Glimadol

Glimadol Uses, Dosage, Side Effects, Food Interaction and all others data.

Tramadol, a centrally-acting analgesic, exists as a racemic mixture of the trans isomer, with important differences in binding, activity, and metabolism associated with the two enantiomers. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to μ-opioid receptors. 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. Opiate antagonist naloxone only partially antagonized tramadol-induced analgesia.

Paracetamol (Acetaminophen) is thought to act primarily in the CNS, increasing the pain threshold by inhibiting both isoforms of cyclooxygenase, COX-1, COX-2, and COX-3 enzymes involved in prostaglandin (PG) synthesis. Unlike NSAIDs, acetaminophen does not inhibit cyclooxygenase in peripheral tissues and, thus, has no peripheral anti-inflammatory affects. While aspirin acts as an irreversible inhibitor of COX and directly blocks the enzyme's active site, studies have found that acetaminophen indirectly blocks COX, and that this blockade is ineffective in the presence of peroxides. This might explain why acetaminophen is effective in the central nervous system and in endothelial cells but not in platelets and immune cells which have high levels of peroxides. Studies also report data suggesting that acetaminophen selectively blocks a variant of the COX enzyme that is different from the known variants COX-1 and COX-2. This enzyme is now referred to as COX-3. Its exact mechanism of action is still poorly understood, but future research may provide further insight into how it works. The antipyretic properties of acetaminophen are likely due to direct effects on the heat-regulating centres of the hypothalamus resulting in peripheral vasodilation, sweating and hence heat dissipation.

Trade Name Glimadol
Generic Paracetamol + Tramadol
Type Tablet
Therapeutic Class Combined analgesics
Manufacturer Nv Lifecare Pvt Ltd
Available Country India
Last Updated: September 19, 2023 at 7:00 am
Glimadol
Glimadol

How Glimadol works

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

Tramadol 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.

Tramadol 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

Glimadol dosage

For the management of pain, the recommended dose is 1 or 2 tablets every 4 to 6 hours as needed for pain relief up to a maximum of 8 tablets per day. The dosing interval should not be less than six hours. This is not recommended in patients under 18 years of age.

Side Effects

The most commonly reported undesirable effects during the clinical trials performed with the Paracetamol/ Tramadol Hydrochloride combination were nausea, dizziness and somnolence.

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

Should be used with caution in opioid dependent patients, or in patients with cranial trauma, in patients prone to convulsive disorder, biliary tract disorders, in a state of shock, in an altered state of consciousness for unknown reasons, with problems affecting the respiratory center or the respiratory function, or with an increased intracranial pressure. Paracetamol in overdosage may cause hepatic toxicity in some patients. At therapeutic doses, Tramadol Hydrochloride has the potential to cause withdrawal symptoms. Rarely, cases of dependence and abuse have been reported.

Interaction

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

Volume of Distribution

Volume of distribution is about 0.9L/kg. 10 to 20% of the drug is bound to red blood cells. Acetaminophen appears to be widely distributed throughout most body tissues except in fat.

The volume of distribution of tramadol is reported to be in the range of 2.6-2.9 L/kg. Tramadol has high tissue affinity; the total volume of distribution after oral administration was 306L and 203L after parenteral administration. Tramadol 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

Tramadol 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

Tramadol 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

The half-life for adults is 2.5 h after an intravenous dose of 15 mg/kg. After an overdose, the half-life can range from 4 to 8 hours depending on the severity of injury to the liver, as it heavily metabolizes acetaminophen.

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

Clearance

Adults: 0.27 L/h/kg following a 15 mg/kg intravenous (IV) dose. Children: 0.34 L/h/kg following a 15 mg/kg intravenous (IV dose).

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

Tramadol 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

Since it is a fixed combination of active ingredients including Tramadol Hydrochloride, it should not be used during pregnancy & lactation.

Contraindication

Hypersensitivity to Tramadol Hydrochloride, paracetamol or to any of the excipients of the medicinal product. Acute intoxication with alcohol, hypnotic drugs, centrally-acting analgesics, opioids or psychotropic drugs. Should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal. Severe hepatic impairment. Epilepsy not controlled by treatment.

Special Warning

Pediatric Use: The safety and effectiveness of Paracetamol IV for the treatment of acute pain and fever in pediatric patients ages 2 years and older is supported by evidence from adequate and well-controlled studies of Paracetamol IV in adults.

Geriatric use: No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Patients with Hepatic Impairment: Paracetamol is contraindicated in patients with severe hepatic impairment or severe active liver disease and should be used with caution in patients with hepatic impairment or active liver disease. A reduced total daily dose of Paracetamol may be warranted.

Patients with Renal Impairment: In cases of severe renal impairment (creatinine clearance < 30 ml/min), longer dosing intervals and a reduced total daily dose of Paracetamol may be warranted.

Paediatric use: The paediatric use of Tramadol 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 Tramadol Hydrochloride can be given in a dose of 1-2 mg/kg body weight. However,suppository (100 mg Tramadol Hydrochloride) should not be administered in children and adolescents below the age of 14 years. Tramadol 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 in cool & dry place, away from children.

Innovators Monograph

You find simplified version here Glimadol

FAQ

What is Glimadol used for?

Glimadol is an orally administered fixed-dose combination of the atypical opioid tramadol and paracetamol, which is indicated in the EU for the symptomatic treatment of moderate to severe pain. Glimadol tablets are indicated for the symptomatic treatment of moderate to severe pain. The use of Glimadol should be restricted to patients whose moderate to severe pain is considered to require a combination of tramadol and paracetamol.

How safe is Glimadol?

Glimadol made with tramadol and paracetamol are taken safe. Do not take tramadol with codeine-containing painkillers you can buy from a pharmacy. You'll be more likely to get side effects.

How does Glimadol work?

Paracetamol is often used with stronger pain medicine such as tramadol. This gives extra pain relief when required. Taking paracetamol regularly with tramadol gives you best pain relieving effect. Your dose of tramadol can be stepped up and down depending on your pain.

What are the common side effects of Glimadol?

The most commonly reported undesirable effects during the clinical trials performed with the  Glimadol combination were nausea, dizziness and somnolence, which were observed in more than 10% of the patients.

Is Glimadol safe during pregnancy?

Tramadol is not thought to be completely safe to take during pregnancy. In early pregnancy, it has been linked to some problems for your unborn baby. If you take tramadol at the end of pregnancy there is a risk that your newborn baby may get withdrawal symptoms. However, it's important to treat pain in pregnancy.

Is Glimadol safe during breastfeeding?

Healthcare professionals should be aware that breastfeeding is not recommended during treatment with tramadol due to the risk of serious adverse reactions in breastfed infants such as excess sleepiness, difficulty breastfeeding, and serious breathing problems, which may result in death.

Can I drink alcohol with Glimadol?

Drinking alcohol in combination with the combined form of  Paracetamol and tramadol in large doses over lengthy periods of time increases the risks of liver damage even further.

When should I take Glimadol?

Glimadol tablets are indicated for the symptomatic treatment of moderate to severe pain. The use of Tramadol/Paracetamol should be restricted to patients whose moderate to severe pain is considered to require a combination of tramadol and paracetamol.

Can Glimadol make me sleepy?

Tramadol can make you sleepy, and this is one of its most common side effects.

Can I drive after taking Glimadol?

Glimadol can also make you dizzy or lightheaded. Do not drive, operate heavy machinery, or participate in dangerous activities until you know how this drug affects you.

Who should not take Glimadol?

In adults and adolescents 12 years and older. The maximum dose of 8 tablets of Tramadol Hydrochloride/Paracetamol should not be exceeded. In order to avoid inadvertent overdose, patients should be advised not to exceed the recommended dose and not to use any other paracetamol or tramadol hydrochloride containing products concurrently without the advice of a physician.

Will Glimadol affect my fertility?

Animal studies do not show an effect of tramadol or of paracetamol on fertility. No study on fertility has been performed with the combination of tramadol and paracetamol. There are no data for effects of the combination on human fertility.

What happens if I overdose of Glimadol?

Glimadol is a fixed combination of active ingredients. In case of overdose, the symptoms may include the signs and symptoms of toxicity of tramadol or paracetamol or of both these active ingredients.


*** Taking medicines without doctor's advice can cause long-term problems.
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