e-ISSN: 2722-3558 Sriwijaya Journal of Surgery [SJS] https://sriwijayasurgery.
Prognostic Factors for Pain Reduction After Balloon Kyphoplasty in Osteoporotic Vertebral Compression Fractures: A Case Series Rachmad Susilo1*.
Rendra Leonas1.
Debby Handayati Harahap2 1Department of Orthopedics Surgery and Traumatology.
Universitas Sriwijaya.
Palembang.
Indonesia 2Medical Study Program.
Faculty of Medicine.
Universitas Sriwijaya.
Palembang.
Indonesia
ARTICLE
ABSTRACT
INFO
Introduction: Osteoporotic vertebral compression fractures (OVCF.
are a leading cause of morbidity and disability worldwide.
While balloon kyphoplasty provides significant pain relief, prognostic factors for optimal pain reduction outcomes remain debated, particularly in Southeast Asian populations with distinct epidemiological characteristics.
Methods: A retrospective case series analysis of 30 patients with OVCFs who underwent balloon kyphoplasty at Dr.
Mohammad Hoesin General Hospital.
Palembang.
Indonesia, between January 2024 and December 2025.
Pain was assessed using the Numerical Pain Rating Scale (NPRS) before surgery and at Seven potential prognostic variables were examined: age, gender, bone mineral density (BMD), kyphotic angle, duration of complaints, number of vertebral levels treated, and preoperative pain severity.
Bivariate analysis using Pearson and Spearman correlation coefficients was performed, followed by multivariate linear regression analysis with entry criteria of p < Results: Mean age was 67.
2 A 7.
39 years .
ange 54-82 year.
, with 80% female patients .
= .
Pain scores decreased significantly from a preoperative mean of 7.
43 A 0.
77 to a postoperative mean of 2.
8 A 0.
< .
, representing a 62.
3% reduction.
Bivariate analysis revealed significant associations for six variables.
Multivariate regression analysis identified two independent prognostic factors: duration of complaints ( = 1.
881, p < 0.
and age ( = -0.
428, p = 0.
, with an adjusted RA of Patients with shorter symptom duration and younger age experienced greater pain reduction.
Asymptomatic cement leakage occurred in two patients .
7%), with no serious complications observed.
Conclusion:
Balloon kyphoplasty effectively reduces pain in osteoporotic vertebral compression fractures.
Duration of complaints and patient age are independent prognostic factors for pain reduction outcomes.
These findings may guide patient selection and expectation management in clinical practice.
Keywords:
Balloon kyphoplasty NPRS Osteoporotic vertebral compression fracture Prognostic factors Pain outcome *Corresponding author:
Rachmad Susilo E-mail address:
susilorachmad88@gmail.
All authors have reviewed and approved the Anal version of the manuscript.
https://doi.
org/10.
37275/sjs.
Introduction Osteoporotic fracture even from minimal trauma or spontaneous 2 Beyond the immediate pathophysiological (OVCF.
represent a significant public health burden, consequences.
OVCFs frequently lead to chronic pain, progressive kyphosis, functional impairment, reduced contributing substantially to morbidity, mortality, and mobility, social isolation, depression, and diminished healthcare costs.
1 The prevalence of OVCFs increases quality of life.
dramatically with age, particularly in postmenopausal The women, due to accelerated bone loss associated with OVCFsAiconsisting of bed rest, analgesics, muscle declining estrogen levels.
These fractures result from loss of trabecular bone integrity and cortical bone inadequate pain relief, particularly in elderly patients thickness, rendering the vertebral body vulnerable to with severe baseline pain or multiple-level fractures.
therapyAioften This However, findings have been inconsistent across hospitalization, complications of immobility, and poor different populations and healthcare settings, with functional outcomes.
The advent of minimally invasive some variables showing significant associations in certain studies but not others.
Furthermore, most previous investigations have been conducted in management of OVCFs by offering rapid pain relief.
Western populations with distinct epidemiological, restoration of vertebral body height, and correction of demographic, and clinical characteristics compared to kyphotic deformity.
Southeast Asian populations.
The distinct genetic Balloon background, dietary patterns, baseline bone quality insertion of an inflatable balloon into the vertebral characteristics, and healthcare access in Southeast body, followed by inflation to restore height and create Asia may influence both the prevalence and outcomes a cavity within the fractured Subsequently, of OVCFs and balloon kyphoplasty treatment.
polymethylmethacrylate (PMMA) cement is injected This retrospective case series was undertaken to into this space to stabilize the fracture and maintain identify prognostic factors for pain reduction outcomes the restored height.
This technique offers several advantages over alternative vertebral augmentation osteoporotic vertebral compression fracture patients methods: superior restoration of vertebral body height, treated at a major academic medical center in reduced kyphotic angle, lower cement leakage rates.
Indonesia.
and superior pain reduction.
Clinical outcomes have associations between multiple potential prognostic consistently demonstrated that balloon kyphoplasty variables and postoperative pain reduction outcomes provides rapid and substantial pain relief in the majority of patients, with pain reduction often occurring within hours of the procedure.
The However, despite the widespread adoption and high clinicians may optimize patient selection, provide more success rates of balloon kyphoplasty, significant accurate preoperative counseling regarding expected variability exists in individual patient outcomes.
Some patients experience dramatic and sustained pain relief, while others achieve only modest improvements.
The specific aim of this study was to identify and a small proportion demonstrate inadequate pain independent prognostic factors for pain reduction after 7 This clinical heterogeneity suggests that balloon kyphoplasty in patients with osteoporotic specific patient characteristics and lesion features Mohammad Hoesin General Hospital.
Palembang, treatment outcomes.
Identifying reliable prognostic Dr.
Indonesia.
factors has important clinical implications, enabling more accurate patient selection, realistic outcome Methods prediction, better informed preoperative counseling.
Study design and setting long-term satisfaction and functional outcomes.
of patients with osteoporotic vertebral compression Previous studies examining prognostic factors in This study was a retrospective case series analysis fractures who underwent balloon kyphoplasty at Dr.
Mohammad Hoesin General Hospital.
Palembang, potentially relevant variables, including age, gender.
Indonesia, during the period from January 2024 to bone mineral density, kyphotic angle, duration of December 2025.
The hospital is a tertiary academic medical center affiliated with Sriwijaya University and symptoms, and number of vertebral levels serves as a regional referral center for orthopedic and Variables and measurements trauma care.
The study protocol was reviewed and The primary outcome measure was postoperative approved by the institutional ethics committee.
All pain reduction, defined as the difference between study procedures were conducted in accordance with preoperative and postoperative pain scores assessed the ethical principles outlined in the Declaration of using the Numerical Pain Rating Scale (NPRS).
The Helsinki and institutional research guidelines.
NPRS is a valid and reliable instrument for pain assessment, consisting of a 0-10 numeric scale where Population and sampling 0 represents no pain and 10 represents the worst The study population consisted of all patients aged possible pain.
Pain assessments were performed 50 years or older who presented with symptomatic immediately preoperatively and at hospital discharge, osteoporotic vertebral compression fractures and typically 24-48 hours after the procedure.
underwent balloon kyphoplasty during the study Seven independent variables were examined as The study sample comprised 30 consecutive patients who met all inclusion and exclusion criteria.
outcomes: .
age in years at time of surgery.
gender Patient .
ale or femal.
bone mineral density T-score systematic review of operating room records and measured using dual-energy X-ray absorptiometry hospital discharge databases during the specified time (DXA).
kyphotic angle measured in degrees on All patients provided informed consent for sagittal spinal imaging.
duration of complaints in participation in the study.
weeks prior to treatment.
number of vertebral levels Inclusion and exclusion criteria ingle, .
preoperative NPRS pain score.
Additional variables Inclusion criteria were as follows: .
age Ou 50 years imaging-confirmed recorded included vertebral level location, type of osteoporotic vertebral compression fracture .
efined fluoroscopy time, and adverse events occurring during as T-score O -2.
5 on bone mineral density assessmen.
or shortly after the procedure.
symptomatic presentation with pain related to the .
treatment with balloon kyphoplasty with Statistical analysis Descriptive .
availability of complete preoperative Continuous variables were reported as and postoperative pain assessments.
minimum mean A standard deviation with range, and categorical follow-up period of 4 weeks postoperatively.
Exclusion criteria included: .
pathological fractures secondary to metastatic disease, myeloma, or other malignancy.
including normality and homogeneity of variance, were .
fractures with retropulsion of bone into the spinal evaluated using appropriate diagnostic tests.
Bivariate canal causing significant neural compromise.
analysis was performed to examine associations infection or osteomyelitis at the fracture site.
between each independent variable and postoperative coagulopathy or anticoagulation therapy that could pain reduction.
Pearson product-moment correlation not be safely managed.
incomplete medical records coefficients were calculated for continuous variables with missing baseline or outcome data.
loss to with normally distributed data, while Spearman rank follow-up prior to 4 weeks postoperatively.
correlation coefficients were calculated for non- Assumptions normally distributed data or ordinal variables.
Pointbiserial correlation coefficients were calculated for dichotomous variables.
All bivariate associations were tested at a significance level of p < 0.
05, two-tailed.
Multivariate Ethical approval This study was approved by the institutional ethics conducted to identify independent prognostic factors committee of the Faculty of Medicine.
Universitas for pain reduction outcomes.
Variables with bivariate Sriwijaya.
associations at p < 0.
25 were entered into the accordance with the Declaration of Helsinki.
All regression model.
A stepwise entry algorithm was employed to identify the final multivariate model.
The Results model's overall significance was evaluated using the F- The study enrolled 30 patients with osteoporotic test, and the proportion of variance in pain reduction explained by the model was assessed using the adjusted R-squared coefficient.
Individual regression baseline clinical characteristics are presented in Table coefficients () were evaluated using t-tests, with 95% The cohort had a mean age of 67.
2 A 7.
39 years confidence intervals calculated for each coefficient.
ange 54-82 year.
, with a predominance of female Diagnostic procedures were performed to assess model patients .
0%, n = .
compared to males .
0%, n assumptions, including evaluation of residuals for = .
Bone mineral density T-scores ranged from -4.
normality and constant variance, detection of outliers 5, with a mean of -3.
29 A 0.
64, confirming and influential observations, and assessment of osteoporosis in all participants.
The mean kyphotic multicollinearity using variance inflation factors.
All angle was 19.
85 A 7.
71 degrees, indicating moderate statistical analyses were performed using SPSS kyphotic deformity.
Duration of complaints prior to 0 (IBM Corporation.
Armonk.
NY.
USA).
treatment ranged from 2 to 38 weeks, with a mean of two-tailed significance level of p < 0.
05 was used for all 57 A 9.
68 weeks.
The majority of patients .
7%, n = .
had single-level vertebral fractures, while 30.
comparisons was employed, given the exploratory .
= .
had two-level fractures and 3.
3% .
= .
had nature of the bivariate analysis and the small sample three-level fractures.
Patient Table 1.
Patient demographics and baseline clinical characteristics.
Variable Age .
, mean A SD Age range Gender, n (%) Female Male BMD T-score, mean A SD BMD range Kyphotic angle (A), mean A SD Duration of complaints .
, mean A SD Duration range .
Number of vertebral levels, mean A SD Single level, n (%) Two levels, n (%) Three levels, n (%) Preoperative NPRS, mean A SD Postoperative NPRS, mean A SD Value 2 A 7.
29 A 0.
6 to -2.
85 A 7.
57 A 9.
37 A 0.
43 A 0.
8 A 0.
Pain reduction of 4.
63 A 1.
16 points on the NPRS scale, or preoperative to postoperative assessment.
The mean 3% relative pain reduction.
All 30 patients .
%) preoperative NPRS score was 7.
43 A 0.
ange 6-.
, experienced some degree of pain reduction, with 26 while the mean postoperative NPRS score at discharge patients .
7%) achieving a pain reduction of at least 8 A 0.
ange 1-.
, as illustrated in Figure 1.
50% and 20 patients .
7%) achieving a pain This reduction in pain scores was highly statistically reduction of at least 60%.
< 0.
, representing a mean absolute Figure 1.
Pain reduction after balloon kyphoplasty.
Preoperative and postoperative numerical pain rating scale (NPRS) scores showed significant pain reduction .
< 0.
Bivariate associated with greater pain reduction.
Kyphotic angle associations between each of the seven independent .
= -0.
499, p = 0.
showed a moderate negative variables and postoperative pain reduction outcomes.
correlation with pain reduction, with greater kyphotic Six of the seven variables examined demonstrated deformity associated with greater pain reduction.
Duration of complaints .
= -0.
747, p < 0.
reduction, as detailed in Table 2.
Age .
= -0.
481, p = demonstrated the strongest correlation among all .
showed a moderate negative correlation with variables, with shorter symptom duration strongly pain reduction, indicating that younger age was associated with greater pain reduction.
The number of associated with greater pain reduction.
Gender .
oint- vertebral levels treated (Spearman rank correlation biserial correlation coefficient = 0.
415, p = 0.
was coefficient = -0.
421, p = 0.
was also significantly significantly associated with pain reduction, with associated with pain reduction, with single-level female patients experiencing greater pain reduction fractures showing greater pain reduction than multi- than male patients.
Bone mineral density T-score .
= level fractures.
Preoperative NPRS pain score .
= 365, p = 0.
demonstrated a significant positive 244, p = 0.
was not significantly associated with correlation with pain reduction outcomes, suggesting postoperative pain reduction outcomes.
that higher T-scores .
ess severe osteoporosi.
were Table 2.
Bivariate correlation analysis Variable Age Gender BMD T-score Kyphotic angle Duration of complaints Number of vertebral levels Preoperative NPRS Correlation coefficient r = -0.
rpb = 0.
r = 0.
r = -0.
r = -0.
rs = -0.
r = 0.
p-value <0.
* p < 0.
05 indicates statistical significance.
Multivariate Age also independently predicted pain performed to identify independent prognostic factors reduction outcomes, with a regression coefficient of for pain reduction outcomes.
All six variables that = -0.
% confidence interval -0.
831 to -0.
025, p demonstrated significant bivariate associations .
< = 0.
, indicating that for each additional year of .
were entered into the multivariate model: age, age, the postoperative pain reduction decreased by gender.
BMD T-score, kyphotic angle, duration of 43 points on the NPRS scale.
complaints, and number of vertebral levels treated.
Therefore, younger patients experienced greater pain The final multivariate regression model retained two reduction than older patients.
independent prognostic factors that significantly The multivariate regression model demonstrated predicted pain reduction outcomes, as presented in excellent fit to the data, with an adjusted RA of 0.
Table 3.
indicating that the two independent prognostic factors Duration .
uration independent predictor of pain reduction, with a 2% of the variance in postoperative regression coefficient of = -1.
% confidence 452 to -1.
310, p < 0.
This indicates significance was demonstrated by the F-statistic (F = that for each additional week of symptom duration 579, p < 0.
These findings indicate that prior to treatment, the postoperative pain reduction duration of symptoms and patient age are strong decreased by approximately 1.
88 points on the NPRS Conversely, patients with shorter symptom treatment success.
The Table 3.
Multivariate linear regression analysis.
Variable Constant Duration of complaints .
Age .
p-value <0.
<0.
95% CI
638 to 24.
452 to -1.
831 to -0.
Model: Adjusted RA = 0.
F = 35.
579, p < 0.
The three-dimensional independent prognostic factors and provides a clinical regression model depicting the relationships between context for understanding how different combinations duration of complaints, age, and postoperative pain of patient characteristics predict pain reduction reduction is illustrated in Figure 2.
This visualization demonstrates the interactive effects of the two Figure 2.
Forest plot of multivariate regression coefficients .
djusted R2=0.
Three-dimensional visualization of a multivariate regression model showing the relationship between duration of complaints, age, and postoperative pain reduction after balloon kyphoplasty.
Postoperative clinical manifestations or neurological deficits.
These monitored and assessed at hospital discharge and cases required no additional intervention.
No patients during subsequent follow-up visits.
The incidence and experienced symptomatic cement leakage, pulmonary types of complications are summarized in Table 4.
Two embolism, neurological deficit, infection, or adjacent- patients .
7%) experienced asymptomatic cement level vertebral fractures during the follow-up period.
leakage into adjacent tissues or the epidural space.
Overall, the procedure demonstrated excellent safety identified on postoperative imaging but without with a low complication rate in this cohort.
Table 4.
Postoperative complications.
Complication n (%) Cement leakage .
Adjacent level fracture Pulmonary embolism Neurological deficit Infection 2 .
To facilitate clinical application of these prognostic points on the NPRS, whereas a 75-year-old patient findings, predicted pain reduction outcomes were with the same symptom duration is predicted to calculated for various combinations of duration of experience a pain reduction of only 0.
7 points.
complaints and patient age using the multivariate Conversely, a 65-year-old patient with 24 weeks of regression equation.
These predicted values are symptom duration is predicted to experience a pain presented in Table 5 and demonstrate how different reduction of approximately -6.
4 points .
ndicating worsening pai.
, suggesting that this patient may be a reduction outcomes.
For example, a 55-year-old patient with 2 weeks of symptom duration is predicted standalone intervention.
to experience a pain reduction of approximately 9.
Table 5.
Predicted postoperative pain reduction based on duration of complaints and age.
Duration .
Age 55 Age 65 Age 75 Predicted pain reduction values are calculated from the multivariate regression equation: Pain Reduction = 16.
- .
881 y Duratio.
- .
428 y Ag.
Discussion strong inverse correlation .
= -0.
747, p < 0.
This retrospective case series demonstrates that between symptom duration and pain reduction, balloon kyphoplasty provides rapid and substantial confirmed in multivariate analysis ( = -1.
881, p < pain relief in patients with osteoporotic vertebral .
, indicates that patients with acute or subacute compression fractures, with a mean pain reduction of 3% occurring within 24-48 hours of the procedure.
reduction than those with chronic complaints.
This More finding has several potential explanations.
First, acute factorsAiduration fractures may be associated with greater inflammatory complaints and patient ageAithat strongly predict postoperative pain reduction outcomes.
These findings respond more readily to the mechanical stabilization have significant implications for patient selection, provided by balloon kyphoplasty.
Second, chronic preoperative counseling, and clinical decision-making compression fractures.
processing, and the development of chronic pain The marked pain reduction achieved in this cohort syndromes that are less responsive to peripheral mechanical interventions.
Third, patients with chronic examining balloon kyphoplasty efficacy.
11 Multiple symptoms may have developed adaptive patterns of randomized controlled trials and systematic reviews muscle guarding, postural dysfunction, and functional limitation that persist despite achievement of fracture techniques, particularly balloon kyphoplasty, produce These mechanisms suggest that the timing of superior pain reduction compared to conservative intervention is critical for optimal outcomes.
The mean pain reduction of 4.
63 points The association between younger age and superior on the NPRS scale observed in this study is within the pain reduction outcomes is consistent with broader range reported in international literature, typically literature in orthopedic surgery, demonstrating that ranging from 3.
5 to 5.
5 points.
The rapid onset of pain younger patients generally achieve better functional reliefAioccurring outcomes following interventional procedures.
15 This procedureAisuggests that the mechanism of pain study observed an independent effect of age ( = - reduction involves both biomechanical stabilization of 428, p = 0.
in the multivariate model, indicating the fracture and potential neurochemical effects related to the injection of cement and restoration of 28-point reduction in pain reduction vertebral body height.
Multiple mechanisms may explain this age- The finding that the duration of complaints is the related effect.
Younger patients may have better strongest independent predictor of pain reduction physiological reserve and healing capacity, superior outcomes is novel and clinically important.
13 The conditions superior pain reduction outcomes .
= 0.
likely reflects gender differences in pain perception, opioid adaptation to mechanical changes.
Additionally, older responsiveness, and psychosocial factors affecting patients more frequently demonstrate chronic pain pain outcomes, although this effect did not remain syndromes, poly-pharmacy affecting pain perception, independent in the multivariate model.
and age-related changes in nociceptor function and The unexpected finding that preoperative pain pain processing.
Understanding these age-related severity (NPRS) was not significantly associated with differences is important for establishing realistic pain reduction outcomes .
= 0.
244, p = 0.
outcome expectations during preoperative counseling, requires discussion.
This suggests that baseline pain particularly for elderly patients.
intensity is not a reliable predictor of the absolute The magnitude of pain reduction achieved.
Patients with adjusted RA of 0.
702, explained approximately 70% of severe baseline pain (NPRS 8-.
were not significantly the variance in pain reduction outcomes.
This more likely to achieve large absolute pain reductions compared to those with moderate baseline pain (NPRS complaints and age are powerful predictors of 6-.
This finding contrasts with some previous studies treatment success, although approximately 30% of the reporting that higher baseline pain scores predict variance remains unexplained.
This residual variance superior pain reduction.
18 The explanation may likely reflects contributions from unmeasured or exceptionally high baseline pain have limited capacity for further pain reduction, while patients with catastrophizin.
, pain phenotype and pain processing moderate baseline pain retain greater capacity for substantial pain reduction.
Alternatively, patients individual patients, quality of preoperative counseling with very high baseline pain may have more severe and expectation setting, and unmeasured technical nociceptive or neuropathic pain pathology, requiring factors related to the procedure itself.
16 Future studies mechanical stabilization alone.
nxiety, assessment and advanced neurobiological measures may further improve prognostic accuracy.
The The safety profile of balloon kyphoplasty in this study was excellent, with only two patients .
experiencing asymptomatic cement leakage and no associations between pain reduction and six of the serious adverse events.
This complication rate is lower seven examined variables.
The finding that kyphotic than many published series, likely reflecting surgeon angle inversely correlated with pain reduction .
= - experience, careful patient selection, appropriate 499, p = 0.
was somewhat unexpected and This finding may reflect the fact that 19 Asymptomatic cement leakage is generally patients with greater kyphotic deformity frequently considered a minor complication without clinical have more advanced osteoporosis, longer symptom significance, and neither of the two patients in this duration, and older ageAiall factors independently series required reoperation or developed subsequent associated with reduced pain relief.
Alternatively, greater kyphotic deformity may indicate more severe complications, pulmonary embolism, neurological vertebral body collapse and greater neurological injury, or infection is notable and validates the safety compression, which could theoretically limit pain of balloon kyphoplasty as a minimally invasive therapeutic option when performed by experienced The positive association between female gender and The practitioners in appropriate clinical settings.
Strengths of this study include the comprehensive contradict the treatment of elderly patients, as even examination of multiple potential prognostic variables, rigorous statistical methodology with appropriate rather, it informs realistic expectation- setting and identification of patients who may benefit preoperative and postoperative data for all study participants, and standardized pain assessment using a validated instrument.
The case series design enabled detailed clinical assessment and documentation of Future research should include prospective studies However, several limitations must be with larger sample sizes, longer follow-up duration.
First, the retrospective study design and moderate sample size .
= .
limit the statistical potential prognostic variables, including detailed power and generalizability of findings.
Second, follow- psychological assessment, pain phenotyping, and up was limited to 4 weeks postoperatively, preventing assessment of long-term pain outcomes and delayed Third, measurement of additional healthcare systems would enhance generalizability.
Investigation of potential mechanisms underlying the psychological factors, pain phenotype, and detailed prognostic effects of symptom duration and age, using advanced imaging and biomarker studies, would variablesAiincluding characteristicsAiwould Multicenter single-center study from Indonesia may not be fully investigation of whether early intervention in patients generalizable to other populations with different with acute vertebral compression fractures improves genetic backgrounds, health systems, or clinical outcomes compared to delayed intervention would Fifth, no control group receiving have important clinical implications for treatment conservative management or alternative interventions timing and health system resource allocation.
potentially improved prognostic accuracy.
Fourth, this Finally, comparative effectiveness.
Finally, the analysis did not Conclusion examine potential interactions between prognostic Balloon factors that might influence outcomes.
Despite these limitations, this study provides osteoporotic vertebral compression fractures, with an important contributions to understanding prognostic average pain reduction of 62.
3% occurring within 24- 48 hours of treatment.
Duration of complaints and osteoporotic vertebral compression fractures.
The patient age are independent prognostic factors that identification of duration of complaints and age as strongly predict pain reduction outcomes, together independent prognostic factors enables clinicians to explaining 70% of the variance in treatment success.
identify patient subgroups with differing outcome Patients with shorter symptom duration and younger expectations and to optimize preoperative counseling age experience significantly greater pain reduction than those with chronic complaints or advanced age.
importance of symptom duration suggests that earlier These findings enable more accurate patient selection, realistic expectation-setting, and identification of expectation-setting.
The supporting more aggressive diagnostic workup and expedited treatment pathways for patients with acute treatment approaches.
Earlier intervention in patients vertebral compression The finding that with acute vertebral compression fractures may younger patients achieve superior outcomes does not optimize pain reduction outcomes and should be evaluated in future prospective studies.
The excellent Clark W.
Bird P.
Gonski P, et al.
Safety and safety profile of balloon kyphoplasty, with minimal efficacy of vertebroplasty for acute painful serious complications, supports its continued role as placebo-controlled appropriate clinical settings.
(VAPOUR):
double-blind.
Lancet.
: 1408-16.
Kallmes DF.
Comstock BA.
Heagerty PJ, et al.
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