Effect of the use of combination uridine triphosphate, cytidine monophosphate, and hydroxycobalamin on the recovery of neurosensory disturbance after bilateral sagittal split osteotomy: a randomized, double-blind trial

Abstract

The change in neurosensory lesions that develop after bilateral sagittal split osteotomy (BSSO) was explored, and the influence of the application of combination uridine triphosphate (UTP), cytidine monophosphate (CMP), and hydroxycobalamin (vitamin B12) on patient outcomes was assessed. This was a randomized, controlled, double-blind trial. The study sample comprised 12 patients, each evaluated on both sides (thus 24 sides). All patients fulfilled defined selection criteria. Changes in the lesions were measured both subjectively and objectively. The sample was divided into two patient groups: an experimental group receiving medication and a control group receiving placebo. The statistical analysis was performed using SPSS software. Lesions in both groups improved and no statistically significant difference between the groups was observed at any time. ‘Severe’ injuries in the experimental group were more likely to exhibit a significant improvement after 6 months. Based on the results of the present study, it is concluded that the combination UTP, CMP, and hydroxycobalamin did not influence recovery from neurosensory disorders.

The osteotomies required during orthognathic surgery are performed near to the sensory nerves. Transient changes in skin sensitivity may develop, attributable to soft tissue swelling and inflammation, or direct or indirect nerve injury, depending on the nerve distribution. The rate and extent of facial sensation recovery are affected by several factors, among which are the type of surgery, the number of procedures performed, and patient age.

Drugs exhibiting neurotrophic characteristics and mimicking neuronal growth factors would be valuable to treat nerve damage; neuronal growth factors synthesized during embryogenesis guide nerve growth towards target organs.

Wattig et al. reported that drugs stimulating neural regeneration would be very useful to treat both minor and severe nerve injuries, and also problems developing after nerve suturing. Such drugs would foster a faster recovery, shorten the time to reinnervation, and minimize secondary injuries caused by denervation of effector areas. In recent years, intensive research has been devoted to this end. Drugs including vitamin B complex (associated or not with corticosteroids), multivitamin preparations, and gangliosides and nucleotides have been investigated as stimulators of peripheral nerve regeneration.

The nucleotide cytidine-5-monophosphate (CMP) improves muscle strength and general neuronal functionality. CMP is a metabolite of the nervous system, serving as a coenzyme of enzymes involved in phospholipid and glycolipid synthesis. Such lipids, which are essential for normal nervous system functionality, undergo continuous cycles of breakdown and synthesis. CMP, which stimulates glycolipid synthetic activity, complemented by the action of uridine 5′-triphosphate (UTP), is an enzyme cofactor that is essential for the maintenance and regeneration of nervous system structures, especially that of the myelin sheath. Recent work in rats has shown that a lack of CMP triggers axonal swelling and neuronal degeneration.

The compound made up of UTP, CMP, and hydroxycobalamin (UTP/CMP/hydroxycobalamin) contains sodium salts of pyrimidine ribonucleotides derived from CMP and UTP contained in RNAs degraded by pancreatic ribonuclease. In vitro studies have shown that the uridine and cytidine are incorporated into RNA early after neuronal injury. In animal tests, the UTP/CMP/hydroxycobalamin compound accelerated axonal maturation and improved the sensory and motor conduction velocities of individual fibres.

In addition, neuronal regeneration is associated with many metabolic, functional, and structural changes in both the neuronal cell body and peripheral nerve fibres. Such changes affect lipid synthesis and use. Protein and carbohydrate levels are also influenced by associated hormones, reflecting the need for the increased synthesis of materials required for axonal transport, growth, and restoration of nerve fibres. In this context, it has been shown that the administration of materials at high concentrations promotes fibre regeneration in normal neuronal tissue. Thus, the administration of UTP and CMP (together with hydroxycobalamin (vitamin B12)) may play a useful role: not only are UTP and CMP constituents of DNA and RNA, but these materials also play important roles in the biosynthesis of phospholipids and glycolipids.

Hence, drug therapies that enhance nerve regeneration are required. However a literature search did not identify any studies that have attempted to develop such an approach for the treatment of disturbances caused by bilateral sagittal split osteotomy (BSSO). Thus, the aim of the present study was to quantitatively monitor lesional changes after such surgery and to explore whether the combination UTP/CMP/hydroxycobalamin aides the recovery from neurosensory changes. The hypothesis was that the medication studied would facilitate the recovery of sensation in patients with nerve damage caused by the surgical procedure.

Patients and methods

This was a prospective and cross-sectional study. Patients treated in the department of maxillofacial surgery and traumatology of the university hospital in Pernambuco, Brazil, were recruited. All patients had facial skeletal deformities requiring jaw surgery involving the use of the BSSO technique, and all met the inclusion/exclusion criteria shown in Table 1 . The study sample comprised 12 patients recruited between March and June 2013, who thus formed a non-probabilistic sample of convenience. The project scheme was submitted to and approved by the Ethics Committee of the Brazil Platform. All patients were told of the aim of the work and signed an informed consent form.

Table 1
Inclusion and exclusion criteria.
Criteria Selection of sample
Inclusion criteria • Age 18–35 years
• A facial skeletal deformity requiring mandibular surgery using BSSO of the mandibular ramus; range of motion less than 7 mm
• No craniofacial syndrome
• No history of jaw trauma or nerve injury
• No history of mandibular orthognathic surgery
• No history of a mental disorder
• Agreed to participate after reading the Statement of Informed Consent
• Absence of nerve deficits on objective pre-surgical testing
Exclusion criteria • No neurosensory deficit upon immediate post-surgical testing
• Loss to follow-up
• Contraindications identified by the manufacturer of the medication: acute (not chronic) ischaemic stroke
• Any proliferative disorder
• Use of an antiviral agent or citicoline (posing a risk of a drug interaction)
• Pregnancy

BSSO, bilateral sagittal split osteotomy.

Patients were divided randomly (using the ‘Random.org’ programme) into an experimental group of six patients who received medication and a placebo control group of six patients. The dosage of medication was one ampoule intramuscularly daily for 3 days, followed by one capsule orally three times daily for 60 days, as suggested by the manufacturer for patients with trauma – compressive peripheral neural disorders. The six controls received placebos containing 5 mg starch. Data obtained for the 12 sides of the six patients in group 1 (experimental) were compared to those obtained for the 12 sides of the six patients in group 2 (controls).

This was a double-blind study; the researcher responsible for patient assessment was blinded to the choice of the intervention or control treatment.

All surgical procedures were performed by a single surgeon experienced in the relevant techniques, aided by residents and student surgeons. All patients had similar conditions, and the surgical technique was standardized following the principles of Epker et al.

Risk factors that could negatively influence outcomes served as exclusion criteria. All patients were aged 17–40 years. If the magnitude of movement was not limited (less than 7 mm) and/or if visible damage to the nerve in question was apparent, that patient was excluded ( Table 1 ).

All patients underwent subjective and objective pre-surgery neurosensory testing to define existing deficits and also to provide baseline data to which data obtained postoperatively could be compared. The subjective test used was a visual analogue scale (VAS) and the objective evaluations comprised sensitivity tests exploring the effects of touch and pressure, a pain discrimination test, a two-point discrimination test, a directional discrimination test, and a thermal sensitivity test. The tests were repeated postoperatively to diagnose nerve damage and to monitor recovery thereafter. Tests were run immediately after surgery and at 1, 3, and 6 months post-surgery. All tests were administered by the same researcher. Calibration was assessed by means of the intra-host kappa test.

Skin patterns were created on the lower lip and chin to allow test standardization. The lower lip was located at the centre of a rectangle delimited by the horizontal line of the commissure, the mental fold line, the commissural vertical line, and the midline. The mental region was located midway between the mental fold line and the mandibular rim of the commissural vertical line. Subjective and objective tests were run, as described below.

Subjective tests

A questionnaire and VAS were used to derive data on the extent of sensitivity loss. The subjective questions were taken from questionnaires described in the literature. The VAS was a smooth straight line 10 cm in length, with one end representing normal sensitivity and the other representing a complete change in sensitivity. During data collection, a VAS categorizing point-by-point data was superimposed on the VAS marked-up by the patient.

Objective tests

The Semmes–Weinstein (SW) test of sensitivity to touch/pressure was used; the test kit contains calibrated filaments that are mounted on bearings and protected in transparent tubes. Each tube contains two identical strands, one for immediate use and the other for later evaluation. Six tubes serve as rods holding filaments in positions appropriate for application. The seventh tube contains two of the finer filaments and may be supported on a surface, to hold rods that are assembled prior to use. The monofilaments in the kit differ in diameter.

Filaments were positioned perpendicular (2 cm apart) to a rod touching the skin of each patient, after which the skin was gradually touched until the monofilament bended; this position was maintained for 1.5 s. Each patient then reported on what he or she had felt; these data were recorded on a standardized form. In short, the test detected and monitored functional disorders of the peripheral nerves.

These filaments are characterized by direct laboratory measures of the axial forces required to initiate buckling. Although ‘pressure’ is often mentioned in the literature, any pressure transmitted can be determined only via calculation, because pressure depends on both the applied force and the contact area, which can vary during filament application.

For the statistical analysis, points were awarded for each monofilament sensed. There were six filaments in total; a numerical value of 6 was assigned to the thinnest monofilament and 0 to the thickest, thus a score closer to 0 suggests poorer sensitivity.

The two-point discrimination test was used to evaluate the patient’s ability to discriminate between two points measured with a slide calliper. The two ends of the clamp were made to touch the skin simultaneously at a light pressure and with the patient’s eyes closed. The separation of the two ends was reduced gradually from 20 mm in the chin region and from 10 mm in the lower lip region, until the moment when the patient reported being able to feel just one point. The measurement was taken with the aid of a millimetre ruler. The minimum distance at which two points were felt was recorded.

The ability to feel pain was evaluated using a sterile dental explorer to probe possibly affected sites. If pain was reported, sensation was considered normal. The absence of pain was considered to reflect nerve injury. If no pain was felt in three or all four regions tested, the sensory loss was graded as severe. If pain was felt in only two regions, the change was considered moderate. If pain was felt in three regions, this change was considered mild. If pain was felt in all regions, it was recorded that no change had occurred.

The directional discrimination test evaluated sensitivity to brushing, including pain and shock. A Tiger model 267 brush was used to repeatedly stroke the skin, in various directions, and the patient reported the directions taken. When the reports were 75% accurate, it was considered that sensitivity was normal. The pain sensitivity criteria described above were used to categorize the responses.

The thermal sensitivity test employed heated gutta-percha and cotton balls wrapped in Endo-Frost (−50 °C). The presence or absence of sensitivity was noted. The pain sensitivity criteria described above were used to categorize the responses.

Statistical analysis

Statistical analyses were performed using SPSS version 17.0 software (SPSS Inc., Chicago, IL, USA). Categorical variables were compared using the χ 2 test or Fisher’s exact test, as appropriate. The Kolmogorov–Smirnov test was used to check that continuous variables were normally distributed. Between-group comparisons were performed using the Student t -test or the Mann–Whitney test for non-parametrically or parametrically distributed data, respectively.

A difference was considered significant at P < 0.05. The results were compared with calculations of sample size and power. G*Power software version 3.1.9.2 (University of Kiel, Germany) was used for the calculation.

Results

Table 2 shows the changes in Semmes–Weinstein values over time. Improvements were significant in both groups at all evaluation times, compared to the immediate postoperative period, at which time high incidences of sensory change were evident. At 1 month, a significant between-group difference was apparent; the control group improved notably. The average monofilament sensation scores were used to derive these data, because an assessment of overall recovery was required. Thus, when it is considered that the mean score in the experimental group was 0.2, which increased to 5, whereas the control score rose from 1.2 to 5, it is apparent that tactile sensitivity in the experimental group evolved more rapidly than in controls.

Table 2
Semmes–Weinstein values over time, in treated and untreated patients; mean (SD) values.
Pre-surgery Post-surgery 1 month 3 months 6 months P -value a P -value b P -value c
Experimental group (G1)
( n = 12)
6.0 (0.0) 0.2 (0.3) 1.0 (0.7) 2.9 (2.2) 5.0 (1.5) 0.003 * 0.001 * <0.0001 *
Control group (G2)
( n = 12)
6.0 (0.0) 1.2 (1.7) 2.5 (2.4) 4.2 (2.5) 5.0 (1.8) 0.01 * 0.001 * <0.0001 *
P -value d 1.0 0.07 0.04 * 0.2 0.9

a Post-surgery vs. 1 month.

b Post-surgery vs. 3 months.

c Post-surgery vs. 6 months; paired t -test.

d G1 vs. G2, Student’s t -test.

* Significant difference.

Table 3 shows the means of the smallest distances at which patients could distinguish between two different points. Pre- and postoperative data were compared to assess the extent of recovery. Significant improvements were evident at all test times, but no significant between-group difference was noted.

Table 3
Two-point discrimination results over time, in treated and untreated patients; mean (SD) values.
Pre-surgery Post-surgery 1 month 3 months 6 months P -value a P -value b P -value c P -value d
Experimental group (G1)
( n = 12)
5.0 (1.2) 14.6 (1.0) 13.8 (2.1) 11.2 (3.4) 8.4 (3.4) <0.10 −4 * <0.10 −4 * 0.0003 * 0.01 *
Control group (G2)
( n = 12)
5.4 (1.3) 14.9 (0.2) 13.2 (3.1) 12.4 (3.7) 11.0 (3.9) <0.10 −4 * <0.10 −4 * <0.10 −4 * 0.0002 *
P -value e 0.4 0.3 0.5 0.4 0.1

a Pre-surgery vs. post-surgery.

b Pre-surgery vs. 1 month.

c Pre-surgery vs. 3 months.

d Pre-surgery vs. 6 months; paired t -test.

e G1 vs. G2, Student’s t -test.

* Significant difference.

As shown in Table 4 , pain sensitivity improved significantly in both groups over time, but no significant between-group difference was evident. By 6 months, all experimental sites had improved, compared to 83.3% of control sites.

Table 4
Pain sensitivity over time, in treated and untreated patients.
Pre-surgery Post-surgery 1 month 3 months 6 months P -value a P -value b P -value c
Experimental group (G1)
No change 12 0 5 11 12 0.03 * <0.0001 * <0.0001 *
Change 0 12 7 1 0
Moderate 0 3 4 1 0
Severe 0 9 3 0 0
Control group (G2)
No change 12 0 6 10 10 0.01 * <0.0001 * <0.0001 *
Change 0 12 6 2 2
Moderate 0 2 4 2 2
Severe 0 10 2 0 0
P -value d 1.0 1.0 0.4

a Post-surgery vs. 1 month.

b Post-surgery vs. 3 months.

c Post-surgery vs. 6 months; paired t -test.

d G1 vs. G2, Fisher’s exact test.

* Significant difference.

As shown in Table 5 , many patients showed abnormal results in terms of directional discrimination after their procedures. There was gradual improvement over time in both groups. Significance was attained 3 months postoperatively in the control group, but only at 6 months postoperatively in the test group. However, in the immediate postoperative period, all 12 experimental sites exhibited severe sensitivity changes, but only two sites failed to recover completely by month 6 of assessment; these sites showed ‘moderate’ changes. In the control group, all 12 sites exhibited postoperative changes, of which nine were ‘severe’; however, by month 6, four sites still scored as ‘severe’. Thus, although the between-group difference was not significant, the improvement in the experimental group was somewhat greater.

Table 5
Directional discrimination over time, in treated and untreated patients.
Pre-surgery Post-surgery 1 month 3 months 6 months P -value a P -value b P -value c
Experimental group (G1)
No change 12 0 0 2 10 0.47 <0.0001 *
Change 0 12 12 10 2
Moderate 0 0 0 1 2
Severe 0 12 12 9 0
Mild 0 0 0 0 0
Control group (G2)
No change 12 0 3 6 8 0.21 0.01 * 0.001 *
Change 0 12 9 6 4
Moderate 0 3 0 1 0
Severe 0 9 9 5 4
Mild 0 0 0 0 0
P -value d 0.21 0.19 0.64

a Post-surgery vs. 1 month

b Post-surgery vs. 3 months

c Post-surgery vs. 6 months; paired t -test

d G1 vs. G2, Fisher’s exact test.

* Significant difference.

As shown in Table 6 , there was gradual improvement over time in perception of the ‘hot’ sensation, but this was significant only after 6 months in both groups. No significant between-group difference was apparent, although at 6 months the experimental group had a higher number of sites showing no change; there was no site in the ‘severe’ category and there were three in the ‘moderate’ category. In the controls, three sites were in the ‘severe’ category. Both groups contained seven patients with ‘severe’ changes evident at 3 months. Thus, an interesting improvement was apparent in the experimental group.

Table 6
Thermal sensitivity (hot) over time, in treated and untreated patients.
Pre-surgery Post-surgery 1 month 3 months 6 months P -value a P -value b P -value c
Experimental group (G1)
No change 12 0 0 2 9 0.47 0.47 0.0003 *
Change 0 12 12 10 3
Moderate 0 0 0 3 3
Severe 0 12 12 7 0
Control group (G2)
No change 12 0 2 4 8 0.47 0.09 0.001 *
Change 0 12 10 8 4
Moderate 0 2 1 1 1
Severe 0 10 9 7 3
P -value d 0.47 0.64 1.0
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Jan 16, 2018 | Posted by in Oral and Maxillofacial Surgery | Comments Off on Effect of the use of combination uridine triphosphate, cytidine monophosphate, and hydroxycobalamin on the recovery of neurosensory disturbance after bilateral sagittal split osteotomy: a randomized, double-blind trial
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