YIJOM-3252; No of Pages 8

Int. J. Oral Maxillofac. Surg. 2015; xxx: xxx–xxx

http://dx.doi.org/10.1016/j.ijom.2015.09.007, available online at http://www.sciencedirect.com

Clinical Paper
Orthognathic Surgery

Effect of the use of combination C. L. Vieira1,

B. C. do E. Vasconcelos2,
J. C. Leão3, J. R. Laureano Filho2

uridine triphosphate, cytidine

1
Dentistry School, University of Pernambuco,
Recife, Pernambuco, Brazil; 2Department of
Maxillofacial Surgery and Traumatology,
University of Pernambuco, Recife,

monophosphate, and Pernambuco, Brazil; 3Oral Medicine Unit,

Department of Clinics and Preventive
Dentistry, University of Pernambuco, Recife,

hydroxycobalamin on the
Pernambuco, Brazil

recovery of neurosensory
disturbance after bilateral
sagittal split osteotomy: a
randomized, double-blind trial
C. L. Vieira, B. C. doE. Vasconcelos, J. C. Leão, J. R. Laureano Filho: 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. Int. J. Oral Maxillofac. Surg. 2015;
xxx: xxx–xxx. # 2015 Published by Elsevier Ltd on behalf of International
Association of Oral and Maxillofacial Surgeons.

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 Key words: orthognathic surgery; mandibular-
more likely to exhibit a significant improvement after 6 months. Based on the results nerve; nervous system trauma; therapeutics.
of the present study, it is concluded that the combination UTP, CMP, and
hydroxycobalamin did not influence recovery from neurosensory disorders. Accepted for publication 11 September 2015

0901-5027/000001+08 # 2015 Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons.

Please cite this article in press as: Vieira CL, et al. 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
YIJOM-3252; No of Pages 8
2 Vieira et al.
The osteotomies required during orthog-
nathic 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.1
Drugs exhibiting neurotrophic charac-
teristics and mimicking neuronal growth
factors would be valuable to treat nerve
damage; neuronal growth factors synthe-
sized during embryogenesis guide nerve
growth towards target organs.2
Wattig et al.3 reported that drugs stim-
ulating 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 in-
cluding vitamin B complex (associated or
not with corticosteroids), multivitamin
preparations, and gangliosides and nucleo-
tides have been investigated as stimulators
of peripheral nerve regeneration.
The nucleotide cytidine-5-monopho-
sphate (CMP) improves muscle strength
and general neuronal functionality. CMP
is a metabolite of the nervous system,
serving as a coenzyme of enzymes in-
volved 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 gly-
colipid synthetic activity, complemented
by the action of uridine 50 -triphosphate
(UTP), is an enzyme cofactor that is
essential for the maintenance and regen-
eration of nervous system structures, es-
pecially that of the myelin sheath. Recent
work in rats has shown that a lack of CMP
triggers axonal swelling and neuronal
degeneration.4
The compound made up of UTP, CMP,
and hydroxycobalamin (UTP/CMP/hydro-
xycobalamin) contains sodium salts of py-
rimidine ribonucleotides derived from
CMP and UTP contained in RNAs degrad-
ed 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 im-
proved the sensory and motor conduction
velocities of individual fibres.5
Please cite this article in press as: Vieira CL, et al. 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
In addition, neuronal regeneration is maxillofacial surgery and traumatology of
associated with many metabolic, function- the university hospital in Pernambuco,
al, and structural changes in both the Brazil, were recruited. All patients had
neuronal cell body and peripheral nerve facial skeletal deformities requiring jaw
fibres. Such changes affect lipid synthesis surgery involving the use of the BSSO
and use. Protein and carbohydrate levels technique, and all met the inclusion/exclu-
are also influenced by associated hor- sion criteria shown in Table 1. The study
mones, reflecting the need for the in- sample comprised 12 patients recruited
creased synthesis of materials required between March and June 2013, who thus
for axonal transport, growth, and restora- formed a non-probabilistic sample of con-
tion of nerve fibres.6 In this context, it has venience. The project scheme was submit-
been shown that the administration of ted to and approved by the Ethics
materials at high concentrations promotes Committee of the Brazil Platform. All
fibre regeneration in normal neuronal tis- patients were told of the aim of the work
sue. Thus, the administration of UTP and and signed an informed consent form.
CMP (together with hydroxycobalamin Patients were divided randomly (using
(vitamin B12)) may play a useful role: the ‘Random.org’ programme) into an
not only are UTP and CMP constituents experimental group of six patients who
of DNA and RNA, but these materials also received medication and a placebo control
play important roles in the biosynthesis of group of six patients. The dosage of medi-
phospholipids and glycolipids.4 cation was one ampoule intramuscularly
Hence, drug therapies that enhance daily for 3 days, followed by one capsule
nerve regeneration are required. However orally three times daily for 60 days, as
a literature search did not identify any suggested by the manufacturer for patients
studies that have attempted to develop with trauma – compressive peripheral neu-
such an approach for the treatment of ral disorders. The six controls received
disturbances caused by bilateral sagittal placebos containing 5 mg starch. Data
split osteotomy (BSSO). Thus, the aim of obtained for the 12 sides of the six patients
the present study was to quantitatively in group 1 (experimental) were compared
monitor lesional changes after such sur- to those obtained for the 12 sides of the six
gery and to explore whether the combina- patients in group 2 (controls).
tion UTP/CMP/hydroxycobalamin aides This was a double-blind study; the re-
the recovery from neurosensory changes. searcher responsible for patient assess-
The hypothesis was that the medication ment was blinded to the choice of the
studied would facilitate the recovery of intervention or control treatment.
sensation in patients with nerve damage All surgical procedures were performed
caused by the surgical procedure. by a single surgeon experienced in the
relevant techniques, aided by residents
and student surgeons. All patients had
Patients and methods similar conditions, and the surgical tech-
This was a prospective and cross-sectional nique was standardized following the prin-
study. Patients treated in the department of ciples of Epker et al.7
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.
YIJOM-3252; No of Pages 8
Risk factors that could negatively influ-
ence 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 pro-
vide 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 dis-
crimination test, a two-point discrimina-
tion 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.8
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 lit-
erature.9–12 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 sen-
sitivity 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
Please cite this article in press as: Vieira CL, et al. 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
Effect of UTP/CMP/hydroxycobalamin after BSSO
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 perpendicu-
lar (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 disor-
ders of the peripheral nerves.
These filaments are characterized by
direct laboratory measures of the axial
forces required to initiate buckling. Al-
though ‘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 dur-
ing filament application.
For the statistical analysis, points were
awarded for each monofilament sensed.
There were six filaments in total; a numer-
ical value of 6 was assigned to the thinnest
monofilament and 0 to the thickest, thus a
score closer to 0 suggests poorer sensiti-
vity.
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 simul-
taneously 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 nor-
mal. 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 consid-
ered mild. If pain was felt in all regions, it
was recorded that no change had occurred.
The directional discrimination test eval-
uated sensitivity to brushing, including
pain and shock. A Tiger model 267 brush
was used to repeatedly stroke the skin, in
3
various directions, and the patient reported
the directions taken. When the reports
were 75% accurate, it was considered that
sensitivity was normal. The pain sensitiv-
ity 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 8C). The
presence or absence of sensitivity was
noted. The pain sensitivity criteria de-
scribed 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 x2 test or Fish-
er’s exact test, as appropriate. The Kol-
mogorov–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-para-
metrically or parametrically distributed
data, respectively.
A difference was considered significant
at P < 0.05. The results were compared
with calculations of sample size and pow-
er. 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. Improve-
ments were significant in both groups at
all evaluation times, compared to the im-
mediate 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 ex-
perimental group evolved more rapidly
than in controls.
Table 3 shows the means of the smallest
distances at which patients could distin-
guish 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.
YIJOM-3252; No of Pages 8

4 Vieira et al.

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-valuea P-valueb P-valuec
* *
Experimental group (G1) 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*
(n = 12)
Control group (G2) 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*
(n = 12)
P-valued 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. 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-valuea P-valueb P-valuec P-valued
4* 4* *
Experimental group (G1) 5.0 (1.2) 14.6 (1.0) 13.8 (2.1) 11.2 (3.4) 8.4 (3.4) <0.10 <0.10 0.0003 0.01*
(n = 12)
Control group (G2) 5.4 (1.3) 14.9 (0.2) 13.2 (3.1) 12.4 (3.7) 11.0 (3.9) <0.104* <0.104* <0.104* 0.0002*
(n = 12)
P-valuee 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, com-
pared to 83.3% of control sites.
As shown in Table 5, many patients
showed abnormal results in terms of di-
rectional discrimination after their proce-
dures. 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. Howev-
er, 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 ‘moder-
ate’ 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 differ-
ence was not significant, the improvement
in the experimental group was somewhat
greater.
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 ‘mod-
erate’ 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 in-
teresting improvement was apparent in the
experimental group.
As shown in Table 7, the two groups
exhibited similar patterns with regard to
cold sensitivity, with significant improve-
ments apparent by 3 months. No signifi-
cant between-group difference was
noted.

Table 4. Pain sensitivity over time, in treated and untreated patients.

Pre-surgery Post-surgery 1 month 3 months 6 months P-valuea P-valueb P-valuec
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-valued – – 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.

Please cite this article in press as: Vieira CL, et al. 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
YIJOM-3252; No of Pages 8

Effect of UTP/CMP/hydroxycobalamin after BSSO 5

Table 5. Directional discrimination over time, in treated and untreated patients.

Pre-surgery Post-surgery 1 month 3 months 6 months P-valuea P-valueb P-valuec
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-valued – – 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.

Table 6. Thermal sensitivity (hot) over time, in treated and untreated patients.
Pre-surgery Post-surgery 1 month 3 months 6 months P-valuea P-valueb P-valuec
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-valued – – 0.47 0.64 1.0
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.

Table 7. Thermal sensitivity (cold) over time, in treated and untreated patients.
Pre-surgery Post-surgery 1 month 3 months 6 months P-valuea P-valueb P-valuec
Experimental group (G1)
No change 12 0 2 7 11 0.47 0.004* <0.0001*
Change 0 12 10 5 1
Moderate 0 2 2 3 1
Severe 0 10 8 2 0
Control group (G2)
No change 12 0 2 7 10 0.47 0.004* <0.0001*
Change 0 12 10 5 2
Moderate 0 5 3 1 0
Severe 0 7 7 4 2
P-valued – – 1.0 1.0 1.0
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.

Please cite this article in press as: Vieira CL, et al. 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
YIJOM-3252; No of Pages 8
6 Vieira et al.
Table 8. Concordance of the results of the visual analogue scale (VAS) with objective tests.
Monofilaments
VAS vs. time
Concordance Kappa
Post-surgery 83.3% 0.091
1 month 41.6% 0.215
* *
3 months 25.0%
6 months 50.0% 0.333
*
Values not calculated because the response categories were not the same (condition necessary for calculating the kappa value).
Table 8 shows the relationships between
the subjective test (VAS) and all of the
cited objective tests.
Discussion
The reported incidence of immediate and
long-term neurosensory deficits varies
considerably (from <5% to >90%), be-
cause of a variety of poorly controlled
factors inherent in study designs.
Nakajima10 reported that both subjec-
tive and objective assessments of the in-
ferior alveolar and lingual nerves are
effective, but that data from several tests
should be combined to increase reliability.
Indeed, in the present study, various tests
were used in order to measure neurosen-
sory changes. It appears that only a few
studies have combined the various tests
used in the present study to analyze nerve
function. In this study, fibres involved in
the perception of vibration, pressure, tac-
tile sensations, temperature, and acute and
chronic pain were evaluated.
Kabasawa et al.13 considered that con-
ventional thermal measurements (hot/
cold) did not allow the quantitative assess-
ment of sensation; they favoured the use of
the device of Oka and Matsusima.14 This
apparatus allows responses to be quanti-
fied, affording several advantages, includ-
ing a reduction in test time and separate
measurements of the hot and cold thresh-
olds.
The present study showed that the ob-
jective tests could present lower or higher
results compared to the subjective test.
With regard to the existence or otherwise
of nerve injury, the subjective test used in
this study was shown to be effective, with
similar patterns of compliance to the ob-
jective tests used. In the early postopera-
tive period, the magnitude of the
sensorineural change felt by the patient
appeared to be greater than that demon-
strated by the objective tests. To obtain
more reliable results with respect to the
evaluation of nerve function, in order to
quantify and monitor the various neuro-
sensory disorders, multiple tests should be
used, since each evaluates particular types
Please cite this article in press as: Vieira CL, et al. 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
Pain Cold
Concordance Kappa Concordance Kappa
* *
75.0% 75.0%
* *
41.6% 58.3%
* *
25.0% 8.3%
* *
16.6% 25.0%
of fibre involved with the specific objec-
tive results.
Many articles have sought to quantify
sensorineural damage. These have sug-
gested changes in surgical techniques
and have described new surgical instru-
ments permitting careful tissue handling.
Improved fixation methods have been de-
scribed, as have the associations thereof
with certain risk factors. The overall aim is
to reduce the frequency of damage.12–23
In general, high levels of neurosensory
disturbance are evident in the immediate
postoperative period, gradually improving
over time. This suggests that most nerve
injuries observed in the cited studies were
axonotmesis or neuropraxia. Abarca et al.9
reported that it is difficult for a clinician to
assess nerve damage such as demyelin-
ation caused by compression (neuro-
praxia), Wallerian degeneration distal to
the tubes of intact cells (axonotmesis), or
proximal or distal Wallerian degeneration
of the tubes of various Schwann cells
(neurotmesis). Mensink et al.23 considered
that most injuries generated in the BSSO
were combinations of neuropraxia and
partial axonotmesis.
It is, therefore, very likely that such
lesions were present in many of the
patients in the present study. The literature
shows that all such injuries improve sig-
nificantly within 3–6 months, as revealed
by a variety of tests. In a longitudinal
study with long-term monitoring after
BSSO procedures, it was observed that
neurosensory changes had largely normal-
ized at about 1 year after surgery.20 In the
present study, the proportion of patients
with ‘severe’ sensory changes decreased
progressively over the evaluation period,
and the proportion of these with ‘mild’ or
no changes increased, irrespective of the
group, as expected when the types of
injury suffered are considered. This was
especially evident over the first 3 months,
in agreement with the data of Park et al.,19
who found that the recovery rate from
nerve damage was highest after the first
3 months.
Panula et al.24 emphasized that even
when surgery meets all standards of
Directional
Hot discrimination
Concordance Kappa Concordance Kappa
*
91.6% 0.625 91.6%
*
33.3% 0.086 33.3%
*
25.0% 25.0%
*
33.3% 0.213 25.0%
competence and no intraoperative compli-
cation is apparent, severe mental and lower
lip paresthesia may develop postoperative-
ly in the absence of any visible damage to
the nerve. Thus, other mechanisms may be
involved; these may include haematoma,
oedema, stretching, or compression. How-
ever, it is believed that most damage is
caused by compression, which injures my-
elinated A-delta and A-beta fibres more so
than C fibres.13
Navarro et al.25 explored the physiology
of nerve damage and suggested that after
inflammation and swelling around the
nerve resolve, sensory changes can be
attributed to anatomical and functional
changes within the nerve, or central ner-
vous system changes induced by the neu-
ral injury. The biological response has
three phases; these include the initial re-
sponse of the nerve cell body, active re-
covery of any loss of axonal continuity
and/or reconstruction of the axonal diam-
eter and remyelination, and remodelling of
the cortical representation of the tissue
innervated by the damaged axon.
After orthognathic surgery, such as
BSSO, similar recovery patterns are ob-
served, but injuries of the neurotmesis
type are rare. Also, nerve injuries associ-
ated with this procedure most often feature
demyelination or partial axonal injury, and
most patients do not complain of post-
surgical neuropathic pain.1,12
It is well-established that mixtures of
nucleotides and vitamin B complex alle-
viate neuropathic pain.5,26,27 Wattig et al.
suggested that such substances might rep-
resent a new therapeutic modality for the
treatment of traumatic neuromuscular
injuries.28 Goldberg et al. cited several
preclinical works seeking to define the
roles played by nucleotides in peripheral
neuropathies of various types.29 Nucleo-
tides increased nerve conduction velocity,
the area and thickness of axonal myelin,
and the levels of neuronal cell membrane
phospholipids.
Connolly and Duley reviewed the func-
tions of uridine and nucleotide derivatives
thereof, with an emphasis on features ren-
dering such molecules promising future
YIJOM-3252; No of Pages 8
candidates to treat a variety of diseases.30
The actions of such compounds in the
central nervous system are being mapped,
and research on the development of in-
creasingly selective agents binding to P2
receptors continues. Lacanna showed that
a UTP/CMP/hydroxycobalamin complex
aided recovery from spinal cord injury in
rats.31
Wattig et al. found that both the myelin
sheaths and axons of rat peripheral nerves
were involved in regeneration, which was
accelerated by nucleotide administration,
particularly the combination UTP/CMP.6
Venhoff et al. studied peripheral and cen-
tral neurodegeneration in the mouse, at-
tributable to the mitochondrial toxicity of
antiviral drugs, and concluded that uridine
supplementation attenuated all aspects of
neurotoxicity.32 Goldberg et al. concluded
that a combination of uridine, cytidine,
and hydroxycobalamin was useful to treat
degenerative orthopaedic disorders featur-
ing neuronal compression.29 Lacanna
studied post-injury neurotmesis in the
rat sciatic nerve.31 A control group exhib-
ited better motor recovery than did a group
treated with a combination of UTP, CMP,
and vitamin B12, suggesting that these
materials did not aid recovery from this
injury. In such instances, surgery may be
indicated. Wattig et al. showed that nucle-
otide metabolism continued in crushed
peripheral neurons, contributing to both
nucleic acid synthesis and myelin sheath
formation, as did energy metabolism.28
This suggests that patients with traumatic
peripheral nerve injuries may benefit from
nucleotide administration, which should
increase the rate of regeneration.
In addition, the drug contains vitamin
B12 in the form of hydroxycobalamin, a
cofactor in the conversion of homocyste-
ine to methionine, an amino acid of axonal
tubulin. Thus, the drug should aid recov-
ery of the neuronal transport system. Vi-
tamin B12 is actively absorbed from the
gastrointestinal tract via binding to ‘intrin-
sic factor’ (a glycoprotein secreted by the
gastric mucosa). The vitamin is essential
for normal metabolic maintenance, eryth-
ropoiesis, cell replication and growth, and
the synthesis of nucleoprotein and myelin.
The significance of the vitamin in the
neuronal context increases after neurolog-
ical damage.29
Although gradual improvement in nerve
damage over time may be expected even
without intervention, the present study
suggests that the combination UTP/CMP/
hydroxycobalamin may indeed be useful.
Thus, although early improvements were
not noted, it is possible that the drug affects
long-term lesional evolution, as some tests
Please cite this article in press as: Vieira CL, et al. 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
Effect of UTP/CMP/hydroxycobalamin after BSSO
showed that improvements in neurosensory
disorders were slower in the control group
than in the experimental group.
The notion that the combination UTP/
CMP/hydroxycobalamin may be useful to
treat the sequelae of orthognathic surgery is
well-supported in the literature. Such se-
quelae are compressive in nature, being
principally neuropraxia and axonotmesis.
The combination UTP/CMP/hydroxycoba-
lamin should be an appropriate medication.
In conclusion, no statistically signifi-
cant between-group difference in nerve
injury after BSSO was found between
the test and control groups, and thus it
is concluded that the combination uridine
triphosphate, cytidine monophosphate,
and hydroxycobalamin did not influence
recovery from neurosensory disorders.
However, further studies using various
drug doses (to the maximum permitted,
thus two tablets three times daily for 60
days), accompanied by long-term moni-
toring are required.
Funding
None.
Competing interests
None declared.
Ethical approval
Ethics Committee of the Brazil Platform
(approval number CAAE12641313.3.0000.
5207/425 018).
Patient consent
Not required.
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Address:
José Rodrigues Laureano Filho
Dentistry School
Program in Oral Maxillofacial Surgery
University of Pernambuco
Av. General Newton Cavalcanti
1650 Camaragibe
CEP 54.753-220
Pernambuco
Brazil
Tel: +55 81 3458 2867;
Fax: +55 81 3458 2867
E-mail: laureano.filho@upe.br