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Tramadol ®

Grünenthal GmbH
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Tramadol (Ultram, Tramal is a centrally-acting analgesic, used for treating moderate to moderately severe pain.
Tramadol was developed by the German pharmaceutical company Grünenthal GmbH in the late 1970s.[1][2]
Tramadol possesses agonist actions at the μ-opioid receptor and affects reuptake at the noradrenergic and serotonergic systems. Tramadol is a compound with mild and delayed μ-agonist activity.
Tramadol is a synthetic stripped-down piperidine-analog of the phenantherane alkaloid CodeineOpioid and also a pro-drug (Codeine is metabolized to Morphine, Tramadol is converted to M-1 aka O-desmethyltramadol). Opioids are chemical compounds which act upon one or more of the human opiate receptors (the euphoria, addictive nature and respiratory depression are mainly caused by the Mu(μ) 1 and 2 receptor. The opioid agonistic effect of Tramadol and its major metabolite(s) are almost exclusively mediated by the substance’s action at the μ-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.

and, as such, is an


Tramadol is used similarly to Codeine, to treat moderate to moderately severe pain and most types of neuralgia, including trigeminal neuralgia.[6] Another popular use of Tramadol is as a remedy for opiate/opioid withdrawal, especially since it being uncontrolled has led to many addicts weaning down or altogether stopping their addiction to opiates. Tramadol is somewhat pharmacologically similar to Levorphanol (albeit with much lower μ-agonism), as both opioids are also NMDA-antagonists which also have SNRI activity (other such opioids to do the same are Kratom, Dextropropoxyphene (Darvon) & M1-like molecule Tapentadol (Nucynta, a new synthetic atypical opioid made to mimic the agonistic properties of Tramadol’s metabolite, M1(O-Desmethyltramadol). It has been suggested that Tramadol could be effective for alleviating symptoms of depression, anxiety, and phobias[7] because of its action on the noradrenergic and serotonergic systems, such as its “atypical” opioid activity.[8] However, health professionals have not endorsed its use for these disorders,[9][10] claiming it may be used as a unique treatment (only when other treatments failed), and must be used under the control of a psychiatrist.[11][12]
In May 2009, the United States Food and Drug Administration issued a warning letter to Johnson & Johnson, alleging that a promotional website commissioned by the manufacturer had “overstated the efficacy” of the drug, and “minimized the serious risks”.[13] However, nothing ever came of it besides a letter. The company which made it, the German pharmaceutical company Grünenthal GmbH, were the ones guilty of “minimizing” the addictive nature and proposed efficacy of the drug (in Grünenthal’s defense, they never said it wasn’t a narcotic, they said it was a narcotic with little abuse liability in preliminary tests (Tramadol scored slightly higher than NSAID’s on the abuse liability scale, with Vicodin (Hydrocodone/APAP) taking the top (they compared Tramadol and Hydrocodone basically and found it to be less than half as addictive as Hydrocodone.)


Tramadol is 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 injectionintravenous and/or intramuscular) and oral administration. It is also available in conjunction with APAP (Paracetamol, Acetaminophen) as Ultracet, a non-generic (and therefore expensive) form of a smaller dose of 37.5 mg Tramadol and 325 mg of APAP. Many patients preferred the generic 50MGs (and the more potent Tramadol Extended Release, which comes in doses of 100-400MG).[14] 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
  • ampoules 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 and other agents.

Tramadol has been experimentally 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 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. Its relative effectiveness via transmucosal routes (sublingual, buccal, rectal) is around that of codeine, and, like codeine, it is also metabolized in the liver to stronger metabolites (see below).
The maximum dosage for tramadol in any form is 400 mg/day. Certain manufacturers or formulations have lower maximum doses. For example, Ultracet (37.5 mg/325 mg tramadol/APAP tablets) is capped at 8 per day (300 mg/day). Other popular formulations such as Ultram ER are available in 100, 200, and 300 mg/day doses. Patients with impaired liver function or using SSRIs should consult with their doctor regarding adjusted dosing.

Off-label and investigational uses


Tramadol is used to treat post-operative, injury-related, and chronic (e.g., cancer-related) pain in dogs and cats[26] as well as rabbits, coatis, many small mammals including rats and flying squirrels, guinea pigs, ferrets, and raccoons. Tramadol comes in ampoules in addition to the tablets, capsules, powder for reconstitution, and oral syrups and liquids; the fact that its characteristic taste is not very bitter and can be masked in food and diluted in water makes for a number of 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 Deprenyl or any other psychoactive ingredient such as serotonin reuptake inhibitors, tricyclic antidepressants, or mono-amine 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.
Dosage and administration of tramadol for animals: in dogs a starting dosage of 1–2 mg/kg twice a day will be useful for pain management. Cats are administered 0.5-1 mg/kg twice a day.

Pregnancy and breastfeeding

Tramadol is in FDA pregnancy category C; animal studies have shown its use to be dangerous during pregnancy and human studies are lacking. Therefore, the drug should not be taken by women that are pregnant unless “the potential benefits outweigh the risks”.[27]
Tramadol causes serious or fatal side-effects in a newborn[28] including neonatal withdrawal syndrome, if the mother uses the medication during pregnancy or labor. Use of tramadol by nursing mothers is not recommended by the manufacturer because the drug passes into breast milk.[27] However, the absolute dose excreted in milk is quite low, and tramadol is generally considered to be acceptable for use in breastfeeding mothers when absolutely necessary.[29]

Adverse effects and drug interactions

Main side effects of tramadol. Red color denotes more serious effects, requiring immediate contact with health provider.[30]The most commonly reported adverse drug reactions are nausea, vomiting, memory loss, sweating and constipation. Drowsiness is reported, although it is less of an issue than for non-synthetic opioids. Patients prescribed tramadol for general pain relief along with other agents have reported uncontrollable withdrawal-like nervous tremors if weaning off the medication happens too quickly. 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). 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” (Labate 2005)[citation needed]. 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 syndrome, 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 2- to 6-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.[31] Dosages of coumadin/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,[32][33][34][35] Some have also stressed the negative effects of opioids on cognitive functioning and personality.[36]

although tramadol, in contrast to typical opioids may enhance immune function.


Structurally, tramadol closely resembles a stripped down version of codeine. Both codeine and tramadol share the 3-methyl ether group, and both compounds are metabolised 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 M1 metabolite, O-desmethyltramadol. The closest chemical relative of tramadol in clinical use is Venlafaxine (Effexor), the SNRI. The two molecules are nearly identical. Both tramadol and Venlafaxine share SNRI properties, while Venlafaxine is devoid of any opioid effects.

Comparison with related substances

Structurally, Tapentadol is the closest chemical relative of tramadol in clinical use. Tapentadol is also an opioid, but unlike both tramdol and venlafaxine, tapentadol represents only one stereoisomer (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, whilst tapentadol lacks this feature. In reality, the closest structural chemical entity (to tapentadol) in clinical use, is the OTC active, phenylephrine. Both share a meta phenol, attached to straight chain hydrocarbon. And in both cases, the hydrocarbon terminates in an amine.

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