Investigational Drugs for the Treatment of Postherpetic Neuralgia: Systematic Review of Randomized Controlled Trials

The pharmacological treatment of postherpetic neuralgia (PHN) is unsatisfactory, and there is a clinical need for new approaches. Several drugs under advanced clinical development are addressed in this review. A systematic literature search was conducted in three electronic databases (Medline, Web of Science, Scopus) and in the ClinicalTrials.gov register from 1 January 2016 to 1 June 2023 to identify Phase II, III and IV clinical trials evaluating drugs for the treatment of PHN. A total of 18 clinical trials were selected evaluating 15 molecules with pharmacological actions on nine different molecular targets: Angiotensin Type 2 Receptor (AT2R) antagonism (olodanrigan), Voltage-Gated Calcium Channel (VGCC) α2δ subunit inhibition (crisugabalin, mirogabalin and pregabalin), Voltage-Gated Sodium Channel (VGSC) blockade (funapide and lidocaine), Cyclooxygenase-1 (COX-1) inhibition (TRK-700), Adaptor-Associated Kinase 1 (AAK1) inhibition (LX9211), Lanthionine Synthetase C-Like Protein (LANCL) activation (LAT8881), N-Methyl-D-Aspartate (NMDA) receptor antagonism (esketamine), mu opioid receptor agonism (tramadol, oxycodone and hydromorphone) and Nerve Growth Factor (NGF) inhibition (fulranumab). In brief, there are several drugs in advanced clinical development for treating PHN with some of them reporting promising results. AT2R antagonism, AAK1 inhibition, LANCL activation and NGF inhibition are considered first-in-class analgesics. Hopefully, these trials will result in a better clinical management of PHN.


Introduction
Herpes zoster (HZ) is caused by reactivation of the varicella-zoster virus.Postherpetic neuralgia (PHN) is a complication of HZ that produces a chronic pain syndrome with a high incidence (5-30% of HZ patients) and increasing socioeconomic impact [1,2].Patients develop severe pain persisting for more than three months after recovery from skin lesions [3].PHN produces constant or intermittent pain in the absence of stimuli (spontaneous pain) with neuropathic pain (NP) characteristics, especially marked mechanical allodynia and thermal hyperalgesia [3,4].The development of PHN involves mechanisms at both the central and peripheral nervous system levels [5,6], as summarized in Figure 1.
involves mechanisms at both the central and peripheral nervous system levels [5,6], as summarized in Figure 1.On the one hand, there is peripheral nociceptor sensitization with a reduction in the excitation threshold, the appearance of spontaneous ectopic discharges in peripheral and central axons, and a loss of descending pain inhibitory controls.On the other hand, central sensitization occurs through neuronal sensitization, along with spinal hyperexcitability [7].
Regarding treatment, clinical guidelines emphasize the importance of prevention and acute treatment after early diagnosis of HZ, all with the aim of avoiding the chronification of pain toward PHN [6][7][8].This is crucial because once PHN is established, it is usually refractory to treatment with temporary or incomplete improvements despite multimodal therapy.First-line systemic drugs for PHN are tricyclic antidepressants (such as amitriptyline, nortriptyline, and desipramine) and gabapentinoids (gabapentin and pregabalin), despite producing adverse effects that limit their use [3,9].If the patient does not respond to monotherapy, it is common to combine several drugs, usually opioids or topical treatments (e.g., lidocaine patches) [10].However, the efficacy of pharmacological management remains suboptimal, so there is still a need for new treatments [1,11].The aim of this systematic review is to summarize the results of drugs evaluated in Phase II/III/IV clinical trials between 2016 and 2023 in order to provide an overview and make predictions for the molecules and pharmacological targets that may be available in the On the one hand, there is peripheral nociceptor sensitization with a reduction in the excitation threshold, the appearance of spontaneous ectopic discharges in peripheral and central axons, and a loss of descending pain inhibitory controls.On the other hand, central sensitization occurs through neuronal sensitization, along with spinal hyperexcitability [7].
Regarding treatment, clinical guidelines emphasize the importance of prevention and acute treatment after early diagnosis of HZ, all with the aim of avoiding the chronification of pain toward PHN [6][7][8].This is crucial because once PHN is established, it is usually refractory to treatment with temporary or incomplete improvements despite multimodal therapy.First-line systemic drugs for PHN are tricyclic antidepressants (such as amitriptyline, nortriptyline, and desipramine) and gabapentinoids (gabapentin and pregabalin), despite producing adverse effects that limit their use [3,9].If the patient does not respond to monotherapy, it is common to combine several drugs, usually opioids or topical treatments (e.g., lidocaine patches) [10].However, the efficacy of pharmacological management remains suboptimal, so there is still a need for new treatments [1,11].The aim of this systematic review is to summarize the results of drugs evaluated in Phase II/III/IV clinical trials between 2016 and 2023 in order to provide an overview and make predictions for the molecules and pharmacological targets that may be available in the future therapeutic arsenal.The chosen time period specifically corresponds to the year preceding the approval of Shingrix (shingles vaccine) by the FDA.

Protocol and Registration
The methodology used in this review was specified in advance and documented in a protocol that was registered in the CRD (Centre for Reviews and Dissemination) York website PROSPERO (International Prospective Register of Systematic Reviews) under the registration ID CRD42023423305.The study was performed adhering to the last version (2020) of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines on systematic reviews and meta-analyses [12].

Inclusion and Exclusion Criteria
Inclusion Criteria: randomized controlled trials in which adult patients with PHN were treated with any drug trialed in Phase II, III or IV studies.
Exclusion Criteria: review articles, systematic reviews, in vitro experiments, animal studies, studies including no relevant information and violation of any of the above inclusion criteria.

Article Selection
Titles and abstracts of studies were retrieved using the search strategy by two review authors (MAH and BGP) in a blind manner to identify studies that potentially met the inclusion criteria.Full texts of these potentially eligible studies were retrieved and independently assessed for eligibility by two team members (MAH and BGP).The selection process was completed using the software Rayyan (Rayyan Systems Inc., Cambridge, MA, USA).Disagreements between them over the eligibility was resolved through discussion with a third reviewer (ASA).

Data Extraction
Extracted information included drug evaluated, pharmacological target, administration route, dosage, clinical trial code, phase, and completion date.Two authors (MAH and BGP) extracted data independently (blind).Discrepancies were identified and resolved through discussion with a third author where necessary (ASA).

Article Selection
A summary flow chart is shown in Figure 2. The search yielded 558 articles (418 articles after removing duplicates).Then, the titles and abstracts were evaluated, and 344 articles were excluded for the following reasons: 150 because they were not original articles (mainly reviews or systematic reviews), 87 due to the population being different to PHN patients (mainly patients with other forms of neuropathic pain), 103 because they did not use a pharmacological intervention (mainly cognitive or physical therapies), and 4 for the reason that they evaluated an outcome different to pain (mainly evaluating pharmacokinetics).Of the 74 remaining full-text articles that were assessed for eligibility, 56 were excluded for different reasons: 10 articles because they were reviews (mainly meta-analyzing data of published RCT), 6 articles because the population was not PHN patients exclusively, 8 articles because the drug was used before PHN was established (for prevention), 30 studies because they were not Phase II, III or IV RCT, and 2 articles due to the intervention were procedures instead of drugs.Finally, for this systematic review, we selected a total of 18 studies that evaluated in Phase II, III or IV clinical trials the efficacy of different molecules to alleviate established PHN.

Study Characteristics
The complete list of included articles with detailed characteristics (pharmacological target, drug, route, dosage, clinical trial code, phase and completion date) is shown in Table 1.The most repeated main pharmacological target, referring to the one that explains the analgesic effect, was subunit α2δ of voltage-gated calcium channels (VGCCs) [13][14][15][16][17][18],

Study Characteristics
The complete list of included articles with detailed characteristics (pharmacological target, drug, route, dosage, clinical trial code, phase and completion date) is shown in Table 1.The most repeated main pharmacological target, referring to the one that explains the analgesic effect, was subunit α2δ of voltage-gated calcium channels (VGCCs) [13][14][15][16][17][18], which was followed by Voltage-Gated Sodium Channels (VGSCs) in its different subtypes [19,20] and mu opioid receptor [21][22][23].Other mechanisms included were Angiotensin II Type 2 Receptor (AT2R) [24], Cyclooxygenase-1 (COX-1) [25], Adaptor-Associated Kinase 1 (AAK1) [26], Lanthionine Synthetase Component C-like protein (LANCL) [27], an unknown mechanism [28], N-Methyl-D-Aspartate Receptor (NMDAR) [29] and Nerve Growth Factor (NGF) [30].The majority of the included clinical trials (14 of 18) were registered in the registry of the United States National Library of Medicine (NLM) at the National Institutes of Health (clinicaltrials.gov).The rest were registered in Chinese (ChiCTR), Japanese (JRCT) and Australian (ANZCTR) registries, with 2, 1 and 1 trials registered, respectively.Eight of them were Phase III trials, seven were Phase II and the remaining 3 were Phase IV trials.The most common administration route was oral, but topical, intravenous, intranasal, transdermal and subcutaneous were also used.The most important efficacy information on primary outcomes is summarized in Table 2. Information about other secondary outcomes can be found in Supplementary Data S1 (Table S1).Safety main results are summarized in Table 3, while information about serious adverse events can be found in Supplementary Data S1 (Table S2).
Bowel movements: LAT8881 (AOD9604) [27] Patients that experienced ≥1 AE: Upper RTI (nasopharyngitis) Headache (In both groups) SR419 [28] Data not published Data not published Esketamine [29] Data not published No differences between esketamine and morphine (study for postoperative pain [31]) A tendency to a higher frequency of nystagmus in esketamine A tendency to a higher frequency of dry mouth in morphine SR tramadol (NZ-687) [21] Total AEs:  There is increasing evidence implicating the Renin-Angiotensin System (RAS) in multiple facets of NP [32].Specifically, there are many studies highlighting the location of type 2 receptors in important pathways for NP signaling, and there are numerous preclinical studies showing efficacy in animal models of NP [33].However, there is also controversy regarding the role of Angiotensin II Type 2 receptors in pain, with studies suggesting both pro-algesic and anti-hyperalgesic characteristics [34].Olodanrigan (EMA401) is a highly selective Angiotensin II Type 2 receptor antagonist developed by Novartis [35].It has been evaluated in Phase II in the EMPHENE study [24] and in ACTRN12611000822987 [36] for PHN.It has also been evaluated for diabetic peripheral neuropathy (DPN) in EMPA-DINE [24].In all studies, it showed promising results in both efficacy and safety (absence of drug-related SAEs).However, the last two trials were prematurely halted due to observed long-term hepatotoxicity in preclinical studies, although it was not observed in these clinical trials [24].CFTX-1554 is the alternative Angiotensin II Type 2 antagonism proposed by Confo Therapeutics [37].Although it is in an earlier phase of clinical development, it has recently established a collaboration with Eli Lilly to continue its development in Phase II [38].

Voltage-Gated Calcium Channel (VGCC) α2δ Subunit Inhibition
The involvement of this target in NP has been known for years [39].Inhibitors such as gabapentin or pregabalin (gabapentinoids) have been used for its treatment for years [40], despite their initial indication being for the treatment of epilepsy [41,42].Pregabalin, as mentioned, is a first-line treatment for PHN, and its superiority over gabapentin is demonstrated [43].New dosage forms of pregabalin have been developed for improving adherence to treatment, such as controlled-release pregabalin [16].There is evidence suggesting that using strategies that involve minor dosing frequency of oral medications results in better adherence to treatment [44], which is confirmed by a meta-analysis comparing adherence of different dosages strategies [45,46].Another new dosage form (once-daily sustained-release pregabalin formulation, YHD1119 tablets [18]) was developed in order to solve some problems related with variable absorption (attributed to the narrow absorption window of pregabalin [47]) of a previous approved controlled-release formulation (LYRICA ® CR, pregabalin extended-release tablets).YHD1119 uses a technology based on a floating and swelling gastroretentive drug delivery system [48].In addition, the use of pregabalin is usually accompanied by undesirable adverse effects, such as dizziness, drowsiness, and peripheral edema.Because of this, in recent years, researchers have developed molecules also capable of blocking this target and being effective but with less central adverse effects.One example is mirogabalin, which has a high potency and selectivity to the α2δ-1 subunit [49,50].Furthermore, in vitro studies confirmed that it has a slower dissociation rate from α2δ-1 than α2δ-2 compared with pregabalin [51].Mirogabalin showed good results in several clinical trials including Phase III trial NEUCOURSE (NCT02318719) for PHN [52], which was complemented by an open label extension for long-term assessment [15].Finally, it was approved in Japan for treating PHN in 2019 (Tarlige ® ) [53], but it is not approved yet by the EMA or FDA.Another example is crisugabalin (HSK16149), which was developed by the Chinese pharmaceutical company Haisco Pharmaceuticals.It has greater selectivity than pregabalin for the receptor, which could improve short-and long-term analgesia as well as reduce its central adverse effects.A Phase III trial in PHN patients was recently completed, but data have not been published (NCT05140863) [13].In addition, a large Phase II trial with 300 patients (NCT05763550) [54] has recently begun, and the results are expected in July 2023.Recently, positive results were published of a Phase III evaluating HSK16149 for DPN [55].Moreover, preclinical data demonstrate greater efficacy and fewer central adverse effects compared to pregabalin [56].The most commonly reported AEs for HSK16149, mirogabalin, pregabalin CR, sustained release pregabalin, and standard pregabalin when compared with placebo included somnolence, dizziness, weight increase and edema.SAEs occurred more frequently in all mirogabalin groups at higher doses; incidence was significantly higher with pregabalin CR and standard pregabalin compared to placebo.

Voltage-Gated Sodium Channel (VGSC) Blockade
The importance of Voltage-Gated Sodium Channel (VGSC) blockade in pain transduction is well known.A clear probe is that loss-of-function mutations in Nav1.7, a VGSC subtype, causes congenital insensitivity to pain in humans [57].There are eight other α subunit isoforms (Nav1.1-1.9) which also are involved in pain neurotransmission [58].Lidocaine, which is a classical drug widely used as a local anesthetic, was approved by the FDA for PHN in 1999 as topical administration (Lidoderm ® patch) [59].Lidocaine is also FDA approved and widely used for local or regional anesthesia by infiltration techniques (nerve blocks).However, although there are some clinical experiences of systemic treatment of PHN with lidocaine [60,61], it is not approved for PHN.Recently, a Phase III clinical trial was performed evaluating the intravenous infusion of lidocaine for PHN, and the results showed an improvement of pain management, less analgesic consumption and faster recovery [20].The most common AEs after intravenous lidocaine infusion were somnolence, dry mouth, and mild peripheral numbness.Interestingly, there are several novel VGSC blockers in clinical development for the treatment of NP, and some of them have been trialed for PHN [57].One example is eslicarbazepine (BIA 2-093), which was evaluated in 2012 for PHN and DPN (NCT01124097 [62], NCT01129960 [63]).These studies were terminated early due to a high incidence of adverse events (e.g., vertigo, nausea, fatigue, dizziness, and headaches).A more recent compound included in this systematic review is funapide, a topical selective Nav1.7 and Nav1.8 VGSC blocker [64], which was tested in a Phase II clinical trial for PHN (NCT01195636) showing promising results (although statistical improvements in pain were not reported, a subgroup analysis showed that patients with a particular polymorphism in the Nav1.7 gene achieved statistical significance) [19].The incidence of AEs was similar between funapide and placebo.However, application site-related AEs were more frequent in the placebo group than in the funapide treatment group.At the end of 2019, Flexion Therapeutics acquired funapide from Xenon Pharmaceuticals in order to develop a new candidate, FX301, which will combine funapide with a novel thermosensitive hydrogel for the treatment of postoperative pain [65]; this clinical trial started in 2021, but results are not yet available [66].There are other VGSC blockers which showed efficacy for PHN in preclinical studies.One interesting example is tetrodotoxin, which is in Phase III for cancer-related pain [67] and showed promising results in a rat model of PHN [68].

Cyclooxygenase-1 (COX-1) Inhibition
Cyclooxygenase inhibitors are effective and widely used for inflammatory pain treatment, but efficacy in NP is controversial [69].Selective COX-2 inhibitors were effectively developed to solve some side effects (mainly gastrointestinal) but are associated with other security issues (such as cardiovascular side effects) [70].Selective COX-1 inhibitors elicited less therapeutic interest, although some authors suggest that this therapeutic target should be reconsidered [71].Interestingly, while the role of COX-2 in inflammatory pain is unquestionable, recent investigation suggests that COX-1 could be also implicated in inflammatory pain [72] and be even more important for NP [73].Also, there is evidence of the fundamental role of COX-1 in animal models of pain with a neuropathic component [74,75].TRK-700 is a COX-1 inhibitor developed by Toray Industries which was evaluated in a Phase II clinical trial for PHN [25].TRK-700 showed efficacy in fibromyalgia and other models of NP [76], but human clinical results have not been published.It must be highlighted that unlike that reported for some analgesic drugs, TRK-700 did not show sedative effects.

Adaptor-Associated Kinase 1 (AAK1) Inhibition
Preclinical studies have shown that the genetic depletion of AAK1 reduces pain in models of persistent pain but not acute pain without showing side effects or motor deficiencies [77].In addition, AAK1 knockout mice were also resistant to the development of mechanical allodynia after spinal nerve ligation, confirming that AAK1 plays an important role in the development of NP [77].It is suggested that the analgesic effect of AAK1 inhibitors is related with the reduced endocytosis of cell surface levels of µ2-containing GABA-A channels [77,78].LX9211 is a potent AAK1 inhibitor developed by Lexicon Pharmaceuticals in collaboration with Bristol-Myers Squibb [79].Results from two Phase I clinical trials were reported, and the most common AEs were mild: headache, dizziness and constipation.Nausea and vomiting were reported as moderate in severity, and they occurred more frequently compared to the placebo group [80].A Phase II clinical trial is currently underway for DPN and another for NPH [78].Recently, the company has announced that they are planning to continue with the development in Phase IIb and Phase III studies for DPN [81].In addition, regarding preclinical evidence, it reduced thermal hyperalgesia in a nerve injury rat model and also reduced established mechanical allodynia in a rat model of DPN [77].

Lanthionine Synthetase C-like Protein (LANCL) Activation
LANCL1 and LANCL2 are peptide-modifying enzymes that can promote cell protection and survival by reducing oxidative stress [82].Studies at the neuronal level demonstrate that the LANCL1 transgene is neuroprotective by a mechanism related with glutathione [83][84][85].LANCL1 was also identified as an immune marker of NP and may be a protective factor [86].Meanwhile, the modulation of LANCL2 has been proposed as anti-inflammatory in some inflammatory conditions [87,88], with proved human safety [89].Specifically, LANCL2 regulation reduced NP by regulating spinal neuroinflammation and nociceptive processing [90].LANCL1 and LANCL2 activation could constitute a first-inclass target for analgesia.LAT8881 (AOD9604) is a synthetic C-terminal fragment of human growth hormone (GH) developed by Lateral Pharma that is in Phase II clinical trials for PHN (NCT03865953) [27].This molecule is a particularly unique case, as no analgesic properties of a GH fragment were known.In fact, the neuroprotective and antioxidant effects of LAT8881 are not mediated by hormonal activity, they are attributed to its neuroprotective activity via a mechanism dependent on LANCL1 or LANCL2 [82].LAT8881 showed efficacy in some preclinical models of inflammatory conditions such as arthritis [82,91], and it also showed good tolerability in both animal and human studies [92,93].The results of the mentioned clinical trial were recently published showing disappointing results (no statistical differences versus placebo were found in any of the evaluated outcomes).The reported AEs included upper respiratory tract infection and headache, which were the same in both the placebo and LAT8881 treatment groups.
3.3.7.N-Methyl-D-aspartate (NMDA) Receptor Antagonism NMDA receptor antagonists have been suggested for the treatment of NP for years, as they participate in the transmission of pain signals [94,95].In fact, the persistent stimulation of pain-involved receptors leads to the activation and positive regulation of synaptic NMDA receptors in the dorsal horn of the spinal cord, resulting in an amplification of pain signal transmission to the brain (central sensitization) [95].Therefore, numerous clinical trials have been conducted with classic NMDA receptor antagonists that are already approved for other indications, such as memantine, dextromethorphan, amantadine, or ketamine [96,97].Esketamine is the dextro form of ketamine.Ketamine is an NMDA receptor antagonist with a peculiarity: in addition to reducing pain by blocking the NMDA receptor, it can also activate inhibitory pain pathways and have anti-inflammatory effects [98].Esketamine has a higher affinity for NMDA receptors and was recently approved as a nasal spray for the treatment of treatment-resistant depression [99].Due to the higher affinity, the doses required to produce analgesia are lower.Ketamine has been used in the treatment of PHN [100,101], so a superior efficacy can be expected with esketamine.In this regard, there are some small clinical experiences for postoperative pain treatment where intranasal esketamine combined with intranasal midazolam was similar in effectiveness, satisfaction and safety compared with standard intravenous PCA with morphine.Intranasal esketamine spray did not report a difference in the number/severity of AEs compared to PCA with morphine.However, a high frequency of nystagmus was reported for the esketamine group and of dry mouth for the morphine group [31].Also, there were case reports such as the case of a patient with potent PHN (9/10) in which treatment with esketamine along with trigeminal thermocoagulation produced a marked decrease in pain intensity to 2/10 that lasted for 2 months without adverse effects [102].To generate evidence of its efficacy in a larger population, a Phase IV clinical trial of intranasal esketamine (NCT04664530) is underway including 48 participants with results expected by the end of 2023 [29].

Mu Opioid Agonism
Mu opioids agonists are one of the oldest drugs ever (p.eg.morphine).Despite this, they are the most potent drugs for analgesia, and new structures with improved characteristics have been developed [103].However, its efficacy in NP is less clear (secondline therapy in NeuPSIG guidelines) and even lesser for PHN (third-line therapy) [11].Nevertheless, there are several new dosage forms of classical mu opioid agonists in clinical development for PHN.For example, a transdermal oxycodone patch was trialed in Phase IIa for PHN.The efficacy of oral oxycodone for the treatment of PHN was demonstrated [104], but transdermal administration presents some advantages (better adherence, less firstpass metabolism of the drug and less gastrointestinal side effects) [22].Transdermal oxycodone was very safe with less systemic exposure (minor incidence of AEs for the oxycodone than for the control patch and any AE led to study discontinuation), but it did not produce analgesia for the broad PHN indication (only was effective in a subpopulation with high levels of paresthesia) [22].Another case of novel dosage form was intravenous Patient-Controlled Analgesia (PCA) with hydromorphone, which was evaluated in a Phase IV clinical trial [23].PCA can increase the improvement in pain intensity and patient satisfaction while similar rates of side effects were reported [105].The clinical trial concluded that intravenous PCA hydromorphone provides a rapid onset of pain relief and can improve the current management of PHN [23].The most frequent AEs in the hydromorphone group were nausea and dizziness, whilst the control group reported dizziness and somnolence.No patients exhibited respiratory depression in either group, and any AE led to study discontinuation.The last example is NZ-687, which is a sustainedrelease tramadol (bilayer formulation: 65% sustained release/35% immediate release) developed by Nippon Zoki Pharmaceutical Co. (Twotram ® tablets) [106] that was trialed in a Phase III study for PHN [21].Tramadol is a particular case because it also acts as an SNRI, which makes this drug more interesting for NP treatment (second-line) [21].NZ-687 was effective and well tolerated for PHN.Nausea, constipation, nasopharyngitis, somnolence, vomiting, and congestive heart failure were reported with no dose-dependent increase.Two patients discontinued tramadol treatment, while three discontinued in the placebo group [21].

Nerve Growth Factor (NGF) Inhibition
It is well established, based on animal and human studies, that NGF is fundamental for nociception modulation [107].A variety of NGF inhibitors, mostly monoclonal antibodies, have been developed and trialed for treating some musculoskeletal and nonmusculoskeletal disorders (mainly osteoarthritis and low back pain) [108].Despite several Phase II and III trials showed positive efficacy results using anti-NGF molecules (such as tanezumab), there is not any FDA-approved anti-NGF therapy due to safety concerns (rapid progression of osteoarthritis) [109].However, the clinical usefulness of anti-NGF therapies for treating NP is less explored [108], and the one included in this systematic review (fulranumab; NCT00964990) is the first clinical trial inhibiting this target for treating PHN [30].The results of this small Phase II clinical trial were disappointing (limited by the small sample size), and only some evidence of pain reduction was found at the highest dose of fulranumab (10 mg) [30].Interestingly, fulranumab was well-tolerated in all doses (similar incidence of AEs between groups and no AE led to fulranumab discontinuation), so larger clinical studies are needed to assess efficacy in PHN [30].
3.3.10.Other Targets SR-419: Although the company states on its website and in press releases that the molecule is a first-in-class molecule, there is no known mechanism of action for this drug [28].Additionally, there is no preclinical information of any kind on this molecule in different databases.With such opaque development as that being carried out by Shanghai SIMR Biotechnology, it is difficult to draw conclusions.

Limitations
The main limitation of this systematic review is the lack of published information regarding some of the identified clinical trials.Some of them were completed several years ago, and the results were never published (e.g., TRK-700), which was possibly due to the absence of efficacy or safety concerns.In other cases, such as SR419, neither mechanism of action is reported.There are currently other ongoing clinical trials, and their results will be available soon (crisugabalin, LX9211 and esketamine).Another possible limitation may be that only one clinical trials registry (clinicaltrials.gov)and three different databases (Medline, Scopus and Web of Science) were explored, so it is possible that we missed some articles and clinical trials that were not included in these sources.The probability is however low, since clinicaltrials.govis the largest available clinical trials registry, and all high-quality journals are indexed in the cited databases.

Conclusions
Since 2016, 15 different molecules have been evaluated in Phase II, III and IV clinical trials for PHN.Specifically, eight drugs were evaluated in Phase II (olodanrigan, funapide, TRK-700, LX9211, LAT8881, SR419, oxycodone and fulranumab), five were evaluated in Phase III (crisugabalin, mirogabalin, pregabalin, lidocaine and tramadol), and three were evaluated in Phase IV (pregabalin, esketamine and hydromorphone).Mirogabalin, modified-release pregabalin, lidocaine, tramadol and hydromorphone showed positive results while funapide, LAT8881, oxycodone patches and fulranumab lacked efficacy or had safety concerns (olodanrigan).Results are not published for crisugabalin, LX9211, SR419 and esketamine.Among them, we found four first-in-class targets for the treatment of PHN: AT2R antagonism, AAK1 inhibition, LANCL activation and NGF inhibition.These studies will result in novel drugs for a better pharmacological management of PHN.

Figure 1 .
Figure 1.Summary of the sensory alterations experienced during postherpetic neuralgia.

Figure 1 .
Figure 1.Summary of the sensory alterations experienced during postherpetic neuralgia.
What drugs have been evaluated in Phase II/III/IV clinical trials for the treatment of PHN since 2016 (after Shingrix vaccine approval by the FDA)?
(O) Pain reduction, quality of life improvement and side effects; and (S) Randomized controlled trials.

Table 1 .
Main characteristics of included studies.

Table 2 .
Information about primary outcomes regarding efficacy in the included studies.

Table 3 .
Main information regarding drug safety in the included studies.