Quality of life of patients with Peripheral Diabetic Neuropathy Pain and the analgesic effect and safety of gabapentin-carbamazepine combination in an animal model and its formulation

Abstract

Background: Peripheral Diabetic Neuropathy (PDN) is a late manifestation of uncontrolled Diabetes Mellitus (DM). PDN has a wide variety of clinical manifestations, at somatic, autonomic and central nervous system levels and can significantly modify the quality of life. Peripheral Diabetic Neuropathy Pain (PDNP) is a result of injury to the peripheral nervous system. PDNP is often chronic, and if inadequately managed, patients often experience anxiety and depression. Despite the evaluation of many pharmacologic and nonpharmacological therapies, there are few drugs approved by Food and Drug Administration (FDA) as a treatment of PDNP. Objectives: There are three main scopes of objectives include epidemiology study of PDNP, evaluate the effectiveness and safety of gabapentin (GBP) and carbamazepine (CBZ) combination therapy in an animal model, as well as to develop and formulate a suitable pharmaceutical dosage form of GBP and CBZ combination. Methodology: To evaluate the quality of life (QoL) of PDNP patients, the study adopted a cross-sectional design, and the Douleur Neuropathy 4 (DN4) and Audit of Diabetes-Dependent Quality of Life (ADDQoL) questionnaires were used for data collection. In addition, to explore the factors influencing the severity of pain in patients suffering from PDNP, the Short-Form McGill Pain Questionnaire (MPQ) was applied. In the animal study, PDN was produced in rats by a single intraperitoneal injection of streptozotocin (STZ) at 60 mg/kg. CBZ, GBP, and their combination were orally administered at varying doses comparable to their therapeutic doses in humans. Nociceptive responses in the diabetic rats were assessed using hot plate test. The safety of concurrent use of two medications was explored after one month of treatment at moderate therapeutic doses calculated by using drug load formula in an animal model. The formulation of a fixed dose combination of GBP and CBZ was done by a standard method of capsule preparation. Results: The results of this study indicated that individuals with diabetes and PDNP have a low QoL, particularly, with regard to “freedom to eat”, “freedom to drink”, “physical health”, “family life”, and “living condition”. Certain ADDQoL domain scores are adversely impacted by factors such as female sex, younger age, lack of employment, marriage, good financial position, diabetes duration, and insulin-based treatment. The majority of PDNP patients experienced mild pain, and the severity of pain may be affected by ethnicity and the long duration of diabetes. The combination of GBP and CBZ in the hot-plate test at doses equivalent to human therapeutic doses (GBP 90 mg + CBZ 20 mg) of the two drugs was more efficacious than GBP and CBZ given separately. Concurrent administration of GBP and CBZ at moderate therapeutic doses appeared safe and may be reasonable with fewer adverse effects compared with high doses of single drug or combination. Finally, a fixed dose combination of CBZ and GBP capsule has been easily formulated by the standard method. Conclusion: PDNP is a serious problem and need more attention regarding the health care and management. Combination therapy of GBP and CBZ at moderate dose can be used to control the pain with few side effects and easily can be formulated in a fixed pharmaceutical dosage form.