Lower back pain (LBP) is one of the most common presenting complaints worldwide since about 80% of the population experience this symptom at least once in their lifetime. It has been assumed that a percentage ranging from 5% to 10% of patients with LBP also present a radiculopathy [1-2]. Lumbar radiculopathy is caused by herniated intervertebral disc compression of the nearby nerve roots and dorsal root ganglia in about 90% of cases [3-5]. Lumbar disc herniation (LDH) is relatively common, with an incidence of 5-20 cases/1000 adults/year. It is most prevalent in the third to the fifth decade of life, with a male to female ratio of 2:1. Approximately 95% of disc herniations in the lumbar segment occur at L4-L5 or L5-S1 [1, 6].  Clinically, intervertebral LDH may cause both sensory symptoms, including pain and paresthesias (i. e., numbness and tingling), and motor deficits; it is furthermore associated with significant economic, social and health impact, mainly due to work absenteeism [7-8]. Several guidelines support the use of a conservative strategy as the primary approach to treat the early stages of lumbar radiculopathy, in the absence of neurological deficits [9-11]. Conservative management includes rest, appropriate patient education, judicious use of analgesics and anti-inflammatory drugs, controlled exercises, and physical therapies; corsets may also be useful in selected cases [12]. Surgery is recommended in cases of acute, severe, or progressive paresis, and is offered to patients suffering from intractable radicular pain (still pain after 6-8 weeks of conservative treatment) [8, 13]. International literature, however, points out how surgery can improve the short-term but not the long-term prognosis of pain and perceived disability [14-15]. The aim of this study is to evaluate the efficacy of the integration of acetyl L-carnitine (ALC), alpha lipoic acid (ALA) and Ribes nigrum (RN) on patients affected by lumbar radiculopathy (both on surgical and conservatively treated ones), analyzing the impact on pain and perceived disability.

Population and Evaluation Scores.

In the period between January and December 2020, 54 patients referred to our Institution (Policlinico Umberto I, “Sapienza” University of Rome) for the treatment of LDH. Three different approaches were chosen: surgery alone (Group A), surgery plus integration of ALC, ALA and RN (Group B), conservative treatment alone, including intramuscular betamethasone (4 mg twice a day for 4 days, then once a day for 3 days) and Ketoprofen (200 mg extended-release capsules, 1 capsule per day for 10 days) plus integration of ALC, ALA and RN (Group C). When administered, integration of ALC, ALA and RN was given in the form of Xnerv ® (Mc Stone Italia), one tablet twice a day for 60 days. Xnerv ® contains 1000 mg of acetyl-L-carnitine, 600 mg of alpha lipoic acid and 200 mg of Ribes nigrum (glyceric macerate of fresh blackcurrant buds). Inclusion criteria for surgery were: (a) age between 25 and 65 years, (b) clinical evidence of radiculopathy with a congruous radiological finding, in case of neurological deficits or no response to conservative treatments during the last 6-8 weeks prior to surgery, (c) pure, single level, disc herniation (patients with segmental stenosis and clear radiological evidence of osteophytic beaks were excluded from this study). All patients in the “surgical groups” (Groups A and B) were subjected to careful preoperative medical and neurological case history review, objective neurological examination, and magnetic resonance imaging (MRI) scan. All patients (Groups A, B, and C) were assessed before and at 1, 3 and 6 months after treatment using: Visual Analogue Scale (VAS) [16-18], a unidimensional measure for lower back (BP)/leg pain (LP) intensity (patients were asked to indicate their perceived pain intensity along a 100 mm horizontal line; the score was then measured from the left edge of the line), Oswestry Disability Index (ODI) questionnaire [19] to quantify disability from LBP (final score/index ranges from 0 – minimal disability, to 100% – bed-bound), Sciatica Bothersomeness Index (SBI) [20], which deals with leg pain (LP), numbness or tingling in the leg, foot or groin (paresthesias, P), weakness in the leg/foot (W), and back or leg pain while sitting (S) (the severity of each symptom is rated on a scale from 0 to 6, with anchors at 0 – not bothersome, 3 – somewhat bothersome, and 6 – extremely bothersome; in this study, a symptom score of 4–6 was de?ned as “bothersome” [21].

For each group (A, B, and C) a detailed analysis of variance (ANOVA) was performed to evaluate changes in the VAS, ODI and SBI scores before treatment and at 1, 3, and 6 months after treatment. The slope of recovery/rate of improvement of sensory symptoms between the different time points were compared, and – to find to find means being significantly different from each other – the Tukey’s Range Test was performed in conjunction with ANOVA (post-hoc analysis). The statistical software JMP version 11.0 (SAS Institute, Cary, North Carolina) was used. P-values of 0.05 or less were considered statistically signi?cant.

Results are summarized in Tables 1 and 2. Please refer to Figures 1-14 all the same. 

A total number of 54 patients were included in the study. 30 were males and 24 women with a M/F ratio of 1.25:1. Each group (A, B, C) was composed of 18 patients. Mean age was 46.7 years in Group A, 47.2 in Group B and 47.5 in Group C. A strong, statistically significant difference was found in the values of VAS LP at 1 month between Groups A-B and Group C (24.8-20.61 vs 56.4, p<0.0001). The association of ALC, ALA and RN determined also an early and lasting improvement of pain in the postoperative period (Group B VAS LP at 1-3-6 months: 20.6-10.7-1.2), compared to the group of patients treated with surgery alone (Group A VAS LP at 1-3-6 months: 24.8-15-5.4); p-values =0.002, <0.0001, <0.0001 respectively. Similar statistically significant results were obtained for VAS BP and ODI values. Regarding paresthesias, a significant difference in terms of SBI P between Groups A and B at 1 month (3.1 vs 2, p=0.0002), at 3 months (2.1 vs 1, p=0.0008), and at 6 months (1.1 vs 0.1, p<0, 0001) was found.

Table 1:  Our data. Group A: surgery alone, Group B: surgery plus integration of ALC (1000 mg), ALA (600 mg) and RN (200 mg), Group C: conservative treatment alone. VAS=Visual Analogue Scale. ODI=Oswestry Disability Index. SBI= Sciatica Bothersomeness Index. BP=back pain. LP=leg pain. P=paresthesias. W= weakness in the leg/foot. S= back or leg pain while sitting.

Table 2: Table 2: Statistical analysis and comparison (between groups) of the collected data. Group A: surgery alone, Group B: surgery plus integration of ALC (1000 mg), ALA (600 mg) and RN (200 mg), Group C: conservative treatment alone. VAS=Visual Analogue Scale. ODI=Oswestry Disability Index. SBI= Sciatica Bothersomeness Index. BP=back pain. LP=leg pain. P=paresthesias. W= weakness in the leg/foot. S= back or leg pain while sitting.

Figure 1: VAS BP mean values ??in the three groups at 1 (A), 3 (B) and 6 (C) months of follow-up. VAS=Visual Analogue Scale, BP=back pain. “Tutte le coppie” = All couples.

Figure 2: Trend of VAS BP mean values ??in the three groups during follow-up. VAS=Visual Analogue Scale, BP=back pain.

Figure 3: VAS LP mean values ??in the three groups at 1 (A), 3 (B) and 6 (C) months of follow-up. VAS=Visual Analogue Scale, LP=leg pain. “Tutte le coppie” = All couples.

Figure 4: Trend of VAS LP mean values ??in the three groups during follow-up. VAS=Visual Analogue Scale, LP=leg pain.

Figure 5:  ODI mean values ??in the three groups at 1 (A), 3 (B) and 6 (C) months of follow-up. ODI= Oswestry Disability Index. “Tutte le coppie” = All couples.

Figure 6: Trend of ODI mean values ??in the three groups during follow-up. ODI= Oswestry Disability Index.

Figure 7: SBI P mean values ??in the three groups at 1 (A), 3 (B) and 6 (C) months of follow-up. SBI= Sciatica Bothersomeness Index. P=paresthesias. “Tutte le coppie” = All couples.

Figure 8: Trend of SBI P mean values ??in the three groups during follow-up. SBI= Sciatica Bothersomeness Index. P=paresthesias.

Figure 9: SBI LP mean values ??in the three groups at 1 (A), 3 (B) and 6 (C) months of follow-up. SBI= Sciatica Bothersomeness Index. LP=leg pain. “Tutte le coppie” = All couples.

Figure 10: Trend of SBI LP mean values ??in the three groups during follow-up. SBI= Sciatica Bothersomeness Index. LP=leg pain.

Figure 11: SBI W mean values ??in the three groups at 1 (A), 3 (B) and 6 (C) months of follow-up. SBI= Sciatica Bothersomeness Index. W=weakness in the leg/foot. “Tutte le coppie” = All couples.

Figure 12: Trend of SBI W mean values ??in the three groups during follow-up. SBI= Sciatica Bothersomeness Index. W=weakness in the leg/foot.

Figure 13: SBI S mean values ??in the three groups at 1 (A), 3 (B) and 6 (C) months of follow-up. SBI= Sciatica Bothersomeness Index. S= back or leg pain while sitting. “Tutte le coppie” = All couples.

Figure 14: Trend of SBI S mean values ??in the three groups during follow-up. SBI= Sciatica Bothersomeness Index. S= back or leg pain while sitting.

LBP constitutes a major health problem throughout the world. Estimates of the annual prevalence of sickness absence due to LBP range from 9% to 32% [22]. Among LBP patients, those with sciatica tend to have more severe pain and lower rates of return to work [23-29]. The gold standard in the treatment of LDH, leading cause of the problem, has been widely discussed in literature. Several factors must be considered for the best therapeutic choice: age, general clinical conditions, duration of symptoms from the onset, presence of neurological deficits, and – of course – patient’s will. Each patient should be clearly informed about the different treatment options. Surgery is unanimously offered to patients with a clear neurological deficit or in case of persistent pain despite conservative treatment (at least 6-8 weeks) [9-11, 13-15]. Patients who do not fall into these categories should be aware that, in the long term, the percentage of recovery is similar between surgical and conservative groups of treatment [30]. The healing time, however, is extremely variable with conservative treatment, while surgery guarantees – in most cases – a rapid relief from symptoms. One of the major challenges in the treatment of LDH is represented by pain and paresthesias, not only in conservatively treated patients, but also in patients who undergo surgery. In fact, the persistence of intense pain and paresthesias in the postoperative course is common and invalidating. The International Association for the Study of Pain (IASP) recommends using the term “dysesthesias” to describe unpleasant, abnormal sensations and “paresthesias” to define abnormal sensations that are not unpleasant; in this study, however, we use the term “paresthesia” to refer to both “paresthesia” and “dysesthesia” [31]. The purpose of this study is to analyze the potential effectiveness of the association of three well-known antioxidant/cytoprotective agents, i. e., acetyl L-carnitine, alpha lipoic acid and Ribes nigrum, in the treatment of pain and paresthesias in LDH, both in surgically and conservatively treated patients. Several studies show how pain and paresthesias improve after nerve root decompression at a different rate [32-33]. Between these two sensory components, pain usually recover fastest, while paresthesias improve at a much slower speed. Patients with radiculopathy recover, indeed, from pain within 6 weeks after surgical decompression, and this is followed by the improvement in paresthesias that reach a plateau 3 months after surgery [32-34]. The knowledge of the pathophysiology of sensory symptoms in radiculopathy is mandatory to explain this evidence. There are two major classes of nerve fibers associated with the transmission of pain: (a) unmyelinated (slow) C fibers, and (b) myelinated (fast) A-δ fibers. C sensory fibers (0.2–1.5 µm) respond to mechanical, thermal (heat), and chemical stimuli producing the sensation of diffuse, dull, aching, scorching, and delayed pain. On the other hand, myelinated A-δ fibers (1–5 μm) respond to mechanical (pressure) and thermal (cold) stimuli producing the sensation of sharp, localized, and fast pain [35-36]; dysfunction of these fibers has been involved in the pathogenesis of paresthesias occurring in compression/entrapment neuropathies [37]. In a study by Nygaard et al., the recovery rate after surgical decompression in sensory modalities transmitted by small, unmyelinated nerve ?bers (C) was reported to be faster and more complete than that of myelinated nerve ?bers (A-δ) [38]. This anatomic feature could explain why pain recovers faster than paresthesias. The rationale behind using drugs with antioxidant properties in the treatment of radicular pain lies in the scientific evidence of increased free oxygen radical levels and reduced activity of antioxidant enzymes in peripheral nerve trauma [39]. Acetyl-L-carnitine (ALC) is the acetylated form of L-carnitine (L-β-hydroxy-γ-trimethylammonium butyrate). It is synthesized through reversible acetylation of carnitine in mitochondria by acetyl-L-carnitine transferase and represents a form of storage of acetyl groups and carnitine within cells. Homeostasis of carnitine involves a balance among nutritional absorption (mainly from animal cardiac and skeletal muscles and from dairy products), endogenous biosynthesis, and renal reabsorption [40]. Carnitine is used to transport fatty acids into mitochondria for β-oxidation, i. e., “carnitine shuttle” [41]. The “carnitine shuttle” is essential to prevent accumulation of long chain fatty acids which can be deleterious to cells, especially for neural ones [42-43]. It is made up of three steps, the first two occurring on the outer mitochondrial membrane, the last one on the inner one: (1) fatty acid activation into fatty acyl–CoA (tioesterification; acyl-CoA synthetase isozymes), (2) (first, transient) transesterification with carnitine to fatty acyl–carnitine (carnitine acyltransferase I), and finally (3) fatty acyl–CoA regeneration (last transesterification; carnitine acyltransferase II), with release of carnitine which can be recycled [44]. ALC has also been successfully used in clinical trials for the treatment of neuropathy and neuropathic pain, cognitive disorders, and depression [45-51]. It enhances repairing processes and cellular trophism increasing nerve growth factor (NGF) uptake by upregulating the expression and affinity of its receptors [45]. It improves stability and conductivity of the neural membrane and, by extension, peripheral nerve function [48]. ALC can also delay degeneration of sensory neurons in the dorsal root ganglia after peripheral nerve injury [49]. It can greatly reduce early retrograde death of spinal motor neurons after ventral root avulsion and can also attenuate degeneration of spinal motor neurons after spinal cord injury. Moreover, ALC reduces the activity of microglia and macrophages and promotes axonal sprouting in the injured segment of the cord. The anti-apoptotic, anti-inflammatory, and pro-regenerative effects of ALC treatment after spinal cord injury are observed at an early point after initial trauma and persist over a period of several weeks postoperatively [50-51]. In the work by Gu?lc?in et al., L-carnitine was found to be an effective antioxidant agent in different in vitro assays, mainly in relation to its ability to “scavenge” hydrogen peroxide and superoxide radical and chelate transition metal ions [52]. This protective, antioxidant property was confirmed by in vitro studies on SH-SY5Y neuroblastoma cells [53] and human hepatocyte HL7702 cell line [54]. It may also protect the endogenous antioxidant defense system from peroxidative damage and is known to be efficient in normalizing age-associated alterations of oxidative status [55]. These findings led us to assume a potential, strong, beneficial role of oral ALC integration in patients affected by lumbar radiculopathy. Alpha lipoic acid (1,2-dithiolane-3-pentanoic acid; ALA), a disulfide derivative of octanoic acid, is known to act as an efficient endogenous antioxidant just like ALC [56-59]. It acts as a cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase and maintains homeostasis of α-tocopherol and ascorbate by reacting with α-tocopheryl and ascorbyl radicals. Thanks to this property, it has an extremely effective cytoprotective action against free radicals and cellular oxidative stress [59]. Several studies have shown that ALA can improve neural trophism and increase neural cell self-repairing capacity. It has also been demonstrated that it can also decrease ischemia-reperfusion injuries in the cerebral cortex and peripheral nerves [56-58]. Human biosynthesis, though possible, does not offer a satisfactory source of ALA. It is, indeed, necessary to obtain it from dietary sources like meat, spinach, Brussels sprouts, broccoli, peas, or potatoes. An adequate, “therapeutic” level of ALA can be, however, obtained only through oral integration [60]. Similar properties were found in blackcurrants (Ribes nigrum, RN). RN is a deciduous, woody shrub in the family Grossulariaceae whose potent antioxidant and anti-inflammatory properties are currently well understood [61]. Blackcurrants are broadly recognized for containing high concentrations of polyphenols, in particular anthocyanins and proanthocyanidins, in contrast to other berries [62]. Blackcurrants are also rich in ascorbic acid and this, together with a similarly high flavonoid content, sustains the antioxidant “aptitude” of the extract [62-65]. The anti-inflammatory activity attributed to the blackcurrant bud extract is related to its “cortison-like” action. It acts indeed directly stimulating the adrenal cortex, thus increasing the concentration of serum cortisol [66-67]. It is also an established fact that vitamin C can strengthen neutrophil chemotaxis, thereby enhancing the immune response [68]. Our study confirms the scientific evidence that surgery represents the most rapid and effective therapeutic choice for pain (VAS LP Groups A-B vs Group C at 1 month: 24.8-20.61 vs 56.4, p<0,0001). The administration of ALC, ALA and RN in association with surgery showed a statistically significant efficacy in the improvement of the symptoms of radiculopathy (both pain and paresthesias). In fact, it can be able to determine an early and lasting improvement of pain in the postoperative period (Group B VAS LP at 1-3-6 months: 20.6-10.7-1.2), compared to the group of patients treated with surgery alone (Group A VAS LP at 1-3-6 months: 24.8-15-5.4, p =0,002, <0,0001, <0,0001). Similar data were obtained, as previously stated, for VAS BP and ODI values. As for paresthesias, integration turned out to be extremely effective and rapid in reducing this annoying symptom in the postoperative period (SBI P Group A vs B at 1 month: 3.1 vs 2 – p=0.0002, at 3 months: 2.1 vs 1 – p= 0.0008, at 6 months: 1.1 vs 0.1 – p<0.0001).

Our data confirm that surgery is the most effective and rapid treatment in resolving pain. Integration of acetyl L-carnitine (ALC), alpha lipoic acid (ALA) and Ribes nigrum (RN) proved to be an excellent therapeutic aid in patients both surgically and conservatively treated, being able to effectively reduce pain and, above all, paresthesias.

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