Tramadol
Ralivia ER™, Ralivia™ Flashdose®, Ultram®
Classification: Analgesics
Description: Tramadol is a centrally-acting analgesic with a unique, dual mechanism of action. Tramadol exists as a racemic mixture of the trans isomer. Important differences in binding, activity, and metabolism are associated with the two enantiomers. Tramadol is a synthetic analog of codeine; however, tramadol has a lower affinity for opioid receptors than codeine. Tramadol has less potential for abuse or respiratory depression than other opiate agonists, but both may occur. Comparative studies with other analgesics for the treatment of postoperative pain indicate that tramadol is equivalent in analgesic relief to codeine but is less potent than acetaminophen-codeine and acetaminophen-hydrocodone combinations for the treatment of dental and acute musculoskeletal pain. Tramadol has been shown to be effective as an adjuvant to NSAID therapy in patients with osteoarthritis who experience breakthrough pain. The World Health Organization guidelines for cancer pain management classify tramadol as a step II agent. For patients with severe cancer pain, morphine is superior and most patients treated with tramadol require a change to a more potent opioid after a few weeks of treatment. The lack of significant cardiac effects and no association with peptic ulcer disease make tramadol an alternative in some patients who may not tolerate NSAIDs. Tramadol has been effective in the control of post-operative pain when given intravenously but may not be suitable as an adjunct to anesthesia because of low sedative properties and a high incidence of postoperative respiratory depression. Tramadol has been widely used in Europe since the late 1970s where it is available as intravenous, rectal, and oral formulations. The FDA approved oral tramadol on March 3, 1995. There are no plans to market intravenous tramadol in the United States. In March 1996, the manufacturer issued a warning of the possibility of drug abuse, seizures, and anaphylactoid reactions associated with tramadol use. The FDA approved an extended-release tramadol HCL tablet formulation by Biovail Corporation in September 2005. The once-daily, oral extended-release drug is for the treatment of moderate to moderately severe pain and is expected to be available in early 2006. An orally disintegrating tablet (Ralivia™ FlashDose®) was approved by the FDA in May 2005, but the date of commercial availability in the U.S. is currently unknown.
Mechanism of Action: Tramadol has a unique dual mechanism of pain relief. Tramadol has central opiate receptor agonist activity and thus, exerts an analgesic effect from binding of the parent drug and the O-desmethyltramadol metabolite (M1) to µ-receptors. The relative contribution of tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound (see Pharmacokinetics). There are limited data available on the efficacy of tramadol for pain in poor versus extensive CYP2D6 metabolizers. Data from a randomized, double-blind, crossover study suggest that receipt of tramadol 2 mg/kg orally produces a greater analgesic effect, especially after the first 4 hours after dosing in extensive metabolizers whereas the analgesic effect in poor metabolizers is more modest but is sustained up to 10 hours after dosing. The threshold for pressure pain detection, tolerance, nociceptive reflex, and peak pain as compared with placebo was greater in extensive metabolizers as compared with the difference between placebo and tramadol receipt in poor metabolizers. The affinity of tramadol for µ-receptors is 10-fold less than codeine, 60-fold less than propoxyphene, and 6000-fold less than morphine. The M1 metabolite has 4 - 200 times greater affinity for the µ-receptor than tramadol. Opiate receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Opiate agonists decrease intracellular cAMP by inhibiting adenylate cyclase which modulates the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and norepinephrine. The stimulatory effects of opioids are the result of ‘disinhibition’ as the release of inhibitory neurotransmitters such as GABA and acetylcholine is blocked. The exact mechanism how opioid agonists cause both inhibitory and stimulatory processes is not well understood.
In addition to central opiate receptor agonist activity, tramadol exerts norepinephrine and serotonin reuptake inhibition in the CNS, which inhibits pain transmission in the spinal cord. The monoaminergic reuptake blockade, similar to MAOIs, is an important contribution to the analgesic and adverse event profile of tramadol. The inhibitory reuptake effects of tramadol on norepinephrine and serotonin are 100 - 1000 times less than those of imipramine.
Pharmacokinetics: Tramadol is administered orally, rectally, or intravenously; however, only the oral formulation is available in the United States. Absorption is rapid and bioavailability is 68% after single doses and approaches 100% after multiple doses. The increase in bioavailability with multiple doses is thought to be due to saturable first-pass metabolism. Bioavailability increases with age and decreased liver or renal function. Following IM or rectal administration, the bioavailability of tramadol is 100% and 78%, respectively. The rate and extent of oral absorption are not significantly affected by food. Tramadol is detected in plasma within 15 - 45 minutes of oral dosing. Peak plasma concentrations of tramadol occur about 2 hours post-dose. Peak plasma concentrations of the active metabolite M1 occur about 3 hours after an oral dose. The time to analgesia onset is within 1 hour of administration with a peak effect around 2 - 3 hours. Analgesia lasts about 6 hours. Steady state concentrations are achieved after two days of multiple dosing. Tramadol has a high tissue affinity. Minimum protein binding occurs (about 20%). Tramadol crosses the placenta and about 0.1% is distributed into breast milk.
Chemical Structure For: Tramadol
Tramadol undergoes significant first-pass metabolism following oral administration. Hepatic metabolism takes place via two metabolic, phase I pathways to form N- and O-demethylated tramadol. Of a tramadol dose, 60% is metabolized by the liver, including cytochrome P450 isoenzymes 2D6 and 3A4. The metabolism of tramadol is also stereoselective with the (-) enantiomer undergoing O-demethylation selectively, while the (+) enantiomer preferentially undergoes N-demethylation. The O-demethylated metabolites are further conjugated (phase II reactions). Of eleven identified metabolites, only the O-demethylated metabolite (M1) has analgesic activity, which appears to be critical to the activity of tramadol. The production of M1 depends on the P-450 cytochrome isoenzyme 2D6 (CYP2D6). Patients receiving concurrent medications that affect CYP2D6 may experience an altered response to tramadol (see Tramadol Interactions). Also, approximately 7% of the population has reduced CYP2D6 activity. In these patients, tramadol concentrations were approximately 20% higher and M1 concentrations were 40% lower as compared with normal CYP2D6 activity patients. The full pharmacologic effect of reduced CYP2D6 activity on either safety or efficacy of tramadol is unknown (see Mechanism of Action). In normal healthy adults, the elimination half-lives of tramadol and its non-active metabolites are between 5 and 6 hours. The corresponding half-life of M1 is 6 to 7 hours. Excretion of tramadol and its metabolites is mostly renal. About 90% of the dose is excreted via the kidneys, with about 10% appearing in the feces.
- Special Populations: Dosage adjustments of tramadol are required in patients with renal or hepatic dysfunction (see Dosage). In patients with a creatinine clearance < 80 ml/min, the half-life of tramadol increases 1.5 - 2 times as compared to patients with normal renal function. Tramadol and M1 are removed by dialysis to a limited extent (approximately 7% of the dose). Patients with cirrhosis or significant liver dysfunction the half life of tramadol and M1 increases 2 - 3 times as compared to normal due to decreased liver clearance. Elderly patients may require lower doses due to underlying renal or hepatic impairment (see Dosage).
[1 of 5 - Click here to see more photos]
Order Online
Related entries
Monthly Archives
Syndicate
Allergies
