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.
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