Neurotrophins, also known as neurotrophic factors, were first described in the 1960's by Rita Levi-Montalcini, as reported by Bradshaw et al.¹ Currently, it is known that they are proteins that modulate the processes of neuronal differentiation, maturation, growth, regeneration, survival and death and that they regulate the mechanisms involved in synaptic processes and neuronal plasticity.^2-5 Likewise, they induce differentiation of progenitor cells for the formation of new neurons.

Neurotrophin production was initially identified in tissues considered as targets, on which actions of the nervous system are performed; however, it is now commonly accepted that its production is both central and peripheral.⁶ It has also been demonstrated that these molecules belong to a family of growth factors and that they bind to receptors in neuronal cells.

There are two types of receptors to which neurotrophins can bind: p75 and the Trk family (tyrosine kinase), which, once activated, trigger intracellular signaling cascades that end with the expression of the genes responsible for neuronal response.^7-9

The neurotrophins described in humans to date are nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3) and neurotrophin 4/5 (NT-4/5).^10-12 Others such as NT-6 and NT-7 have recently been found in some animal species.¹³

NGF is released by the target cells of the nervous system. It plays a fundamental role in the survival and maintenance processes of sympathetic and sensory neurons, has a high affinity for TrkA receptors, and is considered an inflammatory mediator and pain modulator.¹⁴

BDNF acts on neurons of the central and peripheral nervous system and aims to maintain the survival of existing neurons and promote the growth and differentiation of new ones, keeping synaptic mechanisms in optimal conditions. It has been identified in the hippocampus, the cerebellum, the cerebral cortex, the ventral tegmental area, and the basal forebrain, which are areas involved in the mechanisms of learning, memory, and motivation. Likewise, BDNF is one of the most active neurotrophins in neurogenesis, has also been detected in several peripheral tissues, and its receptors are TrkB and p75.¹⁵

NGF and BDNF are responsible for the optimal maintenance of the communication mechanisms of the nervous system, both central and peripheral, and therefore alterations in their concentration are observed in pathological states.^16,17

In 2018, Patatel et al.¹⁸ confirmed that NGF is an important peripheral pain mediator, especially in relation to inflammation, since elevated levels are associated with hyperalgesia. Likewise, García-Cosamalón et al.¹⁹ reported an increase in NGF and BDNF serum levels and their receptors in cases of pain associated with diseases of the intervertebral disc; moreover, this increase was related to the activity of pro-inflammatory cytokines.

On the other hand, neural therapy is a medical treatment that involves the use of local anesthetics such as procaine or lidocaine in low doses, taking into account their cell membrane stabilizing action, dielectric capacity and other properties that influence the nervous system and are the object of research. When applied to specific sites, determined based on each patient's medical history, this therapy modifies interferences in signaling systems and restores the proper functioning of the biological program.^20-22

Considering the above, the objectives of this study were to analyze changes in NGF and BDNF serum levels in patients with chronic pain after receiving neural therapy and to determine the impact of this type of intervention on their quality of life.

The median age of the participants was 40.5 years (IQR: 33-45) and most patients were female (80%). All patients consulted for pain in various body areas with a median duration of 9 years (IQR: 5-16) and all reported having received treatment with conventional or alternative medicine previously (Table 1).

Table 1

Patient	Age (years)	Sex	Type of pain	Pain duration
1	53	Female	Abdominal and lumbar pain	2 months
2	33	Female	Thoracolumbar pain	19 years
3	39	Male	Low back pain	16 years
4	26	Female	Pelvic pain and dysmenorrhea	10 years
5	42	Female	Pain in the left breast due to chronic mastitis	5 months
6	45	Female	Headache	5 years
7	40	Female	Joint pains	11 years
8	41	Female	Low back pain	25 years
9	27	Female	Joint pains	8 years
10	56	Male	Lower limb pain	7 years

Source: Own elaboration.

The median score obtained by participants in the SF-12 questionnaire tended to improve in the follow-up visits, being more evident in the first one. At the initial consultation, it was 34.5 (IQR: 30-37); in the first follow-up, 39.5 (IQR: 34-43), and in the second follow-up, 38 (IQR: 36-41) (Figure 1).

Figure 1 Source: Own elaboration.

The median NGF serum levels tended to decrease after the intervention, particularly in the first follow-up. During the initial consultation, it was 157.6 (IQR: 51.9-237.8); in the first follow-up, 42.95 (IQR: 25.9- 90.4), and in the second follow-up 62.2 (IQR: 0-223.7) (Figure 2).

Figure 2 Source: Own elaboration.

BDNF serum levels also had an overall downward trend. In the initial consultation, the value was 29.96 (IQR: 26.76-33.4); in the first follow-up, 19.24 (IQR: 16.43-24.52), and in the second follow-up, 20.43 (IQR: 12.81-35.18) (Figure 3).

Figure 3 Source: Own elaboration.

After analyzing the results, it was found that there was a correlation between the decrease in BDNF and NGF levels in the first follow-up in 9 patients, which was less evident in the second follow-up, and that there was a general correlation between decreased BDNF and NGF levels before the intervention versus the first and second follow-ups in 7 patients. Overall, there was an improvement in quality of life and a decrease in neurotrophin serum levels.

Considering that the nervous system is the most elaborate communication system in humans and that its plasticity allows it to interact with other systems, there is an increasing interest in analyzing variations in neurotrophin serum levels when using neural therapy to treat patients with chronic pain.

The present study found that interventions with this type of therapy resulted in an overall improvement in pain symptoms, which were assessed using the parameters of the SF-12 questionnaire, as well as in a decrease in the median NGF and BDNF serum levels, bearing in mind that, compared with the measurement before the intervention, they showed a downward trend in the two follow-up consultations. These findings coincide with those reported by authors such as McKelvey et al.²⁹ and Miller et al.³⁰ in patients who have experienced improvements after undergoing pain treatments that inhibit the action of these neurotrophins.

The literature has reported that the clinical course of patients undergoing chronic pain treatment varies depending on factors related to the initial causes of the manifestations, which could explain the variations in the quality of life and behavior of the serum levels of neurotrophins in these patients.³¹ Furthermore, many aspects about neurotrophins, which are associated with biological processes involving the nervous system, are still unknown.³²

Similarly, there is evidence of elevated BDNF serum levels in post-traumatic situations related to multiple traumas involving painful processes, such wars, which are known as post-traumatic brain injury and post-traumatic stress disorders.³³

It should be noted that the effects of neural therapy are not always evident since the beginning; in fact, pain may worsen at first and subsequently improve.³⁴

As stated by Fisher,³⁵ one of the fundamental pillars of neural therapy is the autonomic system. It controls communication in all human biological systems through circuits (communication and feedback) organized vertically, creating an information network that runs from the periphery to the central levels.

The findings of this study lead us to consider that, after improving biological conditions by removing the interfering fields that keep patients in a constant state of inflammation, neural therapy not only improves symptoms and, thus, quality of life, but also lowers neurotrophin serum levels because the irritation caused by the inflammatory process is reduced. This has been reported in studies comparing analgesics and other conventional strategies, which have shown a decrease in neurotrophin levels as a result of treatment.^36-38

Therefore, analyzing the behavior of neurotrophin serum levels following neural therapy interventions could be used as a biomarker for therapeutic success and follow-up of chronic pain patients.³⁹ This is corroborated by Tu et al.,⁴⁰ who evaluated the response of neurotrophins with interventions such as acupuncture and obtained results similar to those of the present study.

The neural therapy intervention resulted in a reduction in NGF and BDNF serum levels, which had increased in response to each patient's pathological processes and improved their quality of life. Consequently, it is considered that the behavior of serum levels of these neurotrophins could be a biomarker for the diagnosis, treatment, and follow-up of patients with chronic pain. However, further studies with larger samples and longer follow-up times are necessary to confirm the findings reported here.