Methods

This systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to guarantee strict methodology.

Registration

This systematic review has been registered on PROSPERO, registration number CRD42024578582.

Databases and Search Strategy

A manual literature search was conducted in PubMed including Medline, Cochrane Library, Google Scholar, Plos One, Science Direct, and clinicaltrials.gov from 2013 until 2023. The last search date was 31 December 2023. The complete search strategy and selection of studies are depicted in the PRISMA flowchart in Figure 1.

The databases and search methods are presented in Table 1 as follows:

Eligibility Criteria

Studies were screened based on their respective types: randomized controlled trials (RCTs), systematic reviews, meta-analyses, and observational studies. The inclusion criteria included studies conducted on human adults, published in the last 10 years (2013 to 2023), and written in English. In contrast, non-English studies, studies with unavailable full texts or incomplete outcome data, studies involving pediatric populations, and studies published before 2013 were excluded. A detailed description of the inclusion and exclusion criteria is given in Table 2.

Quality Appraisal

We used standardized quality assessment techniques to rigorously evaluate the quality of 13 selected studies. The Cochrane Risk of Bias tool for randomized controlled trials (RCTs), the SANRA (Scale for the Assessment of Non-Systematic Review Articles) tool for observational studies, and the AMSTAR (A Measurement Tool to Assess Systematic Reviews) checklist for systematic reviews were used to evaluate the quality of the studies as elucidated in Table 3 below. Three reviewers independently conducted the quality assessment. Any and all disputes were resolved through mutual discussion. A fourth reviewer was consulted if the need arose.

Figure 2, Table 4, and Table 5 present the specific overall scores for risks of bias for every study that was chosen.

Results

Three authors worked on the data extraction and compilation of subsequent results. We extracted data from the 13 studies included in our article. The results are presented in Table 6 and discussed below.

Gabapentinoids

Seven of the included studies evaluated the role of gabapentinoids in managing neuropathic pain [11,14-17,19,21]. They are considered the first-line treatments for various conditions causing neuropathic pain. Gabapentin and pregabalin, the two main drugs in this class, have shown efficacy in relieving central poststroke pain, painful diabetic neuropathy, and postherpetic neuralgia [17]. Their effects are modulated via binding of the α2δ-1 subunit of voltage-gated calcium channels, distributed throughout the nervous system. Their binding causes the release of excitatory neurotransmitters, including glutamate, substance P, and norepinephrine, reducing neuronal hyperexcitability and pain signal transmission [21].

Tricyclic Antidepressants (TCAs)

Four of the pooled studies examined the use of TCAs for treating neuropathic pain [11,13,14,17]. Of these studies, three identified TCAs as a first-line treatment [11,13,17], while one suggested they may come as a secondary choice given their potential side effects [14]. Among TCAs, amitriptyline and nortriptyline are the most extensively studied antidepressants for neuropathic pain. These medications have demonstrated efficacy in treating various neuropathic pain conditions, including peripheral neuropathy, postherpetic neuralgia, and pain following spinal cord injury. TCAs work primarily by blocking the reuptake of norepinephrine and serotonin in the central nervous system. The increase in noradrenaline, in particular, is thought to be central to their analgesic effects. Despite their effectiveness, TCAs are associated with potential side effects. Nortriptyline is often preferred over amitriptyline due to its milder side effect profile [13].

Serotonin-Norepinephrine Reuptake Inhibitors​​​​​​​ (SNRIs)

Four articles reported the use of SNRIs for neuropathic pain [11,13,14,21]. Venlafaxine, duloxetine, and other SNRIs are antidepressants that have been used for neuropathic pain, and they perform the same as TCAs. Majdinasab et al. showed that they are effective by elevating the concentrations of serotonin and norepinephrine in the central nervous system, which are involved in pain regulation [21]. Alles and Smith have described SNRIs as being among the first-line management options in the same way as TCAs [14]. However, Obata H pointed out that even though SNRIs are effective, they might not be as effective as TCAs in the treatment of neuropathic pain, but they are better tolerated than the latter [13].

Opioids

Two studies report the effects of opioids on neuropathic pain [11,14]. Endogenous opioids work by using the mu, delta, and kappa receptors, which subsequently upregulate the inhibitor G protein, thus inhibiting the adenylate cyclase along with the cAMP. However, mechanisms common to both endogenous and exogenous opioids include their coupling to the calcium and potassium channels, contributing to their role as central analgesics. However, Fornasari et al. have tagged opioids as second and third-line agents when it comes to neuropathic pain. A major factor for this nomination is their poor side effect profile, including but not limited to addiction, diversion, and abuse potential [11]. Alles and Smith have categorized opioids as second-line agents in neuropathic pain due to the loss of u-opioid receptors in any kind of nerve injury [14]. Furthermore, they have extended the debate to include that any form of pain that is resistant to opioid use is likely neuropathic in nature due to the same mechanism [14].

Anticonvulsants

Besides gabapentinoids, other anticonvulsants like carbamazepine and oxcarbazepine play a crucial role in managing neuropathic pain, particularly trigeminal neuralgia [15]. Three of the included studies reported findings on anticonvulsants [15-17]. These medications primarily act by modulating voltage-gated sodium channels, reducing the excessive firing of neurons associated with this condition. By stabilizing neuronal membranes and inhibiting repetitive action potentials, they effectively alleviate pain. However, potential side effects include somnolence, dizziness, and drowsiness [16,17].

Selective Serotonin Reuptake Inhibitors​​​​​​​ (SSRIs)

Three articles focused on the application of SSRIs for neuropathic pain, among which fluoxetine was the most common [11,13,20]. These drugs are known to help by increasing serotonin levels in the brain. Foley et al. demonstrated that while serotonin is widely associated with mood regulation since it is a neurotransmitter, it also influences pain transmission by altering pain channels, possibly resulting in the relief of pain [20]. However, Obata et al. indicated that often, SSRIs are not regarded as a very effective modality in managing chronic neuropathic pain [13].

Cannabinoids

Bennici et al. mention the use of cannabis and cannabinoids for neuropathic pain relief, the review mentions that nabiximoles, products of cannabidiol and delta-9-tetrahydrocannabinol (THC), are approved for neuropathic pain and spasticity due to multiple sclerosis in certain regions [18]. Cannabinoids (CB) work by activating two receptors within the endocannabinoid system: cannabinoid receptor type 1 (CB1) and type 2 (CB2). The endocannabinoid system (eCS) is a biological network comprising endocannabinoids-endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors and cannabinoid receptor proteins distributed throughout the vertebrate central nervous system. Common side effects include dizziness, headache, nausea, mild neurocognitive impairment, sedation, and a "drug high," while severe adverse events are rare.

N-Methyl-D-Aspartate ​(NMDA) Receptor Blockers

Martin et al. reported that Ketamine is effective for postoperative pain, post-herpetic neuralgia, and phantom limb pain [22]. However, due to its poor side effect profile, including hepatic, cardiovascular, and psychodysleptic side effects, other NMDA receptor blockers like dextromethorphan and memantine can be used in its place to prolong ketamine’s analgesic effects [22]. Another benefit of these alternative options is that they can be administered orally, as opposed to the intravenous route of ketamine, improving medication compliance [22].

Paracetamol

Wiffen et al. have reported that paracetamol, with or without codeine or hydrocodone, is one of the first-line drugs used in postherpetic neuralgia, painful diabetic neuropathy, neuropathic low back pain, and phantom limb pain. The mechanism of paracetamol is still a point of debate, but it is said to be working by inhibiting the cyclooxygenase (COX) receptors in the brain, spleen, and lungs. However, there is no high-quality evidence supporting or contesting paracetamol’s efficacy in reducing neuropathic pain [2].

Emerging Therapies

Ongoing research is exploring novel drug targets for neuropathic pain management. These include specific ion channels, such as transient receptor potential vanilloid-1 (TRPV-1) and P2X purinoceptor 4 (P2X4), as well as receptors like adenosine A3. Additionally, pathways involved in pain modulation, such as glial cell activation and inflammatory processes, are being investigated as potential therapeutic targets [14]. Kersten et al. showed that any neurotransmitter that inhibits the EGFR (Epidermal Growth Factor Receptor) system blocks the MAPK (mitogen-activated protein kinases) pathway, eventually resulting in the inhibition of neuropathic pain. Another proposed mechanism of the EGFR-inhibitor drugs is their effect on the sodium channels, as demonstrated by improved outcomes when used alongside gabapentin and pregabalin in tumor cell lines [12].

Discussion

Neuropathic pain is challenging to manage and significantly impacts a patient’s quality of life [23]. Understanding the involvement of receptors and neurotransmitters can help tailor a regimen specific to the patient. Neuropathic pain can be central or peripheral, but regardless of the origin, gabapentinoids, TCAs, and SNRIs are the recommended first-line therapy [24]. However, conditions like trigeminal neuralgia, a type of peripheral neuropathic pain, do not respond well to these treatments and require carbamazepine or oxcarbazepine as a specific, effective therapy [25]. Similarly, opioids like tramadol and tapentadol, are the recommended second-line therapy [24]; however, the first line in intermittent exacerbation of neuropathic pain and cancer-related pain [26]. The National Institute for Health and Care (NICE) recommends that for managing neuropathic pain pharmacologically, patients should be offered a choice among amitriptyline, duloxetine, gabapentin, or pregabalin as initial treatment options (excluding trigeminal neuralgia). If the first, second, or third medications are ineffective or poorly tolerated, it is recommended to switch the medication [2]. This difference could be because of variations in underlying disease pathophysiology, differences in nerve involvement, and variability in pain receptors and neurotransmitters involved.

Antidepressants

Antidepressants exert their pharmacological effect by binding to noradrenaline and serotonin receptors, leading to increased levels of serotonin and norepinephrine in the synaptic cleft. According to a review by Obata et al., antidepressants that inhibit the reuptake of both neurotransmitters have stronger analgesic effects than a drug that selectively inhibits only one neurotransmitter. Additionally, norepinephrine plays a greater role than serotonin in the analgesic effect, and the number needed to treat (NNT) for SSRIs is higher than that for TCAs and SNRIs [13]. The exact mechanism of neuropathic analgesia of antidepressants is still unknown and requires further high-quality research. One proposed mechanism is that these drugs act by exerting their effects on the norepinephrine and serotonin neurotransmitters in the spinal pain pathway. Additional proposed mechanisms involve the modulation of histamine and sodium channels [27]. P2X4 is an adenosine 5’-triphosphate (ATP) cation channel receptor that plays a role in neuroinflammation. So far, duloxetine is one drug that has been shown to inhibit these receptors, thereby improving neuropathic pain. However, more in-depth research is yet to be seen [28].

Anticonvulsants

Anticonvulsants such as pregabalin and gabapentin bind to alpha-2-delta calcium channels. Gabapentinoids decrease the calcium channel currents by influencing the number of available calcium channels in the plasma membrane [29]. These drugs bind the pre-synaptic calcium channels that modulate the release of excitatory neurotransmitters by blocking calcium entry [30]. Gabapentin has been shown to reduce presynaptic gamma-aminobutyric acid (GABA) release in the locus coeruleus via the GABA-B receptors, which subsequently increases the glutamate neurotransmitter [31]. Between gabapentin and pregabalin, the latter has a bioavailability of more than 90% in contrast to the 30-60% of gabapentin. In addition, pregabalin has a linear dose-response relationship as it is absorbed in the small intestine as well as the proximal colon as compared to only small intestinal absorption of gabapentin. Admittedly, the absorption of pregabalin significantly decreases by food intake, but that of gabapentin does not [32]. This difference in pharmacokinetics could be of potential importance to patients with small intestinal absorptive or transit conditions. Active Crohn’s disease, radiation enteritis, hyperthyroidism, and neuroendocrine tumors decrease the small intestinal transit time, thereby potentially decreasing gabapentin absorption [33]. However, purely malabsorptive conditions like celiac disease do not alter pregabalin absorption [34]. Lamotrigine has shown efficacy as an adjunct therapy to TCAs, SNRIs, and gabapentinoids for spinal cord injury-induced neuropathic pain and intractable trigeminal neuralgia [35,36].

Topical Lidocaine

Topical lidocaine is considered a second-line agent and blocks voltage-gated sodium channels when administered as a patch [37], with mild local reactions as side effects [38]. Notedly, topical anesthetics should be distinguished from topical patches, as the latter have major systemic absorption as their primary mechanism, while the former only exert their effects close to the site of injection. Lidocaine can provide local anesthetic effects in the form of medicated plasters, gels, and sprays [39]. Topical lidocaine can be used as an adjunct in opioid-sparing pain management as it has been shown to be beneficial in post-surgical persistent pain (PSPP), PHN, diabetic peripheral neuropathy (DPN), carpal tunnel syndrome (CTS), chronic lower back pain (CLBP), and osteoarthritis (OA) [40].

Opioids

Strong opioids like morphine, oxycodone, and hydromorphone, as well as weaker opioids such as tramadol, have shown efficacy in treating neuropathic pain, comparable to antidepressants in terms of the NNT. Despite their effectiveness, opioids are typically considered second or even third-line treatments due to the risk of adverse reactions, potential for abuse, diversion, and addiction [41]. The analgesic effects of opioids arise from their actions in the brain, brainstem, spinal cord, and, under certain conditions, the peripheral terminals of primary afferent neurons. Endogenous opioid peptides, including β-endorphin, enkephalins, and dynorphins, bind to G protein-coupled receptors, classified into mu, delta, and kappa receptors. These receptors are linked to inhibitory G proteins, and their activation inhibits adenylate cyclase and intracellular cAMP production. A key mechanism of opioid-induced analgesia involves the coupling of these receptors to calcium and potassium channels [42].

Within the dorsal horn of the spinal cord, mu receptors predominate, with over 70% located pre-synaptically at the central terminals of nociceptors (C and A delta fibers). The remaining 30% are found post-synaptically on dendrites of second-order spinothalamic neurons and interneurons [42]. These interneurons are primarily responsible for releasing endogenous opioids like beta-enkephalin and endorphins, which act on mu receptors in the dorsal horn. Interneuron activation depends on descending pathway activity or direct stimulation by descending fibers. Activation of presynaptic mu receptors inhibits calcium ion channels, preventing neurotransmitter release, while activation of postsynaptic mu receptors opens potassium ion channels, causing potassium efflux and hyperpolarization of the projecting cell. Thus, stimulating mu-opioid receptors in the spinal cord effectively blocks synaptic transmission, reducing nociceptive stimuli reaching the thalamus and cortex, where pain is consciously perceived [42]. Despite their efficacy, the long-term use of opioids for nonmalignant pain remains controversial due to concerns about the potential development of tolerance to their analgesic effects, and the risk of addiction [42].

Riluzole and Amiloride

Riluzole is known to inactivate voltage-dependent sodium channels and depress glutamatergic neurotransmission, offering another potential avenue for pain management. Amiloride, which blocks acid-sensing ion channels implicated in both central and peripheral pain mechanisms, is used in the treatment of migraines. These insights into various drug mechanisms emphasize the need for continued research to enhance our understanding and treatment of neuropathic pain [20].

Riluzole was initially reported to be of little to no use for treating peripheral neuropathic pain [43]. However, recent studies have shown improved outcomes for patients experiencing cervical myelopathy who were treated with riluzole versus placebo [44]. Riluzole provides benefits to patients with Alzheimer’s disease by preserving cerebral glucose metabolism and to ALS patients by improving survival. It has also shown benefits to patients with spinal cord injury (SCI) in decreasing their pain [45,46].

Amiloride is a sodium channel-blocking diuretic that is commonly used for congestive heart failure and hypertension. One of its mechanisms of action is to inhibit the acid-sensing ion channels (ASIC). This effect has been shown to improve neuropathic pain by adopting the intrathecal injection approach for acute and chronic pains [47].

Vitamin B Complex

The Vitamin B complex including thiamine (B1), pyridoxine (B6), folic acid (B9), and cyanocobalamin (B12) have shown improvements in neuropathic pains of various etiologies, specifically diabetic neuropathy. These vitamins have the added advantage of being neuroprotectors of the entire nervous system, where B1 has a site-directed antioxidant property, B6 modulates nerve metabolism, and B12 stabilizes the myelin sheaths, blocks sensory nerve conduction, and decreases ectopic nerve firing. It is worth noting that B12 has a special role in nerve-regenerating activities as well. It has been shown to not only improve neuropathic pain symptoms but also completely regenerate and recover lost myelin sheaths and physiological nerve conduction velocities [48-51]. B12 is of particular importance for diabetic patients who are taking metformin, as this drug has been shown to decrease B12 absorption in the body, contributing to increased neuropathic pain [52].

Cannabinoids

Cannabinoids work by activating the cannabinoid receptors CB1 and CB2. The cannabinoid receptors work by blocking the voltage-gated calcium channels, inhibiting adenylate cyclase, and decreasing the cAMP levels [53]. Cannabinoids have been shown to have efficacy for improving neuropathic pain but only for the short term. This is due to their shorter efficacy window as well as a multitude of side effects, including neurological and psychiatric disorder development with long-term use [54]. Limitations to cannabis use for neuropathic pain also include a risk of dependence leading to cannabis use disorder. In addition to dependence, long-term use can also increase the risk of withdrawal symptoms once therapy is ceased, including but not limited to symptoms of anger, aggression, decreased appetite, irritability, restlessness, and insomnia [55].

Capsaicin

Capsaicin, a natural spice, has been historically used for its topical anesthetic effects. It exerts its effects through the activation of the transient receptor potential vanilloid-1 (TRPV1) on nerve fibers. Capsaicin use avoids the systemic side effects of systemic drugs and works by inducing a momentary discomfort at the application area, followed by a prolonged anesthetic response [56]. Capsaicin has primarily shown efficacy in treating postherpetic neuropathic pain and HIV neuropathy. The main adverse effects are transient pain and erythema over the application site [57].

Paracetamol

Paracetamol is one of the most commonly used analgesics and antipyretics. It is postulated to work by the inhibition of the central COX pathway, leading to an enhanced descending serotonergic effect. However, it is distinct from non-steroidal anti-inflammatory drugs (NSAIDs) as it does not have any peripheral anti-inflammatory effects [58]. Paracetamol is the first-line therapy for patients with OA [59]. OA has been shown to have a neuropathic pain component, as evidenced by a pathological innervation of the degenerative cartilage in the joint space [60]. Furthermore, the efficacy of paracetamol is being debated for OA, especially for long-term use. However, it is postulated that paracetamol has good synergistic actions when used as a combination therapy for neuropathic pain [61]. Paracetamol has shown considerable efficacy when used in combination with opioids for rheumatoid arthritis (RA), OA, and diabetic neuropathy [58].

Neuropathic pain has multiple etiologies, and it stands to reason that the identification of each of these underlying pathologies and their mechanisms can aid in improved outcomes for this condition. However, drug side effects may also depend on the etiology, for example, drugs with CNS-related side effects may be less tolerated in patients with CNS lesions [41]. Majdinasab et al. presented a proposal for painful diabetic peripheral polyneuropathy (PDPP). The proposal suggested that other pain-controlling medications, such as TCAs or gabapentin, should be used in the first week. After one week, these medications should be discontinued, and only duloxetine should be used [21], considering that gabapentin works fast, and duloxetine works late but shows lesser side effects. Although this proposal needs more investigations and further studies, it hints at the importance of combined therapy.

Limitations

Our systematic literature review has limitations. We only included studies that provided free, full text, and paid or closed-access articles were excluded. Our study only includes English-based journals/articles, and this can be perceived as a major limitation as a lot of great research exists in the non-English literature and language, just like any other parameter should not be a barrier towards scientific advancement. Neuropathic pain has several manifestations, and though we tried to include the most common ones, there are still other forms and etiologies of it that were not discussed in this article. Similarly, we tried to include the most common drugs used for neuropathic pain, as well as novel and less common therapies, yet there may be several other therapies that were not discussed. Evidence of efficacy for drugs like paracetamol was lacking in any high-quality information, and evidence for the emerging therapies might still be in their early stages. Further high-quality research is awaited on many of this condition's avenues.