Tramadol Drugs Wiki Information

Tramadol marketed as the hydrochloride salt by Janssen Pharmaceutica as Ultram in the United States,
Ralivia by Biovail in Canada and many other companies throughout the world is a centrally-acting atypical opioid
analgesic with additional serotonin-norepinephrine reuptake-inhibiting effects used to treat moderate to moderately
severe pain.

It was launched and marketed as Tramal by the German pharmaceutical company Grünenthal GmbH in 1977 in
West Germany, even though it would take another 20 years for it to be launched in English-speaking countries
such as the UK, US and Australia.

Tramadol is marketed as a racemic mixture of both R and S stereoisomers. This is because the two isomers
complement each other's analgesic activity. It is often combined with paracetamol as this is known to improve the

efficacy of tramadol in relieving pain. Tramadol is an atypical opioid because it is a serotonin-norepinephrine
reuptake inhibitor of and, by itself, a fairly weak μ-opioid receptor agonist.

Tramadol is metabolised to O-desmethyltramadol, which is a significantly more potent opioid with additional
norepinephrine reuptake-inhibiting properties, making it analogous to tapentadol.

When taken as an immediate-release oral formulation, the onset of pain relief usually occurs within about an hour.
Despite the original belief that tramadol was a purely synthetic opioid it has been found in a South African tree.

Medical Uses Tramadol

Tramadol is used primarily to treat moderate-severe pain, both acute and chronic.
Tramadol is recommended for the management of pain in fibromyalgia by the European League Against Rheumatism.
Its analgesic effects take about one hour to come into effect and 2-4 hours to peak after oral administration with an

immediate-release formulation. On a dose-by-dose basis tramadol has about one-tenth the potency of morphine
and is approximately equally potent when compared to pethidine and codeine.

For pain moderate in severity its effectiveness is equivalent to that of morphine; for severe pain it is
less effective than morphine.These painkilling effects peak at about 3 hours, post-oral administration and
last for approximately 6 hours.

These analgesic effects are only partially reversed by naloxone, hence indicating that its opioid action is
unlikely the sole contributing factor; tramadol's analgesic effects are also partially reversed by α2 adrenergic
receptor antagonists like yohimbine and the 5-HT3 receptor antagonist, ondansetron.

Pharmacologically, tramadol is similar to levorphanol and tapentadol in that it not only binds to the mu opioid
receptor, but also inhibits the reuptake of serotonin and norepinephrine due to its action on the noradrenergic and
serotonergic systems, such as its "atypical" opioid activity.
Available dosage forms include capsules, tablets, including extended release formulations and injections.

Investigational Uses Tramadol

Diabetic neuropathy
Antidepressant
Postherpetic Neuralgia

Acute Opioid Withdrawal Management
Obsessive-compulsive Disorder

Premature Ejaculation
Post-traumatic Stress Disorder
Pregnancy and Lactation

Its use in pregnancy is generally advised against as it may cause some reversible withdrawal effects in the newborn.
Despite this a small prospective study in France found that while there was an increased risk of miscarriages there

were no major malformations reported in the newborn. Its use during lactation is also generally advised against but a
small trial found that infants breastfed by mothers taking tramadol were exposed to about 2.88% of the dose the mothers
were taking and despite this there was no evidence of this dose having a harmful effect on the newborn.

Labour and Delivery

Its use as an analgesic during labour is generally advised against due to its long-onset of action (one hour).
The ratio of the mean concentration of the drug in the foetus compared to that of the mother when it is given
intramuscularly for labour pains has been estimated to be 94.

Children and Tramadol

Its use in children is generally advised against, although it may be done under the supervision of a specialist.

Elderly and Tramadol

There is an increased risk of opioid-related adverse effects such as respiratory depression, falls, cognitive impairment
and sedation.

Liver and Kidney Failure

It is advised that the drug be used with caution in those with liver or kidney failure, due to the high dependence of the drug
on the liver and kidneys for metabolism to O-desmethyltramadol and elimination, respectively.

Adverse Effects Tramadol

The most common adverse effects of tramadol include nausea, dizziness, dry mouth, indigestion, abdominal pain, vertigo,
vomiting, constipation, drowsiness and headache. Compared to other opioids respiratory depression and constipation is
considered less of a problem with tramadol.
By Incidence

The most common side effects in order of decreasing incidence are:
Note: Serious adverse effects are in bold.
Very common (>10% frequency) adverse effects include:

Dizziness
Nausea
Constipation
Vertigo

Headache
Vomiting
Somnolence

Common (1-10% frequency) adverse effects include:

Agitation
Anxiety
Emotional lability
Euphoria
Nervousness

Spasticity
Dyspepsia (indigestion)
Asthenia (weakness)
Pruritus (itchiness)
Dry mouth

Diarrhoea
Fatigue
Sweating
Malaise

Vasodilation (dilation (widening) of blood vessels)
Confusion
Coordination disturbance
Miosis

Sleep Disorder
Rash
Hypertonia
Abdominal Pain
Weight Loss
Visual Disturbance
Flatulence
Menopausal Symptoms
Urinary Frequency
Urinary Retention (being unable to urinate)

Uncommon (0.1-1% incidence) adverse effects include:

Cardiovascular regulation anomalies (palpitation, tachycardia, postural hypotension or cardiovascular collapse)
Retching
Gastrointestinal irritation (a feeling of pressure in the stomach, bloating)

Urticaria (hives)
Trembling
Flushing

Rare (0.01-0.1% incidence) adverse effects include:

Bradycardia
Hypertension (high blood pressure)
Allergic reactions (e.g. dyspnoea (shortness of breath), bronchospasm, wheezing, angioneurotic oedema)
Anaphylaxis

Changes in appetite
Paraesthesia (pins and needles)
Hallucinations
Tremor

Respiratory depression
Epileptiform convulsions
Involuntary muscle contractions

Abnormal coordination
Syncope (fainting)
Blurred vision
Dyspnoea (shortness of breath)

Tinnitus (ringing in the ears)
Migraine
Stevens-Johnson syndrome/Toxic epidermal necrolysis (potentially fatal skin reactions)
Motorial weakness

Creatinine increase
Elevated liver enzymes
Hepatitis (liver swelling)

Stomatitis (mouth swelling)
Liver failure
Pulmonary oedema (fluid in the lungs)

Gastrointestinal bleeding
Pulmonary embolism
Myocardial ischaemia (lack of blood supply to the heart muscles)

Speech disorders
Haemoglobin decrease
Proteinuria (protein in the urine; usually indicative of kidney damage)

There are suggestions that chronic opioid administration may induce a state of immune tolerance,
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.

Interactions

Its serotonergic effects enable it to interact, potentially fatally, with other serotonergics such as antidepressants
(such as monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors,

serotonin-norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants, serotonin
antagonist and reuptake inhibitors, etc.), certain analgesics (such as pethidine (meperidine), tapentadol, oxycodone,

dextromethorphan and fentanyl), certain anxiolytics (such as the SSRIs and buspirone), certain antibiotics
(namely, linezolid and isoniazid), certain herbs (e.g. St. John's wort, syrian rue, passiflora, etc.), certain recreational
drugs (e.g. MDMA), phentermine, lithium, methylene blue and numerous other therapeutic agents.

As it is a substrate of CYP3A4 and CYP2D6, hence any agents with the ability to inhibit or induce these enzymes will
likely interact with tramadol.

Contraindications

Its use is advised against in people lacking any CYP2D6 enzymes (which accounts for about 6-10% of Caucasians
and 1-2% of Asians) as they are crucial to the therapeutic effects of tramadol, by means of enabling tramadol's
metabolism to O-desmethyltramadol.

Overdosage Tramadol

Fatalities with tramadol overdose have been reported and are increasing in frequency in Northern Ireland; the majority of
these overdoses involve other drugs including alcohol. Recognised risk factors for tramadol overdose include depression,

male gender, addiction and seizures.
Naloxone only partially reverses the toxic effects of tramadol overdose and may increase the risk of seizures.

Physical Dependence and Withdrawal

Long-term use of high doses of tramadol may be associated with physical dependence and a withdrawal syndrome.
The atypical withdrawal symptoms are probably related to tramadol's effect on serotonin and norepinephrine reuptake.
Symptoms may include those of SSRI discontinuation syndrome, such as anxiety, depression, anguish, severe mood

swings, aggressiveness, brain "zaps", electric-shock-like sensations throughout the body, paresthesias, sweating,
palpitations, restless legs syndrome, sneezing, insomnia, vivid dreams or nightmares, micropsia and/or macropsia,
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 those 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 SNRI properties and, when the time

comes to discontinue their tramadol, they do so gradually over a period of time that will vary according to the individual,
dose and length of time on the drug.

Psychological Dpendence and Recreational Use

Because of the possibility of convulsions at high doses for some users, recreational use can be very dangerous.
Tramadol can cause a higher incidence of nausea, dizziness, loss of appetite compared with opiates, which could
deter abuse. Compared to hydrocodone, fewer persons choose to abuse tramadol.

It may also have a 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 of opiates 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 quantified 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.

Chemistry

Synthesis and stereoisomerism

The chemical synthesis of tramadol is described in the literature.
Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at the
cyclohexane 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 (1R,2R)-isomer and the (1S,2S)-isomer as the main products.
Minor amounts of the racemic mixture of the (1R,2S)-isomer and the (1S,2R)-isomer are formed as well. The isolation of

the (1R,2R)-isomer and the (1S,2S)-isomer from the diastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer]
is realized by the recrystallization of the hydrochlorides. The drug tramadol is a racemate of the hydrochlorides of the

(1R,2R)-(+)- and the (1S,2S)-(-)-enantiomers. The resolution of the racemate [(1R,2R)-(+)-isomer / (1S,2S)-(-)-isomer]
was described[55] 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[56] of the (1R,2R)- and (1S,2S)-isomers,
because the racemate showed higher analgesic activity than either enantiomer in animals and in humans.

Mechanism of Action Tramadol

Tramadol acts as a μ-opioid receptor agonist, serotonin releasing agent, norepinephrine reuptake inhibitor,
NMDA receptor antagonist (IC50=16.5 μM), 5-HT2C receptor antagonist (EC50=26 nM), (α7)5 nicotinic acetylcholine
receptor antagonist, TRPV1 receptor agonist,[66] and M1 and M3 muscarinic acetylcholine receptor antagonist.

Tramadol has inhibitory actions on the 5-HT2C receptor. Antagonism of 5-HT2C 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-HT2C blockade may also account for its lowering of the seizure threshold, as 5-HT2C 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.

Pharmacokinetics

Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2B6, CYP2D6 and CYP3A4,
being O- and N-demethylated to five different metabolites. Of these, O-desmethyltramadol 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 reduced CYP2D6 activity
(hence reducing metabolism), there is therefore a reduced analgesic effect. Those with decreased CYP2D6 activity
require a dose increase of 30% in order to achieve the same degree of pain relief than those with a normal level
of CYP2D6 activity.

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.
Its volume of distribution is approximately, 306 L after oral administration and 203 L after parenteral administration.

Society and Culture Tramadol

Legal Status Tramadol

The U.S. Food and Drug Administration (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 10 May 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.

In November 2013, the United States Drug Enforcement Administration initiated classification of Tramadol as a
schedule IV controlled substance, pending a review process.

Several states, including Arkansas, Georgia, Kentucky, Illinois, Mississippi, New York, North Dakota, Oklahoma,
Tennessee, West Virginia, Wyoming and the U.S. military have classified Tramadol as a schedule IV
controlled substance under state law.

Thus, tramadol is classified as a Schedule 4 in the US, Schedule 4 in Australia rather than as a Schedule 8 Controlled
Drug like opioids.Similarly, unlike opioid analgesics, tramadol is not currently scheduled as a controlled substance
by the U.S. Drug Enforcement Administration. However, it is controlled in certain states.

Sweden, as of May 2008, has chosen to classify tramadol as a controlled substance in the same way as codeine and
dextropropoxyphene. This means that the substance is a scheduled drug. But unlike codeine and dextropropoxyphene,
a normal prescription can be used at this time.

Brand Names Tramadol

Grünenthal GmbH, 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)

Astadol (combined with paracetamol)(Pakistan)
Boldol (Bosnia, Herzegovina)
Calmador (Argentina)
Campex (Pakistan)

Citra 50 (Mexico)
Contramal (Belgium, France, India, Italy, Turkey, Sudan, Hungary)
Crispin
Cramol (Nepal)

Dolcet (combined with paracetamol)(Philippines)
Dolol (Denmark)
Dolzam (Belgium, Luxembourg)
Dromadol (United Kingdom)
Durela (Canada)
Exopen (South Korea)

Hovid (Malaysia)
Ixprim (combined with paracetamol) (France, Ireland)
Lumidol (Bosnia, Herzegovina, Croatia)

Mabron (Bahrain, Bangladesh, Bulgaria, Czech Republic, Estonia, Iraq, Jordan, Latvia, Lithuania, Malaysia,
Oman, Romania, Singapore, Sri Lanka, Sudan, Yemen)
Mandolgin (Denmark)
Mandolgine

Mosepan
Matrix (combined with paracetamol) (Honduras, Guatemala)
Mavidol TR (combined with Ketorolac) (México)

Nobligan (Argentina, Denmark, Iceland, Mexico, Norway, Portugal, Sweden)
Nomal (Oman)

Osteodol (India)
Oxxalgan PR (Greece)
Pazital (combined with paracetamol) (Spain)

Palitex (India)
Poltram (Poland)
Pyredol (combined with paracetamol) (Vietnam, Bolivia)
Ralivia (Canada)

Ryzolt (United States)
Sinergix (combined with ketorolac) (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, Romania, Slovakia)

Tralodie (Italy)
Tramacet (combined with paracetamol) (Canada, Mexico, Costa Rica, South Africa)
Tramacip (India)

Tramadex (Israel)
Tramadin (Finland)
Tramadol HEXAL (Denmark, Finland, Germany, Hungary)

Tram Proxyvon (INDIA)
Tranophen (combined with paracetamol) (South Korea)
Trexol (Mexico)
TRIMIF (India)
Trumen (Bangladesh)

Tramadol (Australia, Belgium, Canada, Chile, Egypt, 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 (Slovakia, Costa Rica, Bulgaria, Colombia, Ecuador, Pakistan, Netherlands, Estonia, Finland, Croatia,
Morocco, Slovenia, Austria, Poland, Brazil, Chile, Romania, Australia, New Zealand, Germany, Switzerland,
Lebanon, Israel, Philippines, Egypt, Thailand, Portugal)

Tramalgic (Hungary)
Tramal Gotas (Ecuador)

Tramazac (India, Myanmar, Sri Lanka, South Africa)
Tramazac Co (combined with paracetamol) (South Africa)
Tramed
Tramedo (Australia)
Tramoda (Thailand)

Trasic (Thailand)
Tramól (Iceland)
Tramundal (Austria)

Tridol (South Korea)
Tridural (Canada)
Trodon (Serbia)

Ultracet (combined with paracetamol) (Brazil, United States)
Ultradol (Bangladesh)

Ultram and Ultram ER (United States)
Ultramed (combined with paracetamol) (India)
Veldrol (Mexico)
VAMADOL PLUS (India)

Volcidol (Thailand)
Zafin (combined with paracetamol) (Chile)
Zaldiar (combined with paracetamol) (Australia, Belgium, Chile, Croatia, the Czech Republic, France, Mexico, Poland,
Portugal, Slovenia, Spain, Switzerland, Russia)

Zaledor (combined with paracetamol) (Chile)
Zamadol (United Kingdom)
Zamudol (France)

Zodol (Chile, Ecuador, Peru)
Zoftadol (India)
Zydol (United Kingdom, Ireland, Australia)

Zytram (Canada, Iceland, New Zealand, Spain)
Zytrim (Spain)

Veterinary Medicine And Tramadol

Tramadol may be used to treat post-operative, injury-related, and chronic (e.g., cancer-related) pain in dogs and cats as
well as rabbits, coatis, many small mammals including rats and flying squirrels, guinea pigs, ferrets, and raccoons.