Tramadol hydrochloride (Ultram, Tramal) is a centrally acting synthetic opioid analgesic used in treating severe pain. The drug has a wide range of applications, including treatment for Rheumatoid arthritis, restless legs syndrome and fibromyalgia. It was developed by the pharmaceutical company Grünenthal GmbH in the late 1970s.
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. 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.
Tramadol is used similarly to codeine, to treat moderate to moderately severe pain. 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 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). Tramadol is also molecularly similar to venlafaxine (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 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”. 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
100mg tramadol injection, marketed by the original ‘Contramal’ trade-mark owner, Grünenthal GmbH.(Hungarian release)
50 mg Tramadol HCl tablets (generic Ultram) marketed by Akyma Pharmaceuticals. Immediate release tramadol HCl is available in many generic preparations.
Bottle of 30 tablets of 200 mg extended-release tramadol HCl (generic Ultram ER) marketed by Patriot. Extended-release tramadol is commonly available in 100, 200, and 300 mg strengths to be taken once daily. It is often prescribed with tramadol-APAP (Ultracet) or regular immediate-release tramadol HCl (Ultram/Tramal/Rybix) for breakthrough pain.
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 injection (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 (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)
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 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, 50 mg water-soluble tramadol tablets has strawberry-flavouring, no matter which company manufactured it, to distinguish every, same-looking and same sized Mirtazapine sublingual tablets, which has orange flavouring irrespective of 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 
postherpetic neuralgia 
acute opioid withdrawal management
antidepressant withdrawal aid (proven to be effective, especially with withdrawal from its distant relative venlafaxine (Effexor)).
obsessive-compulsive disorder 
 Adverse effects
Probability of adverse effects Effect Probability (%)
Any adverse effect 71
Dry Mouth 5
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. 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, vivid dreams or nightmares, nonsense and weird thoughts, 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 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”. Using tramadol as recreational drug may be 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.
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. 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.