Mechanism of Action of Anticonvulsants as Analgesic Drugs

SUMMARY

Anticonvulsant drugs provide meaningful pain relief for many patients with chronic pain. The exact mechanisms by which they exert their beneficial effects are not always known, although the most commonly used drugs appear to work through inhibition of voltage-gated sodium and calcium channels. Many anticonvulsants, however, exhibit polypharmacology, which may aid their overall efficacy in treating both epilepsy and pain. We discuss here what is known about two major classes of anticonvulsant drugs. We also consider more recent developments that highlight new mechanisms involving γ-aminobutyric acid A (GABA _A ) receptor modulators, GABA transporter inhibitors, carbonic anhydrase and SV2A inhibitors, and potassium channel openers. The range of anticonvulsants working through different mechanisms can be seen as an advantage for patients with chronic pain. It increases the options for clinicians, who can switch medication when a drug targeting one particular mechanism has not shown efficacy or has been associated with an unacceptable side effect profile. Clinicians regularly use combinations of drugs to increase efficacy. However, there are relatively few clinical trial data on such studies. With increasing numbers of molecular targets comes an increasing chance of identifying valuable synergies between drugs. The example of acetazolamide synergizing with midazolam is an excellent example of two mechanisms of action reinforcing each other in the same pathway.

Unfortunately, the beneficial properties of anticonvulsants for pain relief have to be counter-balanced by the well-known side effects of this class of molecules, including dizziness, ataxia, nausea, and other central nervous system– and cardiovascular-related events. Often, these well-described side effects are managed by careful dose titration regimens specific for each anticonvulsant drug.

The huge investment in basic research for voltage-gated sodium and voltage-gated calcium channels has provided invaluable insight into their functional properties and highlighted their key role in pain physiology. Moreover, knowledge gained from the mechanisms of action of the anticonvulsant molecules that interact with these channels is driving the race toward the next generation of safer and more efficacious pain-killing drugs. The combination of selectivity and state-dependent block appears to provide the best opportunity to achieve this goal.

Introduction

This chapter focuses on the mechanism of action of anticonvulsants used for the management of patients with pain. Anticonvulsants cover a range of drug classes and exert their mechanism of action through several molecular targets. Although many anticonvulsants demonstrate polypharmacology, two mechanisms of action predominate: the first involves direct blockade of voltage-gated sodium channels, and we discuss in detail the nature of the functional pharmacology that underlies the efficacy/safety profile of these molecules. The second main mechanism of action involves indirect blockade of voltage-gated calcium channels, as observed with the gabapentinoids. It now appears that the gabapentinoids can inhibit trafficking of the α ₂ δ subunit of voltage-gated calcium channels.

Both sodium and calcium channel blockers require careful dose escalation, when used clinically, to reach their required therapeutic exposure and are dose-limited by central nervous system (CNS) and cardiovascular side effects. The knowledge gained from extensive research on the mechanism of action of these anticonvulsants has enlightened and informed the search for novel, safer, and more efficacious analgesic compounds. The next generation of analgesic compounds targeting these key ion channels will most likely consist of more potent, more selective compounds that exhibit a state-dependent block. Finally, as newer anticonvulsants emerge, such as levetiracetam and retigabine, then so do new targets for analgesic drug development, such as synaptic vesicle 2A (SV2A) protein and voltage-gated potassium channels.

Anticonvulsants with a Mechanism of Action Against Voltage-Gated Sodium Channels

The primary mechanism of action of anticonvulsants such as lamotrigine, lacosamide, carbamazepine, valproate, phenytoin, and topiramate is inhibition of voltage-gated sodium channels. This section focuses on the relevance of targeting these channels for the treatment of pain and the precise mechanism of action of anticonvulsants in the context of their efficacy and safety/tolerability profile. Finally, we consider new opportunities and challenges for the future discovery of more efficacious and safer sodium channel–blocking analgesics in light of recent technological advances, as well as better understanding of the underlying mechanisms of pain pathophysiology.

Involvement of Sodium Channels in Pain Pathophysiology

Anticonvulsants are effective in treating clinical conditions driven by hyperexcitability of affected neuronal circuits, such as in epilepsy or chronic pain. Many anticonvulsants are able to decrease the hyperactivity of the pain network by targeting the ionic channels involved in the generation and propagation of neuronal firing, such as voltage-gated sodium channels, which may therefore be considered as points of convergence in pain signaling. In epilepsy, hyperactivity of neuronal networks involves paroxysmal depolarization and high-frequency firing, which results in seizures. The neurobiological basis of pain is usually an electrical signal that is initiated at the periphery and propagates within a neuronal network via the spinal cord to eventually reach the somatosensory cortex, where one becomes aware of it. Pain signaling is subject to very complex and diverse modulation at the peripheral, spinal, and supraspinal levels, the end point of which is to shape and set the firing pattern of the underlying neuronal network. In chronic pain, not only is the balance between excitatory and inhibitory influences changed, but functional plasticity processes also modify the integration properties of the pain network and thereby result in a state of neuronal hyperexcitability and hyperactivity ( , , ). The origin of this imbalance can be very diverse because many modulators and their receptors are involved in the control of nociceptive processing and often interact with each other ( ).

At the primary afferent level, the manifestation of hyperexcitability is an increased action potential firing frequency in response to stimulation, modification of the discharge patterns (including the occurrence of high-frequency burst firing), and ectopic spontaneous discharges. These features have been observed extensively in preclinical models of neuropathic pain via in vivo electrophysiology ( , ), as well as in the clinic with microneurography techniques ( ). Parallel hyperactivity has been observed in the spinothalamic neurons of rodents and primates ( , ). Generally, higher firing frequencies are recorded in Aδ than in C fibers for the periphery, and central neurons discharge at higher frequencies than do primary afferents ( , , ). At clinically relevant concentrations, phenytoin, carbamazepine, and lamotrigine were shown to inhibit the enhanced firing resulting from nerve injury or inflammation in peripheral nerve and spinal neurons ( , , , ).

Voltage-gated sodium channels play a central role in driving neuronal excitability in excitable cells, in the underlying ionic conductance of the action potential rising phase ( ), and in modulating the resting membrane potential and shaping subthreshold oscillations ( ). Each sodium channel subtype has unique biophysical properties that confer different voltage-dependent activation, inactivation, and repriming kinetics that influence cell resting membrane potential, excitability, and firing patterns.

To date, nine sodium channel subtypes have been identified (Na _v 1.1–Na _v 1.9). Na _v 1.7, Na _v 1.8, and Na _v 1.9 are prevalently expressed in the peripheral nervous system and Na _v 1.2 in the brain. Na _v 1.1, Na _v 1.3, and Na _v 1.6 are expressed in both the CNS and peripheral nervous system ( ). Na _v 1.5 is the principal subtype in the heart, and Na _v 1.4 is predominant in skeletal muscle. Sodium channels are trafficked to distinct subcellular locations, which leads to the complex control of cell excitability. For example, immunocytochemistry studies of the human brain ( ) have shown that Na _v 1.1, Na _v 1.3, and Na _v 1.6 are expressed on neuronal cell bodies and dendrites whereas Na _v 1.2 and Na _v 1.6 are observed in axons, the latter being the main channel present at the node of Ranvier. Na _v 1.6, Na _v 1.7, Na _v 1.8, and Na _v 1.9 are highly expressed in nociceptive sensory neurons; on nerve terminals, where they probably participate in sensory transduction; on axons, where they are essential for propagation of action potentials; and on cell bodies ( ). The combination of different tissue and cellular expression patterns for each sodium channel subtype, each with subtly different gating properties, offers the potential for fine-tuning of cell excitability and intrinsic firing properties.

Much evidence shows that modifications in sodium channel expression, activity, and biophysics, in peripheral as well as central neurons, are associated with the development of chronic pain ( ). In the absence of truly selective pharmacological tools for sodium channel subtypes, abundant literature data combining immunocytochemistry, electrophysiology, and knockout or knockdown studies have identified Na _v 1.3, Na _v 1.7, Na _v 1.8, and Na _v 1.9 as major contributors to neuropathic and inflammatory pain. Importantly, expression of Na _v 1.3, Na _v 1.7, and Na _v 1.8, which are all likely to be involved in the generation of ectopic discharges, is increased in human painful neuromas ( , ). Recently, however, the strongest body of evidence contributing to an understanding of the role of sodium channel subtypes in human pain has come from genetic data. Although functional mutations displaying abnormal pain phenotypes are rare in human biology, two types of functional mutations in Na _v 1.7 have highlighted the importance of this channel for pain processing in humans. Loss-of-function mutations rendering the channel completely inactive are associated with congenital insensitivity to pain.

At the opposite end of the spectrum, a series of mutations leading to a gain of function of the channel are consistent with an experience of extreme pain. Patients with inherited erythromelalgia suffer recurrent attacks of intense pain, erythema, burning sensation, and swelling of the limb extremities. These gain-of-function mutations result in a lowered threshold for channel activation and an increase in current magnitude. In paroxysmal extreme pain disorder, which is characterized by severe rectal, ocular, and mandibular pain, the inherited mutations were found to impair inactivation and hence lead to enhanced channel activity and an increased persistent current ( ). These clinical observations encourage the discovery of drugs with greater potency and selectivity at Na _v 1.7 in the hope of achieving better efficacy without increasing the side effects most likely to occur via targeting of central sodium channels. This has become a major focus for the pharmaceutical industry.

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