Gelotralib

Uses

Gelotralib is used for the treatment of moderate to severe painful conditions. These include: Postoperative pain, Colic and spastic pain, Cancer pain, Joint pain, Neck and back pain & Pain associated with osteoporosis.

Gelotralib is also used to associated treatment for these conditions: Pain, Acute, Premature Ejaculation, Severe Pain, Acute, moderate, severe Pain, Moderate Pain

How Gelotralib works

Gelotralib is a centrally acting μ-opioid receptor agonist and SNRI (serotonin/norepinephrine reuptake-inhibitor) that is structurally related to codeine and morphine. Gelotralib binds weakly to κ- and δ-opioid receptors and to the μ-opioid receptor with 6000-fold less affinity than morphine.

Gelotralib exists as a racemic mixture consisting of two pharmacologically active enantiomers that both contribute to its analgesic property through different mechanisms: (+)-tramadol and its primary metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the μ opioid receptor while (+)-tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake. These pathways are complementary and synergistic, improving tramadol's ability to modulate the perception of and response to pain.

In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding.

Gelotralib has also been shown to affect a number of pain modulators including alpha2-adrenoreceptors, neurokinin 1 receptors, the voltage-gated sodium channel type II alpha subunit, transient receptor potential cation channel subfamily V member 1 (TRPV1 - also known as the capsaicin receptor), muscarinic receptors (M1 and M3), N-methyl-D-aspartate receptor (also known as the NMDA receptor or glutamate receptor), Adenosine A1 receptors, and nicotinic acetylcholine receptor.

In addition to the above neuronal targets, tramadol has a number of effects on inflammatory and immune mediators involved in the pain response. This includes inhibitory effects on cytokines, prostaglandin E2 (PGE2), nuclear factor-κB, and glial cells as well as a change in the polarization state of M1 macrophages.

Dosage

Gelotralib dosage

Capsule or Tablet: Usual doses are 50 to 100 mg every four to six hours. For acute pain an initial dose of 100 mg is required. For chronic painful conditions an initial dose of 50 mg is recommended. Subsequent doses should be 50 to 100 mg administered 4-6 hourly. The dose level and frequency of dosing will depend on the severity of the pain.The total daily dosage by mouth should not exceed 400 mg.

Sustained Release Capsuleor Tablet: One SR capsuleor tablet every 12 hours, for example first one in the morning and then at the same time in the evening. The number of capsules taken at a time will depend upon severity of pain, but it should not be taken more frequently than every 12 hours.The total daily dosage by mouth should not exceed 400 mg.

Injection: A dose of 50-100 mg may be given every 4 to 6 hours by intramuscular or by intravenous infusion. For the treatment of postoperative pain,the initial dose is 100 mg followed by 50 mg every 10 to 20 minutes if necessary to a maximum of 250 mg in the first hour. Thereafter, doses are 50 to 100 mg every 4 to 6 hours up to a total daily dose of 600 mg.

Suppository: Gelotralib suppository should be administered rectally. For adults usual dose is 100 mg Gelotralib Hydrochloride 6 hourly. In general, 400 mg Gelotralib Hydrochloride (4 Gelotralib suppository) per day sufficient. However, for the treatment of Cancer pain and severe pain after operations much higher daily doses can be used.

Side Effects

Commonly occurring side-effects are dizziness/vertigo, nausea, constipation, headache, somnolence, vomiting, pruritus, CNS stimulation, asthenia, sweating, dyspepsia, dry mouth, diarrhoea.

Less commonly occurring side-effects include malaise, allergic reaction, weight loss, vasodilatation, palpitations, abdominal pain, anorexia, flatulence, GI bleeding, hepatitis, stomatitis etc.

Toxicity

The reported LD50 for tramadol, when administered orally in mice, is 350 mg/kg.

In carcinogenic studies, there are reports of murine tumors which cannot be concluded to be carcinogenic in humans. On the other hand, tramadol showed no evidence to be mutagenic in different assays and does not have effects on fertility. However, there are clear reports of embryotoxicity and fetotoxicity.

Precaution

Respiratory depression: When large doses of tramadol are administered with anaesthetic with anaesthetic medications or alcohol, respiratory depression may result. Therefore, tramadol should be administered cautiously in patients at risk for respiratory depression.

Opioid dependence: Gelotralib is not recommended for patients who are dependent on opioids.

Concomitant CNS depressants: Gelotralib should be used with caution and in reduced dosages when administering to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, phenothiazines, tranquilizers or sedative hypnotics.

Concomitant MAO inhibitors: Gelotralib should be used with great caution in patients taking MAO inhibitors, since tramadol inhibits the uptake of norepinephrine and serotonin.

Gelotralib should be used with caution in patients with increased intracranial pressure or head injury and patients with acute abdominal conditions.

Interaction

In general, physician need not be concerned about drugs interacting with Gelotralib. The monoamine oxidase (MAO) inhibitors represent the only drug class not recommended for combination with Gelotralib. Concomitant administration of carbamazepine with Gelotralib causes a significant increase in Gelotralib metabolism and it requires to increase the dose of Gelotralib.

Food Interaction

• Avoid alcohol. Co-administration of alcohol may potentiate the CNS effects of tramadol.
• Take with or without food. Co-administration of food does not affect pharmacokinetics.

[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.

Use in combination may result in additive central nervous system depression and
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Gelotralib Drug Interaction

Major: zolpidem, duloxetine, cyclobenzaprine, pregabalin, acetaminophen / hydrocodone, alprazolam, sertralineModerate: diphenhydramine, celecoxib, cetirizineUnknown: aspirin, omega-3 polyunsaturated fatty acids, atorvastatin, esomeprazole, montelukast, levothyroxine, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol

Gelotralib Disease Interaction

Major: gastrointestinal obstruction, acute alcohol intoxication, drug dependence, respiratory depressionModerate: gastrointestinal conditions, hypoglycemia, hypotension, intracranial pressure, liver disease, renal dysfunction, seizure disorders, suicidal

Volume of Distribution

The volume of distribution of tramadol is reported to be in the range of 2.6-2.9 L/kg. Gelotralib has high tissue affinity; the total volume of distribution after oral administration was 306L and 203L after parenteral administration. Gelotralib crosses the blood-brain barrier with peak brain concentrations occurring 10 minutes following oral administration. It also crosses the placental barrier with umbilical concentrations being found to be ~80% of maternal concentrations.

Elimination Route

Oral Administration

Gelotralib is administered as a racemate, with both the [-] and [+] forms of both tramadol and the M1 metabolite detected in circulation. Following administration, racemic tramadol is rapidly and almost completely absorbed, with a bioavailability of 75%. This difference in absorption and bioavailability can be attributed to the 20-30% first-pass metabolism. Peak plasma concentrations of tramadol and the primary metabolite M1 occur at two and three hours, respectively. Following a single oral dose of 100mg of tramadol, the Cmax was found to be approximately 300μg/L with a Tmax of 1.6-1.9 hours, while metabolite M1 was found to have a Cmax of 55μg/L with a Tmax of 3 hours.

Steady-state plasma concentrations of both tramadol and M1 are achieved within two days of dosing. There is no evidence of self-induction. Following multiple oral doses, Cmax is 16% higher and AUC is 36% higher than after a single dose, demonstrating a potential role of saturable first-pass hepatic metabolism in increasing bioavailability.

Intramuscular Administration

Gelotralib is rapidly and almost completely absorbed following intramuscular administration. Following injection of 50mg of tramadol, Cmax of 166μg/L was found with a Tmax of 0.75 hours.

Rectal Administration

Following rectal administration with suppositories containing 100mg of tramadol, Cmax of 294μg/L was found with a Tmax of 3.3 hours. The absolute bioavailability was found to be higher than oral administration (77% vs 75%), likely due to reduced first-pass metabolism with rectal administration compared to oral administration.

Half Life

Gelotralib reported a half-life of 5-6 hours while the M1 metabolite presents a half-life of 8 hours.

Clearance

In clinical trials, the clearance rate of tramadol ranged from 3.73 ml/min/kg in renal impairment patients to 8.50 ml/min/kg in healthy adults.

Elimination Route

Gelotralib is eliminated primarily through metabolism by the liver and the metabolites are excreted primarily by the kidneys, accounting for 90% of the excretion while the remaining 10% is excreted through feces. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites.

The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing.

Pregnancy & Breastfeeding use

Safe use of Gelotralib in pregnancy has not been established. Gelotralib has been shown to cross the placenta. There are no adequate and well-controlled studies in pregnant women. Therefore, Gelotralib should be used during pregnancy only if the potential benefit justifies the risk to the foetus. Gelotralib Hydrochloride should not be administered during breast feeding as Gelotralib and its metabolites have been detected in breast milk.

Contraindication

Gelotralib is contraindicated in persons having hypersensitivity to this drug. It is also contraindicated in acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs.

Special Warning

Paediatric use: The paediatric use of Gelotralib is not recommended because safety and efficacy in patients under 16 years of age have not been established.

Use in children: Use in children from the age of 1 year Gelotralib Hydrochloride can be given in a dose of 1-2 mg/kg body weight. However,suppository (100 mg Gelotralib Hydrochloride) should not be administered in children and adolescents below the age of 14 years. Gelotralib Hydrochloride 100 mg SR Capsules have not been studied in children. Therefore,safety and efficacy have not been established and the product should not be used in children.

Renal Impairment: Oral:

• CrCl <10: Contraindicated.
• CrCl 10 to <30: Increase dosing interval to 12. Max: 200 mg/day; Contraindicated (extended-release tab).

Parenteral:

• CrCl <10: Contraindicated.
• CrCl 10-30: Increase dosing interval to 12 hrly.

Hepatic Impairment:

• Oral: Severe: Increase dosing interval to 12 hrly; Contraindicated (extended-release).
• Parenteral: Severe: Increase dosing interval to 12 hrly.

Storage Condition

Store below 30° C, protected from light and moisture. Keep all medicines out of reach of children.

Innovators Monograph

You find simplified version here Gelotralib