How Effective Is Gabapentin for Neuropathic Pain?

Gabapentin capsules, indications are 1. Neuralgia after herpes infection: used for the treatment of neuralgia after herpes in adults. 2. Epilepsy: Adjuvant therapy for partial seizures in adults and children over 12 years with or without secondary generalized seizures. Can also be used for the adjuvant treatment of partial seizures in children 3 to 12 years old.

Drug Name: Gabapentin capsules

Drug type: Prescription drugs, medicines for medical workers' injuries
Use classification: Other antiepileptic drugs

Gabapentin capsule ingredients

The main composition is the chemical name of gabapentin: 1-aminomethyl-cyclohexanoic acid.
Chemical Structure:

Molecular formula: C ₉ H ₁₇ NO ₂
Molecular weight: 171.24

Gabapentin capsule properties

This product is a hard capsule with a white or off-white powder.

Gabapentin capsule specifications

0.1g

Gabapentin capsules dosage

1. Neuralgia after herpes infection: take gabapentin 0.3g (3 capsules) in a single dose on the first day; 0.6g (6 capsules) on the second day; take two divided doses; 0.9g (9 capsules) on the third day, Finished in three servings. Subsequently, according to the need for pain relief, the dose can be gradually increased to 1.8 g (18 capsules) per day and taken in three times. In foreign clinical studies, the effect is equivalent in the dosage range of 1.8g (18 capsules) to 3.6g (36 capsules) per day, and dosages exceeding 1.8g (18 capsules) per day have not shown more benefits.
2. Epilepsy: Gabapentin can be combined with other antiepileptic drugs for combined treatment. Gabapentin is administered orally in divided doses (3 times a day). The method of administration is gradually increased from the initial low dose to the effective dose. Patients over 12 years old: 0.3g (3 capsules) once daily on the first day of administration; 0.3g (3 capsules) twice daily on the second day and daily on the third day Three times, 0.3 g (3 capsules) each time, and then maintain this dose. According to foreign research literature, the dosage of gabapentin can be increased to 1.8 g (18 capsules) per day, and some patients can still tolerate the dosage of 2.4 g (24 capsules) per day. The safety of doses after 2.4 g (24 capsules) per day is uncertain.
Pediatric patients 3 to 12 years old: The starting dose should be 10 to 15 mg / kg / d, 3 times a day, and the effective dose will be reached in about 3 days. The effective dose of gabapentin in patients over 5 years old is 25 to 35 mg / kg / d, three times daily. The effective dose for pediatric patients aged 3 to 4 years is 40 mg / kg / d three times daily. If necessary, the dose can be increased to 50 mg / kg / d. Long-term clinical studies have shown that the dose increase to 50 mg / kg / d is well tolerated.
The interval between two doses cannot exceed 12 hours. To reduce the incidence of dizziness and drowsiness, the first day of medication can be taken before bedtime. It is not necessary to monitor the blood concentration of gabapentin during gabapentin administration. Moreover, since gabapentin has no significant interaction with other conventional antiepileptic drugs in terms of pharmacokinetics, the combined treatment with this drug will not change the plasma concentrations of these conventional antiepileptic drugs.
In the course of treatment, the discontinuation of gabapentin or the addition of a new treatment plan must be carried out gradually, for a minimum of one week.
It is difficult to measure creatinine clearance in outpatients. The creatinine clearance (CCr) of patients with stable renal function can be reasonably estimated according to the equations of Cockcroft and Gault:
Female CCr = (0.85) (140-age) (weight) / [(72) (SCr)]
Male CCr = (140-age) (weight) / [(72) (SCr)]
The age unit is years, the weight unit is kilograms, SCr is serum creatinine, and the unit is mg / dL.
The following dosage adjustments are recommended for patients over 12 years of age with impaired renal function or undergoing hemodialysis:
Table Gabapentin dosage according to the patient's renal function to adjust renal function creatinine clearance (ml / min) Total daily medication (mg / day) Dose regimen (mg)
> 60 1200 400T.ID
30-60 600 300B.ID
15-30 300 300Q.D
<15 150 300Q.DODa
Hemodialysis-200-300b
a. Dosing every other day.
b. The initial dose of patients who have not been treated with gabapentin is 300-400mg, and then gabapentin is 200-300mg every 4 hours of dialysis.
Gabapentin use has not been studied in patients with renal impairment under 12 years of age.
Dose for elderly patients:
Because elderly patients are likely to have decreased renal function, care should be taken in dose selection. For these patients, the dose should be adjusted based on creatinine clearance.

Gabapentin capsule adverse reactions

1. Neuralgia after herpes infection:
Mainly dizziness, drowsiness, and peripheral edema. Other adverse events occurred in foreign clinical trials that were higher than 1% and higher than the placebo control group included:
Whole body: weakness, infection, headache, accidental trauma, abdominal pain.
Digestive system: diarrhea, constipation, dry mouth, nausea, vomiting, flatulence.
Metabolic and nutritional disorders: weight gain, hyperglycemia.
Nervous system: ataxia, abnormal thinking, abnormal gait, mismatch, and feeling dull.
Respiratory system: pharyngitis.
Skin and appendages: rash.
Special senses: amblyopia, diplopia, conjunctivitis, otitis media.
2. Epilepsy:
The most common adverse events were drowsiness, fatigue, dizziness, headache, nausea, vomiting, weight gain, tension, insomnia, ataxia, nystagmus, paresthesia, and anorexia.
Occasionally weakness, visual impairment (amblyopia, diplopia), tremor, joint dislocation, abnormal thinking, forgetfulness, dry mouth, depression, and emotional tendency.
Occasionally occurs in clinical studies: indigestion, constipation, abdominal pain, urinary incontinence, increased appetite, rhinitis, pharyngitis, cough, myalgia, back pain, facial and limb or systemic edema, decreased erectile function, abnormal teeth, Gingivitis, pruritus, leukocytopenia, fractures, vasodilation and hypertension.
In addition, aggressive behaviors, emotional instability, hyperactivity (excessive exercise, partially uncontrollable), viral infection, and fever were observed in clinical trials for children under 12 years of age.
Hemorrhagic pancreatitis has been reported in patients treated with gabapentin capsules. (See note)
Allergic reactions have been reported in individual cases when treated with gabapentin capsules (Stevens-Johnson syndrome, erythema polymorphic).
In laboratory-controlled clinical controlled studies, 16% of patients experienced clinically relevant blood glucose fluctuations (<3.3mmol / L or 7.8mmol / L, normal value range of 3.5 to 5.5mmol / L) (see notes). Concomitant use with other antiepileptic drugs has reported increased liver function test results.

Gabapentin capsule contraindications

People who are allergic to any of the ingredients in this drug and patients with acute pancreatitis are prohibited from taking gabapentin capsules. Gabapentin capsules are not effective in patients with primary systemic attacks such as absence.

Gabapentin capsules precautions

Foreign research reports:
Withdrawal of drugs that cause seizures and status epilepticus should not be stopped abruptly because they may increase the frequency of seizures.
In the placebo-controlled study, the incidence of status epilepticus was 0.6% (3/543) in the gabapentin group compared with 0.5% (2/378) in the placebo group. Epilepsy persisted in 31 (1.5%) of 2074 patients treated with gabapentin in all studies (both control and non-control). Fourteen of these patients had not experienced a status epilepticus during previous treatment or when taking other drugs. Since there is not enough medical history data available, it cannot be said whether the treatment of gabapentin is related to a higher or lower incidence of epilepsy status than those who did not use gabapentin.
Potential carcinogenic effects:
The preclinical study of animal carcinogenesis found that the incidence of pancreatic acinar carcinoma in male rats was higher, and the clinical significance of this result is unclear. Pre-marketing clinical studies of gabapentin are unclear to predict its potential to induce human tumors. The clinical study included 2085 patients on long-term medications, and 10 patients had new tumors (2 breast cancer, 3 brain cancer, 2 lung cancer, 1 adrenal cancer, 1 non-Ho (Jekin's lymphoma and 1 case of endometrial cancer), tumor progression in 11 patients (including 9 cases of brain cancer, 1 case of breast cancer, and 1 case of prostate cancer). Since there is no background information on tumor incidence and recurrence rates in a similar population that has not been treated with gabapentin, it is impossible to know whether treatment in this study affected the incidence.
Sudden and unexplained death:
During the pre-marketing study of gabapentin, 8 of 2203 patients (of which 2103 patients were on long-term treatment) experienced sudden and unexplained deaths.
Some of these deaths can be interpreted as deaths due to seizures, such as undetected seizures at night. The incidence of this situation is 0.0038 persons / year. Although this ratio has exceeded the ratio of healthy people of the same age and gender, it is within the range of sudden death rates of epilepsy who have not taken gabapentin (from 0.0005 to 0.003 in ordinary people to 0.003 in clinical trials similar to this trial Or 0.0005 to 0.005 in refractory patients). Therefore, the reliability of the results depends on the comparability and statistical accuracy of the population receiving gabapentin treatment.
Special considerations:
In clinically controlled studies, 16% of patients experienced clinically significant blood glucose fluctuations (<3.3mmol / L or 7.8mmol / L, with normal values ranging from 3.5 to 5.5mmol / L). Therefore, patients with diabetes need to monitor blood glucose frequently, and adjust the dose of hypoglycemic agent at any time if necessary.
Patients with renal insufficiency must take this product in a reduced amount (see Dosage and Administration).
There have been reports of bleeding pancreatitis when taking this product. Therefore, if there are clinical symptoms of pancreatitis (persistent abdominal pain, nausea, repeated vomiting), this product should be discontinued immediately, and a comprehensive physical examination, clinical and laboratory examinations should be performed in order to diagnose pancreatitis as soon as possible.
For patients with chronic pancreatitis, there is no sufficient experience with gabapentin. The use of gabapentin should be determined by the doctor.
Gabapentin may have elevated plasma concentrations in patients who are concurrently treated with morphine. Patients should be carefully observed for signs of central nervous system depression such as lethargy, and the dose of gabapentin or morphine should be appropriately reduced (see Drug Interactions).
Effects on driving and mechanical operation This product acts on the central nervous system and can cause sedation, dizziness or similar symptoms.
Therefore, even taking this product at the prescribed dose can reduce the reaction speed, impair driving ability, ability to operate complex machines, and ability to work in exposed environments, especially at the beginning of treatment, when adding medicine, changing medicine, or at the same time. While drinking.

Gabapentin capsules for pregnant and lactating women

There is currently no experience of using this product in pregnant women, and this product can only be used after a full assessment of benefits / risks.
This product is secreted in breast milk, and it is not yet possible to rule out the possibility that this product can cause serious adverse events in the infant. Therefore, breastfeeding women should stop breastfeeding or stop using this product when taking this product into consideration (considering the anti-epilepsy of the mother) The need for treatment).

Gabapentin capsules for children

For usage and dosage of children, please refer to Usage and dosage.

Gabapentin capsules for elderly

The same dose for treating neuralgia after herpes infection is better for patients 75 years and older than younger patients. But the influence of other factors cannot be ruled out. With the exception of peripheral edema and ataxia that increase with age, the type and incidence of side effects are similar across age groups.
Treatment of epilepsy in people over 65 years of age has not been systematically studied. However, clinical observations have shown that adverse event performance in this age group is not different from that of younger people.

Gabapentin capsule drug interactions

Gabapentin is rarely metabolized and does not interfere with the metabolism of other commonly used antiepileptic drugs.
The drug interaction data described in this section were obtained from studies in relevant healthy adults and patients with epilepsy.
Phenytoin: A study of single and multiple doses of gabapentin (0.4 g each time, three times a day) in patients with epilepsy (N = 8) who have been taking phenytoin for at least two months. The concentration had no effect, and phenytoin had no effect on the pharmacokinetics of gabapentin.
Carbazine: Taking gabapentin (0.4 g each time, three times a day; N = 12) does not affect the steady-state plasma concentrations of carbazine and 10,11 epoxides. Similarly, taking carbamate will not change the pharmacokinetics of gabapentin.
Valproic acid: There was no difference in the average steady-state plasma concentration of valproic acid before and during taking gabapentin (0.4 g each, three times a day; N = 17), and the pharmacokinetic data of gabapentin was not affected by valproate Effects of acids.
Sedative sleeping pills: Whether used alone or in combination, sedative sleeping pills or gabapentin (0.3 g each time, three times a day; N = 12) are the same for steady state pharmacokinetic data evaluation.
Naproxen: The combination of naproxen sodium capsules (250mg) and Neurontin (125mg) increases the absorption of gabapentin by 12% to 15%. Gabapentin has no effect on the pharmacokinetic parameters of naproxen. Both give lower doses than their respective therapeutic doses. The interaction at the recommended dose range is unknown.
Dihydrocodeinone: Cmax and AUC of dihydrocodeinone (10mg, N = 50) are reduced when gabapentin (0.125 to 0.5g; N = 48) is used in combination with the dose of dihydrocodeinone Dependent. The combination of gabapentin (0.125g) reduced the Cmax and AUC of dihydrocodeinone (10mg, N = 50) by about 3% to 4%, and the combination of gabapentin (0.5g) reduced dihydrocodeinone (10mg, N = 50) Cmax and AUC decreased by about 21% to 22%. The mechanism of this interaction is unclear. Dihydrocodeinone can increase the AUC of gabapentin by about 14%. The interactions at other doses are unclear.
Morphine: According to the literature, after giving 60 mg of controlled-release morphine capsules for 2 hours and then 0.6 g of gabapentin capsules (N = 12), the average AUC of gabapentin increased 44% compared to when morphine was not used (see warning). The pharmacokinetic parameters of morphine did not change after taking gabapentin. Interactions with other doses are unknown.
Cimetimiguanine: 0.3 mg of cimetidine each time, 4 times a day (N = 12), the average apparent oral clearance of gabapentin decreased by 14%, and the creatinine clearance decreased by 10%. Thus, cimetidine may alter renal excretion of gabapentin creatinine. The small decrease in gabapentin excretion caused by cimetidine has no significant clinical significance. The effect of gabapentin on cimetidine was not evaluated.
Oral contraceptives: After taking a tablet containing 2.5 mg norethindrone acetate and 50 g ethinyl estradiol, whether or not taking gabapentin (0.4 g each time, three times daily; N = 13), norethindrone acetate and ethynyl The AUC and half-life of estradiol are similar. When coadministered with gabapentin, the Cmax of norethisterone increased by 13%; this interaction has no significant clinical significance.
Antacids (aluminum hydroxide): Aluminum hydroxide reduces the bioavailability of gabapentin by approximately 20%. After taking gabapentin 2 hours after taking aluminum hydroxide, bioavailability decreased by about 5%. Therefore, it is recommended that gabapentin should be taken at least 2 hours after taking aluminum hydroxide.
Probenecid (Carbesulamide): Probenecid is a renal tubular secretion blocker. Comparing the pharmacokinetic parameters of the gabapentin test with or without probenecid, the results confirm that gabapentin cannot flow through the tubule pathway blocked by probenecid.

Gabapentin capsule overdose

Diplopia, slurred speech, lethargy, indifference, and diarrhea can be reported in patients taking an overdose of 49 g of gabapentin. All patients recovered after rescue.
Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in patients with overdose of this product, its clearance can be observed in some patients with impaired renal function.

Gabapentin capsules pharmacology and toxicology

Pharmacological effects The mechanism of gabapentin's anticonvulsant effect is not clear, but animal experiments suggest that gabapentin can suppress seizures similar to other marketed anticonvulsants. The results of maximal electrical shock test in mice and rats, seizure test of benzotetrazole, and other animal tests (such as hereditary epilepsy models, etc.) suggest that gabapentin has antiepileptic effects, but the relevance of these epilepsy models to humans is unclear.
Gabapentin is structurally related to the neurotransmitter GABA, but does not interact with GABA receptors. It can neither be metabolized into GABA or GABA agonists, nor is it an inhibitor of GABA uptake or degradation. Radioligand binding test found that when gabapentin concentration reaches 100 m, it has no affinity for many common receptor sites, including benzodiazepine receptor, glutamate receptor, NMD receptor, quisqualate receptor, and kainic acid receptor , Papaverine-insensitive or -sensitive glycine receptor, 1, 2 or receptor, adenosine A1 or A2 receptor, M or N receptor, dopamine D1 or D2 receptor, H1 receptor Receptors, serotonin S1 or S2 receptors, opioid , or k receptors, nitrendipine or diltiazem-labeled voltage-sensitive calcium channel sites, frog toxin A 20--benzoate-labeled voltage-sensitive Sodium channel sites. Because the results of several commonly used trials to evaluate the effects of drugs on NMDA receptors are opposite, there is no unified understanding of the effects of gabapentin on NMDA receptors.
In vitro studies have shown that the binding sites of gabapentin in the rat brain are distributed in the neocortex and hippocampus, and its high-affinity binding protein has been confirmed as an auxiliary subunit of voltage-activated calcium channels, and related functions have not been elucidated.
Toxicological studies Genopentin Ames test, CHL HGPRT mutation test, CHL chromosome aberration test, Chinese hamster bone marrow chromosome aberration test and micronucleus test, mouse micronucleus test, rat liver cell extra-programmed DNA synthesis test (UDS) results are all Is negative.
Reproductive toxicity General reproductive toxicity: After oral administration of gabapentin (500, 1000, and 2000 mg / kg / day) to rats, all fetuses were affected. Teratogenic sensitivity period: Gabapentin was administered orally to pregnant mice at 1000 or 3000 mg / kg / day, embryo toxicity occurred, and ossification of the skull, vertebrae, forelimbs and hind limbs was delayed. The non-toxic dose was 500 mg / kg / day. Perinatal toxicity: Gabapentin was administered to rabbits at 60, 300, and 1500 mg / kg / day, and the fetal loss rate increased after implantation.
In addition, in general reproductive toxicity tests in rats (oral administration of 2000 mg / kg), teratogenicity toxicity tests (1500 mg / kg), perinatal toxicity tests (500, 1000, and 2000 mg / kg), The incidence of hydroureter and / or hydronephrosis in rats is increased. According to the calculation of body surface area ratio, when the doses of gabapentin to mice, rats and rabbits were 4, 5, and 8 times the human doses respectively, no increase in the incidence of teratogenesis was observed.
Carcinogenic mice and rats were orally given gabapentin 200, 600, 2000 mg / kg / day and 250, 1000, 2000 mg / kg / day, respectively, for 2 consecutive years. The results showed that the incidence of pancreatic acinar cell tumors and pancreatic acinar cell carcinomas of male animals in the high-dose group increased significantly, but did not affect the survival of the animals, nor did they show metastasis and invasion. Studies suggest that gabapentin can promote DNA synthesis in rat pancreatic acinar cells in vitro, so it may be a mitogenic cancer-promoting agent. However, the effect of gabapentin on other cells and species (including humans) to promote cell proliferation is not clear.
Clinical studies show that 2085 patients (longer than 12 years of age) who took long-term medications developed new tumors within 2 years after stopping gabapentin (2 cases of breast cancer, 3 cases of brain cancer, 2 cases of lung cancer, 1 case of adrenal glands). Cancer, 1 case of non-Hodgkin's lymphoma, and 1 case of endometrial cancer), tumor progression in 11 patients (including 9 cases of brain cancer, 1 case of breast cancer, and 1 case of prostate cancer). Since there is no background information on tumor occurrence and recurrence rates in a similar population who have not been treated with gabapentin, it is not certain that the occurrence or worsening of the above tumors is related to the treatment.

Pharmacokinetics of Gabapentin Capsules

According to reports in the literature, all pharmacological effects of gabapentin are derived from the activity of its parent compound, and the metabolism of gabapentin in the human body is not obvious.
Oral bioavailability: The bioavailability of gabapentin is not proportional to the dose. As the dose increases, the bioavailability decreases. The bioavailability of gabapentin in divided doses of 900, 1200, 2400, 3600, and 4800 mg three times daily was approximately 60%, 47%, 34%, 33%, and 27%, respectively. Food only slightly affected the rate and extent of gabapentin absorption (14% increase in AUC and Cmax).
Distribution: Gabapentin mostly does not bind to plasma proteins in the circulation (protein binding rate <3%). The apparent volume of distribution after intravenous injection of gabapentin 150 mg was 58 ± 6 L (mean ± SD). Gabapentin steady-state trough concentration (Cmin) in the cerebrospinal fluid of patients with epilepsy is about 20% of the corresponding plasma concentration.
Elimination: Gabapentin is eliminated from the systemic circulatory system mainly through renal excretion in its original form, and its metabolism is not obvious in the human body. The elimination half-life of gabapentin is 5-7 hours and does not change with dose or multiple administrations. Gabapentin's elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance (see Patients with Renal Insufficiency in Specific Populations). Gabapentin has decreased plasma clearance in elderly patients and patients with impaired renal function. Gabapentin can be removed from plasma by hemodialysis.
Special population: Adult patients with renal insufficiency: Subjects with renal insufficiency (average creatinine clearance of 13 to 114 mL / min) (N = 60) single-dose gabapentin 400mg orally, with an average half-life of 6.5 hours (creatinine Patients with clearance> 60 mL / min) ~ 52 hours (patients with creatinine clearance min), renal clearance of gabapentin is 90 mL / min (patients with creatinine clearance> 60 mL / min) ~ 10 mL / min ( Patients with creatinine clearance <30 mL / min). The mean plasma clearance decreased from approximately 190 mL / min to 20 mL / min.
Patients with renal impairment or patients undergoing hemodialysis need to be dose adjusted.
Pediatric patients with renal insufficiency have not been studied.
Hemodialysis: In a study of patients without anuria (N = 11), the apparent elimination half-life of gabapentin when undialyzed is approximately 132 hours; three times a week (4 hours each), the apparent elimination of gabapentin The half-life was reduced from 132 hours to 51 hours, a reduction of approximately 60%. It can be seen that hemodialysis has a great effect on the elimination of gabapentin in anuria patients.
Patients on hemodialysis need to adjust the dose.
Patients with liver disease: Because gabapentin is not metabolized, patients with liver damage have not been studied.
Age: A study of age effects was performed in subjects 20 to 80 years old. Gabapentin's apparent oral clearance (CL / F) decreased with age, from about 225 mL / min in people under 30 to about 125 mL / min in people over 70. Renal clearance (CLr) and body-adjusted renal clearance also decrease with age; however, the decrease in renal clearance with gabapentin can be largely explained by a decrease in renal function with age. A reduction in gabapentin dose is required in patients with age-related kidney disease.
Pediatrics: The pharmacokinetics of gabapentin were performed in 48 pediatric subjects aged 1 month to 12 years old at a dose of approximately 10 mg / kg. The peak plasma concentration is similar in all age groups, and the peak time is about 2 to 3 hours after administration. In general, pediatric subjects between the ages of one month and less than five years of age are about 30% lower than the observed exposure in children 5 years and older (AUC). Therefore, standardized oral clearance per body weight is higher in younger children. Gabapentin's apparent oral clearance is directly proportional to creatinine clearance. Gabapentin's elimination half-life averages 4.7 hours and results are generally similar across age groups.
According to foreign literature reports, a total pharmacokinetic analysis was performed in 253 pediatric patients aged 1 month to 13 years. Patients receive 10 to 65 mg / kg / day given three times daily. Apparent oral clearance (CL / F) is directly proportional to creatinine clearance, and this relationship is similar at a single dose and at steady state. When calibrated in kilograms of body weight, higher oral clearance values were observed in children younger than 5 years of age than in children 5 years or older. Clearance in infants younger than 1 year is very variable. The standard oral clearances observed in paediatric patients 5 years of age and older are consistent with values after single dose administration in adults. Normalized volume of oral distribution per kg of body weight is constant throughout the age range.
Pharmacokinetic data indicate that the effective daily dose in pediatric patients with epilepsy aged 3 to 4 years should be 40 mg / kg / day, and the average plasma concentration reached is equivalent to that of patients aged 5 or older receiving gabapentin 30 The plasma concentrations achieved at mg / kg / day were similar.
Gender: Although no formal studies have been performed to compare the pharmacokinetics of gabapentin in men and women, the available data show that the pharmacokinetic parameters of men and women are similar and there is no significant gender difference.
Race: The pharmacokinetic differences of race have not been studied. Since gabapentin is mainly excreted by the kidneys and there is no large racial difference in creatinine clearance, there is no difference in the pharmacokinetics of the race.

Gabapentin capsule storage

Keep sealed and avoid high temperature.

Gabapentin capsules

Aluminum plastic blister board, 4 × 12 tablets / board / box.

Gabapentin capsule expiration date

24 months

Gabapentin Capsules

YBH04852004 ^[1]