Tramadol was developed by the German 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.^{[3][4][5][6][7][8][9]}

Tramadol is a synthetic stripped-down piperidine-analog of the phenantherane alkaloid codeine and, as such, is an opioid 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-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.

 Uses

Tramadol is used similarly to codeine, to treat moderate to moderately severe pain and most types of neuralgia, including trigeminal neuralgia.^[10] Another popular use of tramadol is as a remedy for opiate/opioid withdrawal, especially since it being unscheduled has led to many addicts weaning down or altogether stopping their addiction to opiates.^{[citation needed]} 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^[11] because of its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.^[12] However, health professionals have not endorsed its use for these disorders,^[13][14] claiming it may be used as a unique treatment (only when other treatments failed), and must be used under the control of a psychiatrist.^[15][16]

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".^[17] The company which produced it, the German pharmaceutical company Grünenthal GmbH, were the ones alleged to be guilty of "minimizing" the addictive nature and proposed efficacy of the drug, although it showed little abuse liability in preliminary tests.

 Availability and Usage

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 injection (intravenous and/or intramuscular) and oral administration. The most well known dosing unit is the 50mg generic tablet made by several manufacturers. It is also commonly available in conjunction with APAP (Paracetamol, 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 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 (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 for tramadol in any form is 400 mg per day. 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). Ultram ER is available in 100, 200, and 300 mg/day doses and is explicitly capped at 300mg/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 with their doctor regarding adjusted dosing or whether to use Tramadol at all.