Table 1.
Experimental drugs for the treatment of neuropathic pain - a summary.
|
Pharmacological Class
(Example) |
Mechanism of Action in NP | Preclinical Efficacy (Animal Models) | Clinical Efficacy |
|---|---|---|---|
| β2-adrenomimetics (terbutaline, salbutamol) |
↓TNFα | Traumatic nerve injury-related NP; diabetic NP |
Post-thoracotomy NP (salbutamol); post-thoracoscopy NP (terbutaline) |
| Angiotensin AT2 receptor antagonists (EMA-401) | ↓ p38 MAPK; ↓ ERK | Surgically-induced NP | PHN; diabetic NP (withdrawn) |
| H3 receptor inverse agonists (GSK189254, GSK334429) |
↓ central sensitization; ↓ spontaneous neuronal firing |
Surgically- and virally-induced NP models; Spinal nerve ligation NP model |
No data available |
| Acetylcholinesterase inhibitors (donepezil) |
↑ acetylcholine – M2 receptor stimulation |
CIPN; spared nerve injury model |
Diabetic NP; patients with chronic neuropathic pain who are currently taking gabapentin or pregabalin (phase 4) |
| Neurotoxins (botulinum toxin A) |
SNAP-25 degradation; ↓ glutamate; ↓CGRP; ↓ TRPV1 expression; ↓ IL-1β, ↓ IL-18; ↑ IL-10, ↑ IL-1RA; ↓central sensitization sodium channel inactivation |
Diabetic NP; Surgically-induced NP |
Established efficacy in PHN; probable efficacy in trigeminal neuralgia and post-traumatic neuralgia; possible efficacy in diabetic polyneuropathy; insufficient evidence in CRPS, phantom limb and stump pain, and occipital neuralgia |
| Microglial activation inhibitors (minocycline) |
Microglia inhibition; matrix metalloproteinase 3 inhibitor; ↓ chemokines; ↓ TNFα; ↓ IL-1β; ↓iNOS; ↑ IL-1α; ↑ IL-2; ↑ IL-10 |
CIPN; diabetic NP; traumatic nerve injury-related NP |
Prevention of postoperative intercostal neuralgia |
| PPARγ agonists (rosiglitazone, ATx08-001) |
↓ IL-1β, ↓ IL-6; ↓ TNFα; ↓chemokines |
CIPN | PHN |
| Kinase inhibitors (dilmapimod, losmapimod) |
↓ p38 MAPK | NP following traumatic peripheral nerve injury | No longer in development due to low efficacy |
| T-type calcium channel antagonists (ethosuximide, ABT-639) |
T-type calcium channel antagonism | NP following traumatic peripheral nerve injury (ethosuximide, ABT-639); spinal nerve ligation NP model; CIPN (ABT-639) |
Diabetic NP – ABT-639 (no longer in development) |
| Sodium channel antagonists (ambroxol) |
Nav1.8 sodium channel antagonism | CIPN; Spinal cord injury-related NP |
PHN; Post-operative neuralgia; phantom pain; foot neuropathy; deafferentation pain |
| Melatonin MT1/MT2 receptor agonists (ramelteon, melatonin, piromelatine) |
Neuritogenesis stimulation; neuroprotection; ↓ nitro-oxidative stress; induction of autophagy; mitochondrial protection |
CIPN | Ramelteon: terminated (recruitment did not accrue as expected) |
| TRPA1 antagonists (ADM_09; HC-030031 |
↓ oxidative stress; ↓ p38 MAPK |
CIPN; diabetic NP |
No data available |
| 3-Hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors = statins (simvastatin, rosuvastatin) |
↓ oxidative stress; iNOS inhibition; decreased translocation of RhoA; reduced microglial and astrocyte activation; ↓IL-1β secretion; immunomodulation; neuroprotection |
CIPN; CRPS; surgically-induced NP |
Diabetic NP; phantom limb pain |
clinical trials that it prevents the development of oxaliplatin-induced neuropathy, but further detailed studies are required to confirm these preliminary observations [106].