The sections above documented that the ectopic pacemaker hypothesis, in conjunction with peripherally driven changes in the CNS, provides a cogent account of the clinical signs and symptoms in a broad range of neuropathic pain conditions. The ultimate test of the hypothesis, however, is its ability to explain the efficacy of known therapeutic agents and to predict new ones.
Pain relieving drugs that suppress electrogenesis act through either membrane processes or synaptic processes. Examples of drugs that act on membrane excitability, but not synapses, are the local anesthetic lidocaine and the anticonvulsant carbamazepine. Drugs thought to act predominantly by a synaptic action include the γ-aminobutyric acid receptor ligands baclofen and midazolam. Anticonvulsants with a purely synaptic action, such as barbiturates, are largely ineffective as pain relievers whereas anticonvulsants that are membrane stabilizers, such as carbamazepine and gabapentin, are effective. Likewise, some antidepressants suppress neuropathic pain—tricyclic antidepressants and serotonin–noradrenaline reuptake inhibitors (SNRIs), for example—whereas others are much less effective (e.g., selective serotonin reuptake inhibitors [SSRIs]). As discussed later, the difference may be due to the ability of the drug to stabilize membranes and suppress ectopia rather than its selectivity for noradrenaline versus serotonin transporters, as is generally presumed.
Agents that modulate membrane properties may act in the PNS or the CNS. Since synapses are virtually absent in peripheral sensory pathways, drugs with an exclusively synaptic action are not usually thought to play a significant role in the PNS. However, this logic may be misleading; synaptically acting drugs may nonetheless modulate membrane excitability in the periphery. As noted above, DRG neurons (and glia) express many neurotransmitter receptors such as opiate receptors, adrenoreceptors, ATP (purinergic) receptors, glutamate receptors, and many others. DRGs lack blood and tissue barriers. Thus, circulating endorphins, ATP, and glutamate–endogenous molecules that are normally thought of as acting synaptically–could directly modulate afferent membrane excitation and excitability. By the same token, therapeutic agents presumed to act synaptically in the CNS may have additional effects on their cognate non-synaptic receptors in the PNS. Indeed, a number of familiar therapeutic agents have dual actions, either for this reason or by virtue of their ability to activate more than one receptor type. Amitriptyline duloxetine, ketamine, and gabapentin are among these (see later discussion). Each acts synaptically in the CNS and also suppresses ectopia by a membrane stabilizing action in the PNS.
In the CNS, hyperexcitability is almost always conceived of as a property of synaptic networks, but in principle, neuropathy could just as well induce pain by affecting the intrinsic electrical excitability of central neurons. This mechanism is engaged following direct injury to the CNS (e.g., spinal cord contusion or epilepsy), but it is unclear whether it is involved in pain following peripheral nerve injury (Balasubramanyan et al 2006, Devor 2006, Lampert et al 2006, Schoffnegger et al 2006, Caspi et al 2009). I will now consider how drugs can modulate neuropathic pain by actions on ectopic pacemaker activity.
A great variety of therapeutic approaches aim at reducing the degree of excitation of nociceptive sensory endings and of ectopic sites of electrogenesis in neuropathic pain conditions. These approaches range from better-fitting prosthetic limbs and surgical repositioning of neuromas to narrow-spectrum drugs that target specific transduction molecules (e.g., TRPV1 antagonists currently in development). The limitation of drugs that target transduction is the plethora of mechano-, thermo-, and chemotransducer molecules that are capable of depolarizing sensory endings. No single agent is likely to block more than a small fraction of the transducer molecules, and the more target selective the drug, the less likely it is to have broad-spectrum analgesic efficacy—or any noticeable analgesic efficacy at all.
Targeting whole families of transducers can be productive. The most important example is the non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs relieve pain by inhibiting the cyclooxygenase (COX) enzymes essential for the synthesis of prostanoid molecules and thus lowering tissue prostanoid concentrations. Prostanoids excite nociceptor endings by binding to specific receptors such as the various prostaglandin receptors. The efficacy of COX inhibitors in inflammatory but not neuropathic pain suggests a limited role for these receptors in neuropathic pain. However, there are other receptor families that could be targeted in a similar manner. For example, by targeting intracellular signaling pathways it might be possible to make agents that selectively inhibit processes that sensitize whole families of transducers. Such signaling pathways tend to be complex and multiplexed, however, and questions of specificity to pain need to be addressed.
Many drugs that target Na+ channels are available. The most widely used are the local anesthetics. Lidocaine and bupivacaine applied directly to nerves at high concentration reliably block impulse conduction and stop pain of all types for the duration of the block. Current efforts to improve their usefulness aim at extending their duration of action, such as by using slow-release formulations (Epstein-Barash et al 2009, Roberson et al 2011, Wang et al 2011) or producing a nociceptor-specific block that spares motor and sensory touch fibers. In an exciting new approach, Binshtok and colleagues (2007) have shown that it is possible to use nociceptor-specific membrane channels (TRPV1) as a conduit to introduce into the axon a local anesthetic agent that acts intracellularly but is ineffective when applied on the outside of the cell (QX-314). Since motor and sensory touch fibers do not bear TRPV1 channels, they are not blocked by applying QX-314 together with a TRPV1 opener whereas nociceptors are. In principle, this idea can be exploited for a broad range of selective targeting needs in the field of pain control and beyond.
Lidocaine administered systemically to patients with neuropathic pain also provides reliable pain relief in a wide range of clinical diagnoses (Wallace et al 1996, McQuay and Moore 1998, Attal et al 2004). Obviously, if drug plasma concentrations were high enough to block nerve conduction, the treatment would be lethal. All neural function would stop. In fact, a typical systemic dose, 3 mg/kg, yields peak serum concentrations of about 2 μg/mL (10 μM). This is some 10,000 times less than the concentrations typically used for blocking nerve conduction (≈100 mM for 2% lidocaine). The pain relief obtained with systemic lidocaine is not due to nerve block. It works because impulse conduction is much less prone to being blocked than is repetitive impulse initiation (Figs. 61-13 and 61-14). It has a far higher “safety factor,” a “therapeutic window” discussed previously. Pain relief with systemic lidocaine and other membrane-stabilizing drugs is apparently due to the ability of low drug concentrations to suppress subthreshold oscillations in injured peripheral nerves and to stop peripheral ectopia (see Fig. 61-14) (Devor et al 1992a, Abdi et al 1998, Xing et al 2001, Xiao and Bennett 2008a). A CNS action may also contribute (Woolf and Wiesenfeld-Hallin 1985, Sotgiu et al 1994a, but see Chaplan et al 1995).
The fact that lidocaine and related systemically active “-caine” local anesthetics are not available in oral form limits their clinical utility, but several other Na+ channel blockers are available orally, including the anticonvulsants carbamazepine and phenytoin, and the antiarrhythmic mexiletine (see Fig. 61-14B). All suppress ectopia at doses far too low to block axonal conduction (Catterall 1987, Macdonald and Greenfield 1997). Other clinically effective pain-relieving drugs that are Na+ channel blockers and suppress ectopia are better known for other pharmacological properties. Prime examples are the antidepressants amitriptyline and duloxetine. Both are generally believed to act by inhibiting catecholamine reuptake and therefore enhancing adrenergic inhibition at central synapses. However, they are also potent Na+ channel blockers and membrane stabilizers, and suppress ectopia (see Fig. 61-14B) (Abdi et al 1998, Pancrazio et al 1998, Song et al 2000, Sudoh et al 2003, Su et al 2009, Wang et al 2010). Ketamine, an NMDA-type glutamate receptor antagonist, is likewise (Zhou and Zhou 2000). Experiments have not yet been undertaken to determine whether the primary analgesic action of these drugs is on membranes or synapses.
Another more recent example is gabapentin and pregabalin. These drugs bind the A2δ subunit of transmembrane Ca2+ channels. Gabapentin and pregabalin are widely presumed to act as Ca2+ channel blockers at intraspinal synapses or by modulating the membrane trafficking of Ca2+ channels to the synaptic membrane (Sarantopulos et al 2002, Bauer et al 2009, Taylor 2009). Reduced Ca2+ entry at the presynaptic afferent terminal is expected to depress neurotransmission. However, these drugs are also known to suppress subthreshold oscillations and peripheral ectopia (Pan et al 1999; Yang et al 2005, 2009). There is evidence that the membrane-stabilizing action is due to selective activity on the slow component of Na+ conductance (Yang et al 2009), although it remains unclear whether this is a direct effect on Na+ channels or indirect via A2δ binding. In each of these cases it is important to know which of the alternative effects is responsible for analgesia.
A final example of alternative concepts about the analgesic mechanism of familiar drugs relates to the corticosteroids. Although presumed to provide pain relief by suppressing the immune response, corticosteroids have long been recognized to have a powerful membrane-stabilizing action. They are effective at suppressing neuropathic ectopia (Kingery et al 2001, Seeman 1966, Meyer et al 2011). Moreover, this action is too rapid to be due to suppression of the inflammatory response (Devor et al 1985, Li et al 2011). It is likely that membrane stabilization rather than (or in addition to) anti-inflammatory action is the primary basis for the pain control provided by corticosteroids, especially when administered at high concentration epidurally or by injection into painful trigger points (Travell and Simons 1984). Corticosteroid molecules may reduce ectopia by binding to membrane neurosteroid receptors rather than to classic intracellular corticosteroid receptors.
Activation of K+ conductance also yields membrane stabilization (see Fig. 61-14B). Several agents, including retigabine (a novel anticonvulsant), certain diclofenac derivatives, and flupirtine (both pain relievers) have been shown to open KCNQ2/3 K+ channels (Devor 1983, Macdonald and Greenfield 1997, Lang et al 2008, Roza and Lopez-Garcia 2008, Brown and Passmore 2009, Peretz et al 2010). These and other K+ channel openers are currently in development as analgesic drugs.
Overall, most of the systemically administered therapeutic agents with documented clinical efficacy in the relief of neuropathic pain suppress ectopic afferent discharge in injured neurons. The major exception is the opiates, which presumably act by CNS synaptic action, although here, too, there may be an additional membrane-stabilizing action (Stein and Zollner 2009). With such a variety of different membrane-stabilizing drugs available for clinical use one needs to consider why so few patients with neuropathic pain obtain satisfactory pain relief. The main practical problem is dose-limiting adverse side effects. Specifically, dose escalation is typically limited by sedation, somnolence, vertigo, and nausea. These side effects are common to all the various membrane-stabilizing drugs that act by suppressing ectopic afferent firing, although not in identical measure. Since the side effects are the same regardless of how these drugs achieve membrane stabilization, one can infer that the common analgesic action of these drugs is closely related to the mechanism whereby they cause sedation and somnolence. The relevant shared action is almost certainly their ability to suppress the tendency of neurons to fire repetitively in the PNS and CNS. Minimizing adverse effects by decoupling analgesia from sedation should be a primary objective of future drug development. This would allow the use of higher, more effective doses while at the same time making the drugs more tolerable to patients. The commercial success of gabapentin and pregabalin, for example, is not due to their efficacy, which is modest at best (number needed to treat [NNT] ≈5 versus amitriptyline with an NNT <3) (Gordh et al 2008, Finnerup et al 2010). Rather, it is due to their relatively mild side effect profile. This, in turn, probably results from their suppression of ectopia by actions other than global suppression of Na+ conductance.
Sedation and the other dose-limiting side effects reflect actions in the CNS. Cardiac toxicity is rarely a problem except at unusually high plasma concentrations or in the presence of prior cardiac morbidity. This suggests several ways of reducing the side effects of drugs used in the treatment of neuropathic pain while maintaining efficacy.
One potential approach is to deliver membrane-stabilizing drugs selectively to sites of problematic electrogenesis. Practical approaches include the use of topical patches (Davies and Galer 2004) or targeted injections using long-acting formulations or indwelling catheters aimed at defined pacemaker sites on the injured nerve or associated DRGs. For individual patients the key site or sites can in principle be identified by using diagnostic lidocaine blocks. An approach still over the horizon is placement of biological “minipumps,” cells or tissue slices that express membrane-stabilizing peptides such as μ-conotoxins, on the surface of DRGs or neuromas (Norton 2010). Membrane-stabilizing drugs themselves are sometimes administered spinally (epidurally or intrathecally) to reach relatively high concentrations locally while minimizing systemic spread. Although presumed to act in the spinal cord, the actual site of drug action may be the DRG. DRGs lie within the intrathecal space (Frumin et al 1953, Byrod et al 2000), are accessed by spinal injection protocols, and are a well-established source of ectopia, at least in animals. In patients in whom the DRG is the effective source of pain, application within the intervertebral foramen is expected to increase specificity. Uncertainty about the actual target of spinal injection, the cord or DRG, also relates to the numerous agents reported to reverse allodynia after intrathecal injection in animal models of neuropathic pain. Investigators need to be alert to the possibility that actions presumed to be on spinal neurons or glia might in fact be on the DRG.
A second approach to minimizing CNS side effects is to develop ligands selective for types of Na+ or K+ channels that occur in the PNS but not in the CNS. Unfortunately, generating channel-selective Na+ channel blockers has proved challenging, and as noted above, observations using knockout and knockdown technologies raise doubt about the promise of this strategy. K+ channel openers are only beginning to be explored in the context of pain control. As noted earlier, the K2p channel TRESK is expressed selectively in the DRG and spinal cord and may therefore be a particularly effective target.
A third approach is to find unique features of the oscillatory process and ectopia in DRG neurons. Global suppression of Na+ conductance, such as with amitriptyline, is a crude tool. Targeting specific channels still has promise. However, it might be possible to suppress ectopia by selectively targeting the key delayed Na+ conductance, a component generated by a variety of channels. Gabapentin, riluzole, ranolazine, and lacosamide have this characteristic (Urbani and Belluzzi 2000, Sheets et al 2008, Gould et al 2009, Wu et al 2009, Yang et al 2009, Patwardhan et al 2010, Hildebrand et al 2011). Currently, we have a general understanding of membrane resonance and the mechanism of subthreshold oscillations in DRG neurons (Wu et al 2001b, Amir et al 2002a, Kovalsky et al 2009), but many details still need to be worked out. Unanticipated opportunities are likely to arise.
A final approach to selective control of PNS ectopia is the development of membrane-stabilizing drugs that fail to enter the brain. Conventional analgesic membrane-stabilizing drugs are lipophilic and cross the BBB. However, a peripherally restricted amitriptyline-like or gabapentin-like drug with preserved suppressive effects on PNS ectopia might provide analgesic activity with reduced sedation and other CNS side effects. Conveniently, the major generators of neuropathic ectopia, nerve injury sites and DRGs, are devoid of a BBB. So exclusion from the brain does not mean exclusion from PNS pacemaker sites. The design of such drugs, however, is not necessarily trivial. Local anesthetics, for example, bind to Na+ channels at the inner pore of the channel on the cytoplasm side of the membrane. Preventing membrane permeability by simply adding a charged moiety will reduce brain access, but it might also prevent the drug from accessing its intracellular target in the PNS. Strategies exist for overcoming this problem (e.g., Tsien 1981, Binshtok et al 2007). In addition, some drugs with therapeutic potential, tetrodotoxin, for example) target extracellular binding sites (Gordon et al 2007, Nieto et al 2012).
Neuropathic pain conditions are highly diverse in their clinical manifestations. They are precipitated by a broad range of factors from trauma to neurotoxins, they affect different body parts and different organ systems (e.g., skin, viscera), and they can be focal or widespread, with pain that is burning or shock-like, spontaneous or stimulus evoked, paroxysmal or constant. Each diagnosis can be subdivided into types and subtypes and can manifest in varying intensity. Likewise, neuropathic pain conditions are treated with drugs drawn from a variety of families with very different molecular structures: anticonvulsants, antidepressants, local anesthetics, antiarrhythmics, steroids, and opiates. For these reasons it is broadly held that neuropathic pain reflects a spectrum of different conditions with considerable diversity in etiology and neural mechanisms (Attal et al 2008, Treede et al 2008).
However, the scene can also be viewed from a different perspective. Even though many events can precipitate painful neuropathy, they all involve a limited set of changes at the structural level (axonopathy and demyelination) and at the functional level (remodeling of specific membrane proteins and enhanced excitability and impulse discharge). Although therapeutic agents come from diverse families including anticonvulsants, antiarrhythmics, antidepressants, NMDA-R blockers, NSAIDs, steroids, and local anesthetics, only particular agents from each family have analgesic efficacy. Consistently these are the agents that stabilize membrane hyperexcitability and reduce ectopia. Finally, the side effects of the effective drugs tend to be similar (sedation, somnolence, etc.), again suggesting that they act by targeting a particular neurophysiological process, namely, excitability. These observations suggest an underlying unity of neural mechanism despite the diversity of clinical diagnoses.
The language of pain signaling is repetitive impulse discharge. The transduction stage of electrogenesis, depolarization of the pacemaker membrane, is a redundant process. Remove one source of excitation and many others remain. Excitability, on the other hand, is not redundant. Suppress excitability and you have eliminated the ability of all mediators that act on membrane transducer and receptor molecules to generate a pain signal. Likewise, although there are numerous central sensitizing mechanisms, most or perhaps all are dynamically maintained by afferent impulse traffic. Therefore, drugs that suppress PNS ectopia are also expected to normalize CNS abnormalities. In contrast, there is little reason to believe that the situation is symmetrical, that CNS-acting drugs might resolve PNS pathophysiology. PNS ectopia is a unique hub in the neuropathic pain network.
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