Preliminary Communication

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Observational pilot study of patients with

carpal tunnel syndrome treated with Nucleo
CMP Forte™
M Povedano*,1 , Y Martı́nez1 , A Tejado1 , P Arroyo1 , C Tebe2,3 , JL Lorenzo4 & J Montero1
1
Servicio de Neurologı́a y Neurofisiologı́a, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain
2
Unitat de Bioestadı́stica (UBiDi), Institut d’Investigació Biomedica de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain
3
Universitat Rovira i Virgili, Reus, Tarragona, Spain
4
Scientific Information & Documentation Department (ScIDD), Ferrer International, Barcelona, Spain
*Author for correspondence: mpovedano@bellvitgehospital.cat

Practice points
• Carpal tunnel syndrome is the most common entrapment neuropathy of the upper extremity, affecting 3% of the
general population.
• Although this syndrome has a considerable impact on a patient’s quality of life, its medical treatment is far from
optimal.
• Nucleotides such as uridine and cytidine play an essential role in the regeneration of the myelin sheath.
• Evidence for the effectiveness of nucleotides in chronic compressive neuropathies is limited.
• The neuroregenerative effects of uridine in various neuropathies have been shown in preclinical and clinical
studies.
• Administration of Nucleo CMP Forte for 6 months decreases the pain associated with mild–moderate carpal
tunnel syndrome and improves the patient’s quality of life.
• Nucleotide-based medications such as Nucleo CMP Forte (combined or not with painkillers) should be considered
as an option in the treatment of mild–moderate carpal tunnel syndrome in patients for whom surgery is not yet
necessary.

Aim: Carpal tunnel syndrome (CTS) is a very common entrapment neuropathy characterized by pain and
paresthesia in the territory of the median nerve. Although this syndrome has a considerable impact on the
patient’s quality of life, its medical treatment is far from optimal. Material & methods: We performed an
observational study to evaluate Nucleo CMP ForteTM in patients with electromyography-confirmed, mild–
moderate CTS. Pain was assessed using a visual analog scale, electromyogram and the SF-36. Results: Pain
decreased significantly after 6 months. Quality of life improved significantly in the pain dimensions. No
significant differences were observed in electromyographic findings. No adverse events were reported.
Conclusions: Nucleotides could prove useful for the nonsurgical treatment of CTS. Further studies are
necessary to confirm this.

First draft submitted: 6 July 2018; Accepted for publication: 24 October 2018; Published online:
19 November 2018

Keywords: carpal tunnel syndrome • electromyography • nucleotides • pain

Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy of the upper extremity, affecting
approximately 3% of general population [1]. It is due to increased pressure in the carpal tunnel that compresses
and damages the median nerve [2]. The initial and the most frequent symptoms are pain and paresthesias along the
median nerve. The trial by Wipperman and Goerl [3] recommended conservative treatment, for example, splinting
and corticosteroids (oral or local injection), although many patients required surgery by one year [4,5]. Vitamins
and other oral treatments are not considered to be effective owing to the lack of scientific evidence [6].
In compressive neuropathies such as CST, the onset of morphologic abnormalities begins with the demyelination
of the paranodal region and continues with demyelination affecting the internodal region, leading to segmental
demyelination. Therefore, regeneration and maintenance of the myelin sheath after a nerve lesion are key elements
in the cure of this kind of neuropathy [7,8]. According to the results of several preclinical studies [9–11], nucleotides,

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Preliminary Communication Povedano, Martı́nez, Tejado et al.

such as uridine and cytidine, play an essential role in the regeneration process. Moreover, nucleotides have shown
a marked antinociceptive effect in neuropathic pain models [12,13].
Various preclinical and clinical studies have shown the neuroregenerative effects of uridine in various neu-
ropathies [10–12,14]. Although these findings encourage the use of nucleotides in chronic compressive neuropathies,
evidence demonstrating their effectiveness in these conditions is limited [15–19]. In order to increase our knowl-
edge of the clinical effect of nucleotides in patients with CTS and to assess the feasibility of a larger-scale, more
rigorous study, we carried out an observational exploratory study to evaluate whether the product Nucleo CMP
Forte (a combination of uridine and cytidine at several levels of phosphorylation) improves the symptoms and
electromyographic parameters of patients with CTS.

Material & methods

We performed an exploratory, open-label, prospective study to assess the effect of Nucleo CMP Forte (3 mg
of uridine monophosphate [UMP] and 5 mg of cytidine monophosphate [CMP]) in patients with CTS. Eligible
patients had previously been referred to the electromyography (EMG) laboratory of Hospital de Bellvitge, Barcelona,
Spain over 6 consecutive months. The hospital is a reference center for neuromuscular disease. The patients enrolled
had a clinical diagnosis of CTS and EMG-confirmed symptoms without signs of axonal degeneration and were
therefore not expected to undergo early surgical treatment. All patients gave their written informed consent to
participate. The study was approved by the Ethics Committee of our hospital and was performed in accordance
with the International Conference on Harmonization Good Clinical Practice guidelines and the Declaration of
Helsinki.
All patients received two capsules of Nucleo CMP Forte every 12 h for 6 months. At baseline, the patients
underwent EMG before treatment. At each control visit (months 1, 3 and 6 after initiation of the study) and at a
follow-up visit (1 month after stopping the medication), the patients underwent a clinical and EMG assessment.
Adherence to treatment was assessed by a weekly telephone call from a nurse and by the count of unused medication
returned at the end of the study.
At the control visits, the patients were assessed using EMG, a visual analog scale (VAS) and the SF-36 question-
naire [20].

Assessment of effectiveness
Clinical measures
The primary outcome measure was the decrease in pain intensity after 6 months of treatment assessed using a
VAS, with values (cm) ranging from 0 to 10. Secondary outcome measures were changes in quality of life evaluated
using SF-36 [20] at the follow-up visit.

EMG measures
The EMG study of the median nerve included sensory nerve conduction velocity, amplitude of sensory nerve action
potential, distal and proximal motor latency, and muscle action potentials in the thenar region. EMG procedures
were always performed by the same technician and using the same EMG device (Synergy) according to conventional
standards established by Kimura [21].

Safety measures
Tolerability was evaluated according to the adverse effects reported by patients at each visit.

Statistical analysis
The VAS score was presented as an ordinal non-normal distribution. The difference in pain intensity (VAS values)
at baseline and 6 months (main outcome measure) was evaluated using the Wilcoxon signed-rank sum test with
continuity correction. A potentially continuous response, such as a VAS score, can be transformed by application
of a rank-based method in an ordinal response variable so as to obtain robust inferences [22]. An ordinal regression
mixed model was used to assess the VAS score over time after adjusting for sex.
Differences between electrophysiological parameters at baseline and 6 months were tested using the Wilcoxon
signed-rank sum test with continuity correction.

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 Nucleotides in carpal tunnel syndrome Preliminary Communication

Table 1. Demographic and clinical characteristics of study participants.

Characteristics n = 40
Age, mean (SD) 53.6 (11.8)
Age, median (IQR) 53.0 (46.8–63.5)
Sex, number (%):
– Women 30 (75.0%)
– Men 10 (25.0%)
Laterality, number (%):
– Right 24 (60.0%)
– Left 16 (40.0%)
IQR: Interquartile range; SD: Standard deviation.

Table 2. Measures of electrophysiological parameters at baseline and at 6 months.

Parameters Baseline n = 40 6 months n = 36 p-value†
Sensory latency, median (IQR) 3.10 (3.00–3.40) 3.12 (2.88–3.31) 0.244
Motor latency, median (IQR) 3.60 (3.23–3.85) 3.55 (3.31–3.93) 0.797
Sensory amplitude, median (IQR) 28.2 (24.1–34.2) 28.9 (24.1–40.1) 0.362
Motor amplitude, median (IQR) 8.40 (7.45–10.6) 8.30 (7.50–9.45) 0.276
Conduction velocity, median (IQR) 39.2 (36.7–47.5) 42.8 (38.8–47.3) 0.314
† Wilcoxon signed-rank sum test.
IQR: Interquartile range.

The difference between the quality of life (SF-36) at baseline and at 6 months was compared using the paired
t-test. The effect size was measured based on the standardized mean difference, which was determined by calculating
the mean difference between the groups and then dividing the result by the pooled standard deviation.
In order to evaluate sensitivity, the main analysis of the reduction in the pain score was repeated in patients with
moderate–severe pain (VAS score above 4 cm). Moreover, missing data were managed using the Last Observation
Carried Forward method, and the principal analysis was repeated on imputed data.
All analyses were conducted on an intention-to-treat basis. Whenever possible, estimators were accompanied by
a 95% CI. The analysis was carried out using the statistical program R, version 3.4.3 [23].

Results
Of the initial 50 participants enrolled, 40 took at least one dose of the medication and 36 eventually completed
the study. Mean age was 53 years, and 75% were female. Withdrawals were due to problems with follow-up and
not due to adverse events. Table 1 shows the baseline demographic characteristics of the 40 study participants.
At baseline, the median VAS was 5 cm, with 25% of participants scoring below 3.75 cm and a further 25%
scoring above 6.25 cm; at 6 months, the median VAS was 2 cm, with only 25% of participants scoring above
2 and up to 6 cm. According to the Wilcoxon signed-rank sum test, the null hypothesis of equal VAS scores at
baseline and at 6 months can be rejected (V = 587.5, p < 0.0001), indicating that 72% of all the pairs favor the
study hypothesis. This significance was maintained when the last observation carried forward approach was used
(V = 693, p < 0.0001) and in the subgroup of patients who scored above 4 cm in the VAS at baseline (V = 693,
p < 0.0001). Moreover, when an ordinal mixed regression model was applied to the VAS score from baseline to 6
months, a significant linear decrease was observed in the VAS score over time (odds ratio: 0.59), as was a sex effect
(odds ratio: 4.16). After baseline, the probability of a lower VAS score was 50% greater than the previous month.
Women were four-times more likely to have a higher VAS score than men. Figure 1 shows the VAS score from
baseline to the sixth month of treatment, as well as the differences between women and men.
The analysis of EMG parameters showed no differences between values at baseline and at 6 months, although
an improvement of 3.6 units in conduction velocity was observed (Table 2).
Quality of life was measured using the SF-36. A significant improvement was observed in dimensions related
to physical function (pain, limitations due to physical health and physical functioning) 1 month after stopping
treatment (Table 3).

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Preliminary Communication Povedano, Martı́nez, Tejado et al.

The product was well tolerated with no adverse events reported during the treatment period.

Global evolution of pain (VAS) overall

10

8
Analogic visual scale

0
0 1 3 6 7
Months from baseline

Differences in pain (VAS) evolution according to sex

Women Men
10

8
Analogic visual scale

0
0 1 3 6 7 0 1 3 6 7

Months from baseline

Figure 1. Evolution of pain (VAS) from baseline to sixth month of treatment and differences between women and
men. (A) Global evolution of pain (VAS) overall. (B) Differences in pain (VAS) evolution according to sex. Black dots
represent the patients’ VAS score at each visit with a small amount of random variation in the location of each point
to handle overplotting. The blue line is a local polynomial regression fitting (LOESS) showing the development of the
trend; the gray area represents the 95% CI around the smoothing spline.
VAS: Visual analog scale.

Discussion
Our results showed that the administration of Nucleo CMP Forte for 6 months decreases the pain associated
with mild–moderate CTS and improves the patient’s quality of life, specifically in the ‘role physical’ and ‘bodily
pain’ dimensions. These effects remained positive when the drug was stopped. Our results agree with those of

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 Nucleotides in carpal tunnel syndrome Preliminary Communication

Table 3. SF-36 dimension scores at baseline and at 1 month after the end of treatment.
Dimensions n Baseline Final Mean difference 95% CI p-value† SMD
Physical 35 77 (21.67) 87.86 (15.4) 10.86 3.34–18.37 0.006 0.58
functioning
Role limitations 35 65.02 (42.09) 91.43 (20.95) 26.41 10.82– 41.99 0.002 0.79
due to physical
health
Role limitations 35 80.03 (36.33) 80 (38.09) -0.03 -15–14.94 0.997 0.00
due to emotional
problems
Energy/fatigue 35 58.86 (24.07) 73.57 (22.35) 14.71 4.83–24.6 0.005 0.63
Emotional 35 73.6 (16.09) 76.57 (21.1) 2.97 -6.25–12.2 0.517 0.16
wellbeing
Social functioning 35 83.57 (20.73) 87.86 (18.06) 4.29 -4.17–12.74 0.310 0.22
Pain 35 57.5 (26.8) 78.43 (20.89) 20.93 9.94–31.92 0.000 0.87
General health 35 58 (18.83) 64.57 (19.79) 6.57 -1.36–14.51 0.102 0.34
† Paired
t-test.
SMD: Standardized mean difference.

studies performed with uridine (alone or in combination with other nucleotides) in various neuropathies, although
differences in their design and population mean that they are not comparable [14–19].
The positive effect of uridine in neuroregeneration is well-accepted. Pyrimidine nucleotides play a major role
in human cellular metabolism, particularly in neuronal tissue. Their main effect is to stimulate the synthesis of
phospho- and glyco- (or sphingo-) lipids, as well as glycoproteins, which are essential structural elements of neuronal
membranes [24]. Moreover, subtypes of the uridine 5-triphosphate (UTP)-activated receptors P2Y2 and P2Y4 in
humans are coupled to G-protein and involved mainly in cellular proliferation and neural circuit remodeling [25].
Therefore, pyrimidines play a highly significant role in the reconstruction of damaged nerve tissue. Of note, nerve
cells cannot produce pyrimidines themselves and, consequently, depend on the external availability of the key
substance UMP [26]. Therefore, it is not surprising that administration of this combination of nucleotides could
improve the symptoms of CST. Although the mechanism of action of nucleotides in CTS remains unclear, a
detailed study of the circumstances and characteristics associated with the clinical effects of these agents would help
to improve our knowledge of the role of uridine in the regeneration of peripheral nerves.
In our study, the effects of treatment on EMG values were less evident, although a tendency to improve the
velocity of motor conduction of the median nerve was observed, thus indicating a possible effect of Nucleo CMP
Forte in the process of myelination of the injured nerve. The low number of study patients may have prevented us
from obtaining more robust results.
We observed marked differences in pain according to sex. These effects were also observed in the quality of
life of the patients according to the significant improvements observed in the SF-36 scale at the end of the study,
albeit only in the dimensions that could be associated with pain (physical dimensions). Our findings reinforce
the observation that nucleotides such as uridine play an important role in perception of pain. In this way, uridine
has also shown analgesic effects in preclinical and clinical studies. In a neuropathic pain model, Okada et al. [13]
evaluated the effects of administration of UTP and UMP on rats with partially ligated sciatic nerves and observed
significant anti-allodynic effects in the rats treated. In a unique observational study with uridine administered
specifically to treat peripheral entrapment neuropathies, Negrão and Nunes [19] observed significant reductions
in pain and in the use of concomitant analgesic medications after the administration of a daily capsule of UMP
(50 mg), folic acid (400 μg) and vitamin B12 (3 μg) for 2 months. Given that doses were not the same and uridine
was combined with minimum doses of vitamins, the studies are not comparable, although they do reinforce the
important role of pyrimidine nucleotides in the treatment of injured nerves. The good tolerability that is always
observed in studies with nucleotides was replicated in our study, where no adverse effects were reported.
We performed a pilot observational study with a short follow-up. As with all studies of this type, it was subject
to the limitations that are inherent to its design (no comparison with placebo, no double-blind approach or
randomization). Our study is also subject to a placebo effect, as many cases of mild CTS remained the same or
improved without active treatment. However, we must remember that these patients had been receiving treatment
for some time without satisfactory improvement. In relative terms, the clinical improvement we observed is

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Preliminary Communication Povedano, Martı́nez, Tejado et al.

noteworthy. Given the exploratory nature of the study, our findings require confirmation in a well-designed,
adequately powered randomized controlled trial.

Conclusion
In conclusion, we found Nucleo CMP Forte to be well-tolerated and think that it could be considered as an option
for the treatment of mild–moderate CTS. Our findings must be confirmed in a more rigorous study.

Acknowledgements
The authors are grateful to P Roset for his contribution to the editing of the paper.

Author’s contributions
J Montero participated in the study design and interpretation of data. Y Martı́nez participated in the acquisition and interpretation
of data. A Tejado participated in the acquisition and interpretation of data. P Arroyo participated in the acquisition, analysis and
interpretation of data. M Povedano participated in the study design and interpretation of data. C Tebe participated in the analysis
and interpretation of data. JL Lorenzo participated in the interpretation of data and in the edition of the manuscript. All of the
authors participated in drafting the manuscript or revising it critically. All of the authors approve the final approval of the version
to be published.

Financial & competing interests disclosure

JL Lorenzo is a Ferrer employee. The authors have no other relevant affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from
those disclosed.
Medical writing support was provided by Content Ed Net (Madrid, Spain) and was funded by Ferrer.

Ethical conduct of research

The study was approved by the Ethics Committee of our hospital and was performed in accordance with the International Confer-
ence on Harmonization Good Clinical Practice guidelines and the Declaration of Helsinki. The authors state that they have obtained
written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.

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