Tramadol Hydrochloride: Pharmacokinetics, Pharmacodynamics, Adverse Side Effects, Co-Administration of Drugs and New Drug Delivery Systems
Tramadol Hydrochloride: Pharmacokinetics, Pharmacodynamics, Adverse Side Effects, Co-Administration of Drugs and New Drug Delivery Systems
Tramadol Hydrochloride: Pharmacokinetics, Pharmacodynamics, Adverse Side Effects, Co-Administration of Drugs and New Drug Delivery Systems
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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.
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) 234–238 235
cation antiporter in the transport of tramadol from blood to brain overdose, or when co-administered with antidepressants or even
[21]. at the recommended dose in patients with history of epilepsy
TrHC was also suggested as an effective medication for pain also [17,26,27].
in diabetic painful neuropathy. Lavasani et al. studied the Some authors hypothesized the mechanism of TrHC-induced
pharmacokinetic changes of the drug after in vivo intraperitoneal seizures. These are likely due to the inhibition of gamma amino-
administration in diabetic rat model showing that they accumulate butyric acid (GABA) pathways, specifically by exerting inhibition of
higher concentrations of TrHC and its metabolites M1 and M2, GABA receptors [14].
comparing with the control group. Since diabetes is a condition As previously reported, nausea and emesis are side effects
known to change the pattern of drug distribution in the body, and commonly observed in analgesic opioids. At clinical plasma
any reduction in fat tissue, which usually happens during diabetic concentrations TrHC potently suppresses the human NET, whereas
state, may produce a reduction in volume of lipophilic drugs it has only a slight effect on the human 5-HT3A receptor. This effect
distribution, such as TrHC. Considering the lipophilicity of TrHC is compatible with a possible mechanism for TrHC-induced early
and the consequent distribution of fat tissue in diabetic individual, emesis involving the serotonergic system. Human 5-HT3 receptors
this phenomenon may also explain its higher plasma concentra- are involved in the mediation of emesis. Serotonin transporters
tion in diabetic rats. Furthermore, the higher production level of (SERT) are membrane proteins responsible for the rapid reuptake,
a1-acid glycoprotein, an acute-phase serum protein which is into presynaptic nerve terminals, of released 5-HT. This transport-
prominent in TrHC protein binding, in diabetic condition may er is not only located in 5-HT nerve endings, but also in platelets
further cause in decrease of volume of distribution and increase in and enterochromaffin cells. Thus, SERT is important both for the
plasma concentration of TrHC in diabetic rats [1]. 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-
3. Adverse side effects sants), may lead to enhanced plasma and synaptic 5-HT
concentrations therefore stimulate 5-HT3 receptors. The serotonin
Opioids are usually prescribed for chronic pain but their use is syndrome may result from the additional 5-HT increase lead by
frequently limited by their side effects. Whilst the long-term use of TrHC, 5-HT3 receptors may be indirectly activated by TrHC because
opiates in patients with chronic pain and also for cancer pain gets the drug increases 5-HT concentrations [28].
worse, evidence, based on a paucity of literature proving efficacy Additionally, TrHC use is associated with dependence, albeit it
for long-term use, suggests that opiates fail to fulfill any of the key is generally considered safe at low dosage. Dopamine release in
outcomes in terms of adequate pain relief, improved quality of life various regions of CNS is responsible for this phenomenon.
or improvements in functional capacity [22,23]. Although para- Agonists of m-opioid receptors, such as TrHC, stimulate the release
doxical, chronic opiate usage may lead to a pro-nociceptive state of dopamine as well as inhibit GABA release, which in turn inhibits
inducing neuroplastic changes, that may enhance hyperalgesia and dopamine release [14].
give rise to tolerance [2,23]. Adverse events are reported particularly from its abuse which
Explanation for the hyperalgesia, as a consequence of the can result in intoxication. In this case, adverse effects can be apnea
neuro-adaptations to chronic opioid exposure, include the up- and even death following co-ingestion of benzodiazepines,
regulation of cholecystokinin in the rostral ventromedial medulla barbiturates and/or drugs with serotonergic effects. There are
causing the activation of descending pain facilitation, increased also few cases of respiratory depression described in the literature
expression of dynorphin (endogenous ligand for some opioid [14].
receptors), paradoxical activation of adenylate cyclase increasing Lota et al. reported a case of deep hyponatremia following a
the levels of cAMP, paradoxical activation of several protein TrHC overdose. Opioids are known to affect renal excretion of
kinases (including PKC), and subsequent paradoxical activation of water and sodium by means of various mechanisms with the result
NMDA receptors system (which co-localize with opioid receptors) of stimulation of ADH release and subsequent anti-diuretic effect
appear to play an important role in hyperalgesia [24]. Also, the [29].
increased level of dynorphin, resulting from ongoing stimulation of The effects of TrHC have been investigated in several animal
m-opioid receptors, enhances the release of excitatory neuro- species such as mice, rats, rabbits, dogs, and also in horses as well
transmitters, such as glutamate, aspartate and substance P from as in humans. Indeed, the drug is also used in veterinary medicine
primary afferents. In addition, the paradoxical activation of [30]. Casella et al. found a significant increase of the maximum
adenilate cyclase also increases cAMP in locus ceruleus that degree and slope of equine platelet aggregation after addition of
regulates the activity of the autonomic nervous system, and TrHC in feeding condition. This could be explained by the fact that
appears to increase the intrinsic firing rate of their noradrenergic the inhibition of NE system blocks the release of prostacyclin and
neurons. These changes probably contribute to the withdrawal nitric oxide, both of which are known to be potent inhibitors of
symptoms mediated by an increased activity of the noradrenergic platelet aggregation [3]. Cox et al. instead, reported short-term
system [2]. agitation, tremors, tachycardia and muscle twitching that occurred
The most commonly reported adverse events upon therapeutic after rapid administration of TrHC in horses [30].
use of TrHC include dizziness, followed by vomiting, nausea, Bloor et al. overhauled the effects of TrHC during pregnancy,
somnolence and constipation, often in sequence. However, TrHC labor, delivery and lactation. TrHC is classified as a category C drug
can be considered a preferable choice for pain relief with respect to by the Australian Therapeutic Goods Administration Evaluation
non-steroidal anti-inflammatory drugs (NSAIDs) since their long- Committee, i.e. drugs which have caused or may be suspected of
term use may lead to renal function deterioration and cause causing harmful effects (that may be reversible) on the human
gastrointestinal impairments, and with respect to other opioid fetus or neonate, without causing malformations. It would seem
compounds for its low addiction rate and favorable safety profile that the most cautious approach is to avoid its use around the time
[25]. Nevertheless, TrHC has been reported as an adjuvant to of conception and during the period of organogenesis, specifically
NSAIDs therapy in patient with osteoarthritis [2]. in the first trimester. There is currently no clear evidence of fetal or
The inhibition of 5-HT and NE reuptake may account for neonatal harm, but increased fetal loss associated with typical
triggering two significant adverse events: seizures and serotonin maternal doses taken during early pregnancy has been reported. If
syndrome, particularly likely in patients receiving the drug in chronic maternal TrHC use has occurred throughout pregnancy,
M. Vazzana et al. / Biomedicine & Pharmacotherapy 70 (2015) 234–238 237
there is a risk of a neonatal withdrawal syndrome. The drug offers controlled drug release and targeting, due to different available
limited analgesic effects during labor. During early lactation and route of administration, small sizes, enhancement of therapeutic
breastfeeding, it appears unlikely to cause harm to healthy term effect, reduction of toxicity and side effects, improvement of
infants. Unfortunately, there are no available data reporting this pharmaceuticals performance and biodistribution/bioavailability,
statement [6]. 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
4. Co-administration of drugs
strategies of delivery for TrHC.
Subramanian et al. have introduced chitosan-graft-poly
In order to optimize pain control and minimize adverse effects,
(2-hydroxyethyl methacrylate-co-itaconic acid) as a drug carrier
opioids are combined with non-opioid analgesic drugs that act via
for oral delivery of TrHC with controlled release [38]. Chen et al.
different mechanisms and provide an additive or synergistic effect
have developed a composite montmorillonite-based as a potential
[27]. For instance, clonidine and other a2-adrenergic agonists are
controlled TrHC release system, by intercalation of TrHC into
commonly used for this purpose. Clonidine potentiates the anti-
montmorillonite by conventional cation exchange [35]. This
nociceptive effects of TrHC, morphine and other opioids. It is
composite can be considered as a potential controlled drug release
possible that 5-HT3, 5-HT2A and 5-HT1A receptors, as well as
system as it showed efficient controlled release in both simulated
glutamatergic and neurokinin-1 receptors are involved in TrHC
gastric fluid and simulated intestinal fluid [35]. Aamir et al. have
anti-nociception [9].
produced controlled-released formulations based on micropar-
Combination of TrHC and acetaminophen provides rapid and
ticles for oral delivery of TrHC that showed sustained drug release
long-lasting analgesic effects resulting from the synergistic activity
within therapeutic levels up to 24 h [39]. Malana et al. have
of these two drugs in chronic low back pain treatment [31].
worked on chemically cross linked Ter-polymeric hydrogels (Ter-
In another study, Aydin et al. showed that, when TrHC and
polymers of methacrylate, vinyl acetate and acrylic acid cross
gabapentin are used in combination, in the acute neuropathic pain
linked with ethylene glycol dimethacrylate) with sustained
models in mice, do not generate additive and synergistic effect at
release indicating that these co-polymeric hydrogels have good
regular doses [32]. Modi et al. worked on the combination of TrHC
potential to be used as colon drug delivery device through oral
and amlodipine, a calcium channel blocker, and concluded that the
administration. [37]. Another strategy is the preparation of
interaction of the two drugs produces significant enhancement of
tramadol–HCL in spray-dried microspheres, but this systems
anti-nociceptive activity of TrHC [8]. Cialdai et al. reported that the
can be affected by the long drug recrystallization time, thus Patel
combination of dexketoprofen and tramadol, administered orally
et al. have been involved in the preparation of TrHC-spray dried
or intra-articularly, produced anti-nociceptive effect at lower
microspheres containing Eudragit1 RS and RL, which showed
doses than those necessary for each drug alone to induce
good physical and chemical properties [40]. Lalani et al. have
comparable effects in monosodium iodoacetate-induced osteoar-
prepared TrHC-loaded PLGA nanoparticles intended for brain
thritis in rats [33]. Subedi et al. evaluated the effects of intrathecal
targeting via ligand (transferrin and lactoferrin) conjugation,
TrHC combined with local anesthetics for post-operative analgesia
which have demonstrated sustained drug release, enhanced
following abdominal and perineal surgery. TrHC used as an adjunct
circulation time and higher pharmacological effect over a period
to bupivacaine for subarachnoid block for cesarean section,
of 24 h, also lactoferrin functionalized nanoparticles exhibited
showed a longer duration of analgesia with a reduced incidence
better anti-nociceptive effect as compared to transferrin function-
of shivering. Moreover, the authors reported drug safety also for
alized nanoparticles [41].
labor analgesia and for the pharmacokinetic profile in neonate
More recently, chitosan nanoparticles have been produced by
[34]. Pergolizzi et al. reported an example of fixed-dose combina-
ionic gelation method, for brain targeting aiming depression
tion analgesics based on TrHC and paracetamol, asserting that this
treatment [42]. Intrasal TrHC-loaded nanoparticles in situ gels
is the only where both the dual mechanism of action of TrHC and
were found to increase drug uptake [42]. Imprinted nanoparticles
the analgesic synergy between the two compounds have been
of different polymers have been produced by precipitation
demonstrated in both preclinical studies (mouse model) and
polymerization method, optimizing the processing parameters
human companion studies [27].
(i.e. molar ratio, volume of polymerization solvent, total mono-
mers/solvent volume ratio, heating or microwave irradiation for
5. Newly developed drug delivery systems polymerization) [43]. The nanoparticles revealed high selectivity,
binding capacity and ability to control TrHC release [43].
Alongside the traditional dosage forms, including capsules and We are facing a new generation of pharmaceutical formulations
tablets, new pharmaceutical technologies are known at present. to encapsulate, protect and deliver TrHC at the desired site aiming
The benefits resulting from the use of innovative drug delivery selective effects and avoiding undesirable side-effects which are a
systems are related to day-long duration and less plasma variation promising in TrHC therapy.
compared with conventional forms, leading to patient’s compli-
ance, therapeutic improvements and reduction of administration
frequency [25]. 6. Conclusions
Due to fast metabolism in human body, the biological activity of
TrHC can be relatively short. Therefore, repeated administrations TrHC is a drug acting on opiate and non-opiate receptors used
are required in order to maintain the effective drug plasma mainly to treat pain, anxiety, depression. It suffers liver
concentration. The consequence is an easiness of habit-forming as metabolization and renal excretion thus it has to be taken several
side effect [35]. times a day, which may lead to some side effects especially in those
Sustained and controlled release formulations are particularly suffering from kidney or liver failure. To avoid these side effects,
advantageous since they are able to prolong the effective new pharmaceutical strategies are needed. We are facing a new
therapeutic time by controlling drug blood concentration generation of pharmaceutical formulations to encapsulate, protect
[36]. To modulate drug release, the most commonly used methods and deliver TrHC at the desired site aiming at improving selective
is to include it in a matrix system [37]. In this regard, lipid-based actions and avoiding undesirable side-effects, which are is a
delivery systems are considered the most advantageous in terms of promising strategy for TrHC therapy.
238 M. Vazzana et al. / Biomedicine & Pharmacotherapy 70 (2015) 234–238