Transdermal Administration of Aqueous Pregabalin Solution as a Potential Treatment Option for Patients with Neuropathic Pain to Avoid Central Nervous System-Mediated Side Effects

Abstract

Pregabalin, (S)-3-isobutyl-γ-aminobutyric acid (GABA), is a widely used adjuvant therapy for patients with neuropathic pain, which is defined as chronic pain caused by lesions or diseases of the somatosensory nervous system. However, dizziness and somnolence (sleepiness) are common dose-limiting side effects, probably due to excessive sedative effects on higher centers of the central nervous system (CNS) which are involved in the anticonvulsant and analgesic actions of pregabalin. We speculated that transdermal delivery would minimize centrally mediated side effects. To test this idea, we evaluated the analgesic effects of pregabalin delivered through the transdermal route in animal models of neuropathic pain. Transdermally administered pregabalin increased the pain thresholds in response to mechanical stimuli in a partial sciatic nerve ligation model in rats and a spinal nerve ligation model in mice, and surprisingly also in normal animals. It is noteworthy that simple transdermal application of an aqueous solution of pregabalin is effective. This could be a useful treatment option to avoid or minimize the CNS-mediated side effects of orally administered pregabalin.Key words neuropathic pain; pregabalin; transdermal administration Neuropathic pain is chronic pain caused by lesion or disease of the somatosensory nervous system. 1-3) It is characterized by allodynia (pain in response to normally innocuous stimuli), hyperalgesia (increased pain evoked by noxious stimuli) and spontaneous pain. Treatment of neuropathic pain remains a clinical challenge, because the pathophysiology of neuropathic pain is complex and the underlying mechanisms remain poorly understood. 4,5) Although chronic neuropathic pain often responds unsatisfactorily to opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), it can be treated effectively with antidepressants and antiepileptics as adjuvant analgesics. 5) The (S)-isomer of 3-isobutyl-γ-aminobutyric acid (GABA), pregabalin, which was identified as an antiepileptic in the early 1990's, is now widely used for treatment of diabetic peripheral neuropathy, postherpetic neuralgia, spinal cord injury nerve pain, fibromyalgia and partial onset seizures. 6-8) Unfortunately, though, central nervous system (CNS)-mediated side effects such as dizziness and somnolence (sleepiness) are common in pregabalin-treated patients and have a significant impact on their quality of life. 9) Therefore, other treatment options that overcome these problems would provide substantial benefits to patients. Topical application through the transdermal route is one possible option to reduce systemic drug exposure and penetration into the brain, and thereby to minimize CNS-mediated side effects. In this study, therefore, we evaluated the analgesic effects of transdermally administered pregabalin in rats and mice. MATERIALS AND METHODSChemicals Pregabalin (free base) used for experiments in rats was obtained from Sequoia Research Products Ltd. (Pangbourne, U.K.). Pregabalin (crystallized free base) used for experim...

DOE Optimization of Nano-based Carrier of Pregabalin as Hydrogel: New Therapeutic & Chemometric Approaches for Controlled Drug Delivery Systems

“…In the present work; inclusion of PG in niosomal hydrogel preparation is of great importance as many reported PG formulations including PG conventional topical gel 15 , PG patch 16 and PG solution 17 were not enhanced with such innovative nano-vesicles, resulting in the lacking of their ability to deliver PG in controlled pattern with good skin permeation profiles to achieve the bioavailability augmentation.…”

Evaluation of in vitro transdermal permeation, mass spectrometric imaging, and in vivo analgesic effects of pregabalin using a pluronic lecithin organogel formulation in mice

“…Some studies have also reported the analgesic effect of transdermal pregabalin preparations, that is, an aqueous solution or PLO gel of pregabalin 9,21 . According to one report, 9 an aqueous solution of pregabalin (0.25 or 0.75%) had a significant analgesic effect 1.5 h after application in a spinal nerve ligation model in mice.…”

“…However, it has side effects, such as dizziness, somnolence (sleepiness), and edema, which may be severe enough to be either dose‐limiting or lead to discontinuation in clinical practice 8 . In a previous study, transdermal application of an aqueous pregabalin solution was reported to be effective against neuropathic pain in rats and mice 9 . Since the central nervous system (CNS)‐mediated side effects of orally administered pregabalin are expected to be avoided or minimized by transdermal delivery of the drug, topical application via the transdermal route would substantially benefit patients.…”

Development and in vitro Characterization of Gastroretentive Formulations as Calcium Pectinate Hydrogel Pellets of Pregabalin by Ionotropic Gelation Method

“…Its primary effect is anticonvulsant, and it is used in epilepsy. 9,10 Its mechanism of action is still not fully resolved, although it has been found to bind to the calcium channel in the central nervous system and reduce calcium flow at the nerve endings. Thus, it is thought to change the release of neurotransmitters that reduce the communication between nerves and be effective in neuropathic pain and epilepsy seizures.…”