Tramadol hydrochloride (Ultram, Tramal) is a centrally acting synthetic
opioidAn opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
analgesicAn analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
used in treating moderate pain. The drug has a wide range of applications, including treatment for
restless legs syndromeRestless legs syndrome or Willis-Ekbom disease is a neurological disorder characterized by an irresistible urge to move one's body to stop uncomfortable or odd sensations. It most commonly affects the legs, but can affect the arms, torso, and even phantom limbs...
and
fibromyalgiaFibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
. It was developed by the
pharmaceutical companyThe pharmaceutical industry develops, produces, and markets drugs licensed for use as medications. Pharmaceutical companies are allowed to deal in generic and/or brand medications and medical devices...
Grünenthal GmbH Grünenthal GmbH is a German pharmaceutical company in Stolberg near Aachen, which holds the patent to Ultram , and its much stronger derivative Nucynta , both used as analgesics with Norepinephrine Reuptake Inhibition...
in the late 1970s.
Tramadol possesses weak
agonistAn agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
actions at the μ-opioid receptor, releases
serotoninSerotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
, and inhibits the reuptake of
norepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
.
While its action is not like that of other opioids, Tramadol is a synthetic analog of the
phenanthrenePhenanthrene is a polycyclic aromatic hydrocarbon composed of three fused benzene rings. The name phenanthrene is a composite of phenyl and anthracene. In its pure form, it is found in cigarette smoke and is a known irritant, photosensitizing skin to light...
alkaloid
codeineCodeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...
. Tramadol is converted to
O-desmethyltramadolO-Desmethyltramadol is an opioid analgesic and the main active metabolite of tramadol.-O-Desmethyltramadol is the most important metabolite of tramadol produced in the liver after tramadol is consumed...
, a significantly more potent μ-opioid agonist. Opioids are chemical compounds which act upon one or more of the human opiate receptors. The euphoria and respiratory depression of opioids are mainly caused by the μ
1 and μ
2 receptors; the addictive nature of tramadol, as well as other opioids, is due to these effects, but tramadol's serotonergic and noradrenergic effects may contribute to possible dependence as well. The opioid agonistic effect of tramadol and its major metabolite(s) are almost exclusively mediated by the substance's action at the μ-opioid receptor. This characteristic distinguishes tramadol from many other substances (including
morphineMorphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
) of the opioid drug class, which generally do not possess tramadol's degree of subtype selectivity.
Medical uses
Tramadol is used similarly to
codeineCodeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...
, to treat moderate to moderately severe pain. Tramadol is somewhat pharmacologically similar to
levorphanolLevorphanol is an opioid medication used to treat severe pain. It is the levorotatory stereoisomer of the synthetic morphinan and a pure opioid agonist, first described in Germany in 1948 as an orally active morphine-like analgesic...
(albeit with much lower μ-agonism), as both opioids are also NMDA-antagonists which also have
SNRISerotonin–norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...
activity (other such opioids to do the same are
dextropropoxypheneDextropropoxyphene, manufactured by Eli Lilly and Company, is an analgesic in the opioid category. It is intended to treat mild pain and has, in addition, anti-tussive and local anesthetic effects. It has been taken off the market in Europe and the US due to concerns of fatal overdoses and...
(Darvon) & M1-like molecule
tapentadolTapentadol is a centrally acting analgesic with a dual mode of action as an agonist at the μ-opioid receptor and as a norepinephrine reuptake inhibitor. While its analgesic actions have been compared to tramadol and oxycodone, its general potency is somewhere between tramadol and morphine in...
(Nucynta, a new synthetic atypical opioid made to mimic the agonistic properties of tramadol's metabolite, M1(O-Desmethyltramadol). Tramadol is also molecularly similar to
venlafaxineVenlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
(Effexor) and has similar SNRI effects, with antinociceptive effects also observed. It has been suggested that tramadol could be effective for alleviating symptoms of depression, anxiety, and phobias because of its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity. However, health professionals have not endorsed its use for these disorders, claiming it may be used as a unique treatment (only when other treatments failed), and must be used under the control of a psychiatrist.
In May 2009, the United States Food and Drug Administration issued a
Warning LetterThe United States Food and Drug Adminstration defines a Warning Letter as "...a correspondence that notifies regulated industry about violations that FDA has documented during its inspections or investigations...
to Johnson & Johnson, alleging that a promotional website commissioned by the manufacturer had "overstated the efficacy" of the drug, and "minimized the serious risks". The company which produced it, the German pharmaceutical company Grünenthal GmbH, were alleged to be guilty of "minimizing" the addictive nature and proposed efficacy of the drug, although it showed little abuse liability in preliminary tests. The 2010 Physicians Desk Reference contains several warnings from the manufacturer, which were not present in prior years. The warnings include more compelling language regarding the addictive potential of tramadol, the possibility of difficulty breathing while on the medication, a new list of more serious side effects, and a notice that tramadol is not to be used in place of opiate medications for addicts. Tramadol is also not to be used in efforts to wean addict patients from opiate drugs, nor to be used to manage long-term opiate addiction.
Availability and usage
Tramadol is classified as a central nervous system drug usually marketed as the hydrochloride salt (tramadol hydrochloride); the tartrate is seen on rare occasions, and rarely (in the US at least) tramadol is available for both
injectionAn injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
(intravenous and/or intramuscular) and oral administration. The most well known dosing unit is the 50 mg generic tablet made by several manufacturers. It is also commonly available in conjunction with APAP (
paracetamolParacetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
, acetaminophen) as Ultracet, in the form of a smaller dose of 37.5 mg tramadol and 325 mg of APAP. The solutions suitable for injection are used in patient-controlled analgesia pumps under some circumstances, either as the sole agent or along with another agent such as morphine.
Tramadol comes in many forms, including:
- capsules (regular and extended release)
- tablets (regular, extended release, chewable, low-residue and/or uncoated tablets that can be taken by the sublingual and buccal routes)
- suppositories
- effervescent tablets and powders
- ampules of sterile solution for SC, IM, and IV injection
- preservative-free solutions for injection by the various spinal routes (epidural, intrathecal, caudal, and others)
- powders for compounding
- liquids both with and without alcohol for oral and sub-lingual administration, available in regular phials and bottles, dropper bottles, bottles with a pump similar to those used with liquid soap and phials with droppers built into the cap
- tablets and capsules containing (acetaminophen/APAP), aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
and other agents.
Tramadol has been regularly used in the form of an ingredient in multi-agent topical gels, creams, and solutions for nerve pain, rectal foam, concentrated retention enema, and a skin plaster (transdermal patch) quite similar to those used with lidocaine.
Tramadol has a characteristic and unpleasant taste which is mildly bitter but much less so than morphine and codeine. Oral and sublingual drops and liquid preparations come with and without added flavoring. Also, 50mg water-soluble tramadol tablets has strawberry-flavouring, no matter which company manufactured it, to distinguish every, same-looking and same sized
MirtazapineMirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...
sublingual tablets, which has orange flavouring irrespectively the manufacturer. This different flavouring is considered to be a standard. Its relative effectiveness via transmucosal routes (i.e. sublingual, buccal, rectal) is similar to that of codeine, and, like codeine, it is also metabolized in the liver to stronger metabolites (see below).
The maximum dosage per day is 400 mg for oral use and 600 mg for parenteral use. Certain manufacturers or formulations have lower maximum doses. For example, Ultracet (37.5 mg/325 mg tramadol/APAP tablets) is capped at 8 tablets per day (300 mg/day) due to its acetaminophen content. Ultram ER is available in 100, 200, and 300 mg/day doses and is explicitly capped at 300 mg/day as well.
Patients taking SSRIs (Prozac, Zoloft, etc.), SNRIs (Effexor, etc.), TCAs, MAOIs, or other strong opioids (oxycodone, methadone, fentanyl, morphine), as well as the elderly (> 75 years old), pediatric (< 18 years old), and those with severely reduced renal (kidney) or hepatic (liver) function should consult their doctor regarding adjusted dosing or whether to use Tramadol at all.
Investigational uses
- diabetic neuropathy
Diabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. These conditions are thought to result from diabetic microvascular injury involving small blood vessels that supply nerves in addition to macrovascular conditions that can culminate in diabetic neuropathy...
- antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
- postherpetic neuralgia
Postherpetic neuralgia is a neuralgia caused by the varicella zoster virus. Typically, the neuralgia is confined to a dermatomic area of the skin and follows an outbreak of herpes zoster in that same dermatomic area...
- acute opioid withdrawal management
- antidepressant withdrawal
SSRI discontinuation syndrome, also known as SSRI withdrawal syndrome or SSRI cessation syndrome, is a syndrome that can occur following the interruption, dose reduction, or discontinuation of SSRI or SNRI antidepressant medications...
aid (proven to be effective, especially with withdrawal from its distant relative venlafaxineVenlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
(Effexor)).
- obsessive-compulsive disorder
Obsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...
- premature ejaculation
Premature ejaculation is a condition in which a man ejaculates earlier than he or his partner would like him to. Premature ejaculation is also known as rapid ejaculation, rapid climax, premature climax, or early ejaculation....
Adverse effects
Probability of adverse effects
| Effect |
Probability (%) |
| Any adverse effect |
71 |
| Drowsiness |
17 |
| Nausea |
17 |
| Dizziness |
15 |
| Constipation |
11 |
| Headache |
11 |
| Vomiting |
7 |
| Diarrhea |
6 |
| Dry Mouth |
5 |
| Fatigue |
5 |
| Indigestion |
5 |
| Seizure |
<1 |
The most commonly reported
adverse drug reactionAn adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s are nausea, vomiting, sweating, itching and
constipationConstipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
. Drowsiness is reported, although it is less of an issue than for non-synthetic opioids. Patients prescribed tramadol for general pain relief with or without other agents have reported withdrawal symptoms including uncontrollable nervous tremors, muscle contracture, and 'thrashing' in bed (similar to restless leg syndrome) if weaning off the medication happens too quickly. Anxiety, 'buzzing', 'electrical shock' and other sensations may also be present, similar to those noted in Effexor withdrawal. Respiratory depression, a common side-effect of most opioids, is not clinically significant in normal doses. By itself, it can decrease the
seizure thresholdAn epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
. When combined with SSRIs,
tricyclic antidepressantTricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s, or in patients with epilepsy, the seizure threshold is further decreased. Seizures have been reported in humans receiving excessive single oral doses (700 mg) or large intravenous doses (300 mg). However, there have been several rare cases of people having grand-mal seizures at doses as low as 100–400 mg orally. An Australian study found that of 97 confirmed new-onset seizures, eight were associated with tramadol, and that in the authors' First Seizure Clinic, "tramadol is the most frequently suspected cause of provoked seizures". There appears to be growing evidence that Tramadol use may have serious risks in some individuals and it is contra-indicated in patients with uncontrolled epilepsy (BNF 59). Seizures caused by tramadol are most often tonic-clonic seizures, more commonly known in the past as grand mal seizures. Also when taken with SSRIs, there is an increased risk of
serotonin toxicitySerotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
, which can be fatal. Fewer than 1% of users have a presumed incident seizure claim after their first tramadol prescription. Risk of seizure claim increases two- to six-fold among users adjusted for selected comorbidities and concomitant drugs. Risk of seizure is highest among those aged 25–54 years, those with more than four tramadol prescriptions, and those with a history of alcohol abuse, stroke, or head injury. Dosages of
warfarinWarfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
may need to be reduced for anticoagulated patients to avoid bleeding complications.
ConstipationConstipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
can be severe especially in the elderly requiring manual evacuation of the bowel. Furthermore, there are suggestions that chronic opioid administration may induce a state of
immune toleranceImmune tolerance or immunological tolerance is the process by which the immune system does not attack an antigen. It can be either 'natural' or 'self tolerance', in which the body does not mount an immune response to self antigens, or 'induced tolerance', in which tolerance to external antigens can...
, although tramadol, in contrast to typical opioids may enhance immune function. Some have also stressed the negative effects of opioids on cognitive functioning and personality.
Physical dependence and withdrawal
Tramadol is associated with the development of
physical dependencePhysical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
and a severe withdrawal syndrome. Tramadol causes typical opiate-like withdrawal symptoms as well as atypical withdrawal symptoms including seizures. The atypical withdrawal symptoms are probably related to tramadol's effect on serotonin and norepinephrine re-uptake. Symptoms may include those of
SSRI discontinuation syndromeSSRI discontinuation syndrome, also known as SSRI withdrawal syndrome or SSRI cessation syndrome, is a syndrome that can occur following the interruption, dose reduction, or discontinuation of SSRI or SNRI antidepressant medications...
, such as
anxietyAnxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
,
depressionMajor depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
, anguish, severe mood swings, aggressiveness, brain "zaps", electric-shock-like sensations throughout the body, paresthesias,
sweatingPerspiration is the production of a fluid consisting primarily of water as well as various dissolved solids , that is excreted by the sweat glands in the skin of mammals...
, palpitations,
restless legs syndromeRestless legs syndrome or Willis-Ekbom disease is a neurological disorder characterized by an irresistible urge to move one's body to stop uncomfortable or odd sensations. It most commonly affects the legs, but can affect the arms, torso, and even phantom limbs...
, sneezing,
insomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, vivid dreams or nightmares, nonsense and weird thoughts,
micropsiaMicropsia is a condition affecting human visual perception in which objects are perceived to be smaller than they actually are. Micropsia can be caused by either optical distortion of images in the eye or by a neurological dysfunction. The condition of micropsia can be caused by more factors than...
and/or
macropsiaMacropsia is a neurological condition affecting human visual perception, in which objects within an affected section of the visual field appear larger than normal, causing the subject to feel smaller. Macropsia, along with its opposite condition, micropsia, can be categorized under dysmetropsia...
, tremors, and headache among others. In most cases, tramadol withdrawal will set in 12–20 hours after the last dose, but this can vary. Tramadol withdrawal lasts longer than that of other opioids; seven days or more of acute withdrawal symptoms can occur as opposed to typically three or four days for other codeine analogues. It is recommended that patients physically dependent on pain killers take their medication regularly to prevent onset of withdrawal symptoms and this is particularly relevant to tramadol because of its SSRI and SNRI properties, and, when the time comes to discontinue their tramadol, to do so gradually over a period of time that will vary according to the individual patient and dose and length of time on the drug.
Psychological dependence and recreational use
Some controversy regarding the abuse potential of tramadol exists. Grünenthal has promoted it as an opioid with a lower risk of opioid dependence than that of traditional opioids, claiming little evidence of such dependence in clinical trials (which is true; Grünenthal never claimed it to be non-addictive). They offer the theory that, since the M1 metabolite is the principal agonist at μ-opioid receptors, the delayed agonist activity reduces abuse liability. The norepinephrine reuptake inhibitor effects may also play a role in reducing dependence.
It is apparent in community practice that dependence to this agent may occur after as little as three months of use at the maximum dose—generally depicted at 400 mg per day. However, this dependence liability is considered relatively low by health authorities, such that tramadol is classified as a Schedule 4 Prescription Only Medicine in Australia, and been rescheduled in Sweden rather than as a Schedule 8 Controlled Drug like
opioidAn opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
s. Similarly, tramadol is not currently scheduled by the U.S. DEA, unlike opioid analgesics. It is, however, scheduled in certain states. Nevertheless, the prescribing information for Ultram warns that tramadol "may induce psychological and physical dependence of the morphine-type". Using tramadol as recreational drug may preferred also because at this time, tramadol is the only opioid, that cannot be detected by the standard urinal drug-tests, due to its atypical binding to μ-opioid receptors. So, independently the contentration of tramadol in body-fluids or urine, quick-tests give false negative results to opioids.
Dependence on Tramadol has been reported to be a major social problem in the Gaza Strip. The Hamas government has attempted to cut off supplies of the drug, and in April 2010 burnt 2 million tablets which had been intercepted while being smuggled into the territory.
Because of the possibility of convulsions at high doses for some users, recreational use can be very dangerous. Tramadol can, however, via agonism of
μ opioid receptorThe μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...
s, produce effects similar to those of other opioids (codeine and other weak opioids), although not nearly as intense due to tramadol's much lower affinity for this receptor. Tramadol can cause a higher incidence of
nauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, dizziness, loss of appetite compared with opiates which could deter abuse to some extent. Tramadol can help alleviate withdrawal symptoms from opiates, and it is much easier to control the quantity of its usage than street drugs. It may also have large effect on sleeping patterns and high doses may cause insomnia. (Especially for those on methadone, both for maintenance and recreation. Though there is no scientific proof tramadol lessens effects or is a mixed agonist-antagonist, some people get the impression it is, while someone else might benefit being prescribed both for pain and breakthrough pain.)
Detection in biological fluids
Tramadol and
O-desmethyltramadol may be quantitated in blood, plasma or serum to monitor for abuse, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or a sudden death. Most commercial opiate immunoassay screening tests do not cross-react significantly with tramadol or its major metabolites, so chromatographic techniques must be used to detect and quantitate these substances. The concentrations of
O-desmethyltramadol in the blood or plasma of a person who has taken tramadol are generally 10–20% those of the parent drug.
Mechanism of action
Tramadol acts as a μ-opioid receptor
agonistAn agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
,
serotonin releasing agentA serotonin releasing agent is a type of drug which induces the release of serotonin from the pre-synaptic neuron into the synapse...
,
norepinephrine reuptake inhibitorA norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
,
NMDA receptorThe NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
antagonistA receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
,
5-HT2C receptorThe 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gq/G11 and mediates excitatory neurotransmission. HTR2C denotes the human gene encoding for the receptor, that in humans is located at the...
antagonist,
(α7)5The alpha-7 nicotinic receptor, also known as the α7 receptor, is a type of nicotinic acetylcholine receptor, consisting entirely of α7 subunits....
nicotinic acetylcholine receptorNicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
antagonist,
TRPV1The transient receptor potential cation channel subfamily V member 1 ', also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene...
receptor agonist, and
M1The muscarinic acetylcholine receptor M1, also known as the cholinergic receptor, muscarinic 1, is a muscarinic receptor.This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve, is common in exocrine glands and in the CNS.It is predominantly found bound to G proteins...
and
M3The muscarinic acetylcholine receptor M3, also known as the cholinergic receptor, muscarinic 3, is a muscarinic acetylcholine receptor. It is encoded by the human gene CHRM3....
muscarinic acetylcholine receptorMuscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
antagonist.
The analgesic action of tramadol has yet to be fully understood, but it is believed to work through modulation of serotonin and norepinephrine in addition to its mild agonism of the μ-opioid receptor. The contribution of non-opioid activity is demonstrated by the fact that the analgesic effect of tramadol is not fully antagonised by the μ-opioid receptor antagonist
naloxoneNaloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...
.
Tramadol is marketed as a
racemicIn chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
mixture of the (1
R,2
R)- and (1
S,2
S)-enantiomers with a weak affinity for the μ-opioid receptor (approximately 1/6000th that of
morphineMorphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
; Gutstein & Akil, 2006). The (1
R,2
R)-(+)-
enantiomerIn chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
is approximately four times more potent than the (1
S,2
S)-(–)-enantiomer in terms of μ-opioid receptor affinity and 5-HT reuptake, whereas the (1
S,2
S)-(–)-enantiomer is responsible for noradrenaline reuptake effects (Shipton, 2000). These actions appear to produce a synergistic analgesic effect, with (1
R,2
R)-(+)-tramadol exhibiting 10-fold higher analgesic activity than (1
S,2
S)-(–)-tramadol (Goeringer et al., 1997).
The
serotonergicSerotonergic or serotoninergic means "related to the neurotransmitter serotonin". A synapse is serotonergic if it uses serotonin as its neurotransmitter...
-modulating properties of tramadol give it the potential to interact with other serotonergic agents. There is an increased risk of
serotonin toxicitySerotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
when tramadol is taken in combination with serotonin reuptake inhibitors (e.g.,
SSRIs Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
), since these agents not only potentiate the effect of 5-HT but also inhibit tramadol metabolism. Tramadol is also thought to have some NMDA antagonistic effects, which has given it a potential application in neuropathic pain states.
Tramadol has inhibitory actions on the 5-HT
2C receptor. Antagonism of 5-HT
2C could be partially responsible for tramadol's reducing effect on depressive and obsessive-compulsive symptoms in patients with pain and co-morbid neurological illnesses. 5-HT
2C blockade may also account for its lowering of the
seizureAn epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
threshold, as 5-HT
2C knockout mice display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death. However, the reduction of seizure threshold could be attributed to tramadol's putative inhibition of GABA-A receptors at high doses.
The overall
analgesicAn analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
profile of tramadol supports intermediate pain, especially chronic states. It is slightly less effective for acute pain than
hydrocodoneHydrocodone or dihydrocodeinone is a semi-synthetic opioid derived from either of two naturally occurring opiates: codeine and thebaine. It is an orally active narcotic analgesic and antitussive...
, but more effective than
codeineCodeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...
. It has a dosage ceiling similar to
codeineCodeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...
, a risk of seizures when overdosed, and a relatively long half-life making its potential for misuse relatively low amongst intermediate strength analgesics.
Tramadol's primary active
metaboliteMetabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
,
O-desmethyltramadol, is a considerably more potent μ-opioid receptor agonist than tramadol itself, and is so much more so that tramadol can partially be thought of as a
prodrugA prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
to
O-desmethyltramadol. Similarly to tramadol,
O-desmethyltramadol has also been shown to be a
norepinephrine reuptake inhibitorA norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
, 5-HT
2C receptor antagonist, and M
1 and M
3 muscarinic acetylcholine receptor antagonist.
Characteristics
Structurally, tramadol closely resembles a stripped down version of codeine. Both codeine and tramadol share the 3-methyl ether group, and both compounds are metabolized along the same hepatic pathway and mechanism to the stronger opioid, phenol agonist analogs. For codeine, this is morphine, and for tramadol, it is the
O-desmethyltramadol.
Comparison with related substances
Structurally,
tapentadolTapentadol is a centrally acting analgesic with a dual mode of action as an agonist at the μ-opioid receptor and as a norepinephrine reuptake inhibitor. While its analgesic actions have been compared to tramadol and oxycodone, its general potency is somewhere between tramadol and morphine in...
is the closest chemical relative of tramadol in clinical use. Tapentadol is also an opioid, but unlike both tramadol and venlafaxine, tapentadol represents only one stereoisomer and is the weaker of the two, in terms of opioid effect. Both tramadol and venlafaxine are racemic mixtures. Structurally, tapentadol also differs from tramadol in being a phenol, and not an ether. Also, both tramadol and venlafaxine incorporate a cyclohexyl moiety, attached directly to the aromatic, while tapentadol lacks this feature. In reality, the closest structural chemical entity to tapentadol in clinical use is the over-the-counter drug phenylephrine. Both share a meta phenol, attached to a straight chain hydrocarbon. In both cases, the hydrocarbon terminates in an amine.
Synthesis and stereoisomerism
(1
R,2
R)-Tramadol (1
S,2
S)-Tramadol
(1
R,2
S)-Tramadol (1
S,2
R)-Tramadol
The chemical synthesis of tramadol is described in the literature. Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at the
cyclohexaneCyclohexane is a cycloalkane with the molecular formula C6H12. Cyclohexane is used as a nonpolar solvent for the chemical industry, and also as a raw material for the industrial production of adipic acid and caprolactam, both of which being intermediates used in the production of nylon...
ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist in
four different configurational forms:
- (1R,2R)-isomer
- (1S,2S)-isomer
- (1R,2S)-isomer
- (1S,2R)-isomer
The synthetic pathway leads to the racemate (1:1 mixture) of (1
R,2
R)-isomer and the (1
S,2
S)-isomer as the main products. Minor amounts of the racemic mixture of the (1
R,2
S)-isomer and the (1
S,2
R)-isomer are formed as well. The isolation of the (1
R,2
R)-isomer and the (1
S,2
S)-isomer from the
diastereomerDiastereomers are stereoisomers that are not enantiomers.Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more of the equivalent stereocenters and are not mirror images of each other.When two diastereoisomers differ from each other at...
ic minor racemate [(1
R,2
S)-isomer and (1
S,2
R)-isomer] is realized by the recrystallization of the
hydrochlorideIn chemistry, hydrochlorides are salts resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base . This is also known as muriate, derived from hydrochloric acid's other name: muriatic acid....
s.
The drug tramadol is a racemate of the hydrochlorides of the (1
R,2
R)-(+)- and the (1
S,2
S)-(–)-enantiomers.
The resolution of the racemate [(1
R,2
R)-(+)-isomer / (1
S,2
S)-(–)-isomer] was described employing (
R)-(–)- or (
S)-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects of the (1
R,2
R)- and (1
S,2
S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals and in humans.
Metabolism
Tramadol undergoes hepatic metabolism via the cytochrome P450
isozymeIsozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes...
CYP2B6Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. CYP2B6 is a member of the Cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.- Function :...
,
CYP2D6Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
and
CYP3A4Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
, being
O- and
N-demethylated to five different metabolites. Of these,
O-desmethyltramadolO-Desmethyltramadol is an opioid analgesic and the main active metabolite of tramadol.-O-Desmethyltramadol is the most important metabolite of tramadol produced in the liver after tramadol is consumed...
is the most significant since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of nine hours, compared with six hours for tramadol itself. As with codeine, in the 6% of the population that have increased CYP2D6 activity (increased metabolism), there is therefore an increased analgesic effect. Those with decreased CYP2D6 activity will experience less analgesia. Phase II hepatic metabolism renders the metabolites water-soluble, which are excreted by the kidneys. Thus, reduced doses may be used in renal and hepatic impairment.
Legal status
Tramadol (as the racemic,
cis-hydrochloride salt), is available as a generic in the U.S. from any number of different manufacturers, including Amneal, Caraco, Mylan, Cor Pharma, Mallinckrodt, Pur-Pak, APO, Teva, and many more. Typically, the generic tablets are sold in 50 mg tablets. Brand name formulations include Ultram ER, and the original Ultram from Ortho-McNeil (cross-licensed from
Grünenthal GmbH Grünenthal GmbH is a German pharmaceutical company in Stolberg near Aachen, which holds the patent to Ultram , and its much stronger derivative Nucynta , both used as analgesics with Norepinephrine Reuptake Inhibition...
). The extended-release formulation of tramadol—which, amongst other factors—was intended to be more abuse-deterrent than the instant release) allegedly possesses more abuse liability than the instant release formulation. The U.S.
Food and Drug AdministrationThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) approved tramadol in March 1995 and an extended-release (ER) formulation in September 2005. It is covered by U.S. patents nos. 6,254,887 and 7,074,430. The FDA lists the patents as scheduled for expiration on May 10, 2014. However, in August 2009, U.S. District Court for the District of Delaware ruled the patents invalid, which, if it survives appeal, would permit manufacture and distribution of generic equivalents of Ultram ER in the United States.
Sweden, as of May 2008, has chosen to classify tramadol as a
controlled substanceA controlled substance is generally a drug or chemical whose manufacture, possession, or use are regulated by a government. This may include illegal drugs and prescription medications ....
in the same way as
codeineCodeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...
and
dextropropoxypheneDextropropoxyphene, manufactured by Eli Lilly and Company, is an analgesic in the opioid category. It is intended to treat mild pain and has, in addition, anti-tussive and local anesthetic effects. It has been taken off the market in Europe and the US due to concerns of fatal overdoses and...
. This means that the substance is a scheduled drug. But unlike codeine and
dextropropoxypheneDextropropoxyphene, manufactured by Eli Lilly and Company, is an analgesic in the opioid category. It is intended to treat mild pain and has, in addition, anti-tussive and local anesthetic effects. It has been taken off the market in Europe and the US due to concerns of fatal overdoses and...
, a normal
prescriptionA prescription is a health-care program implemented by a physician or other medical practitioner in the form of instructions that govern the plan of care for an individual patient. Prescriptions may include orders to be performed by a patient, caretaker, nurse, pharmacist or other therapist....
can be used at this time. In
MexicoThe United Mexican States , commonly known as Mexico , is a federal constitutional republic in North America. It is bordered on the north by the United States; on the south and west by the Pacific Ocean; on the southeast by Guatemala, Belize, and the Caribbean Sea; and on the east by the Gulf of...
, combined with paracetamol and sold under the brand name Tramacet, it is widely available without a prescription. In most Asian countries such as the
PhilippinesThe Philippines , officially known as the Republic of the Philippines , is a country in Southeast Asia in the western Pacific Ocean. To its north across the Luzon Strait lies Taiwan. West across the South China Sea sits Vietnam...
, it is sold as a capsule under the brand name Tramal, where it is mostly used to treat labor pains.
Proprietary preparations
Grünenthal GmbH Grünenthal GmbH is a German pharmaceutical company in Stolberg near Aachen, which holds the patent to Ultram , and its much stronger derivative Nucynta , both used as analgesics with Norepinephrine Reuptake Inhibition...
, which still owns the patent on Tramadol, has cross-licensed the drug to pharmaceutical companies internationally. Thus, Tramadol is marketed under many trade names around the world, including:
- Acugesic (Malaysia, Singapore)
- Adolonta (Spain)
- Algifeno (Bolivia)
- Algesia (Philippines)
- Anadol (Bangladesh, Thailand)
- Boldol (Bosnia, Herzegovina)
- Calmador (Argentina)
- Campex (Pakistan)
- Contramal (Belgium, France, India, Italy, Turkey, Sudan, Hungary)
- Crispin
- Dolcet (combined with paracetamol)(Philippines)
- Dolol (Denmark)
- Dolzam (Belgium, Luxembourg)
- Dromadol (United Kingdom)
- Exopen (South Korea)
- Ixprim (France, Ireland)
- Lumidol (Bosnia, Herzegowina, Croatia)
- Mabron (Bahrain, Bangladesh, Bulgaria, Czech Republic, Estonia, Iraq, Jordan, Latvia, Lithuania, Malaysia, Oman, Romania, Singapore, Slovakia, Sri Lanka, Sudan, Yemen)
- Mandolgin (Denmark)
- Mandolgine
- Mosepan
- Matrix (combined with paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
) (Honduras, Guatemala)
- Nobligan (Argentina, Denmark, Iceland, Mexico, Norway, Portugal, Sweden)
- Osteodol (India)
- Oxxalgan PR (Greece)
- Palitex (India)
- Poltram (Poland)
- Pyredol (combined with paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
) (Vietnam, Bolivia)
- Ralivia (Canada)
- Ryzolt (United States)
- Sinergix (combined with ketorolac
Ketorolac or ketorolac tromethamine is a non-steroidal anti-inflammatory drug in the family of heterocyclic acetic acid derivative, often used as an analgesic...
) (Mexico)
- Sintradon (Serbia)
- Siverol (Philippines)
- Tandol (South Korea)
- Tiparol (Sweden)
- Tonoflex (Pakistan)
- Topalgic (France)
- Tradol (Bangladesh, Ireland, Mexico, Singapore, Venezuela)
- Tradolan (Austria, Denmark, Finland, Iceland, Romania, Sweden)
- Tradolgesic (Thailand)
- Tradonal (Belgium, Indonesia, Italy, Luxembourg, Netherlands, Philippines, Spain, Switzerland)
- Tralgit (Czech Republic, Georgia
Georgia is a sovereign state in the Caucasus region of Eurasia. Located at the crossroads of Western Asia and Eastern Europe, it is bounded to the west by the Black Sea, to the north by Russia, to the southwest by Turkey, to the south by Armenia, and to the southeast by Azerbaijan. The capital of...
, Romania, Slovakia)
- Tralodie (Italy)
- Tramacet (combined with paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
) (Canada, Mexico, Costa Rica, South Africa)
- Tramacip (India)
- Tramadex (Israel)
- Tramadin (Finland)
- Tramadol HEXAL (Denmark, Finland, Germany, Hungary)
- Trexol (Mexico)
- Trumen (Bangladesh)
- Tramadol (Australia, Belgium, Canada, Chile, Estonia, France, Netherlands, Romania, New Zealand, Norway, Spain, United Kingdom, United States)
- Tramadol Stada (Sweden)
- Tramadol-Sandoz (Hungary)
- Tramadol-Ratiopharm (Hungary, many European countries)
- Tramadolor (Austria, Estonia, Germany, Hungary, Latvia, Lithuania, Luxembourg, Romania)
- Tramadolor ID (Hungary)
- Tramalgic (Hungary, Czech Republic, Slovakia)
- Tramagit (Romania)
- Tramahexal (Australia)
- Tramake (United Kingdom)
- Trama-Klosidol (Argentina)
- Tramal (Bulgaria, Colombia, Pakistan, Netherlands, Finland, Croatia, Morocco, Slovenia, Austria, Poland, Brazil, Chile, Romania, Australia, New Zealand, Germany, Switzerland, Lebanon, Israel, Philippines, Egypt, Thailand)
- Tramalgic (Hungary)
- Tramal Gotas (Ecuador)
- Tramazac (India, Myanmar, Sri Lanka)
- Tramed
- Tramedo (Australia)
- Tramoda (Thailand)
- Tramól (Iceland)
- Tramundal (Austria)
- Tridol (South Korea)
- Tridural (Canada)
- Trodon (Serbia)
- Ultracet (combined with paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
) (Brazil, United States)
- Ultradol (Bangladesh)
- Ultram and Ultram ER (United States)
- Ultramed (combined with paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
) (India)
- Veldrol (Mexico)
- VAMADOL PLUS (India)
- Volcidol (Thailand)
- Zafin (combined with paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
) (Chile)
- Zaldiar (combined with paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
) (Belgium, Chile, Croatia, the Czech Republic, Mexico, Poland, Portugal, Slovenia, Spain, Russia)
- Zaledor (combined with paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
) (Chile)
- Zamadol (United Kingdom)
- Zamudol (France)
- Zodol (Chile, Ecuador, Peru)
- Zydol (United Kingdom, Ireland, Australia)
- Zytram (Canada, Iceland, New Zealand, Spain)
- Zytrim (Spain)
Veterinary medicine
Tramadol may be used to treat post-operative, injury-related, and chronic (e.g., cancer-related) pain in dogs and cats as well as
rabbitRabbits are small mammals in the family Leporidae of the order Lagomorpha, found in several parts of the world...
s, coatis, many small mammals including
ratRats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...
s and
flying squirrelFlying squirrels, scientifically known as Pteromyini or Petauristini, are a tribe of 44 species of squirrels .- Description :...
s,
guinea pigThe guinea pig , also called the cavy, is a species of rodent belonging to the family Caviidae and the genus Cavia. Despite their common name, these animals are not in the pig family, nor are they from Guinea...
s,
ferretThe ferret is a domesticated mammal of the type Mustela putorius furo. Ferrets are sexually dimorphic predators with males being substantially larger than females. They typically have brown, black, white, or mixed fur...
s, and
raccoonProcyon is a genus of nocturnal mammals, comprising three species commonly known as raccoons, in the family Procyonidae. The most familiar species, the common raccoon , is often known simply as "the" raccoon, as the two other raccoon species in the genus are native only to the tropics and are...
s. Tramadol comes in ampules in addition to the tablets, capsules, powder for reconstitution, and oral syrups and liquids; the fact that its characteristic taste is distasteful to dogs, but can be masked in food, makes for a means of administration. No data that would lead to a definitive determination of the efficacy and safety of tramadol in reptiles or amphibians is available at this time, and, following the pattern of all other drugs, it appears that tramadol can be used to relieve pain in marsupials such as North American opossums,
Short-Tailed OpossumsThe gray short-tailed opossum is a small member of the Didelphidae family of opossums. It was the first marsupial to have its genome sequenced. It is naturally found in arboreal habitats in Bolivia, Brazil and Paraguay. The opossum is used as a research model in science, and is also frequently...
,
sugar gliderThe sugar glider is a small gliding possum originating from the marsupial family.The sugar glider is native to eastern and northern mainland Australia and is also native to New Guinea and the Bismarck Archipelago.- Habitat :Sugar gliders can be found all throughout the northern and eastern parts of...
s,
wallabiesA wallaby is any of about thirty species of macropod . It is an informal designation generally used for any macropod that is smaller than a kangaroo or wallaroo that has not been given some other name.-Overview:...
, and
kangarooA kangaroo is a marsupial from the family Macropodidae . In common use the term is used to describe the largest species from this family, especially those of the genus Macropus, Red Kangaroo, Antilopine Kangaroo, Eastern Grey Kangaroo and Western Grey Kangaroo. Kangaroos are endemic to the country...
s among others.
Tramadol for animals is one of the most reliable and useful active principles available to veterinarians for treating animals in pain. It has a dual mode of action: mu agonism and mono-amine reuptake inhibition, which produces mild anti-anxiety results. Tramadol may be utilized for relieving pain in cats and dogs. This is an advantage because the use of some non-steroidal anti-inflammatory substances in these animals may be dangerous.
When animals are administered tramadol, adverse reactions can occur. The most common are constipation, upset stomach, decreased heart rate. In case of overdose, mental alteration, pinpoint pupils and seizures may appear. In such case, veterinarians should evaluate the correct treatment for these events. Some contraindications have been noted in treated animals taking certain other drugs. Tramadol should not be co-administered with selegiline or any other psychoactive class of medication such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, or monoamine oxidase inhibitors. In animals, tramadol is removed from the body via liver and kidney excretion. Animals suffering from diseases in these systems should be monitored by a veterinarian, as it may be necessary to adjust the dose.
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