First lumbar treatment of chronic mixed low back pain with high dose Capsaicin 8 % patch

Methods: This prospective stratified study included 54 chronic, mixed, LBP patients with spontaneous pain >3/10 on the NRS (0-10) and a painDETECT Questionnaire (PDQ) score >12 meaning possible or likely (>18) NeP. Pain intensity, PDQ, and quantitative sensory testing (QST) were assessed at baseline. After a one-hour capsaicin 8% treatment on the low back, follow-up was carried out regularly over three months. Response was determined at one month (≥30% pain reduction) and predictors were compared accordingly.


Introduction
Chronic low back pain (LBP) is one of the most common pain syndromes, with a reported lifetime prevalence of up to 84% [1,2]. A recent widely accepted hypothesis addresses underlying pain mechanisms in LBP to allow for individual appropriate treatment [3]. This concept is based on the fact that LBP may present as nociceptive, neuropathic, or mixed pain, the latter combining both pain types [4]. Up to half of LBP patients exhibit symptoms of neuropathic pain [5]. Prevalence estimates the neuropathic component in the range of 4-13% and indicates worse pain and lower quality of life in these patients [3,6,7].
One of the tools of identifying patients with a neuropathic pain component is the use of the painDETECT Questionnaire (PDQ), validated for neuropathic pain (NeP) in patients with back pain [3].
Despite considerable research effort, the treatment of neuropathic pain remains difficult and efficacy low [8]. A more recent therapeutic option for peripheral NeP has emerged in the form of capsaicin 8% patch (QUTENZATM). The patch is applied once, delivering a high dose of locally active capsaicin, followed by a pain relief up to 12 weeks. Capsaicin patch has been tested mostly in post herpetic neuralgia (PHN) and HIV-associated neuropathy (HIV-AN) in randomized-controlled trials (RCTs) and in large noninterventional trials of various types of NeP with consistent, positive results [9][10][11]. In a large variety of neuropathic patients of our study centers more than 40% responders were found one month after the treatment [12]. However, at date, data on lumbar capsaicin for chronic low back pain, especially mixed low back pain, is scarce. Earlier repeated applications of low -dose capsicum patch in non-specific chronic LBP patients reported positive results [13,14]. However, application methods have changed since, and no data is available on the efficacy of a single high-dose application. It is generally accepted that capsaicin is applied to the peripheral neuropathic painful area. This has also been shown recently in painful radiculopathy [15]. However, capsaicin treatment leads to a reduction of the area of secondary hyperalgesia [12], which suggests the possibility of a central effect, at least in part. Hence, capsaicin may also act via the dorsal branch of the lumbar nerve innervating the lumbar skin and a mere lumbar application may be sufficient for pain relief.
The aim of this study was to investigate the efficacy of exclusively lumbar topical capsaicin 8% patch in chronic, neuropathic and mixed, low back pain, as well as to establish possible predictors of response including quantitative sensory testing (QST) profiles.
Our hypothesis was that capsaicin is an effective treatment in chronic LBP with a neuropathic pain component determined by the mean change of spontaneous pain intensity four weeks after treatment.

Patients
Patients were screened at two hospital-based pain centers (Vienna and Klagenfurt). All patients, male or female, of at least 18 years of age, with low back pain of at least three months' duration, with a numerical pain intensity of at least 4/10 during the 24 hours prior to inclusion, a painDETECT Questionnaire score of 13 or more, without analgesics or on stable (for least 1 week prior to inclusion) pain treatment were included, unless they met any of the exclusion criteria (see Table 1). All patients gave written informed consent prior to inclusion. Demographic information was documented at baseline. First line treatment for treatment related discomfort was cooling packs, which could be applied starting 30 minutes or later after start of application.

Treatment
Patients were informed of the availability of intravenous opioids (Piritramide, Dipidolor®; Janssen Cilag, Austria) as rescue medication. If requested, a medical doctor titrated increments of 3 mg intravenously.

Assessment of Pain
Throughout the study, pain was assessed using the Numeric Rating Scale (0-10, with 0 being "no pain" and 10 being "the most intense pain imaginable"). Pain was assessed before, during and after the capsaicin patch application and at the follow-up visits after 1 day, 1 week, 2 weeks, 1 month, 2 months, and 3 months, and via telephone every 2 weeks between the first and third month.

Use of topic analgesics within 7 days prior to inclusion
Prior use of capsaicin patch Alcohol or drug abuse Pre-existing psychiatric condition Unstable arterial hypertension Acute skin diseases in relevant areas, allergy to capsaicin or any other relevant component or medication Scheduled intervention or surgery within 3 months Pregnancy Court proceedings, planned or ongoing requests for occupational disability or early retirement related to the low back pain of the subject

Quantitative Sensory Testing (QST)
The Quantitative Sensory Testing battery was carried out as already described previously (for details

Study design and data analysis
This was a prospective trial; patients were treated with a single, one-hour capsaicin 8% patch application. The primary outcome parameter was defined as reduction of spontaneous pain four weeks after treatment. For further analysis, group allocation was undertaken as follows: to discern treatment effects we defined a "clinically meaningful response" as at least 30% pain reduction on the numeric rating scale from baseline, in accordance with general practice [15,19,20]. This was done at four weeks after treatment, and patients were stratified into two groups -"responders" and "non-responders". Secondary outcome parameters were defined as number and respective percentage of treatment responders at four weeks, mean change of pain intensity from baseline after one week, eight weeks, and 12 weeks, as well as change in quality of life (SF-36, EuroQuol, and HADS (anxiety and depression)).
Baseline characteristics (pain intensity, duration of LBP, painDETECT Questionnaire score, and QST parameters) were explored for possible prediction of treatment response.
As a sub-analysis patients were also stratified according to painDETECT Questionnaire scores (≥19 meaning "likely neuropathic pain" and 13-18 meaning "possible neuropathic pain") and percentage of responders in each group was assessed.
Statistical analysis was performed using SPSS  duration of pain, NRS, or painDETECT score (see Table 2 for baseline characteristics).

PDQ
QST None of the quantitative sensory testing parameters differed between groups at baseline or four weeks after treatment (see Table 4).    which is considered a good response [15]. These response [11]. Similar results are reported by a Cochrane systematic review [21] and recent data from a non-interventional study in 1000 patients [10].

Response rate, Pain reduction and improvement of QoL
In the past, Capsaicin has been applied rarely to irradiating neuropathic back and neck pain with comparable results to mere neuropathic pain, and further investigation had been suggested [15]. Now, our results demonstrate for the first time that the topical dorsal approach is enough to reduce both lumbar and irradiating mixed low back pain and may therefore act via a common -more central than  [10,13] and underline the importance of this essential long-term outcome in patients who are not pain-free [24][25][26]. Based on the sensitized nociceptor hypothesis [29][30][31] we expected to identify predictors of response to the TRPV1 receptor agonist capsaicin.

Predictors of response
QST discerned different etiologies in neck pain syndromes, as well as altered central pain processing in patients with low back pain [32,33]. None of our quantitative sensory testing demonstrated any difference of responders at baseline. This is once again in agreement with an earlier study on neuropathic pain patients treated with capsaicin 8% patch conducted by our group, where no QST predictors could be identified [12]. In contrast to results of a recent meta-analysis [27], reporting predictive value of absence of allodynia, we could not demonstrate any difference between the groups concerning allodynia. Nevertheless, the absence of allodynia in low back pain is a normal feature.
Another explanation may be, that the so-called peripheral defunctionalization following capsaicin application [34] is not the mode of action in our patients, since , as in our previous study [12], no loss of sensory function was demonstrated in our study. This raises the question whether "neuropathic pain" in itself is a prerequisite for treatment or relevant for the outcome respectively. Further prospective studies are necessary to elucidate this question.

Limitations of the study
The median duration of pain was more than three years in our trial and might explain the moderate overall pain relief, since chronic back pain is difficult to treat and only short pain duration of 6 months increased response in neuropathic pain [10].
The authors admit that the dropout rate, especially amongst the non-responders, may limit group comparison for later time points. Application of the LOCF method for the main outcome parameter is an accepted approach in these cases, and bias towards overestimation of treatment efficacy is less likely, since data of dropped out non-responders were carried forward in the analysis. Hence, we concluded that the LOCF method was warranted, risking underestimation of a beneficial effect, but becoming more robust against errone ously reporting great efficacy. Nevertheless, it cannot be ruled out that resulting selection bias influenced assessment notably of QST parameters and predictors.
In conclusion, we demonstrate for the first time, that capsaicin patch applied to the lower back in