New Drug Info Page for Tramadol - In the works

Tramadol: Drug Information

Drug Description

Tramadol is a synthetic non opium based compound created as a structural analogue of codeine with multimodal activity (note the similarity in structure on the left). The drug is available for oral use as a single entity product by the brand name Ultram; as a compound with acetaminophen by the brand name Ultracet; or as a solution for parenteral use. Tramadol as a branded drug is marketed by its creator Grunenthal, a german pharmaceutical firm.

Tramadol is a centrally acting analgesic with opioid and non opioid activity; used in the US and elsewhere for the treatment of moderate to moderately severe acute or chronic pain.

Tramadol is pharmacologically related to tapentadol, i.e. Nucynta. And structurally related to the popular antidepressant drug venlafaxine, known by its brand name Effexor, or the newer stereospecific product, Pristiq.

Use

Despite only mild opioid action, tramadol is effective as an analgesic, and is reported to be euphoric by some opiate naive users. Its use in medicine is relief of mild to moderately severe pain. If tramadol is the only option available, it might very well be effective in cases of severe pain, most likely in those not already taking narcotics for pain. Tramadol is usually given for acute pain such as that associated with urgent care or ER visits. Ultram is often given by doctors to suspected "drug-seekers" in either of the aforementioned settings. It may be used for dental pain such as a simple toothache, or after minor procedures such as fillings, root canal, or tooth removal. Tramadol is a good choice for burn or laceration pain, and for the pain of a severe tension headache or migraine. Tramadol has been given long term for fibromyalgia, diabetic neuropathy, and other cases of neurological pain, usually taken 'as needed' - for pain flare-ups. A long acting tablet form of tramadol is currently available as Ultram ER, offering analgesia aound the clock.

Tramadol has been used off label to treat symptoms of major depressive or anxiety disorders, usually after various tireless courses of the more toxic but morally acceptable tricyclics, SSRI's & SNRI's, MAOI's, benzodiazepines and perhaps amphetamines have failed. Its particular efficacy for depression and anxiety derives from the addition of opioid activity as a complement to the serotonin-norepinephrine enhancing properties. The opioid component provides unquestionable efficacy as an antidepressant, with a lesser level of dependence than a full agonist, even codeine. The opioid component also provides greater anxiolysis than an SSRI without the cognitive or psychomotor impairment seen with long term benzodiazepine use, and may smooth out some dirty or lethargic side effects of the monoaminergic activity.

Pharmacology

Tramadol is a racemic compound composed of a (1R, 2R) enantiomer and a (1S, 2S) enantiomer. The (R) enantiomer is responsible for the opioid and serotonergic effects while the (S) enantiomer is responsible for the noradrenergic effects.

Tramadol has a dual mode of action acting as a weak opioid agonist and a serotonin-norepinephrine reuptake inhibitor. The drug is highly selective at the mu opioid receptor but with a weak efficacy - meaning it produces a weak agonist effect. Some literature classifies tramadol as a partial opioid agonist. Though the parent drug itself contributes to the SNRI effects of the drug, tramadol relies on its more potent O-demethylated metabolite, O-desmethyltramadol (or M1), for most of its mu opioid analgesic activity. M1 is believed to be 6x more potent of an analgesic than tramadol, with roughly 200x tramadol's affinity for the mu receptor, and additional activity at the norepinephrine transporter. To summarize its pharmacodynamic profile; The SRI efficacy is produced by tramadol itself; while the NRI activity is produced by both tramadol and O-desmethyltramadol.

The multimodal action of tramadol and similar drugs derives its efficacy from the synergistic action between the opioid system and the serotonergic and noradrenergic systems. While mu receptors stem the flow of pain to the brain and changes the experience of pain; serotonin and to some extent norepinephrine modulate spinal pain modulation pathways which run from the brain to the dorsal horn; stimulating the endogenous opioid system and further stemming pain flow to the brain. Tramadol induced analgesia is only partially antagonized by naloxone, supporting the notion that the SNRI actions contribute to its efficacy. Current research continues to identify previously unknown connections between the serotonergic/noradrenergic and the opioid system. This could raise many more questions pertaining to a role of the opioid systems in modulation of anxiety or depressive disorders.

Tramadol is well absorbed orally with a bioavailability of 75%. Tramadol is metabolized by the liver, undergoing N and O-demethylation, sulfation, and glucuronidation. O-demethylation carried out by CYP2D6 forms its active M1 metabolite - making it susceptible to drug interactions or a lack of response in those who lack the 2D6 enzyme (i.e. about 7% of the population). Those who are non responsive to codeine may be non responsive to tramadol. Tramadol is additionally a substrate of CYP3A4. The parent drug and its metabolites undergo second phase conjugation, and are excreted renally - i.e. mainly through the urine.

Tramadol begins to produce effects one hour after dosing, which reach a peak at 2 to 3 hours. Tramadol itself has an elimination half life of 6.3 hours, M1 has a half life of 7.4 hours. As such, tramadol is longer acting than codeine, hydrocodone, and other opiates, with efects which may last up to 8 hours. Tramadol is typically given every 4 to 6 hours when prescribed for pain. Steady state blood levels are generally reached within 2 days with regular dosing (every 6 hours).

Effects


Being a mild opioid, tramadol produces some subjective effects and side effects that are similar to opioids such as codeine. Although these effects may be less pronounced, or unattainable in the opioid tolerant individual.

Subjective effects may include analgesia, anxiolysis, wakefulness or trouble sleeping, a sense of motivation, relaxation, a sense of well being and a positive effect on mood. Tramadol is much less sedating than typical opioids, due to its effects on norepinephrine (i.e. noradrenaline).

Side effects may include miosis, constipation, nausea and vomiting, respiratory depression, myoclonus, headache, ear ringing, orthostatic hypotension, sweating, and hot flashes. Little or no significant histamine release has been observerved in studies, though itching has been reported by individuals. As with any opioid, tramadol can cause respiratory depression which can be harmful or fatal, though this is rare with tramadol, and occurs mainly in naive individuals with excessive doses. One hazard which sets tramadol apart from other opioids is the very real risk of serotonin syndrome and grand mal seizure - Doses in excess of 400mg in 24 hours is likely to provoke seizures and in severe cases death.