Gadol

Pharmacological properties

Gadol combines the analgesic action of gabapentin, thiamine and cyanocobalamin; which exert a synergistic action to decrease neuropathic pain.

Gabapentin is an amino acid structurally related to gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter; however, its activity seems to be unrelated to direct effects on the gabaergic system. Although gabapentin has GABA-mimetic properties, its mechanism of action is unclear. Gabapentin does not bind to GABA or benzodiazepine receptors, nor does it influence GABA neuronal reuptake. Gabapentin has been postulated to increase GABA synthesis and to have effects on central serotonin metabolism. Gabapentin slightly reduces the release of monoaminergic neurotransmitters.

Gabapentin was originally used for the treatment of epilepsy, and later analgesic properties were attributed to it, mainly for the treatment of pain of neuropathic origin.

The analgesic effect of gabapentin has been demonstrated in animal models of pain, in which it prevents or diminishes allodynia and hyperalgesia. However, the mechanism by which it exerts these effects is unknown.

B vitamins are involved in cell metabolism for energy production; however, its greater activity predominates in the maintenance and function of the central nervous system.

Thiamine (vitamin B1): it exerts its physiological antineuritic and detoxifying action on the nervous system and intervenes in the synthesis of the neurotransmitter acetylcholine. It is necessary for the formation of thiamine triphosphate, a coenzyme that acts on the nervous system, regulating the permeability of chlorine channels and electrical conduction.

The active form of thiamine is thiamine pyrophosphate, which is involved in carbohydrate metabolism as a cofactor of dehydrogenases and transketolase. Among the metabolic processes affected by thiamine deficiency is the neuronal energy supply, by inhibiting the breakdown of carbohydrates, which also prevents the regeneration of the axonal membrane. Thiamine pyrophosphate is involved in the presynaptic synthesis and release of acetylcholine, as demonstrated by high concentrations of phosphorylated thiamine at cholinergic nerve endings.

The thiamine-induced antinociceptive effect could result from guanylate cyclase activation. In diabetic rats, thiamine can produce analgesia by increasing the speed of nerve conduction. It has been observed that thiamine supplementation reduces the severity of the signs and symptoms of diabetic neuropathy and that the intensity of the symptoms of neuropathy is greater in diabetic patients with low serum thiamine levels.

Cyanocobalamin (vitamin B12): acts as a coenzyme in various metabolic functions such as fat and carbohydrate metabolism and protein synthesis. It is necessary for growth, cell replication, hematopoiesis, and nucleoprotein and myelin synthesis, due in large part to its effects on the metabolism of methionine, folic acid, and malonic acid. Vitamin B12 participates in the formation of red blood cells by activating the coenzymes of folic acid. Both cyanocobalamin and its analog – hydroxycobalamin – are synthetic forms of vitamin B12, and have a hematopoietic action.

Cyanocobalamin is necessary for the maintenance of myelin sheaths in the nervous system. It has an anabolic action, since it is necessary for cell duplication, in high turnover tissues, such as bone marrow, skin, mucosa and liver, therefore, it is necessary for the growth and development of tissues. As a component of several coenzymes, vitamin B12 is important in the synthesis of nucleic acids, it intervenes in cell maturation and the maintenance of the integrity of the nervous system. It has anti-allergic properties, because it participates in the formation of myelin sheaths by regulating the electrical impulse in the axons.

Deficiency of vitamins B1 (thiamine), B6 ​​(pyridoxine), and B12 (cyanocobalamin) is associated with the development of painful conditions accompanied by axonal demyelination, neuropathy, peripheral neuritis, and sensitivity disorders in the extremities. According to recent clinical observations, the combination of vitamins B1 and B12 has antinociceptive activity, which results in substantial analgesic effects. For these reasons, combinations of these vitamins at pharmacological doses have been used in the treatment of various painful conditions, either alone, or in combination with NSAIDs or other agents (synergistic interaction between gabapentin and B vitamins in the decrease of neuropathic pain).

Pharmacodynamics

Gabapentin: Following administration of a 300mg dose orally, peak plasma concentrations of gabapentin (4.02 ug / ml) occur within two to three hours. Its bioavailability is close to 60%. Its elimination half-life is 5 to 7 hours. It does not bind to plasma proteins, its volume of distribution is 57.7 liters. In epilepsy patients, cerebrospinal fluid (CSF) concentrations of gabapentin are 20% of the minimum steady state plasma concentrations. Gabapentin is eliminated exclusively by renal excretion. There is no evidence of metabolism in man.

Thiamine (vitamin B1): Gastrointestinal absorption of thiamine occurs through an active transport mechanism, except when high doses are administered that are absorbed by passive diffusion. Tissues break down completely about a milligram of thiamine per day. When ingestion is less than this amount, thiamine is not excreted in the urine; but when this amount is exceeded, first the tissue deposits are saturated and, later, it is excreted without modification or as its catabolite, pyrimidine.

Cyanocobalamin: once absorbed, it reaches its maximum serum concentration within one hour of administration. It has an affinity to bind to proteins and is transported by the blood to the liver and other organs where it remains as a reserve and where a total body turnover of the order of 0.05 to 0.2% per day is performed and the losses of B12 are estimated to be due to excretion. in bile.

Therapeutic indications

Gadol is indicated for Neuropathic Pain: prevention and treatment of neuropathy after an infection from herpes zoster, painful diabetic neuropathy, acute or chronic, chronic postoperative pain, trigeminal neuralgia, traumatic nerve injury, neuropathy in cancer patients, neuropathy in patients with multiple sclerosis or with human immunodeficiency virus infection, complex regional pain syndrome and phantom limb syndrome.


Posology

 

Neuropathic pain in adult patients: The starting dose is one full dose every eight hours. This dose should be adjusted according to the response of the patients up to a maximum dose of four caplets every eight hours.

Maintenance: Dose at which the patient’s response is achieved. Do not exceed the maximum dose.

One caplet is recommended on day one, one caplet every 12 hours on day two and, one caplet every 8 hours on day three, the dose can be increased to 1,800 mg / day of gabapentin, divided into three doses. No additional benefits above 1,800 mg / day of gabapentin have been observed.

Dosage adjustment is recommended in patients with compromised renal function or who are on hemodialysis, since gabapentin is eliminated exclusively by the renal route.

Drug and other interactions

Thiamine can increase the effect of neuromuscular blockers, its clinical importance being unknown.

Aminosalicylic acid and omeprazole reduce the absorption of vitamin B12. Ascorbic acid can destroy significant amounts of vitamin B12 and intrinsic factor, so this possibility should be considered when large doses of ascorbic acid are administered concomitantly with vitamin B12, orally. Concomitant administration of chloramphenicol and vitamin B12 can antagonize the hematopoietic response to the vitamin.

Simultaneous administration of gabapentin with antacids containing aluminum and magnesium, reduces its bioavailability by approximately 20%. It is recommended that gabapentin be taken two hours after the antacid. Renal excretion of gabapentin is not altered by probenecid. Cimetidine may slightly decrease renal excretion of gabapentin, while morphine increases it.

Side effects

Mild diarrhea, hives, and pruritus have been reported occasionally during cyanocobalamin therapy.

During gabapentin therapy, the following have been reported:

Cardiovascular: peripheral and facial edema (1.7%), vasodilation (1.1%), and hypertension.

Dermatological: Alopecia, acne, eczema, pruritus, erythema, and rarely Stevens-Johnson syndrome.

Endocrines: Weight loss secondary to anorexia or weight gain related to increased appetite. Glycemic fluctuations in diabetic patients.

Gastrointestinal: Abdominal pain, flatulence, nausea, vomiting, constipation, diarrhea, dental abnormalities, dry mouth and gingivitis.

Hematologic: Leukopenia and purpura.

Musculoskeletal: Arthralgia, back pain or low back pain, myalgia and fractures.

Neurological: Amnesia, asthenia, confusion, emotional instability, nystagmus, abnormal thinking, involuntary movements, muscle spasms, tremor, dysarthria, insomnia, malaise, drowsiness, nervousness and tremor. Fatigue (11%), dizziness (17%) and ataxia (12.5%) are the most common adverse events, generally reported during the first days of treatment, and which decrease with continued treatment.

Ophthalmic: Blurred vision, amblyopia and reduction of the visual field.

Genitourinary: urinary incontinence and sexual dysfunction.

Respiratory: Rhinitis, pharyngitis and cough.

Composition

Each coated caplet contains:

Gabapentin     300 mg

Thiamine Mononitrate (vitamin B1)     100 mg

Cyanocobalamin (vitamin B12)     0.200 mg

C.S.P. excipients     1 coated caplet


Administration route

Oral


Presentation

Box containing one blister with 10 coated caplets.

Box containing three blisters with 10 coated caplets each.

 


Storage

Store below 30 °C. Protect  from moisture and light.

 


Alterations in the results of laboratory tests

Simultaneous administration of gabapentin with other anticonvulsant drugs may produce false positives in the Ames N-Multistix SG test strip test.

Contraindications

Gadol is contraindicated in case of hypersensitivity to the components of the formula or to cobalt. Vitamin B12 should not be used in Leber’s hereditary optic neuropathy.

General precautions

In cases of neuropathic pain, safety and efficacy in patients under 18 years of age have not been established.

Cyanocobalamin therapy may mask signs of polycythemia vera.

Patients previously treated with morphine may require an increase in the dose of gabapentin; it is recommended to adjust the dose of morphine or gabapentin and monitor data for depression of the central nervous system, such as drowsiness.

Use restrictions during pregnancy and lactation

Do not use during pregnancy or lactation.

Warnings

Sale by prescription. Keep out of reach of children.