TRAMADOL PAIN TREATMENT

Tramadol hydrochloride (Ultram, Tramal) is a centrally acting opioid analgesic, used in treating moderate to severe pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia. It was developed by the pharmaceutical company Grünenthal GmbH in the late 1970s.[1][2]

Tramadol possesses weak agonist actions at the μ-opioid receptor, releases serotonin, and inhibits the reuptake of norepinephrine.

While its action is not like that of other opioids, Tramadol is a synthetic analog of the phenanthrene alkaloid codeine. Tramadol is converted to O-desmethyltramadol, 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 μ1 and μ2 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.[citation needed] 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 morphine) of the opioid drug class, which generally do not possess tramadol's degree of subtype selectivity.

Adverse effects

Probability of adverse effects Effect
Probability (%)
Any adverse effect     
Drowsiness          
Nausea    
Dizziness    
Constipation   
Headache   
Vomiting    
Diarrhea
Dry Mouth    
Fatigue    
Indigestion    
Seizure
    <1
Main side effects of tramadol. Red color denotes more serious effects, requiring immediate contact with health provider.
The most commonly reported adverse drug reactions are nausea, vomiting, sweating, itching and constipation. 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 threshold. When combined with SSRIs, tricyclic antidepressants, 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 toxicity, 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 warfarin may need to be reduced for anticoagulated patients to avoid bleeding complications. Constipation can be severe especially in the elderly requiring manual evacuation of the bowel.[citation needed] Furthermore, 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.
Physical dependence and withdrawal

Tramadol is associated with the development of physical dependence 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 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, 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 opioids.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".

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 receptors, 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 nausea, dizziness, loss of appetite compared with opiates which could deter abuse to some extent.[44] Tramadol can help alleviate withdrawal symptoms from opiates, and it is much easier to control the quantity of its usage than street drugs.[45] 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 agonist,serotonin releasing agent, norepinephrine reuptake inhibitor, NMDA receptor antagonist, 5-HT2C receptor antagonist,
(α7)5 nicotinic acetylcholine receptor antagonist,TRPV1 receptor agonist, and M1 and M3 muscarinic acetylcholine receptor 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 naloxone.

Tramadol is marketed as a racemic mixture of the (1R,2R)- and (1S,2S)-enantiomers with a weak affinity for the μ-opioid receptor (approximately 1/6000th that of morphine; Gutstein & Akil, 2006). The (1R,2R)-(+)-enantiomer is approximately four times more potent than the (1S,2S)-(–)-enantiomer in terms of μ-opioid receptor affinity and 5-HT reuptake, whereas the (1S,2S)-(–)-enantiomer is responsible for noradrenaline reuptake effects (Shipton, 2000). These actions appear to produce a synergistic analgesic effect, with (1R,2R)-(+)-tramadol exhibiting 10-fold higher analgesic activity than (1S,2S)-(–)-tramadol (Goeringer et al., 1997).

The serotonergic-modulating properties of tramadol give it the potential to interact with other serotonergic agents. There is an increased risk of serotonin toxicity when tramadol is taken in combination with serotonin reuptake inhibitors (e.g., SSRIs), since these agents not only potentiate the effect of 5-HT but also inhibit tramadol metabolism.[citation needed] 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-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.

The overall analgesic profile of tramadol supports intermediate pain, especially chronic states. It is slightly less effective for acute pain than hydrocodone, but more effective than codeine. It has a dosage ceiling similar to codeine, 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 metabolite, 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 prodrug to O-desmethyltramadol. Similarly to tramadol, O-desmethyltramadol has also been shown to be a norepinephrine reuptake inhibitor, 5-HT2C receptor antagonist, and M1 and M3 muscarinic acetylcholine receptor antagonist.

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 agonist,^[50][51] serotonin releasing agent,^{[3][4][52][53]} norepinephrine reuptake inhibitor,^[51] NMDA receptor antagonist,^[54] 5-HT_2C receptor antagonist,^[55] (α7)₅ nicotinic acetylcholine receptor antagonist,^[56] TRPV1 receptor agonist,^[57] and M₁ and M₃ muscarinic acetylcholine receptor antagonist.^[58][59]
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 naloxone.
Tramadol is marketed as a racemic mixture of the (1R,2R)- and (1S,2S)-enantiomers with a weak affinity for the μ-opioid receptor (approximately 1/6000th that of morphine; Gutstein & Akil, 2006). The (1R,2R)-(+)-enantiomer is approximately four times more potent than the (1S,2S)-(–)-enantiomer in terms of μ-opioid receptor affinity and 5-HT reuptake, whereas the (1S,2S)-(–)-enantiomer is responsible for noradrenaline reuptake effects (Shipton, 2000). These actions appear to produce a synergistic analgesic effect, with (1R,2R)-(+)-tramadol exhibiting 10-fold higher analgesic activity than (1S,2S)-(–)-tramadol (Goeringer et al., 1997).
The serotonergic-modulating properties of tramadol give it the potential to interact with other serotonergic agents. There is an increased risk of serotonin toxicity when tramadol is taken in combination with serotonin reuptake inhibitors (e.g., SSRIs), since these agents not only potentiate the effect of 5-HT but also inhibit tramadol metabolism.^{[citation needed]} 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.^[60] 5-HT_2C blockade may also account for its lowering of the seizure 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.^[54]
The overall analgesic profile of tramadol supports intermediate pain, especially chronic states. It is slightly less effective for acute pain than hydrocodone, but more effective than codeine. It has a dosage ceiling similar to codeine, 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 metabolite, 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 prodrug to O-desmethyltramadol. Similarly to tramadol, O-desmethyltramadol has also been shown to be a norepinephrine reuptake inhibitor, 5-HT_2C receptor antagonist, and M₁ and M₃ muscarinic acetylcholine receptor antagonist.^{[citation needed]}

[edit] Chemistry

[edit] 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.

[edit] Comparison with related substances

Structurally, tapentadol 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.

[edit] Synthesis and stereoisomerism

 
(1R,2R)-Tramadol     (1S,2S)-Tramadol
 
(1R,2S)-Tramadol     (1S,2R)-Tramadol
The chemical synthesis of tramadol is described in the literature.^[61] 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^[62] 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 ^[63] of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals^[64] and in humans.^[6

Metabolism

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 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). 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.[citation needed] The U.S. Food and Drug Administration (FDA) approved tramadol in March 1995 and an extended-release (ER) formulation in September 2005.[67] It is covered by U.S. patents nos. 6,254,887[68] and 7,074,430.[69][70] The FDA lists the patents as scheduled for expiration on May 10, 2014.[69] 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.[71]

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.[72] In Mexico, combined with paracetamol and sold under the brand name Tramacet, it is widely available without a prescription. In most Asian countries such as the Philippines, it is sold as a capsule under the brand name Tramal, where it is mostly used to treat labor pains.

==Proprietary preparations==

[[Grünenthal|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:
{{Multicol}}

* '''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)
* '''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]]) (Honduras, Guatemala)
{{Multicol-break}}
* '''Nobligan''' (Argentina, Denmark, Iceland, Mexico, Norway, Portugal, Sweden)
* '''Osteodol''' (India)
* '''Oxxalgan PR''' (Greece)
* 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 (country)|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)
* '''Trexol''' (Mexico)
* '''Trumen''' (Bangladesh)
{{Multicol-break}}
* '''Tramadol''' (Australia, Belgium, Canada, Chile, Estonia, France, Netherlands, Romania, New Zealand, Norway, Spain, United Kingdom, United States)
* '''Tramadol Stada''' (Sweden)
* '''Tramadolor''' (Austria, Estonia, Germany, Hungary, Latvia, Lithuania, Luxembourg, Romania)
* '''Tramagit''' (Romania)
* '''Tramahexal''' (Australia)
* '''Tramake''' (United Kingdom)
* '''Trama-Klosidol''' (Argentina)
* '''Tramal''' (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)
{{Multicol-break}}
* '''Ultracet''' (combined with [[paracetamol]])
* '''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]]) (Belgium, Chile, Croatia, the Czech Republic, Mexico, Poland, Portugal, Slovenia, Spain, Russia)
* '''Zaledor''' (combined with [[paracetamol]]) (Chile)
* '''Zamadol''' (United Kingdom)
* '''Zamudol''' (France)
* '''Zodol''' (Chile, Ecuador, Peru)
* '''Zydol''' (United Kingdom, Ireland, Australia)
* '''Zytram''' (Canada, Iceland, New Zealand, Spain)
* '''Zytrim''' (Spain)
{{Multicol-end}}

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 rabbits, coatis, many small mammals including rats and flying squirrels, guinea pigs, ferrets, and raccoons. 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 Opossums, sugar gliders, wallabies, and kangaroos 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.

Definition of Analgesic

analgesic [an″al-je´zik]

1. relieving pain.

2. pertaining to analgesia.

3. an agent that relieves pain without causing loss of consciousness.

narcotic analgesic opioid analgesic.

nonsteroidal antiinflammatory analgesic (NSAIA) nonsteroidal antiinflammatory drug.

opiate analgesic (opioid analgesic) any of a class of compounds that bind with a number of closely related specific receptors (opioid receptors) in the central nervous system to block the perception of pain or affect the emotional response to pain; such compounds include opium and its derivatives, as well as a number of synthetic compounds, and are used for moderate to severe pain. Chronic administration or abuse may lead to dependence.

---

Definition of Tramadol

Tramadol,

a central analgesic.

indications It is used to manage moderate to severe pain.

contraindications Factors that prohibit its use are known hypersensitivity to this drug or acute intoxication with any central nervous system depressant.

adverse effects Seizures and GI bleeding are life-threatening effects. Other adverse effects are dizziness, central nervous system stimulation, somnolence, headache, anxiety, confusion, euphoria, hallucination, nausea, constipation, vomiting, dry mouth, diarrhea, abdominal pain, anorexia, flatulence, vasodilation, orthostatic hypotension, tachycardia, hypertension, abnormal electrocardiograms, pruritus, rash, urticaria, vesicles, urinary retention or frequency, menopausal symptoms, dysuria, and menstrual disorders.

Mosby's Medical Dictionary, 8th edition. © 2009, Elsevier.

MIMS Class

Analgesics (Opioid)

Mechanism of Action

Tramadol inhibits reuptake of norepinephrine, serotonin and enhances serotonin release. It alters perception and response to pain by binding to mu-opiate receptors in the CNS.
Onset: Oral (conventional tablet): 1 hr.
Duration: Oral (conventional tablet): 3-6 hr.
Absorption: Readily absorbed from the GI tract (oral).
Distribution: Widely distributed. Crosses the placenta and enters breast milk.
Metabolism: Extensive hepatic first-pass metabolism; converted to O-desmethyltramadol (active) by N- and O-demethylation via the cytochrome P450 isoenzymes CYP3A4 and CYP2D6 and glucuronidation or sulfation.
Excretion: Via urine (as metabolites); 6 hr (elimination half-life).

Storage

Oral: Store at 20-25°C (68-77°F). Parenteral: Do not store above 30°C.

Pregnancy Category (US FDA)

 
Category C: Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Drug Interactions

Possible increase in anticoagulation with warfarin. Increased risk of seizures with SSRI, TCA. Increased risk of serotonin syndrome with mirtazapine, venlafaxine, SSRI and MAOI; tramadol should not be given to patients receiving MAOIs or within 14 days of their discontinuation. Reduced analgesic efficacy of tramadol with carbamazepine, 5-HT₃-receptor antagonist e.g. ondansetron. Increased respiratory and CNS depression with CNS depressants e.g. alcohol, opioids, anaesthetic agents, narcotics, phenothiazines, tranquilisers or sedative hypnotics.

Adverse Drug Reactions

Sweating, dizziness, nausea, vomiting, dry mouth, fatigue, asthenia, somnolence, confusion, constipation, flushing, headache, vertigo, tachycardia, palpitations, miosis, insomnia, orthostatic hypotension, seizures, CNS stimulation e.g. hallucinations.
Potentially Fatal: Respiratory depression.

Special Precaution

Hypothyroidism; adrenocortical insufficiency; renal or hepatic impairment; history of epilepsy or increased risk of seizures; inflammatory or obstructive bowel disease; myasthaenia gravis; respiratory depression; prostatic hyperplasia. Pregnancy.

Contraindications

Suicidal patients, acute alcoholism; head injuries; raised intracranial pressure; severe renal impairment; lactation.

Overdosage

Symptoms:

Miosis,
vomiting,
cold and clammy skin,
respiratory depression,
lethargy,
flaccid skeletal muscle,
coma,
seizures, 
bradycardia, 
hypotension,
cardiac arrest, 
cardiac collapse and death.

Management: Treatment is supportive and ensure adequate ventilation. Although naloxone will reverse some, but not all, symptoms of tramadol overdosage, there is an increased risk of seizures which has to be taken into consideration. Haemodialysis is unlikely to be helpful.

Administration

May be taken with or without food.

Dosage

Oral
moderate to severe pain
Adult: As conventional tablet: 50-100 mg every 4-6 hr. Max: 400 mg daily. As extended-release tablet: 50-100 mg once or twice daily. Max: 300 mg daily.
Elderly: Lower initial dose. Max: 300 mg daily (>75 yr).
Max Dosage: 400 mg daily.

CrCl (ml/min)	Dosage Recommendation
10-<30	As conventional tablet: increase dosage interval to 12 hr; max: 200 mg/day.
<10	Contraindicated.

Hepatic impairment: As conventional tablet: Increase dosage interval to 12 hr in severe impairment e.g. 50 mg bid in hepatic cirrhosis. As extended-release tablet: Contraindicated in Child Pugh Class C.
Parenteral
moderate to severe pain
Adult: IM/IV inj over 2-3 min/IV infusion: 50-100 mg given every 4-6 hr.
Elderly: Lower initial dose. Max: 300 mg daily (>75 yr).

CrCl (ml/min)	Dosage Recommendation
10-<30	Increase dosage interval to 12 hr.
<10	Contraindicated.

Hepatic impairment: Severe: Increase dosage interval to 12 hr.
Parenteral
Postoperative pain
Adult: IM/IV inj over 2-3 min/IV infusion: Initially, 100 mg followed by 50 mg every 10-20 min if necessary up to 250 mg for the 1st hr. Maintenance: 50-100 mg every 4-6 hr. Max: 600 mg daily.
Elderly: Lower initial dose. Max: 300 mg daily (>75 yr).

CrCl (ml/min)	Dosage Recommendation
10-<30	Increase dosage interval to 12 hr.
<10	Contraindicated.

Hepatic impairment: Severe: increase dosage interval to 12 hr.
Rectal
moderate to severe pain
Adult: 100 mg suppository up to 4 times daily.
Elderly: Lower initial dose. Max: 300 mg daily (>75 yr).

CrCl (ml/min)	Dosage Recommendation
<30	Increase dosage interval to 12 hr.
<10	Contraindicated.

Hepatic impairment: Severe: Increase dosage interval to 12 hr.

Incompatibility: Incompatible with injections of diazepam, diclofenac sodium, indometacin, midazolam, piroxicam, phenylbutazone, aciclovir, clindamycin and lysine aspirin if mixed in the same syringe.

Indication

Listed in Dosage.

Tramadol

This medication is used to help relieve moderate to moderately severe pain. Tramadol is similar to narcotic analgesics. It works in the brain to change how your body feels and responds to pain.
How to use tramadol Oral

Take this medication by mouth as directed by your doctor, usually every 4 to 6 hours as needed for pain relief. You may take this drug with or without food. If you have nausea, it may help to take this drug with food. Ask your doctor or pharmacist about other ways to decrease nausea (such as lying down for 1 to 2 hours with as little head movement as possible).

The dosage is based on your medical condition and response to treatment. To reduce your risk of side effects, your doctor may direct you to start this medication at a low dose and gradually increase your dose. Follow your doctor's instructions carefully. The maximum recommended dose is 400 milligrams per day. If you are older than 75 years, the maximum recommended dose is 300 milligrams per day. Do not increase your dose, take the medication more frequently, or take it for a longer time than prescribed. Properly stop the medication when so directed.

Pain medications work best if they are used as the first signs of pain occur. If you wait until the pain has worsened, the medication may not work as well.

If you have ongoing pain (such as due to arthritis), your doctor may direct you to also take long-acting narcotic medications. Other non-narcotic pain relievers (such as acetaminophen, ibuprofen) may also be prescribed with this medication. Ask your doctor or pharmacist if you have any questions about using tramadol safely with other drugs.

This medication may cause withdrawal reactions, especially if it has been used regularly for a long time or in high doses. In such cases, withdrawal symptoms (such as restlessness, watering eyes, runny nose, nausea, sweating, muscle aches) may occur if you suddenly stop using this medication. To prevent withdrawal reactions, your doctor may reduce your dose gradually. Consult your doctor or pharmacist for more details, and report any withdrawal reactions immediately.

When this medication is used for a long time, it may not work as well. Talk with your doctor if this medication stops working well.

Along with its benefits, this medication may rarely cause abnormal drug-seeking behavior (addiction). This risk may be increased if you have abused alcohol or drugs in the past. Take this medication exactly as prescribed to lessen the risk of addiction.

Tell your doctor if your pain persists or worsens.