Injury leads to activation of Transient Receptor Potential (TRP) nociceptors in the periphery; subsequent opening of cation channels results in depolarization and action potential propagation along afferent sensory fibers to the dorsal horn synapse. Presynaptic vesicles release excitatory non-peptide transmitter (glutamate, AMPA and NMDA receptor agonist), and peptide transmitters [Substance P (SP) (NK1 neurokinin receptor 1 agonist) and Calcitonin Gene-Related Peptide (CGRP) (Calcitonin like Receptor and Receptor Activity Modifying Protein complex agonist)]. Neuropeptide Y (NPY) and CGRP receptors co-localize extensively; the two neurotransmitters have mostly opposite effects (Nelson and Taylor, 2021). NPY acts at Y2 receptors on the central terminals of primary afferents to inhibit SP release (Duggan et al., 1991).

In blood vessels, CGRP acts as a potent vasodilator when compared to several known vasodilators such as histamine, prostaglandin E2 and SP. Inhibitors of the CGRP receptor are identified by the suffix–gepant (ubrogepant; atogepant). AMPA receptor antagonists are identified by the suffix–ampanel (perampanel) (De Caro et al., 2020). Kynurenic acid is one of the endogenous antagonists at ionotropic AMPA, NMDA (glycine-site ligand), and kainate glutamate receptors.

Second neuron: After crossing to the contralateral side, the signal travels in the ascending lateral spino-thalamic tract (TST) to the thalamus.

Third neuron: From the thalamus to the sensory cortex in the parietal lobe in the thalamo-cortical tract TTC (Brodmann areas 1, 2, and 3) allowing pain localization (Figure 2).

Descending noradrenergic (norepinephrine; NE) and serotoninergic (5-HT) fibers influence pain perception. Most noradrenergic fibers originate from the pontine locus coeruleus (LC; blue spot) while descending serotonergic pathways originate from the floor of the medulla oblongata from the nucleus raphe magnus (NRM). Both NE and 5-HT induce membrane hyperpolarization while decreasing the excitatory transmitter release from primary Aδ and C afferent fibers pre-synaptically and increasing the release of inhibitory GABA and glycine from interneurons (Yoshimura and Furue, 2006). The administration of 5-HT produces membrane hyperpolarization in about 50% of dorsal horn neurons, while NE hyperpolarizes more than 80% of them, suggesting the need to augment both NE and 5-HT concentrations in order to suppress algesia. Neither atomoxetine (selective noradrenaline reuptake inhibitor) nor an SSRI alone have such a marked effect (Miyahara et al., 2019).

Norepinephrine exerts via α2-adrenoceptors an inhibitory influence on neuropathic pain while α1-adrenoceptors exacerbate it (Kim et al., 2005).

As to the receptors involved in serotoninergic pain modulation findings indicate a role for 5-HT₇ receptors in antinociception, and a role for 5-HT₃ in pro-nociceptive facilitation (Dogrul et al., 2009). Activation of 5-HT₇ receptors does not directly inhibit nociceptive dorsal horn neurons because these receptors are positively coupled to adenylate cyclase and their stimulation is excitatory. However, activation of 5-HT₇ receptors localized on spinal inhibitory enkephalinergic or GABAergic interneurons, to evoke the release of enkephalins or GABA, produces an inhibition of nociceptive transmission (Brenchat et al., 2009; Liu et al., 2020) (Figure 3).

The activity of the feed-back loop consisting of (afferent) nociceptive input, and modulatory (efferent) output is markedly influenced by the composition of the “cytokine soup” at the site of origin and synaptic relay stations, with an ATP-rich environment promoting inflammation and nociception while an adenosine-rich environment having the opposite effect.

In an injured environment glia cells release intracellular ATP via the vesicular nucleotide transporter (VNUT) into the extracellular space. ATP activates purinergic P2X ionotropic and metabotropic P2Y receptors that increase the sodium and calcium conductance of various TRP receptors. Cell surface (ecto)nucleotidases by degrading nucleotides serve to terminate purinergic signaling; their function is analogous to the activity of cholinesterase at cholinergic synapses (Liu et al., 2017; Stokes et al., 2017).

Extracellular adenosine generated by metabolic break-down of nucleotides activates adenosine receptors (A1, A2A, A2B, and A3) that decrease the sodium and calcium permeability of TRP receptors (Figure 4) (Battastini et al., 2021). The antinociceptive activity of adenosine is mediated mainly via activation of adenosine A1 receptors; activation of A3A receptors seems to play a role as well. However, the function of adenosine A2A and A2B receptors is more debatable as their activation causes both nociception and anti-nociception effects (Vincenzi et al., 2020).

The purinergic influence is complemented by a plethora of pro- and anti-nociceptive substances, both oligopeptide [endogenous opioid peptides, the anti-opioid cholecystokinin (CCK), bradykinin, and cytokines] and non-peptide (histamine, prostanoids, leukotrienes).

Non-steroidal anti-inflammatory drugs (NSAIDs) are effective in nociceptive pain and controlling pain associated with inflammation via inhibition of cyclooxygenase-2. They are commonly prescribed for neuropathic pain however; there is not sufficient evidence to support the usage of NSAIDs for such pain and thus are not listed in the major guidelines addressing the treatment of neuropathic pain (Vane and Botting, 1998; Cohen and Mao, 2014; Moore et al., 2015; Kappelmann et al., 2018). One has to consider however that pain is rarely exclusively neuropathic or nociceptive.

Nociceptive pain is the physiologic response to nociceptor activation, and -as it is conducive to protective responses-it serves a useful purpose. Pain independent of nociceptor activation is called neuropathic; it is -most likely-not beneficial and it is the result of sensitization and autonomous ectopic activity of various pro-nociceptive entities, at the most basic level sodium and calcium channels. Dull nociceptive pain is contrasted by the sharp neuropathic one. There is overlap between chronic and neuropathic pain: neuropathic pain is chronic but not all chronic pain is neuropathic.

Most likely as a result of increased activity of the endogenous pro-nociceptive neuropeptide CCK, neuropathic pain does not respond well to opioids (Wiesenfeld-Hallin et al., 2002). The predominant form of CCK in the central nervous system is an octapeptide (Bowers et al., 2012). Opioid-induced CCK release is one of the postulated mechanisms explaining opioid tolerance and hyperalgesia (Smith, 2012). Recently, heterodimerization of opioid and CCK receptors subsequent to CCK octapeptide binding was demonstrated. This interaction was identified as the basis of the inhibition of opioid signal transduction and the antagonism of morphine analgesia (Yang et al., 2018; Bernard et al., 2021). CCK antagonists enhance the analgesic efficacy of endogenous opioids in animal models of pain (Inoue, 2017). NPY is pro-analgesic and naloxone administration reduces NPY analgesia (Upadhya et al., 2009). Even though opioids have been very effective in the treatment of pain but in recent years opioid overdose has been a major challenge for the clinical management of pain. Indeed, the most tragic reported drug overdose epidemic in US history was due to opioids. The introduction of a slow-release formulation of oxycodone, in 1996 was found to play a major role in this overdose death or so-called US opioid epidemic (Egilman et al., 2019; Dyer, 2020; Alpert et al., 2021).

The TRP channel superfamily consists of many cation channels divided into six subfamilies. The TRPA1 (ankyrin subfamily, member 1) is known as the wasabi receptor (typical ligand is allyl isothiocyanate, the main pungent compound of wasabi), while the TRPV1 (vanilloid subfamily, member 1) is known as the hot chili pepper receptor [typical ligand is capsaicin (Figure 6), the pungent compound of hot chili pepper]. TRPA1 and TRPV1 have been associated with pain perception (Gouin et al., 2017). Remarkably, it has been reported that almost all sensory neurons expressing TRPA1 (approximately 97%) also express TRPV1 (Story et al., 2003). Functional cross-desensitization has also been reported between the typical agonists of TRPA1 (allyl isothiocyanate; wasabi) and TRPV1 (capsaicin) (Mihara and Shibamoto, 2015). Furthermore, studies have shown that TRPA1 and TRPV1 can form a complex in the plasma membrane, and therefore influence each other’s characteristics (Staruschenko et al., 2010). Thus, Fernandes et al. (2012) described TRPA1 and TRPV1 channels as “partners in crime.”

Ligands at these receptors act from the intracellular side. The best-known activators of TRPV1 are temperature greater than 43°C (109°F), hydrogen ions, capsaicin, allyl isothiocyanate (mustard oil) and resiniferatoxin (Aloum et al., 2021).

Resiniferatoxin (RTX) is a chemical found in some Euphorbia species from Africa. Pure RTX is two-to three orders of magnitude hotter than pure capsaicin on the eponymous scale devised by Wilbur Scoville (1865–1942).

Capsaicin has been available as transdermal therapeutic system for many years. On dermal application (8%), it causes pain (dolor) and vasodilation (rubor); many pain specialists advise for use of lidocaine gel/cream prior (1 h) to capsaicin application. Tramadol given well before patch application is considered as an alternative pretreatment option in patients receiving capsaicin patch treatment (Jensen et al., 2014). Resiniferatoxin also causes burning sensation, thus anesthesia or nerve block can be used prior to resiniferatoxin injection (Salas et al., 2017).

Subsequently chronic pain relief sets in with various degrees of efficacy and duration. The assumed mechanism of action is depletion of SP and other proalgesic compounds and/or desensitization of receptors. Overall, the therapeutic approach is less successful than initially hoped for.

Anandamide is an endocannabinoid with anxiolytic and hypoalgesic properties (Habib et al., 2019). The name “anandamide” is derived from the Sanskrit word for bliss or delight ananda, and amide (Fride and Mechoulam, 1993). In addition to effects mediated via cannabinoid receptors, anandamide is also an endogenous ligand (agonist?) for TRP receptors, contributing i.e. to the vasodilation component of inflammation (Russell et al., 2014). Hypothermia, vasodilation, memory impairment, and immunosuppression are side effects of anandamide (Greenberg, 2003) Many other candidates that belong to the cannabinoids family has been used for the management of neuropathic pain as reviewed in (Aviram and Samuelly-Leichtag, 2017; Romero-Sandoval et al., 2017; Bruni et al., 2018; Lee et al., 2018; Mücke et al., 2018; Romero-Sandoval et al., 2018; Boyaji et al., 2020; Meng et al., 2020; Mlost et al., 2020; Urits et al., 2020; Campos et al., 2021). Recently, after the opioid epidemic, attention was diverted to cannabinoids as a therapeutic option for the treatment of pain (Urits et al., 2020).

TRPV1 activity is subject to regulation by a host of intracellular signaling cascades and extracellular events. As such, modulation of these is a possible and attractive avenue for chronic pain treatment. The fundamental premise as stated by (De Marchi et al., 2019) and other groups is that ATP-induces a pro-inflammatory milieu while an anti-inflammatory environment is adenosine-driven. ATP is released from microglia, keratinocytes, and other cells via the activity of the VNUT; inhibition of the transporter reduces the ATP concentration and thus its pro-inflammatory effect mediated via interaction with both ionotropic (P2X) and metabotropic (P2Y) purinergic receptors.

Clodronate (Figure 7), a first-generation non-nitrogen-containing bisphosphonate, is a potent and selective inhibitor of the VNUT and thus an inhibitor of ATP release. In vitro clodronate inhibits VNUT at an IC₅₀ ≈ 16 nM without affecting other vesicular neurotransmitter transporters. Clodronate has the potential to suppress inflammatory and neuropathic pain by shifting the balance ATP/adenosine from pro-inflammatory ATP to anti-inflammatory adenosine (Kato et al., 2017; De Marchi et al., 2019; Miras-Portugal et al., 2019; Hasuzawa et al., 2020). Osteonecrosis of the jaw and clinically silent hypocalcemia are side effects associated with the usage of clodronate (Frediani et al., 2018). The gastrointestinal irritation (such as nausea, dyspepsia) is less severe compared to nitrogen-containing bisphosphonates (Suri et al., 2001).

P2X ionotropic purinergic receptors mediate excitatory postsynaptic responses; the main pharmacological distinction between the members of the P2X purinoceptor family is their relative sensitivity to the antagonist suramin (the drug used for the treatment of trypanosomial-induced human sleeping sickness). Seven different P2X receptor subtypes (P2X1-7) have been identified to date; trimeric assembly creates various ionic channels. P2X₄ receptors have the highest permeability for calcium ions and are thus viewed as most relevant to pain.

P2X4 activation in spinal microglia results in pain hypersensitivity (Inoue, 2017; Stokes et al., 2017; Tozaki-Saitoh et al., 2022).

P2X4 receptor activity is positively modulated by ivermectin, a broad-spectrum anti-parasitic agent included in the WHO essential medicines list for several parasitic diseases (Nörenberg et al., 2012).

The selective serotonin and norepinephrine reuptake inhibitor (SSNeRI) duloxetine (Figure 8) reduces pain via augmenting serotonin and norepinephrine mediated inhibitory pain pathways (Smith and Nicholson, 2007). It might alleviate chronic pain also through P2X4 receptor blockade Duloxetine was able to almost completely suppress P2X4 receptor-mediated response to micromolar ATP (Yamashita et al., 2016). The same applies for the selective serotonin reuptake inhibitor (SSRI) paroxetine, and to a lesser extent (≈30% of control) to maprotiline (secondary amine), classical (tertiary amine) tricyclic antidepressants (TCA) (≈50% of control) (amitriptyline and clomipramine) and possibly to most antidepressants used in chronic pain treatment. No effect on P2X4 receptor activity was noticed for mirtazapine and bupropion (Yamashita et al., 2016; Kohno and Tsuda, 2021).

Amitriptyline and duloxetine are recommended first-line treatment for neuropathic pain. Amitriptyline and duloxetine both increase the risk of suicidal thoughts and behaviors, serotonin syndrome, and bleeding; only the former precipitates anticholinergic effects (Bryson and Wilde, 1996; Dougherty et al., 2002; Friedman and Leon, 2007; Leon, 2007; Bartlett, 2017; Bixby et al., 2019; Dhaliwal et al., 2022). The NNT and NNH values are 3.6 (3.0–4.4) and 13.4 (9.3–24.4) for amitriptyline and 6.4 (5.2–8.4) and 11.8 (9.5–15.2) for duloxetine, respectively. Amitriptyline has a selectivity ratio serotonin-to-norepinephrine transporters of approximately 3:1, whereas duloxetine has a 10-fold selectivity for serotonin transporters (Bymaster et al., 2001; Finnerup et al., 2015; Patel and Dickenson, 2022).

The superior NNT for amitriptyline vs. duloxetine contrasts their blocking ability at P2X4 receptor (50% vs. >90%). Several explanations are possible, such as that efficacy for neuropathic pain treatment requires additional mechanisms beyond P2X4 antagonism and that a balanced reuptake inhibition (serotonin to norepinephrine) is of equal, if not greater importance.

While such a line of thinking is perfectly plausible, an alternative explanation is the fact that NNTs are estimated against placebo; a highly sedating tertiary amine such as amitriptyline (IC₅₀ = 1 nM for the histamine H1 receptor) would have a perceived “beneficiary” effect of facilitating sleep that is difficult to separate from pain reduction. Duloxetine, a non-sedating agent with an IC₅₀ = 2,300 nM for the histamine H1 receptor would not have such a benefit (Bymaster et al., 2001). Milnacipran, a non-sedating agent with a selectivity ratio serotonin-to-norepinephrine transporters of approximately 1:3 (mirror values of amitriptyline) has a modest effect in chronic pain with a NNT of only 6 to 10.

The mechanism of action of antidepressants in chronic pain remains highly controversial (Stokes et al., 2017).

Historically ethanol (Figure 8) is one of the oldest analgesics and sedative-hypnotics known to mankind. The molecule being quite promiscuous, the mechanism of action of alcohol is certainly complex. P2X4 are the most ethanol sensitive P2X receptors in the central nervous system and likely mediate some if not the main effect of ethanol on the brain. As the ethanol concentration increases, P2X₄ activity decreases (Zhang et al., 2020). Alcohol acts as a negative allosteric modulator that blocks the open channel; ivermectin can antagonize the inhibitory effect of ethanol on P2X₄ and is thought to interfere with ethanol binding to the channel (Kanellopoulos et al., 2021). Chronic alcohol consumption is associated with cirrhosis, dementia, cardiovascular disease (such as hypertension, heart failure, atrial fibrillation), neuropathy, nutritional deficiencies, and certain cancers (Bielinska-Kwapisz and Mielecka-Kubien, 2011; Obad et al., 2018).

Antagonism at P2X7 receptors is assumed to provide multiple benefits (Mishra et al., 2021). Oxidized ATP irreversibly antagonizes P2X7 receptor activation, but lacks selectivity (Murgia et al., 1993; Savio et al., 2018; Rotondo et al., 2022). Brilliant Blue G produced a non-competitive inhibition of human P2X₇ receptors with IC₅₀ values of 200 nM.

While no clinically used compounds interacting selectively/exclusively with P2X7 receptor are available, dexmedetomidine, a centrally acting α2-adrenoceptor agonist used for sedation, was proposed to attenuate neuropathic pain i.a. through inhibition of spinal P2X7 receptor expression (Lin et al., 2018; Zhao et al., 2020) (Figure 9). Bradycardia, hypotension, and hypertension are the most commonly reported side effects (Kaye et al., 2020).

Gefapixant (Merck-7264), structurally similar to trimethoprim, is a P2X3 receptor antagonist named in honour of Geoffrey Burnstock (1929–2020), the father of purinergic pharmacology. Japan authorities approved gefapixant for adults with refractory or unexplained chronic cough. The suffix -pixant was adopted for P2X antagonists. Gefapixant has however a low selectivity for P2X₃ receptors, whereas the newly developed sivopixant has a much higher affinity and selectivity (P2X₃ IC₅₀ ≈ 5 nM). Taste disturbances such as loss or reduced sense of taste are the most reported side effects with gefapixant since P2X₃ receptors plays an important role in taste perception. Other common side effects include nausea and upper respiratory tract infection. However, lower incidence of taste disturbances is conveyed with sivopixant administration (Abu-Zaid et al., 2021; Niimi et al., 2022).

P2Y metabotropic receptors are G-protein-coupled receptors that are stimulated by purine and pyrimidine nucleotides. P2Y1 and/or P2Y2 receptor activation modulates TRP channels by lowering their activation threshold and thus favoring nociception (Tozaki-Saitoh et al., 2022).

Diquafosol, a P2Y₂ receptor agonist that promotes fluid transfer and mucin secretion by activating receptors expressed on the ocular surface, has been approved in Japan and South Korea to treat dry eye disease (Murakami et al., 2004; Keating, 2015; Nam et al., 2019).

In contrast, an experimental P2Y₂ receptor-selective antagonist, reversed allodynia in a chronic pain model (Magni et al., 2015). No P2Y₂ antagonists are clinically available.

CD 39 (EC 3.6.1.5) and CD 73 (EC 3.1.3.5) are ectoenzymes involved in the production of AMP from phosphorylated precursors (CD 39) and adenosine from AMP (CD 73) (Liu et al., 2017). They participate in regulating inflammatory processes and in nociceptive modulation by affecting extracellular adenosine generation.

Cell surface (ecto)nucleotidases serving to terminate purinergic signaling are seen as analogous to the activity of cholinesterases at cholinergic synapses (Stokes et al., 2017). Manipulating extracellular AMP hydrolysis could provide an alternative mechanism to control pain (Zylka, 2011; Liu et al., 2017).

Inhibiting overexpressed ectoenzymes involved in the production of adenosine in cancer cells may improve outcomes of conventional cancer therapy by decreasing adenosine levels and, consequently, promoting antitumor immune cells (Azambuja et al., 2019; Battastini et al., 2021).

Conversely, positive modulators/activators of ectoenzymes, are of potential interest in reducing/modulating pain, contingent on our ability to control off-target effects (Sowa et al., 2010). No positive modulators or antagonists are to date clinically available.

Adenosine is rapidly removed from the extracellular space by nucleoside transporters and metabolic enzymes, including adenosine kinase (intracellular conversion to AMP and trapping) and adenosine deaminase (conversion to inosine). Indeed, the extracellular concentration of adenosine and the antinociceptive effects of adenosine can be increased by pharmacologically inhibiting these metabolic enzymes (Sowa et al., 2010; Pastor-Anglada and Pérez-Torras, 2018).

Clinical development of adenosine kinase inhibitors was stopped due to toxicity (Boison and Jarvis, 2021).

Caffeine (Figure 10), a tri-methylated (1; 3;7) xanthine derivative and the most consumed psychoactive drug worldwide, has putative analgesic and/or anti-nociceptive effects. Its inclusion as an adjuvant in a number of double combination preparations, mostly with an NSAID (ibuprofen, naproxen, acetylsalicylic acid) or acetaminophen and triple combinations with an NSAID and acetaminophen modestly lowers the NNT (the lower the NNT the more efficacious the drug is) (Petersen, 2013; Yancey and Dattoli, 2013). The usual caffeine dose in combination preparations is 65 mg with acetaminophen and 100 mg with ibuprofen. For the general population of healthy adults, Health Canada advises a daily intake of no more than 400 mg.

The exact mechanism(s) of analgesic and/or anti-nociceptive effect(s) of caffeine is/are not known.

Caffeine is a non-selective adenosine receptor (AR) blocker. The affinity for the AR subtypes varies. Researchers from the Swiss Federal Institute of Technology in Lausanne report affinity values of caffeine for the human adenosine receptors as 12 at A1, 2.4 at A2A, 13 at A2B, and 80 μM at A3 (Froestl et al., 2012).

Administration of 160 mg caffeine (≈800 μM), the rough equivalent of one cup of coffee, generates mean maximal plasma concentrations of 18 μM (White et al., 2016). Administration of 100 mg caffeine (≈500 μM) generates mean maximal plasma concentrations of 15 μM (Grzegorzewski et al., 2021). Caffeine concentration in brain structures is about 50% of caffeine level in plasma (Orrego et al., 2016).

With estimated maximal CNS concentrations of caffeine at 10 μM, one can assume that the main inhibitory effect is mediated via A2A receptors; some inhibition of A1 and A2B receptors is possible, while a direct effect at A3 receptors appears unlikely.

A2A have anti-inflammatory effects and modify pain by direct and indirect actions (Sawynok, 2016). A2AR agonists however show some peripheral pro-nociceptive effects (Jung et al., 2022).

Furthermore, caffeine significantly increases plasma adenosine concentration (Conlay et al., 1997). As such, a shift of adenosine effect from caffeine blocked receptors to the unaffected A3R appears possible. A3R have an anti-nociceptive profile via actions on spinal microglia (Sawynok, 2016). Several experimental A3R agonists are being considered as promising analgesic agents (Jung et al., 2022).

Adding further complexity is the propensity of adenosine receptors to form homo-and hetero-dimers such as A1-A2A. In a must-read review titled “Pharmacology of Adenosine Receptors: The State of the Art” the authors point out that: “Low adenosine concentration preferentially stimulates the A1 protomer of the heteromer, which would inhibit glutamatergic transmission. On the other hand, high adenosine concentration activates adenosine A2A protomer of the heteromer that blocks adenosine A1-mediated effects and results in potentiation of glutamate release” (Borea et al., 2018). No information concerning the interaction between caffeine and A1-A2A adenosine receptor dimers is available to us.

In addition, caffeine is also an antagonist at the inositol trisphosphate (IP₃)- receptors subtype 1. High concentrations of caffeine (10–70 mM) selectively inhibit IP₃-R1 without affecting IP₃ binding and oppose the intracellular Ca²⁺ increase (Saleem et al., 2014). The caffeine concentrations required for IP₃-R1 inhibition are in the toxic range and therefore clinically not relevant.

Same applies to the ryanodine receptor where low mM (5 mM) concentrations of caffeine activate the receptor.

Caffeine is also a weak blocker of the ionotropic-glycine receptor (GlyR). Docking simulations indicate that caffeine and strychnine may bind to similar sites at the GlyR. Tested against the EC₅₀ of each GlyR subtype, the inhibitory caffeine concentration (IC₅₀) is in the range of 200–1,000 μM. GlyR produces its inhibitory effects through hyperpolarizing chloride currents (Duan et al., 2009). The caffeine concentrations required for GlyR inhibition are in the toxic range and therefore clinically not relevant for analgesia.

In conclusion, the analgesic/anti-nociceptive mechanism of action of caffeine is unclear. However, the effects are more established including improved alertness, cognitive processes, mood, learning and physical performance (Wikoff et al., 2017; Soós et al., 2021).

Gabapentin and pregabalin are structurally related to the endogenous inhibitory neurotransmitter GABA and to the amino acids leucine and isoleucine; in fact, both gabapentin and pregabalin contain GABA in both name and structure (Figure 11). Despite the similarity, their affinity for GABA receptors is orders of magnitude lower (high Ki) than for the α2δ auxiliary subunit of neuronal Voltage Dependent Calcium Channels (VDDC), which they bind to and block. By doing so, calcium channel permeability and calcium cell influx are reduced, leading subsequently to an unspecific neurotransmitter release reduction, including excitatory pro-algetic ones (Lanzetti and Di Biase, 2022). It is assumed that the endogenous agonists at the α2δ auxiliary subunit are the essential, branched-chain amino acids leucine and isoleucine, and thus gabapentin and pregabalin function as leucine/isoleucine competitive antagonists. While both drugs are recommended as possible first-line treatment for neuropathic pain by various medical authorities, the NNTs are high. Generally, the consensus is that tertiary amine tricyclic antidepressants (TA-TCA; amitriptyline) have superior (low) NNT values, but gabapentinoids are safer drugs (Finnerup et al., 2005). Stated more bluntly, it is easy and often infaust to overdose on TA-TCA, while a similar outcome would require enthusiastic use of gabapentinoids and still not offer any guarantee (Montgomery et al., 1989; Fischer et al., 1994). However, both medications share the most frequently reported adverse effects, which are somnolence and dizziness (Baidya et al., 2011; Chang et al., 2014).