montmorillonite by conventional cation exchange [35]. This
composite can be considered as a potential controlled drug release
system as it showed efficient controlled release in both simulated
gastric fluid and simulated intestinal fluid [35]. Aamir et al. have
produced controlled-released formulations based on micropar-
ticles for oral delivery of TrHC that showed sustained drug release
within therapeutic levels up to 24 h [39]. Malana et al. have
worked on chemically cross linked Ter-polymeric hydrogels (Ter-
polymers of methacrylate, vinyl acetate and acrylic acid cross
linked with ethylene glycol dimethacrylate) with sustained
release indicating that these co-polymeric hydrogels have good
potential to be used as colon drug delivery device through oral
administration. [37]. Another strategy is the preparation of
tramadol–HCL in spray-dried microspheres, but this systems
can be affected by the long drug recrystallization time, thus Patel
et al. have been involved in the preparation of TrHC-spray dried
microspheres containing Eudragit1 RS and RL, which showed
good physical and chemical properties [40]. Lalani et al. have
prepared TrHC-loaded PLGA nanoparticles intended for brain
targeting via ligand (transferrin and lactoferrin) conjugation,
which have demonstrated sustained drug release, enhanced
circulation time and higher pharmacological effect over a period
of 24 h, also lactoferrin functionalized nanoparticles exhibited
better anti-nociceptive effect as compared to transferrin function-
alized nanoparticles [41].
More recently, chitosan nanoparticles have been produced by
ionic gelation method, for brain targeting aiming depression
treatment [42]. Intrasal TrHC-loaded nanoparticles in situ gels
were found to increase drug uptake [42]. Imprinted nanoparticles
of different polymers have been produced by precipitation
polymerization method, optimizing the processing parameters
(i.e. molar ratio, volume of polymerization solvent, total mono-
mers/solvent volume ratio, heating or microwave irradiation for
polymerization) [43]. The nanoparticles revealed high selectivity,
binding capacity and ability to control TrHC release [43].
We are facing a new generation of pharmaceutical formulations
to encapsulate, protect and deliver TrHC at the desired site aiming
selective effects and avoiding undesirable side-effects which are a
promising in TrHC therapy.
6. Conclusions
TrHC is a drug acting on opiate and non-opiate receptors used
mainly to treat pain, anxiety, depression. It suffers liver
metabolization and renal excretion thus it has to be taken several
times a day, which may lead to some side effects especially in those
suffering from kidney or liver failure. To avoid these side effects,
new pharmaceutical strategies are needed. We are facing a new
generation of pharmaceutical formulations to encapsulate, protect
and deliver TrHC at the desired site aiming at improving selective
actions and avoiding undesirable side-effects, which are is a
promising strategy for TrHC therapy.
238 M. Vazzana et al. / Biomedicine & Pharmacotherapy 70 (2015) 234–238
Acknowledgements
Ms. Tatiana Andreani and Ms. Joana Fangueiro wish to
acknowledge Fundação para a Ciência e Tecnologia do Ministério
da Ciência e Tecnologia (FCT, Portugal) under the references SFRH/
BD/60640/2009 and SFRH/BD/80335/2011, respectively. FCT and
European Funds (FEDER and COMPETE) are also acknowledged
under the research projects PTDC/SAU-FAR/113100/2009 and
FCOMP-01-0124-FEDER-022696 (PEst-C/AGR/UI4033/2011). The
Subprograma de Proyectos de Investigación Fundamental no
Orientada del Ministerio de Ciencia e Innovación, Spain, is also
acknowledged under the reference MAT2011-26994.
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