Discussion
We report the changes in PD and BPI outcomes of n=258 LBP patients who
were positive to the BUAS test and hence were treated with gabapentin
for their potential lumbar-RP condition. After the treatment, all
prespecified endpoints of the study were reached. We argue that these
results may be considered a piece of ex-adiuvantibus evidence for
the ability of the BUAS test to detect lumbar-RP in LBP patients.
In a medical context, the term ex adiuvantibus (from Latin,
meaning ”from that which helps”) refers to the method of making an
inference about the presence/cause of a pathological conditionfrom the observed responses of the condition to a giventreatment . In our case, the potential pathological
condition was lumbar-RP, as the BUAS test potentially diagnosed it.
We have recently proposed the BUAS-test as an adjunctive clinical sign
for lumbar-RP 10. We have argued that positive BUAS
test implies potential lumbar-RP, and vice-versa. Lumbar-RP, a known NeP
condition, can be indirectly quantified by measures like the PD
questionnaire and the BPI, which we here used to quantify the observed
responses to the given treatment. We hypothesized that a congruent
treatment for potential lumbar-RP (in our case, gabapentin) might lead
to its clinical improvement. Such improvement is measurable with the
tools mentioned above. Thus, subsequent significant improvement in PD
and BPI outcomes may imply, ex adiuvantibus , that the underlying
pathological condition was indeed lumbar-RP as the BUAS test initially
implied it. Accordingly, we argued that should a significant improvement
in the lumbar-RP condition occur, it would be reasonable to infer that
the BUAS-test did detect the lumbar-RP. To further support this
inference, we assumed that, after treatment, the observed responses
might be considered ’significant improvement’ only should these
responses fulfill restricted prespecified statistical and clinical
endpoints, following the recommendations for achieving MCIC in pain
research 14,15. These endpoints were: over 50% of the
sample should show negative PD-V2 outcome, significant V2-V1 differences
of the BPI-items’ mean-score, and that these differences should be of at
least 2 points for each BPI item.
Lumbar-RP is considered the result of abnormal discharges arising from
afferents of an injured dorsal root, ganglion, or inflamed nerve3. These abnormal discharges are the expression of
nerve roots’ sensitization to mechanical stimulation after sustained and
protracted compression (i.e., Mass Effect), or their response to the
perineural-spread of inflammogenic material arising from the nucleus
polposus (i.e., Chemical Radiculitis) 16. These
mechanisms induce maladaptive neuronal responses that thus have the
potential to generate abnormal responses from the affected nerve17. The differential diagnosis of LBP is complicated
by the variability and possible coexistence of multiple
pathophysiological and presentation patterns. A thorough history and
clinical examination, also in primary care settings, are essential in
establishing diagnosis and treatment in LBP patients. In particular,
symptoms, an accurate neurological examination, imaging, and specific
signs (e.g., SLRT and recently, the BUAS test) for lumbar-RP may guide
differential diagnosis 1.
The rationale for the application of the BUAS test is explained
elsewhere 10. Briefly, animal and human research
assert that applying a strain on an injured nerve, sensitized or
inflamed, may elicit heterospecific discharges, and hence subjective
responses in multiple somatosensory afferents. Such elicited responses
to the applied strain can confirm the presence of RP in various clinical
conditions, including injured/inflamed lumbar dorsal roots and ganglion2,3,5,6,18–25.
With the BUAS test, we proposed to apply the strain on the sciatic nerve
along its course in the buttock. Several reasons support the feasibility
and efficacy of the BUAS test. First, the sciatic nerve, which contains
axons from the L4-S3 levels, often involved in lumbar RP, is easily
identifiable in the buttock. Second, applying the strain at this
proximal sciatic-nerve course, the abnormal responses can be directly
associated with proximal nerve injuries. Third, in the buttock, the
sciatic nerve lies above stable anatomical structures allowing the
strain to be effectively applied. Finally, the BUAS test showed, among
LBP patients, satisfactory sensitivity (92%), specificity (100%),
prior probability, and interrater reliability (Cohen’s Kappa,
0.911)10. It showed no associations with predictors
like gender and age groups while it showed significant associations with
predictors like the pain site (lumbar pain and sciatica), and the PD
questionnaire. These findings imply that the BUAS test is not
compromised by patients’ demographic features and supports its content
validity. By contrast, the SLRT, widely used for the diagnosis of
lumbar-RP, should be considered with caution as it shows crucial
limitations 26. These limitations include the lack of
standard procedure for carrying out and interpreting the SLRT, unclear
underlying mode-of-action, compromised diagnostic reliability related to
specific predictors (the patient’s age, gender, psychosocial factors,
and diurnal variability), and lack of direct correlation with MRI
findings, in case of a herniated disc. Finally, “the diagnostic value
of the SLRT in detecting the presence of lumbar disc herniation may lie
primarily in ruling out its presence because the test sensitivity (0.8)
is far higher than its specificity (0.4)” 26 .
Treating lumbar-RP implies a step-wise approach from diagnosis to
treatment (conservative, invasive, or potential surgery) to ameliorate
or resolve the lumbar-RP condition and to permit patients to achieve a
better functional status and quality of life 27. Based
on moderate or high quality of evidence and efficacy, antidepressants
and anticonvulsants (e.g., pregabalin and gabapentin) have strong GRADE
recommendations for use in all NeP conditions and are thus proposed as
first-line treatment for NeP 7,28,29. Several
controlled studies have found gabapentinoids to be effective for NeP and
lumbar-RP 10,30–34. We chose gababapentin both
because of our positive experience with this drug, its known
pharmacodynamic properties in lumbar-RP, and local favorable economic
characteristics 9. Gabapentin is prescribed with a
starting dose of 300 mg and may be titrated up to 1800-3600 mg/day with
a “low and slow” incremental fashion 8,9,35. For
optimal clinical efficacy gabapentin should be prescribed tidbecause of its short elimination half-life, and saturable absorption
system.
Our inhouse protocol for first-line treatment of potential lumbar-RP
(i.e., patients positive to the BUAS test and/or the SLRT), is a 7 days
titration to 900 mg of gabapentin daily (300 mg tablets tid). Therapy
outcomes and side effects are evaluated in the follow-up visits where
doses may be tapered or increased according to the patients’ clinical
responses. In our sample no patient stopped the therapy because of side
effects even though 1.2% patients reported initial dizziness and
somnolence during the gabapentin titration period, which diminished over
time.
The observed responses to the gabapentin treatment in this paper
were retrieved from the PD and BPI questionnaires. The PD explores the
likelihood of the NeP component in LBP patients. The final score of the
questionnaire yields the three PD outcomes: negative, uncertain, and
positive 11–13. In our sample, PD-V1 outcomes were
positive (45%) or uncertain (55%), while PD-V2 outcomes were mostly
negative (77%). These results imply that over 50% of the sample had a
negative PD-V2 outcome and hence fulfilling the first endpoint of the
study. Interestingly, while the BUAS+/SLART- subset showed only negative
PD-V2 outcome, in the BUAS+/SLART+ subset, several PD-V2 outcomes were
positive (20%) or uncertain (37%). A possible explanation to these
results may be that in the BUAS+/SLART+ subset, the underlying lumbar-RP
condition was somehow severer. Indeed, unlike the BUAS+/SLART- subset,
patients in the BUAS+/SLART+ subset were positive to both SLRT and BUAS
tests. Further, it is possible that in these patients, the gabapentin
dose (300 mg tid ) was not sufficient to manage the severer
lumbar-RP condition. Indeed, recommended daily dose of gabapentin is
higher (1800-3600 mg daily) 8,9,35. Interestingly, we
found that in the BUAS+/SLART+ subset, and compared to PD-V1, the mean
of the positive PD-V2 final-scores decreased from 23.8 to 19.0 (the
lower cutoff of the negative PD outcome) in all patients, and from 18.0
to 15.9 for the uncertain outcome. These results indirectly show that
the treatment did affect the severer lumbar-RP condition but yet, it was
not clinically sufficient. Congruently, it is reasonable to speculate
that the BUAS test may diagnose the presence of potential lumbar-RP also
in the absence of positive SLRT. The presence of both signs may imply a
severer lumbar-RP condition and possibly the necessity of higher doses
of gabapentin or more invasive approach for its treatment. Indeed, in
most patients who did not achieve a negative PD-V2 outcome, gabapentin
dose was increased, or epidural steroid injections were programmed.
We used the BPI to evaluate changes in patients’ pain intensity and its
interference with quality of life, given the clinical importance of pain
as a primary patient-reported outcome in pain research14. This tool permits to follow the key
recommendations for reporting pain research outcomes given its
established content validity, reliability, and the ability to detect
MCIC. In this study, we retrieved information about MCIC from the
comparison between V2 and V1 of the BPI items’ mean score and their
absolute difference. Following literature recommendations for achieving
a prespecified MCIC in pain research 14,15, we have
established that for this study the MCIC should include statistically
significant differences of BPI mean-scores between V2 and V1 and that
such differences will be ≥2 points for each BPI item.
BPI outcomes showed, both in the sample and in the study’s subsets,
significant V2-V1 differences of the BPI-items’ mean-score, and these
differences were of ≥2 points for each of the BPI item. These results
thus fulfill the second and the third endpoints of the study.
Interestingly, although not significant, V2-V1 absolute differences of
the BPI-items’ mean-score in the BUAS+/SLART+ subset were slightly
higher than in the BUAS+/SLART- subset. In particular, in the
BUAS+/SLART+, the BPI pain items (item 1 to 5) showed absolute
differences of roughly 3 points or higher; for the QoL items the trend
of higher absolute difference was less pronounce but still present.
These results indirectly show that the treatment did affect the pain
outcomes of the severer lumbar-RP condition, and thus confirming its
presence as yielded by the BUAS test.
Finally, no significant associations were found between the PD-V2
outcomes and the independent predictors gender, age groups, and pain
sites. These findings imply that the BUAS test was not compromised by
patients’ demographic or clinical features and thus supports its
reliability and content validity. Significant associations were found
between the PD-V2 outcomes and the predictors SLRT-V1 and PD-V1,
respectively. In particular, the presence of positive SLRT at V1 was
associated with the uncertain PD-V2 outcome while its absence with the
negative PD-V2 outcome. These findings imply that, as mentioned above,
the co-presence of both signs may denote a severer lumbar-RP condition.
In such a condition, the treatment was able to shift part of the
positive PD-V1 outcome cases to the uncertain PD-V2 outcome, but not to
a negative one like it could in the absence of positive SLRT. Similarly,
positive and uncertain PD-V1 outcomes were associated, respectively,
with uncertain and negative PD-V2 outcomes. Also, the MLR analysis
confirms that for ‘negative’ SLRT-V1 cases, the risks for ‘positive’ or
‘uncertain’ PD-V2 outcomes to occur decrease versus the Reference
outcome class PD-V2 ‘negative’. Albeit, the results mentioned above
imply that in the presence of positive BUAS test, with or without
positive SLRT, the given treatment (i.e., gabapentin) did affect the
lumbar-RP condition.
Study limitations. The main limitation of the study is its observational
and retrospective nature. The study’s ecological and external validity
may be questioned as to the study design of the indirect assessment of
the BUAS-test diagnostic ability. Indeed, using the effect of gabapentin
on PD and BPI outcomes modifies the direct evaluation method. A direct
evaluation would have implied, for example, a comparison of the BUAS
test outcomes with invasive neurological tests or imaging studies whose
outcomes are not always reliable and conclusive for lumbar-RP diagnosis
and often yield ex-adiuvantibus treatments. In this study, data
were collected within a setting of routine work. The external validity
of such observational study comes from its strong relevance to practice
and the ability to highlight meaningful pain assessment solutions.