Table 1.
Potential and actual therapeutic candidates.
| Channel type | Drug | Mechanism of action | Status |
|---|---|---|---|
| Voltage-gated sodium channels | |||
| Na v 1.3 | • miR-384-5p • miR-30b • miR-96 |
Negative regulation of the SCN3A gene for Nav1.3 (41–43). | Not yet tested in the clinic |
| Diphenylmethyl amide adducts of an aryl sulphonamide series (44) | Channel block | Not yet tested in the clinic | |
| Na v 1.7 | Lacosemide | Inactivated state blocker | Safe and effective, in a randomized, placebo-controlled, double-blind, crossover-design study of Nav1.7 related small fiber neuropathy (45) |
| PF-05089771 | Inactivated state blocker | Failed to reach therapeutic end point in a diabetic neuropathy trial (46) | |
| CNV1014802 (vixotrigine or raxatrigine) | Inactivated state blocker | Trial ongoing for effectiveness in trigeminal neuralgia (47). | |
| Natural and chemically modified toxins such as JNJ63955918 • JzTx-V • PnTx1 • GpTx-1 • ProTx-11, μ-conotoxin KIIIA • μ-TRTX-Tp1a (Tp1a) • Tap1a • Tap1a-OPT1 |
Most of these toxins are gating modifiers | High affinity and selectivity of various toxins for Nav1.7 has been demonstrated (48). None as yet have entered clinical trials. Tap1a also blocks Cav3.2 channels (49). Structural modification of Tap1a may produce especially potent and effective agents (50) | |
| Low dose opioids in combination with Nav1.7 blockers | Augmentation of opioid contribution to effectiveness of Nav1.7 blockers (51–53) | No clinical information presently available | |
| “LATER” (long-lasting analgesia via targeted in vivo epigenetic repression) technology | CRISPR epigenetic technology to suppress Nav1.7 expression | Encouraging results found in hiPSC (54, 55). | |
| Carbamazepine | Channel block | Use primarily restricted to trigeminal neuralgia (56) | |
| Na v 1.8 | A803467 PF-01247324 |
Small molecule pore blockers | Not yet tested in clinic |
| VX-150 | Prodrug metabolized to small molecule pore blocker | Clinical trial ongoing (57) | |
| Tanezemab | Monoclonal antibody directed at nerve growth factor | Trials in several pain states have brought forth encouraging results (58) | |
| Multiple actions on Na+ channels | Cyclic peptides derived from the structures of natural product channel blockers μ-conotoxin KIIIA and (PnTx1) Phoneutria nigriventer toxin 1 (59) | Channel block | Ongoing studies seek to improve toxin selectivity |
| Lidocaine patch | Inactivated state blocker | In clinical use (1) | |
| Cationic local anesthetics combined with TRPV1 activators (60–62) | Local anesthetic effect achieved selectively in TRPV1 expressing neurons by anesthetic permeation of TRPV1 channels | Preclinical research is ongoing, but no reports of clinical investigations | |
| Voltage-gated potassium channels | |||
|
Kv1.1. Delayed Rectifier K+ channels |
2-fluorophenyl glycine | Direct channel activator (63) | Under consideration for use in episodic ataxia type 1, as yet untested in pain models |
|
Kv1.2 Delayed Rectifier K+ channels |
Suberoylanilide hydroxamic acid (Vorinostat) | HDAC2 inhibitor may attenuate pain by increased expression of Kv1.2 and by other mechanisms (64–66) | Clinically approved anti neoplastic agent not yet evaluated in cancer or neuropathic pain |
|
Kv2.1, Kv2.2 Delayed Rectifier K+ channels |
Activators of associated Kv1.9 silent subunits | Formation of hetero—tetramers (Kv1.9–2.1–2.2) may increase overall channel conductance (67) | Suitable compounds or methodology not yet developed |
|
Kv7.2 KCNQ2 or M-channels |
Retigabine | M-channel opener | Failed to meet its efficacy endpoint in post herpetic neuralgia (68) |
| Flupirtine | M-channel opener | Withdrawn because of toxicity issues | |
| SCR 2682 | Kv7.2 opener which also increases KCNQ2 mRNA and Kv7.2 protein expression (69, 70) | Mechanism of action yet to be determined, not yet ready for clinical trials | |
| Mallotoxin Isovaleric acid (E)-2-dodecenal | Natural products that act as Kv7.2/7.3 activators (71, 72) | Effective in animal models of epilepsy, efficacy in pain models not yet examined | |
|
Kv4 A-channel |
NS5806 | Modulation of Kv channel activity by interactions with KChips (73, 74) | Attenuates cold allodynia in a model of trigeminal neuralgia (75) |
|
Kir6.2 KATP channels |
Diazoxide Minoxidil | KATP channel openers (76–79) | Despite efficacy in neuropathic pain models their use in the clinic has not been advocated. |
| Multiple actions on K+ channels Kv7.2 KCNQ2 or M-channels Kv1.4 A-channel KCa1.1 BK Ca2+ sensitive K+ channel |
BIX01294 UNC0638 | Inhibition of histone methyltransferase G9a (80, 81) | Histone methyltransferase inhibitors are being developed as antineoplastic agents, use in clinical pain yet to be established. |
| Voltage-gated calcium channels | |||
| N-type voltage-gated Ca2+ channels (Cav2.2) | Ziconotide (Synthetic ω-conotoxin MVIIA) | Channel block | Administered intrathecally when other treatments fail (82) |
| • Small molecule blockers • ZC88 • A1264087 • TROX-1 • (83–87) |
Channel block | No clinical data yet available | |
| Clonidine | Channel block via α2 adrenoceptor and Gi/o interaction | Only effective in small subgroups of patients (88–92). | |
| Gabapentinoids | Affect Cav2.2 channel trafficking and association with release machinery both peripherally and centrally (93–95) | Classical anti allodynic agent (1), but only effective in 31% of patients (96) | |
| CNCB-2 | Bifunctional, permanently charged molecule blocks Cav2.2 and Nav1.7. (97) | Yet to be examined in animal models of neuropathic pain | |
| T-type voltage-gated Ca2+ channels (Cav3.2) | Ethosuximide | Classical T-current blocker and anticonvulsant | Clinical results in pain are disappointing (98) |
| Suramin | Shows analgesic activity in neuropathic and inflammatory pain models by prevention of action of deubiquitinase, USP5(99, 100) | No clinical data | |
| • TTA-P2 • TTA-A2 |
Small molecule blockers effective in animal models | No clinical data | |
| • Z 944 • ACT709478 |
Small molecule blockers | Promising preliminary data from clinical trials (101) | |
| Tap1a | Toxin derived from tarantula venom | Also blocks Nav1.7 and shown to be effective in murine model of irritable bowel syndrome (49) | |
| BK current, T current, Cav2.2, Nav1.8 | Cannabinoids | (102–105) | Considerable discussion in the literature relates to the efficacy of cannabinoids in neuropathic pain (102, 106–109) |
| Interactions with transduction mechanisms that control nociceptor excitability | |||
| Cercosporamide | MNK 1/2 Inbitor | Suppresses pain in murine models (110) and is approved for management of pain in rheumatoid arthritis | |
| Vorinostat | Histone methyltransferase inhibitor | Alleviates pain in a bone cancer model (66) | |