Unlocking Relief: Investigating the Impact of a Fixed Combination of Acetyl‐L‐Carnitine and Palmitoylethanolamide on Traumatic Acute Low Back Pain

ABSTRACT

Background

Peripheral neuropathies encompass a diverse group of disorders involving peripheral nerve damage, often leading to pain, sensory disturbances, and motor impairments. The etiology is multifactorial, with trauma as a key contributor. The treatment of peripheral neuropathies includes medications targeting the nociceptive component, whereas the neuropathic component is managed with agents such as gabapentinoids or antidepressants, though their prolonged use is limited by significant side effects. Some neuroprotective compounds, such as acetyl‐L‐carnitine (ALC), palmitoylethanolamide (PEA), and alpha‐lipoic acid (ALA), have emerged as potential alternatives due to their anti‐inflammatory and analgesic properties.

Methods

This monocentric, observational, single‐arm longitudinal study evaluated the efficacy of a fixed combination containing ALC, PEA, and ALA (as an adjuvant to the previous two) and Boswellia serrata, Vitamin E, and Vitamin B6 in patients with acute low back trauma. Over 8 weeks, 48 participants received the supplement alongside conventional therapy. The primary end point was improvement in neuropathic pain assessed via the Neuropathic Pain Scale (NPS) and Visual Analogue Scale (VAS). Secondary endpoints included quality of life (SF‐36) changes, reduced NSAID consumption, and adverse events.

Results

The study showed significant reductions in NPS and VAS scores and improvements in physical health‐related SF‐36 domains, with reduced NSAID consumption. Participants with more severe baseline symptoms demonstrated the greatest benefits. No significant changes were observed in emotional parameters. Adverse events were mild and in a very limited number of patients.

Conclusions

Results suggest the combination's potential to improve pain and reduce reliance on conventional therapies; however, further controlled randomized trials are needed to validate these findings.

This monocentric observational study investigates a fixed combination of acetyl‐L‐carnitine, palmitoylethanolamide, and alpha‐lipoic acid in 48 patients with acute low back pain. Over 8 weeks, treatment led to significant reductions in neuropathic pain scores, decreased NSAID consumption, and improvements in quality of life, supporting its potential role as an adjuvant therapy.

1. Introduction

Peripheral neuropathies represent a group of disorders characterized by damage to the peripheral nervous system, affecting the nerves outside the brain and spinal cord. These conditions manifest through a range of symptoms, including pain, numbness, tingling, and muscle weakness, often leading to significant functional impairment and reduced quality of life.

The etiology of peripheral neuropathies is multifactorial, encompassing various genetic, metabolic, autoimmune, infectious, toxic, and traumatic causes [1]. Physical trauma represents the predominant etiology of acquired single‐nerve injuries. Such injuries can occur due to various causes, including automobile accidents, falls, sports‐related incidents, and medical procedures, which can result in the stretching, crushing, or compression of nerves, or their detachment from the spinal cord. Even less severe traumas can lead to significant nerve damage. For instance, fractures or dislocations of bones can exert damaging pressure on adjacent nerves, whereas herniated discs between vertebrae can compress nerve fibers as they emerge from the spinal cord. Lumbosciatalgia, characterized by the compression of lumbar (L4 and L5) or sacral (S1 and S2) nerve roots, stands out as one of the most common forms of compressive peripheral neuropathies [2, 3]. Neurological manifestations of such injuries may include sensory deficits or motor impairments. Sensory symptoms encompass anesthesia, paresthesia, hypoesthesia, hyperesthesia, and pain, whereas motor limitations may manifest as impaired lower extremity function [4, 5].

Despite advancements in diagnostic modalities and therapeutic strategies, the management of peripheral neuropathies remains a clinical challenge. Treatment approaches typically involve a multidisciplinary approach aimed at alleviating symptoms, addressing underlying causes, and preventing further nerve damage. Pharmacological interventions, physical therapy, and lifestyle modifications constitute cornerstone strategies, whereas emerging modalities such as nerve stimulation and regenerative therapies hold promise for future interventions.

Considering that the use of NSAIDs, paracetamol, and opioid analgesics represents the main therapeutic choice in this field for managing the nociceptive component of pain, whereas the neuropathic component is generally managed with agents like gabapentinoids (e.g., gabapentin, pregabalin) or certain antidepressants (e.g., amitriptyline, duloxetine), it is well known that these drugs are associated with significant side effects that limit their use for prolonged periods. On the other hand, a multimodal approach allows for reducing the dosage and side effects of single actives; in this perspective, neuroprotectors, such as acetyl‐L‐carnitine (ALC), Palmitoylethanolamide (PEA) and Alpha‐lipoic acid (ALA) can represent valid candidates with a good efficacy and safety profile [6].

ALC, the acetylated ester of L‐carnitine, is endogenously synthesized in the human body, predominantly within the brain, liver, and kidney, via the enzyme ALC‐transferase. ALC primarily serves as a transporter of fatty acids into mitochondria for ATP production. Additionally, it enhances acetylcholine synthesis, stimulates protein and membrane phospholipid biosynthesis, and participates in nerve growth factor modulation, thereby promoting nerve regeneration. ALC also exhibits analgesic properties via epigenetic mechanisms, influencing the expression of the metabotropic glutamate receptor type 2 (mGlu‐2) [7, 8, 9]. Preclinical and clinical studies have demonstrated ALC's neuroprotective effects, with efficacy shown in alleviating pain and sensory symptoms associated with various neuropathies, including diabetic neuropathy, chemotherapy‐induced neuropathy, antiretroviral toxic neuropathy, and compressive neuropathies [10, 11, 12, 13, 14, 15, 16, 17]. PEA, an endogenous fatty acid amide, belongs to the class of ethanolamides, which are lipid mediators of inflammation. PEA is ubiquitously distributed in mammals and synthesized in response to tissue injury or stress from the lipid bilayer. It regulates numerous physiological processes, including nerve compression pain, respiratory inflammation, neuroinflammation, neurotoxicity, and central nervous ischemia. Since 1975, PEA has been investigated for its therapeutic potential in neuropathic and chronic pain conditions [18, 19, 20, 21, 22, 23]. Clinical studies on various peripheral neuropathies, including compressive neuropathies, have shown that PEA exerts anti‐inflammatory and analgesic effects by inhibiting mast cell degranulation and glial cell activation [8, 9].

ALA, also known as 1,2‐dithiolane‐3‐pentanoic acid or thioctic acid, is a naturally occurring compound found in mammalian mitochondria. ALA serves as a crucial cofactor for mitochondrial α‐ketoacid dehydrogenases, thereby playing a pivotal role in mitochondrial energy metabolism [24, 25, 26]. Renowned for its potent antioxidant properties, ALA acts as a “universal” antioxidant, effective in both lipid and aqueous phases, such as cellular membranes and cytosol. Experimental studies have demonstrated ALA's ability to improve motor nerve conduction velocity in diabetic neuropathy and protect peripheral nerves from ischemic damage in animal models [27, 28]. Clinical trials in patients with diabetic neuropathy have shown that ALA supplementation at 600 mg/day reduces pain, paresthesia, and numbness [29, 30]. Synergy between ALC and PEA has been observed in murine models of neuropathic pain, further enhanced when combined with an antioxidant substance, such as ALA, and registered by a European Patent (n. EP2921167) [31]. Recent research by Parisi et al. suggested that a fixed combination of PEA and ALC reduces pain and improves peripheral neuropathic symptoms secondary to rheumatic diseases [9]. This study aims to evaluate the efficacy of a fixed combination of ALA, ALC, PEA, B. serrata , Vitamin E, and Vitamin B6 (Kalanit Forte, Chiesi Italia S.p.A. – Parma, Italy) in improving neuropathic pain following traumatic events.

2. Patients and Methods

This is a monocentric, observational, single‐arm longitudinal study. Patients between 18 and 65 years of age who experienced acute low back trauma 4 weeks or more before enrollment and who have been taking NSAIDs/paracetamol and/or systemic corticosteroids (SCS) in the period following the trauma for nociceptive pain and trauma‐related inflammation have been enrolled. The exclusion criteria included the presence of neoplasia, metabolic pathologies, autoimmune pathologies, vertebral fractures, and treatment with opioids or antiepileptics. All subjects signed an informed consent; the study was conducted in accordance with the Declaration of Helsinki and was approved by the local Ethical Committee (prot. n. 1538, ver. 3). All subjects were supplemented for 8 weeks once a day with a formulation containing 1000 mg ALC, 1200 mg PEA, 600 mg Alpha‐lipoic acid (ALA), 200 mg B. serrata , 24 mg Vitamin E, and 2.8 mg Vitamin B6.

The primary end point of the study was the evaluation of pain changes from baseline in neuropathic pain and generic pain (Neuropathic Pain Scale—NPS, Visual Analogue Scale VAS, respectively) at the end of the study (8 weeks). Secondary endpoints included the evaluation of changes from baseline of NPS and VAS scores at 4 weeks, changes in quality of life (SF‐36) [32] and consumption of NSAIDs (paracetamol included) and/or SCS as rescue therapy compared to baseline, intended as the number of unit doses taken per week. Other information collected as a secondary end point was the number of low back pain exacerbations, the number of outpatient visits to GPs and/or specialists compared to baseline, and the number of emergency room (ER) visits compared to baseline. We also collected data on any adverse reactions associated with the treatment. For inclusion in the study, we used the Douleur Neuropathique 4 (DN4) score, which is a diagnostic tool used to identify neuropathic pain. It consists of a questionnaire with 10 items, divided into sensory descriptors and sensory examination findings. Each item is scored as either 0 (no) or 1 (yes), with a total score ranging from 0 to 10. A DN4 score greater than 4 indicates a high likelihood of neuropathic pain, and in our protocol, it was the cutoff for inclusion. The severity of pain was confirmed using the Neuropathic Pain Score (NPS) [33]. Pain was also assessed using the VAS scale, and the SF‐36 questionnaire was administered at the beginning of the study and after 8 weeks of treatment. Baseline and 8‐week visits were performed in our clinic, as at 4 weeks the questionnaires were administered to all participants by phone call.

2.1. Statistical Analysis

Statistical analysis was conducted with SPSS for Windows 22.0 (IBM Corp Released 2016, NY, USA). The results obtained were expressed as mean ± standard deviation. In order to analyze the differences between groups, the T‐student test for paired data were used. Statistical significance was considered for a p value of < 0.05.

3. Results

We enrolled 48 subjects, 23 males, and 25 females with an average age of 43 ± 11 years. The anthropometric parameters are expressed in Table 1. The two genders were well matched by age.

TABLE 1.

Anthropometric and clinical parameters of patients enrolled.

Parameters	Males (23)	Females (25)	p
Age (years)	43 ± 13	42 ± 11	NS
Weight (kg)	75 ± 7	59 ± 6	< 0.001
Height (mt)	1.75 ± 0.06	1.63 ± 0.06	< 0.001
BMI (kg/m2)	24.33 ± 1.63	22.32 ± 2.45	< 0.01
Time since the trauma (days)	36 ± 3	35 ± 4	NS

All patients had experienced an accidental compressive trauma to the lumbar spine between 4 and 6 weeks prior to enrollment. The drug daily intake and the adherence to treatment were assessed through a self‐reported diary. None of the patients were on corticosteroids, and they predominantly took ibuprofen or a similar 600 mg or an equivalent—on average 11 tablets per week.

The baseline values of scores and questionnaires are reported in Table 2. Note that in the different domains of the SF‐36 questionnaire, a value of 100 corresponds to the best state of health and the absence of physical and emotional impairment [33].

TABLE 2.

Baseline values of pain scores, NSAIDs consumption, and SF‐36 domain.

Baseline parameters
Mean DN4 score ± SD	5.5 ± 0.8
Mean NPS score ± SD	36.8 ± 8.3
Mean VAS score ± SD	5.4 ± 1.2
Mean NSAID consumption per week ±SD	11.4 ± 5.8
SF‐36 domains
Mean physical efficiency score ± SD	64.3 ± 25.7
Mean physical limitation score ± SD	57.3 ± 21.2
Mean emotional problems score ± SD	75.7 ± 28.2
Mean fatigue score ± SD	40.6 ± 9.1
Mean emotional well‐being score ± SD	55.1 ± 8.4
Mean social functioning score ± SD	67.0 ± 10.4
Mean pain score ± SD	53.2 ± 19.9
Mean general health score ± SD	50.0 ± 16.4

3.1. Efficacy Outcomes

As primary efficacy end point, the treatment exhibited a statistically significant change in pain measured with the NPS and VAS scores at 8 weeks of treatment, respectively from 36.8 ± 8.3 to 33.3 ± 4.7 and from 5.4 ± 1.2 to 3.3 ± 0.9 (p < 0.001 vs. baseline for both) (Figure 1).

FIGURE 1.

Change from baseline in pain score values (NPS and VAS) during the study follow‐up. ***p < 0.001.

NSAIDs consumption too showed a significant reduction at 8 weeks of treatment, from 11.4 ± 5.8 to 5.9 ± 4.1 unit doses taken per week (p < 0.001) (Figure 2).

FIGURE 2.

Change from baseline in weekly NSAIDs consumption during the study follow‐up. ***p < 0.001.

We conducted the intermediate follow‐up after 4 weeks via a phone call. All enrolled patients responded to the call and answered the questions raised. From this initial checkup, a trend toward improvement in these parameters in pain scores and NSAIDs consumption emerged; although statistical significance was not reached (Figures 1 and 2). No patients took SCSs as rescue medication.

The outcomes form SF‐36 questionnaire at 8 weeks confirmed what emerged from the previously described results, showing a significant improvement in physical health, pain, and general health domains. The emotional problems domain, after a nonsignificant worsening at 4 weeks, showed an improvement vs. baseline at the end of the study (Figure 3).

FIGURE 3.

Change from baseline in SF‐36 domains score during the study follow‐up. *p < 0.05; **p < 0.005.

To assess whether the severity of symptoms could influence the treatment's effectiveness, we performed a sub‐analysis on the patients with more severe neuropathic pain at enrollment, using the mean recorded value of 37 NPS score at baseline as the cutoff. The baseline characteristics of the new patients' group with higher neuropathic pain severity are presented in Table 3.

TABLE 3.

The baseline characteristics of patients grouped based on the severity of symptoms (NPS: Neuropathic Pain Score; NSAID consumption; number of pills of nonsteroidal anti‐inflammatory drug).

	NPS ≤ 37	NPS > 37	p
Baseline parameters
No of patients (females)	31 (20)	17 (5)	—
Mean age ± SD	39.1 ± 9.3	48.8 ± 12.6	< 0.05
Mean NPS score ± SD	32.0 ± 3.0	45.6 ± 7.6	< 0.001
Mean VAS score ± SD	4.8 ± 0.5	6.4 ± 1.5	< 0.005
Mean NSAID consumption per week ±SD	9.9 ± 5.9	14.1 ± 4.5	< 0.05
SF‐36 domains
Mean physical efficiency score ± SD	72.6 ± 17.1	49.1 ± 31.9	< 0.05
Mean physical limitation score ± SD	60.5 ± 18.0	51.1 ± 25.7	NS
Mean emotional problems score ± SD	82.8 ± 24.1	62.6 ± 31.0	< 0.05
Mean fatigue score ± SD	42.7 ± 6.6	36.8 ± 11.7	NS
Mean emotional well‐being score ± SD	57.4 ± 9.1	51.1 ± 4.9	< 0.01
Mean social functioning score ± SD	66.5 ± 5,5	68.0 ± 16.1	NS
Mean pain score ± SD	56.4 ± 23.3	47.4 ± 9.7	NS
Mean general health score ± SD	54.8 ± 11.4	41.2 ± 20.3	< 0.05

In the NPS > 37 subgroup, the reduction in pain was greater compared to the whole sample, reaching 42.2 ± 4.8 and 36.6 ± 5.4 for the NPS score, and 5.2 ± 1.0 and 3.4 ± 0.9 for the VAS score, respectively at 4 and 8 weeks, with statistical significance achieved from 4 weeks onwards for both parameters (Figure 4).

FIGURE 4.

Change from baseline in pain score values (NPS and VAS scale) during the study follow‐up in more severe patients' subgroup (NPS > 37). **p < 0.005; ***p < 0.001.

Similarly, the weekly consumption of as needed NSAIDs also decreased compared to baseline (11.1 ± 4.0 at 4 weeks and 7.5 ± 3.8 at 8 weeks of treatment), achieving statistical significance from the 4‐week follow‐up onwards (Figure 5).

FIGURE 5.

Change from baseline in weekly NSAIDs consumption during the study follow‐up in more severe patients' subgroup (NPS > 37). **p < 0.005; ***p < 0.001.

From the analysis of the domains related to the SF‐36 questionnaire, a more marked increase was noted for physical efficiency and general health domains at the end of the study, which reached significance compared to baseline. For physical limitation and emotional problems domains, there was a significant reduction in the score at 4 weeks, which was largely recovered at 8 weeks, with statistical significance or a higher trend of significance if compared to baseline (Figure 6).

FIGURE 6.

Change from baseline in SF‐36 domains score during the study follow‐up in more severe patients' subgroup (NPS > 37). ^# p = 0.053; *p < 0.05; **p < 0.005.

3.2. Adverse Events

None of the subjects required a visit from the General Practitioner (GP) and/or specialist, and none accessed the ER. Five participants dropped out of the study. Of these, one dropout was due to tingling sensations, and four dropouts were due to diarrhea.

4. Discussion

Acute vertebral pain is a significant clinical issue due to its prevalence and impact on quality of life. It is often characterized by sudden onset, severe intensity, and a debilitating nature that can hinder daily activities and reduce functional capacity. The components of back pain are often mixed: alongside nociceptive pain, there is a neuropathic component due to the involvement of nerve structures, which requires a targeted approach [34, 35]. The etiology of acute vertebral pain can be multifactorial, including mechanical stress, inflammation, and neural involvement, which complicates its management [36]. Complete recovery of the acutely compressed or damaged nerve can range from weeks to years, and structural nerve recovery is frequently not synonymous with complete clinical and functional recovery [37]. WHO defines spine‐related pain as “chronical” if it does not resolve within 12 weeks; although some authors believe that the best cutoff to determine chronicity is 6 months, and, considering the latter as valid, a high percentage of patients (between 26% and 32%) go from acute to chronic spinal pain [38, 39].

The switch from acute to chronic neuropathic pain involves inflammation of the peripheral nerves, leading to reparative processes that result in a hyperexcitable state known as peripheral sensitization. However, neuropathic pain mechanisms are characterized by synaptic plasticity due to increased neuronal responses to repeated nociceptive stimulation. Additionally, nociceptive signals can also be altered at the supraspinal level. After peripheral injury, reorganization occurs at the cortical level, and the extent of these changes seems to correlate with the degree of pain, giving rise to the so‐called nociplastic component of pain. Changes occurring in supraspinal regions may explain the strong association between neuropathic pain and mood disorders [40]. On the other hand, a strong correlation between psychiatric disorders and the risk of transition to chronicity was clearly demonstrated [41].

One of the objectives of neuropathic pain management is neuroprotection, which necessitates prolonged treatments. If this phase of treatment is not properly addressed, there is a significant risk of pain becoming chronic; making its management considerably more challenging.

Conventional pharmacological treatments, such as nonsteroidal anti‐inflammatory drugs (NSAIDs), SCs and opioids, are commonly used to alleviate symptoms. However, these treatments can be associated with adverse effects and do not address the underlying causes of pain. Prolonged treatment with these drugs increases the risk of developing side effects, reducing adherence to the therapy, and compromising its effectiveness, particularly against the neuropathic component. Therefore, there is a growing interest in alternative approaches, including neuroprotective compounds and endocannabinoid actives, for the management of acute vertebral pain [42].

In this study we have tested the potential efficacy of a neuroprotective compound's fixed combination (ALC + PEA) in the management of neuropathic back pain following acute trauma in addition to conventional therapeutic approaches. The primary end point of efficacy was the change in pain measured using the NPS and the Visual Analogue Scale (VAS) scores. At the end of the study, we observed a significant improvement in pain parameters on the NPS and VAS scales. Additionally, descriptors of physical health in the SF‐36 questionnaire showed significant improvement. However, emotional health parameters remained apparently unchanged. Supporting these findings, there was a notable reduction in the use of anti‐inflammatory/analgesic drugs per week among almost all patients enrolled in the study. The last finding suggests the possibility to reduce the doses of conventional anti‐inflammatory/analgesic drugs, which are associated with known side effects, increasing the adherence of patients to the treatment and optimizing the management of neuropathic pain that needs a prolonged treatment period.

It must be considered that after the initial phase of post‐traumatic pain in the spine, usually nociceptive, the degranulation of mast cells, which leads to the release of histamine and serotonin in the peripheral nerve, tends to produce edema [43]. This edema can compress the structure, causing ischemic phenomena in the nerve fibers and axonal damage, which are characteristic of neuropathic pain [44]. This phase of axonal distress with consequent sensitization requires prolonged treatment, including the use of neurotrophic and neuroprotective actives, to restore the integrity and functionality of the affected nerve. In this phase, the addition of neuroprotective actives to conventional therapy has a strong rationale [45]. The proposed synergy between ALC and PEA in neuropathic pain management is based on their complementary mechanisms. PEA works by stabilizing mast cells post‐nerve injury, which reduces their degranulation and prevents nerve sensitization. This process prevents nerve sensitization, which would otherwise lead to an increase in glutamate release in the inter‐synaptic space. Glutamate is the main neurotransmitter released by Aδ pain fibers in the spinal cord. Additionally, research indicates that C fiber endings, which also enter the spinal cord, release both glutamate and substance P. PEA helps to control the increase in glutamate release at spinal cord level [46].

Conversely, ALC boosts the expression of the mGlu2 glutamate receptor. This presynaptic receptor binds glutamate in the synapses between the first and second neurons in the dorsal horn, thereby mitigating pain hypersensitivity [47].

Moreover, PEA and ALC can have direct analgesic activity at the central level. PEA enhances the effect of anandamide (AEA) on cannabinoid receptors (CB1 and CB2) and the vanilloid receptor 1. This “entourage effect” might be due to PEA's competitive inhibition of AEA hydrolysis by fatty acid amide hydrolase (FAAH) and/or its direct allosteric effect on the transient receptor potential channel type V1 (TRPV1), also known as the vanilloid receptor type 1. Furthermore, PEA is known to interact with orphan receptors like GPR55. Activation of GPR55 has been proposed to explain some of the effects of certain cannabinoid ligands that are not mediated by CB1 or CB2 receptors [48]. It has been reported that ALC may induce antinociception by a central cholinergic mechanism which involves M1 muscarinic receptors. ALC is chemically similar to acetylcholine (ACh), and ALC can provide acetyl group to choline for ACh synthesis; it has also been shown that ALC has direct agonistic effects on cholinergic receptors [49].

Altogether, these mechanisms suggest that if combined, ALC and PEA may give a synergistic therapeutic effect in reducing neuropathic pain, also confirmed by a specific patent that in a murine model showed a greater synergistic efficacy of the two compounds in reducing pain rather than the sum of single agents. The same patent suggests that the addition of an antioxidant substance, such as ALA, can enhance the synergy of ALC + PEA [31].

An interesting observation is that patients with a more severe clinical profile at the start of the study experienced greater benefits from the treatment. They showed significant improvements in all pain‐related parameters (NPS and VAS scores) by the end of the study, with noticeable improvements beginning at 4 weeks. Similarly, their weekly consumption of NSAIDs significantly decreased, starting from 4 weeks. Notably, by the end of the study, NPS > 37 subgroup patients at enrolment and the total enrolled sample showed similar values in the level of pain and consumption of NSAIDs as rescue medication.

Analyzing the SF‐36 questionnaire data for the subgroup with more severe pain (NPS > 37 subgroup), a marked improvement in physical functioning and general health was detected.

Noteworthy of this subgroup are the domains related to emotional problems and physical limitations, which show a worsening at the 4 weeks timepoint. Specifically, both parameters showed an early decline at 4 weeks, followed by an improvement by the end of the study with a clear trend of significance for the first and statistical significance versus baseline for the second one. These findings could suggest that NPS > 37 subjects are characterized by a greater clinical severity; so consequently, they show greater difficulty in functional recovery. Moreover, we could speculate that for this sub‐sample, transition toward pain chronicity could be affected as a possible risk factor. In this regard, Shaw and colleagues have demonstrated that the risk of pain evolution toward chronicity is 5 times higher for patients with a diagnosis of depressive disorders, 2.5 times higher in cases of generalized anxiety, and 3.2 times higher in cases of post‐traumatic stress [41].

This finding suggests that these neuroprotective molecules can improve the clinical management of pain; and, probably, they could be useful in reducing the risk of pain evolving into chronicity.

Nevertheless, the study had some limitations: the study was conducted in a single center and without a control group, limiting the external validity of the results and the ability to directly compare them with other therapies or a placebo. In addition, the small sample size and the short period of treatment may be insufficient to fully assess the long‐term efficacy of ALC and PEA, especially for neuropathies that may require prolonged treatments.

In addition, compliance with the treatment was assessed through a self‐reported diary, which may be subject to recall bias or self‐assessment errors, and NSAID consumption tracking has to be considered as empirical data, due to differences in posology between drugs in this class.

Finally, the Inclusion/exclusion criteria (such as age and the requirement to not take opioids or antiepileptics) may have excluded patients with more severe conditions, limiting the representativeness of the sample.

In conclusion, whereas acute vertebral pain represents a significant challenge, the potential role of neuroprotective actives offers a promising avenue for enhancing patient outcomes. As the field advances, a multidisciplinary approach incorporating neuroprotective molecules, in the logic of multimodal therapy, may become an integral part of comprehensive pain management strategies.

The integration of neuroprotective compounds into pain management protocols could potentially reduce the reliance on pharmacological interventions and mitigate associated side effects. However, rigorous clinical trials are essential to establish the efficacy and safety of these actives in the context of acute vertebral pain.

Author Contributions

Conceptualization, L.D.C. and M.C.; methodology, L.D.C, M.C., and M.B.; formal analysis, L.D.C. and M.T.V.; investigation, M.C., E.V., and A.C.; data curation, L.D.C., E.V., M.B., and M.T.V.; writing original draft preparation, L.D.C. and M.T.V.; critical review and editing, L.D.C., E.V., and M.T.V. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Cominacini M., Valenti M. T., Braggio M., Caramori A., Vedovi E., and Dalle Carbonare L., “Unlocking Relief: Investigating the Impact of a Fixed Combination of Acetyl‐L‐Carnitine and Palmitoylethanolamide on Traumatic Acute Low Back Pain,” European Journal of Neurology 32, no. 8 (2025): e70334, 10.1111/ene.70334.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.