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Lidocaine patch (5%) is no more potent than placebo in treating chronic back pain when tested in a randomised double blind placebo controlled brain imaging study

Lidocaine patch (5%) is no more potent than placebo in treating chronic back pain when tested in... Background: The 5% Lidocaine patch is used for treating chronic neuropathic pain conditions such as chronic back pain (CBP), diabetic neuropathy and complex regional pain syndrome, but is effective in a variable proportion of patients. Our lab has reported that this treatment reduces CBP intensity and associated brain activations when tested in an open labelled preliminary study. Notably, effectiveness of the 5% Lidocaine patch has not been tested against placebo for treating CBP. In this study, effectiveness of the 5% Lidocaine patch was compared with placebo in 30 CBP patients in a randomised double-blind study where 15 patients received 5% Lidocaine patches and the remaining patients received placebo patches. Functional MRI was used to identify brain activity for fluctuations of spontaneous pain, at baseline and at two time points after start of treatment (6 hours and 2 weeks). Results: There was no significant difference between the treatment groups in either pain intensity, sensory and affective qualities of pain or in pain related brain activation at any time point. However, 50% patients in both the Lidocaine and placebo arms reported a greater than 50% decrease in pain suggesting a marked placebo effect. When tested against an untreated CBP group at similar time points, the patch treated subjects showed significantly greater decrease in pain compared to the untreated group (n = 15). Conclusions: These findings suggest that although the 5% Lidocaine is not better than placebo in its effectiveness for treating pain, the patch itself induces a potent placebo effect in a significant proportion of CBP patients. Keywords: Chronic pain, fmri, Clinical trial, Placebo, Lidocaine, Topical analgesic Background central analgesic effect of Lidocaine has also been sug- Multiple lines of evidence suggest that aberrant activity in gested [5,8]. sodium channels contributes to chronic pain conditions The most advocated mode of Lidocaine administration that involve neuropathy. Blocking sodium channels such is with 5% Lidocaine adhesive patches that are applied to as with systemic Lidocaine reduces evoked intensity of the affected area and act by local absorption [9,10]. The acute pain [1-5] and also relieves pain in some patient systemic absorption is minimal; hence the chances of ad- populations such as in chronic post herpetic neuralgia verse side effects are low. However, the effectiveness of [2,6,7]. The main mechanism through which Lidocaine is patches medicated with Lidocaine (5%) in reducing pain is said to act is by inhibition of ectopic discharge in sensi- less clearly understood. Some recent studies reported that tized and hyperactive cutaneous nociceptors. In addition, a 5% Lidocaine patches either have variable effects or no effects in acute pain models of pain in healthy subjects * Correspondence: a-apkarian@northwestern.edu suggesting a partial and inconsistent block of nociceptors Department of Physiology [11-13]. These findings raised important questions regard- Departments of Anesthesia, Surgery, Northwestern University, Feinberg ing the mechanisms and potential efficacy of Lidocaine School of Medicine, Chicago, Illinois, ,60611, USA Full list of author information is available at the end of the article © 2012 Hashmi et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hashmi et al. Molecular Pain 2012, 8:29 Page 2 of 10 http://www.molecularpain.com/8/1/29 patches in reducing pain and led to the speculation that There was a significant decrease in back pain magni- Lidocaine patches may be more effective in reducing tude with treatment duration (F = 7.8, p< 0.001) but 2,89 pathological pain related with an abnormally increased ex- no treatment type effect (F = 0.72, p = 0.4), and no 1,89 pression of sodium channels [14]. This assumption is significant interaction between type and duration of based on the fact that chronic pain patients with neuro- treatment (F = 0.03, p = 0.99). At baseline, the lidocaine 2,89 pathic pain conditions such as low back pain, painful dia- treated group did not show a significant difference in back betic neuropathy and complex regional pain syndrome pain magnitude from the placebo group (Figure 1A). benefit from treatment with topical Lidocaine, but even Similarly, there was no treatment type effects at the 6 in these conditions, the effects of Lidocaine on pain are hour (F = 0.18, p = 0.89) and 2 week period 1,29 variable between subjects and can range from 29% to (F = 1.06, p = 0.31). 1,29 80% of the studied cases [2,11,14-18]. Whether Lidocaine For both Lidocaine and placebo treated groups, there patches are effective in treating chronic back pain is par- was a decrease in the sensory and affective MPQ scores ticularly unclear since the purported effectiveness of the for treatment duration (Sensory: F =11.6, p< 0.0001; 2,84 treatment is derived from open labelled clinical trials affective F = 22.66, p = 0.0001), but there was no 2,84 [18-21]. fMRI studies have also shown central analgesic treatment type effect at 6 hours (sensory p> 0.5; effects of 5% Lidocaine, but again these studies were not affective p> 0.3) or at 2 weeks (sensory p> 0.1; controlled for a placebo effect [18,20,22-25]. affective p> 0.4) (Figure 1B-E). Overall, the effects of It is not known whether the 5% Lidocaine patch has a Lidocaine patch on CBP pain could not be distin- true pharmacological effect on chronic back pain or if it guished from that of placebo. Yet, we observe decreased is a potent placebo. Here we aimed to study how the 5% pain of CBP with continued treatment for both treat- Lidocaine patch compares with a placebo patch in redu- ment groups. Note that there were no harmful or unin- cing pain of CBP and to investigate brain activity that tended effects reported by subjects in either group. can differentiate between the treatments. We hypothe- sised that pain and related brain activity will diminish more in participants in the active treatment arm. In a Effects of Lidocaine vs. placebo on CBP pain related brain randomised double-blind, placebo controlled clinical activity trial, 30 CBP patients received drug or placebo treatment Average group activity map was generated for 30 CBP and underwent brain imaging to identify activity for fluc- patients to determine brain regions reflecting spontan- tuations of spontaneous pain, at baseline and at two time eous back pain. The spontaneous pain ratings corre- points (6 hours and 2 weeks) after start of treatment. lated significantly with BOLD response in the medial Moreover, we investigated inter-individual differences in prefrontal cortex, extending from the medial frontal pain responses to test whether a subset of patients is pole to the genual anterior cingulate cortex (Figure 2A, more responsive to Lidocaine treatment than placebo Table 1). To correct for task related brain activity con- treatment. founds we subtracted the visual rating activity maps from the pain rating activity maps (whole-brain paired Results t-test). The resultant map showed essentially the same Effects of Lidocaine vs. placebo on CBP pain pattern as the uncorrected map (Figure 2B) (opposite The chronic back pain intensity (peak pain in spontan- contrast was null). Furthermore, contrasting between eous pain ratings on numerical 0-100 scale and visual the Lidocaine and the placebo treated groups (un- analog 0-10 scale values) and back pain properties (sen- paired t-tests, n = 15 subjects per group) at baseline, at sory, 0-33 scale, and affective, 0-12 scale, pain qualities 6 hours, and at 2 weeks of treatment showed no sig- from MPQ) were compared between the two treatment nificant brain activity. The mean activation maps for groups at baseline, 6 hours, and 2 weeks post treatment Lidocaine treated and placebo treated groups (n = 15 using a repeated-measures two-way (drug and placebo subjects per group) at baseline again showed spontan- treatment arms by sessions) repeated-measures analysis eous pain related statistically significant activation in of variance (2-RM-ANOVA). The peak rating of spon- the medial prefrontal and the genual anterior cingulate cortices (Figure 2C & 2D). However, there was no sig- taneous pain and the VAS scores were strongly corre- nificant mean activation at 6 hrs or at 2 weeks of lated with each other (R = 0.53, p< 0.002, n = 30), and treatment in either the Lidocaine treated group, or the since the spontaneous pain was collected during fMRI placebo treated group. Overall, we observe a consistent acquisition, we designated its peak pain rating as the brain activity at baseline for spontaneous pain of CBP. pain intensity criterion for brain activity. Also note that However, as back pain magnitude decreases with treat- at baseline, there was no significant difference (p> 0.05) ment the related brain activity also decreases in both between the two groups in depression scores (BDI), anx- groups. iety scores (BAI) or neuropathic pain scores (NPS). Hashmi et al. Molecular Pain 2012, 8:29 Page 3 of 10 http://www.molecularpain.com/8/1/29 Figure 1 Pain did not differ between chronic back pain (CBP) patients treated with 5% lidocaine patches or with patches containing no active drug (placebo). A. Variation of CBP pain with treatment type and treatment duration. Treatment duration, but not type, significantly decreased CBP pain. B-E. Effect of treatment type and duration on sensory (range 0-33) and affective scores (range 0-12) obtained on the McGill pain Questionnaire (MPQ). Sensory and affective scores decreased with treatment duration for both types of treatment. Error bars represent SEMs. *p< 0.05, ** p< 0.01 differences from baseline. Inter individual differences in patch induced analgesia groups based on a median split. The median of the abso- As a next step, we tested the hypothesis that a subset of lute change in pain in all subjects was 29.4. Thus, all susceptible CBP patients benefits more from Lidocaine subjects that showed more than median change in pain treatment than the placebo treatment. For this analysis, were designated to the CBP decreasing and those less first all subjects were separated objectively into two than median pain change were assigned to the CBP Hashmi et al. Molecular Pain 2012, 8:29 Page 4 of 10 http://www.molecularpain.com/8/1/29 Figure 3 Pain for treated and observed groups, and pain when treated group was subdivided based on pain of CBP decreasing (CBPd) or persisting (CBPp) after 2 weeks. A. Pain at baseline and after 2-weeks (visual analog score, VAS, 0-10 score) in CBP patients who received no interventions or treatment instructions, CBP observed (n = 15), in contrast to the patients who participated in the clinical Figure 2 Different groupings for brain activity for spontaneous trial for an ineffective treatment, CBP (n = 30). The two treatment fluctuations of pain of CBP calculated for brain scans collected groups started at a similar intensity of back pain but only the CBP at baseline. Coordinates x = 8, y = 56, z = 20 for A-D (top row are group showed decrease in back pain after two weeks. Error treatment sagittal, middle horizontal, and bottom coronal slices; middle and bars represent SEMs. * p< 0.05. B. Back pain intensity, in CBPd and bottom rows: left side is left hemisphere). A. Whole-group average CBPp groups, as a function of treatment duration. A median split brain activity for rating spontaneous pain of CBP patients (n = 30 shows that on average the group that showed absolute pain change subjects). Brain activity was limited to medial prefrontal cortex (BA 9) more than the median had significantly lower pain at the 2 week and the genual anterior cingulate cortex (BA 32). B. Contrast time point. between activity for rating spontaneous pain of CBP and rating length of a bar varying in time (control for visual, motor, and task demands; paired t-statistic n = 30 subjects) identifies the same brain activity as in A. C and D. Brain activity was similar between placebo of subjects that showed a more than median decrease in (C) and lidocaine (D) treated groups for spontaneous pain of CBP at pain i.e. the CBP decreasing group. The mean percent baseline (n = 15 subjects per group), and closely matched whole- change in pain in the Lidocaine treated group (54.7%, group activity shown in activity and contrast maps were generated SEM = 9.81) was not significantly different (t = 0.25, using random-effects statistics with z score> 2.3 and cluster p = 0.8) from the placebo treated group (59.7% SEM = threshold p< 0.01, corrected for multiple comparisons. 10.316). Moreover, pain related brain activity was not significantly different between the placebo and Lidocaine persisting groups. Next, we investigated whether the per- treated subjects within the CBPd subset with a less strin- cent change in pain differed between Lidocaine and pla- gent fixed-effects contrast. Using the same technique, cebo treated subjects within a subset of patients. There contrasting brain activity between the Lidocaine and pla- were eight placebo and 7 Lidocaine treated CBP subjects cebo treated subjects within the CBPp group showed no that had reported a more than median (median = 29.4) significant difference between the two groups. decrease in pain after 2 weeks of treatment and the mean percent change = 61.4%, SEM = 2.04. In the remaining subjects (below the median value) there were 7 placebo Is the patch a potent placebo? and 8 Lidocaine treated subjects and the mean percent The effects of 5% Lidocaine patch were indistinguishable change in this group was 3.9%, SEM = 0.13 (Figure 3B). from the placebo patch, but one remaining question was Note that with this grouping, there was no difference in the marked reduction in pain observed in both Lidocaine pain between the groups at the 6 hour time point and placebo treated groups. A greater than 50% reduction (F = 2.7, p = 0.11). in clinical pain in a large proportion of subjects represents 1,29 Next, we compared the change in pain between the a marked effect and this analgesia could have been caused Lidocaine and placebo treated groups within the subset by a number of factors associated with the experiment. For Table 1 Patient clinical characteristics Age Duration Sex BDI BAI NPS Sensory MPQ Affective MPQ MQS Pain Mean 51.36 14.2 14 F 6.6 12.3 55.0 16.5 5.5 4.8 71.6 SD 9.08 12 16 M 4.2 8.8 15.5 7 3.6 6.1 24.1 Scale/Range years years 20 0-63 0-100 0-33 0-12 0-21 0-100 BDI, Beck Depression Inventory; BAI, Beck Anxiety Inventory; NPS, neuropathic pain scale; MPQ, McGill Pain Questionnaire; MQS, Medication Quantification Scale. Hashmi et al. Molecular Pain 2012, 8:29 Page 5 of 10 http://www.molecularpain.com/8/1/29 instance, the clinical trial setting, expectation of pain relief and complex regional pain syndrome, the drug showed from a treatment and the twice daily application of the greater benefit than placebo, but the effectiveness was patch for two weeks may have acted as a potent placebo. variable ranging from 29% to 80% of studied cases Alternatively, the reduction in pain in the CBPd group [11,16-19]. may have been due to other disease related factors such as The mode of action of topical Lidocaine is not clear due to natural fluctuations in pain intensity. Therefore, we and clearly shows inter individual variability in respon- compared back pain between the observational group siveness between patients with neuropathic pain syn- (CBP , n =15) and the treatment group (CBP observed treat- dromes and also in evoked pain responses in healthy , n = 30), at baseline and after two weeks. Within this ment subject after treatment. In one study, several patients time period, VAS rating for back pain significantly with complete loss of electric nerve function and marked decreased for the CBP but not for the CBP treatment observed subepidermal nerve-fiber plexus denervation in the per- group (2-RM-ANOVA for the two groups and visits F ipheral limb showed a response to the Lidocaine patch = 8.33, p = 0.03; post-hoc comparisons show 1. no dif- 2,43 [21]. An important implication of this study was that ference between groups at baseline, p> 0.1, 2. no differ- electric nerve function is not an essential for the ence between baseline and 2-weeks for CBP observed mechanisms of 5% Lidocaine therapeutic action. Even in group p> 0.6, 3. a significant decrease in VAS pain for healthy subjects, 5% Lidocaine was not more effective CBP group between baseline, 6.6 ± 0.07, and 2- treatment than placebo in treating experimental pain and innocu- weeks, 3.8 ± 0.09, t =4.3, p< 0.001) (Figure 3A). Note ous sensation including heat evoked pain, mechanical that between the two groups there was no difference in 1) pain and capsaicin induced pain [11-13]. These negative back pain duration (CBP 14.2 ± 0.39 years, in con- treatment findings led to the speculation that the 5% Lidocaine is trast to CBP 14.5 ± 0.5, t-test p> 0.9), 2) a border- observed too low a dose to effectively block healthy nociceptors, line difference in age (t-test, p = 0.06), 3) no difference in but may block pathological activity associated with upre- gender (Mann Whitney rank sum test, p = 0.4), and 4) no gulated sodium channels that result in neuropathic pain difference in depression (t-test, p> 0.4), attesting to the [11,14]. The Lidocaine patch has been suggested to affect close match between the treatment and observed CBP neuropathic pain by a local non selective stabilization of groups. Therefore, we conclude that the presence of the sodium channels on cutaneous afferents at or near the potential analgesic treatment within the clinical trial set- site of application [1,9]. The findings of the present study ting was critical for the decrease in back pain intensity corroborated by other studies raise some questions in observed after two weeks in the CBP group. treatment this regard and show that Lidocaine was not more effect- ive than placebo in treating chronic back pain that does have a significant contribution from neuropathic sources. Discussion The 5% Lidocaine patch is an off label treatment for Here we demonstrate that 5% Lidocaine patch reduces chronic back pain. This treatment has been increasingly the magnitude of CBP through a mechanism that cannot be distinguished from the effects of the placebo patch. advocated due to its purported effectiveness and is However, pain intensity was reduced in a significant pro- recommended over other treatments due to fewer side portion of subjects in the 5% Lidocaine and placebo trea- effects [19,28,29]. The confidence in the efficacy of the ted groups. These findings indicate that the therapeutic 5% Lidocaine patch especially for treating CBP is based effectiveness of 5% Lidocaine observed in other back mainly on open labelled trials and the role of placebo an- pain studies was due to the potent placebo properties of algesia in mediating the actions of the 5% Lidocaine the patch itself and not due to a pharmacological action patch had not been tested before. Our findings suggest of the drug. that the 5% Lidocaine patch acts as potent placebo and Placebo controlled clinical trials have shown that sys- has no detectable pharmacological effect in either pain temic or topical Lidocaine reduces severity of chronic report or in brain activity. The fact that a nearly equal post-herpetic neuropathy, neuropathic pain, and for pain number of subjects in the Lidocaine and placebo arm associated with inflammatory bowel disease [4,26,27]. reported a marked decrease in pain indicates that the This is the first placebo controlled clinical trial for 5% effects of just the patch itself irrespective of the presence Lidocaine in chronic back pain and our findings indicate of drug can produce analgesia through endogenous pain that the analgesic effects of 5% Lidocaine patch on CBP regulatory mechanisms associated with placebos [30-32]. could not be distinguished from the placebo patch. In A putative placebo mechanism in reducing pain is addition, there was a generalized decrease in sensory and reflected by the fact that only the patch treated group as affective pain qualities after treatment, but even in these a whole showed a significant reduction in pain intensity measurements, the 5% Lidocaine treated group was not when compared to a group of CBP patients that were not given any treatment. This observation explains the significantly different from the placebo group. In other positive findings we had reported in a previous report clinical conditions such as painful diabetic neuropathy Hashmi et al. Molecular Pain 2012, 8:29 Page 6 of 10 http://www.molecularpain.com/8/1/29 where in an open labelled trial, the 5% Lidocaine patch clinical use of the Lidocaine patch in CBP is warranted. was effective in reducing pain intensity on average ac- Overall, based on these findings, we conclude that the companied with related changes in pain related brain ac- 5% Lidocaine patch has no drug mediated action on in- tivation patterns after treatment [20]. However, in the tensity of CBP; however, it does reduce pain intensity in present and in the preliminary study, we observed a more than 50% of subjects that is most likely due to a marked reduction in clinical pain after treatment that placebo effect. Our findings suggest that the patch is a suggests that the patch induces a potent placebo potent agent for inducing placebo analgesia. analgesia. However, the present study also demonstrates that not Methods all subjects responded with analgesia to the patch, and Subjects the percent change in pain was negligible in half of the A sample size of 30 subjects was predetermined based on subjects. Thus, the placebo effect induced by the patches a a review of literature [4,38]. A total of 38 patients were is subject to a prominent inter-individual variability and recruited for the brain imaging and treatment study. As this extent of variability has not been observed in previ- shown in the consort flow chart shown in Figure 4, data ous placebo studies [31,33-35]. This could be because from 7 subjects was not analyzed due to failure to attend most placebo studies have studied healthy subjects and the repeat sessions for non specific reasons and data from placebo responses in clinical populations may be affected 1 subject was excluded from analysis due to technical by disease chronicity. Another prominent factor is that faults. Thus, data from a total of 30 subjects (16 males, unlike most placebo studies where a group of subjects is 14 females, age 51.36 ± 0.30 years, mean ± SEM) was conditioned to believe in the benefits of the treatment included in the brain imaging analysis. An additional 15 [36,37], here all patch treated subjects were given similar patients (10 males, 5 females, age 46.3 ± 0.38 years) were open ended instructions that the treatment may or may recruited and their pain was measured at intervals similar not reduce their pain. Thus the psychobiological to the patch treated groups. Brain imaging data was not mechanisms that lead to reduction or no reduction in collected in this group. pain would be reflective of each individuals own expecta- All subjects were right-handed and gave informed con- tions, belief in the treatment and anxiety about the treat- sent to procedures approved by the Northwestern Uni- ments potential benefits. versity Institutional Review Board. Participants were compensated financially for their time. All patients, One limitation of this study is that the number of sub- recruited by newspaper ads in Chicago area, were diag- jects is lower than what would be required for a clinical nosed with CBP by a clinician and had to fulfill a specific trial. However, corroborated by other studies, these find- list of inclusion/exclusion criteria. Patients were included ings indicate that a large sample size would result in a if they had CBP for >1 year, and a pain score> 4/10 VAS similar outcome. A calculation for the required sample at the baseline visit. Subjects were excluded if they suf- size to achieve a clinically relevant change in pain of 20 fered from co-morbidities, major psychiatric conditions % combined with the present findings required 536 sub- or other medical conditions (Table 2). Patients who jects to achieve a desired power of 0.85 (large effect size). entered the brain imaging and treatment group were Such a large number of chronic back pain subjects would given specific instructions regarding the potential pain be extremely difficult if not unachievable to recruit for relief by the patch and were also told that they had a an fMRI study. Nevertheless, additional studies are 50% chance of receiving either patches containing drug needed that test the effects of the 5% Lidocaine patch or placebo. During the 2 weeks of treatment period, they against a placebo to arrive at a solid conclusion regard- could take up to 2 regular strength acetaminophen ing the efficacy of this treatment in chronic back pain. tablets (325 mg) per day, if needed. All patients were Recently, the 5% Lidocaine patch has emerged as first asked to refrain from taking analgesic medications for line therapy and since side effects are lower than oral or 72 hours prior to the imaging session. Patients who systemic doses, its use has become popular especially in entered the observational group were not given any geriatric populations. Our findings raise some important instructions, were not administered any treatments, and considerations since even though the 5% Lidocaine had were instructed that they can manage their pain by any no direct effect; the patch itself induces analgesia that is means they deemed necessary. two to three folds higher than the accepted clinical level of 20% , but a discussion about the ethics of using place- bos that produce strong analgesic effects is beyond the Subject groups and experimental sessions for brain scope of the objectives of this study. This study brings to imaging with treatment bear “the elephant in the room” issue relating to the ever Efficacy for pain relief by 5% Lidocaine patch was tested in present placebo effect in analgesic trials. This study also a randomised, double blind, placebo controlled longitudinal raises the need for more consideration into whether the study. Of the patients recruited to this part of the study, Hashmi et al. Molecular Pain 2012, 8:29 Page 7 of 10 http://www.molecularpain.com/8/1/29 Figure 4 Consort 2012 flowchart. data from 15 CBP patients that received the patches con- Experimental tasks and fMRI data acquisition taining 5% Lidocaine and 15 age and sex matched CBP Each volunteer in this group participated in three experi- patients that received a patch containing the vehicle and no mental sessions. The first session was conducted imme- Lidocaine (placebo arm) were included in the analysis. Par- diately before start of treatment (baseline), the second ticipants were randomly selected to receive drug or pla- session was performed 6 hours after application of the cebo. The Northwestern University Clinical Unit personnel first set of patches and the third session was after 2 generated the random allocation sequence using a random weeks of using the patches. At baseline, the patients number generator, and held its key to the end of the study. filled out questionnaires related to their pain that All patients and experimenters (while delivering treat- included the McGill pain questionnaire (MPQ), neuro- ments, scanning and analyzing data) were blinded to type pathic pain scale (NPS), Beck depression inventory (BDI) of treatment. The first application of the unlabeled patch and Beck anxiety inventory (BAI). Before scanning, parti- was carried out by a clinician (blinded to type of treatment) cipants were trained on a finger-span device that was whoalsoexplained theproperuse of the patch. The patient later used for acquiring continuous ratings of the fluc- was supplied with a measured number of unlabeled patches tuations of spontaneous pain of CBP, on a numerical (identical between drug and placebo arms) and specific scale ranging from 0-100 during functional scans. This instructions were given to self administer the patch twice device was composed of a potentiometer the voltage of daily at 12 hour intervals for a period of two weeks. There which was digitized and time-stamped in reference to was no difference in the appearance of the patches that fMRI image acquisition and connected to a computer contained Lidocaine or no drug. providing visual feedback of the ratings [39,40]. In Table 2 Coordinates of brain regions activated in relation to spontaneous ratings of CBP Brain Region Z-VALUE co-ordinatesx y z P - values CBP baseline activitypain task r MPFC/gACC 5.29 12 56 22 0.001 (BA 9, 32) CBP baseline activity r MPFC/gACC 4.61 12 42 24 0.004 pain task> visual control (BA 9, 32) Lidocaine: CBP baseline activity r MPFC/gACC 3.66 16 36 20 0.004 pain task (BA 9, 32) 3.25 6 42 18 0.040 Placebo: CBP baseline activity r MPFC/gACC 3.95 12 38 18 0.0003 pain task (BA 9, 32) Hashmi et al. Molecular Pain 2012, 8:29 Page 8 of 10 http://www.molecularpain.com/8/1/29 addition to the pain-rating task, subjects were trained to (FMRIB) Expert Analysis Tool [(FEAT; [41]; http://www. perform a visual rating task [39] during which subjects fmrib.ox.ac.uk/fsl)]. The data pre processing were con- rated the changes in the length of a bar on the 0-100 nu- ducted using the FSL 4.1 [41] and MATLAB 7.9. First, merical rating scale projected on a screen. The length of the skull of brain was extracted and the first 4 volumes the bar varied over time to match the pain ratings were removed to compensate for scanner drifts. More- obtained from the subject in the preceding scan. Thus over, typical FSL preprocessing was implemented which this task serves as a control for task-related activations includes slice-time correction spatial smoothing with such as visual inputs, motor performance, magnitude es- 5mm kernel, intensity normalization, and high-pass fil- timation, attention, and anticipation. tering (150 sec). The mean BOLD signal from white mat- After training, the subjects were placed in the scanner, ter, cerebrospinal fluid, and whole brain without skull T1-weighted structural images and fMRI data were col- and the 6 motion components from motion correction, lected while subjects performed pain or visual rating and motion outlier vectors were regarded as covariates tasks In addition to the pain rating scan, a visual rating of no interest and regressed out from the BOLD signal. task scan was acquired in which the subject rated the In addition, probabilistic Independent Component Ana- length of the bar as it varied over time in conjunction lysis was then implemented in MELODIC (Multivariate with the subjects own pain ratings obtained in one of the Exploratory Linear Decomposition into Independent preceding spontaneous pain rating scans. Components) to select artefact components, using an fMRI data were acquired with a 3-T Siemens Trio automated procedure that identified and removed edge whole body scanner with echo-planar imaging (EPI) cap- components and signal dropout components. The fMRI ability using the standard radio-frequency head coil. signal was then linearly modeled on a voxel by voxel Multislice T2*-weighted echoplanar images were basis using FMRIB’s Improved Linear Model (FILM) with obtained with the following parameters: repetition time local autocorrelation correction [42,43]. (TR) = 2.5 s; echo time (TE) = 30 ms; flip angle = 90°, slice thickness = 3 mm, in-plane resolution = 64 × 64. The 36 Analysis of effects of Lidocaine vs. placebo slices covered the whole brain from the cerebellum to For this step, the experimenter was given a code that the vertex. A total of 244 volumes were acquired per separated the subjects into two groups. However, the ex- condition in all participants and the first 4 volumes were perimenter was not informed about the type of treat- discarded during the preprocessing step. A T1-weighted ment (5% Lidocaine or placebo). The chronic back pain anatomical MRI image was also acquired for each subject intensity (peak pain in spontaneous pain ratings on nu- using the following parameters: TR = 2.1 s, TE = 4.38 ms, merical scale and visual analog scale values) and back flip angle = 8°, field of view = 220 mm, slice thickness = 1 pain properties (sensory and affective pain qualities) mm, in-plane resolution = 0.86 × 0.86 mm , and number were compared between the two groups at all three scan of sagittal slices = 160. sessions using a repeated measures analysis of variance. Session 2 (6 hrs) and 3 (2 weeks) procedures were Brain function in the two groups was assessed for similar to session 1, patients filled out MPQ at all three each session for ratings of spontaneous pain and for vis- time points. Some subjects had missing values in sensory ual control ratings. Ratings were binarized relative to and affective scores (n = 3 at 6 hour and n = 2 at 2 weeks) the mean rating of spontaneous fluctuations of back scores in the MPQ and were not included in correspond- pain [39] and convolved with a canonical hemodynamic ing statistical testing. This was followed by scanning pro- response function (gamma function: lag, 6 s; SD, 3 s). cedures identical to those used at baseline. The significance of the model fit to each voxel time The CBP patients in the observational group received series was calculated, yielding statistical parametric no treatment. They filled out the McGill Pain Question- maps for each subject and condition. All group level naire at baseline and after a two-week period. They too analyses were carried out using FEAT in a random were trained on the finger span device and had fMRI effects analysis after the co-registration of individual scan at their second visit (not analyzed for the present scans to standard space [152 subject average Montreal study). For this group, change in back pain was assessed Neurological Institute (MNI) space, http://www.bic.mni. between baseline and the second visit, using the visual mcgill.ca/cgi/icbm_view/]. Average group activity map analog scale (VAS) of the MPQ questionnaire. was generated for 30 subjects to ascertain the region that corresponds significantly with spontaneous pain Image pre-processing and GLM analysis ratings. The next averaged map was generated by sub- Image analysis to reveal significant brain activity based tracting the visual activity maps from the pain activity on changes in blood oxygen level-dependent (BOLD) sig- maps with a paired t-test. Subsequently, averaged maps nal was performed on each patient’s data using Func- for each group (5% Lidocaine and placebo) were gener- tional Magnetic Resonance Imaging of the Brain ated for the three time points. Furthermore, brain Hashmi et al. Molecular Pain 2012, 8:29 Page 9 of 10 http://www.molecularpain.com/8/1/29 activation was contrasted between the Lidocaine and pla- effects of intravenous alfentanil, S(+)-ketamine, and lidocaine. Anesthesiology 2001, 95:395–402. cebo group at all three time points using a random effects 4. Seifert F, Bschorer K, De Col R, Filitz J, Peltz E, Koppert W, Maihofner C: unpaired t-test analysis. These contrasts result in Z-score Medial prefrontal cortex activity is predictive for hyperalgesia and maps of statistically significant pain-related activity across pharmacological antihyperalgesia. J Neurosci 2009, 29:6167–6175. 5. Koppert W, Ostermeier N, Sittl R, Weidner C, Schmelz M: Low-dose different conditions. To correct for multiple comparisons, lidocaine reduces secondary hyperalgesia by a central mode of action. cluster-based corrections of the Z-statistic images were Pain 2000, 85:217–224. performed. The raw Z-statistic images from the group 6. Luo Z, Yu M, Smith SD, Kritzer M, Du C, Ma Y, Volkow ND, Glass PS, Benveniste H: The effect of intravenous lidocaine on brain activation analysis were thresholded at Z-scores> 2.3. For each during non-noxious and acute noxious stimulation of the forepaw: resulting cluster of spatially connected voxels surviving a functional magnetic resonance imaging study in the rat. Anesth Analg the Z threshold, a cluster probability threshold of p< 0.05 2009, 108:334–344. 7. Tremont-Lukats IW, Challapalli V, McNicol ED, Lau J, Carr DB: Systemic was applied to the computed significance of that cluster, administration of local anesthetics to relieve neuropathic pain: a which corrects for multiple comparisons according to systematic review and meta-analysis. Anesth Analg 2005, Gaussian random field theory [44]. All imaging analyses 101:1738–1749. 8. Woolf CJ, Wiesenfeld-Hallin Z: The systemic administration of local were corrected for confounds due to age, sex and depres- anaesthetics produces a selective depression of C-afferent fibre evoked sion (BDI) scores. activity in the spinal cord. Pain 1985, 23:361–374. 9. Gammaitoni AR, Alvarez NA, Galer BS: Pharmacokinetics and safety of continuously applied lidocaine patches 5%. Am J Health Syst Pharm 2002, Interindividual differences in treatment response 59:2215–2220. To investigate inter individual differences in treatment 10. Ko JC, Maxwell LK, Abbo LA, Weil AB: Pharmacokinetics of lidocaine response we selected the 2 week period as the time point following the application of 5% lidocaine patches to cats. J Vet Pharmacol Ther 2008, 31:359–367. of interest and calculated change in pain from baseline. 11. Krumova EK, Zeller M, Westermann A, Maier C: Lidocaine patch (5%) The median change was used to regroup CBP into per- produces a selective, but incomplete block of Adelta and C fibers. Pain sistent and decreasing (CBPp and CBPd). The question- 2012, 153:273–280. 12. Lam VY, Wallace M, Schulteis G: Effects of lidocaine patch on intradermal naire data was analyzed to assess differences between the capsaicin-induced pain: a double-blind, controlled trial. J Pain 2011, two groups. 12:323–330. 13. Wehrfritz A, Namer B, Ihmsen H, Mueller C, Filitz J, Koppert W, Leffler A: Competing interests Differential effects on sensory functions and measures of epidermal The author(s) declare that they have no competing interests. nerve fiber density after application of a lidocaine patch (5%) on healthy human skin. Eur J Pain 2011, 15:907–912. Acknowledgments 14. Campbell JN: How does topical lidocaine relieve pain. Pain 2012, We thank Judy L. Paice for help in instructing participants for proper use of 153:255–256. therapy. We thank all participants in the study, and Apkarian lab personnel 15. Baron R, Mayoral V, Leijon G, Binder A, Steigerwald I, Serpell M: 5% for help in various aspects of the study and insightful discussions. The study lidocaine medicated plaster versus pregabalin in post-herpetic neuralgia was funded by Endo Pharmaceuticals and in part by National Institutes of and diabetic polyneuropathy: an open-label, non-inferiority two-stage Health R01 NS35115. Endo Pharmaceuticals provided financial aid, Lidocaine RCT study. Curr Med Res Opin 2009, 25:1663–1676. and placebo patches, but had no involvement in other aspects of the 16. Baron R, Mayoral V, Leijon G, Binder A, Steigerwald I, Serpell M: Efficacy and project. The registration number for ClinicalTrials.gov is NCT015540 and the safety of combination therapy with 5% lidocaine medicated plaster and registry name is “Brain imaging of Lidoderm for chronic back pain”. The full pregabalin in post-herpetic neuralgia and diabetic polyneuropathy. Curr trial protocol can be accessed at clinicaltrials.gov. Med Res Opin 2009, 25:1677–1687. 17. Binder A, Bruxelle J, Rogers P, Hans G, Bosl I, Baron R: Topical 5% lidocaine Author details (lignocaine) medicated plaster treatment for post-herpetic neuralgia: 1 2 3 Department of Physiology, Department of Rheumatology, Department of results of a double-blind, placebo-controlled, multinational efficacy and Anesthesia, Surgery, Northwestern University, Feinberg School of Medicine, safety trial. Clin Drug Investig 2009, 29:393–408. Chicago, Illinois, 60611, USA. 18. Argoff CE, Galer BS, Jensen MP, Oleka N, Gammaitoni AR: Effectiveness of the lidocaine patch 5% on pain qualities in three chronic pain states: Authors’ contributions assessment with the Neuropathic Pain Scale. Curr Med Res Opin 2004, 20 JAH carried out statistical analysis and drafted the manuscript. MB (Suppl 2):S21–S28. carried out part of statistical analysis. LH participated in preprocessing 19. Galer BS, Gammaitoni AR, Oleka N, Jensen MP, Argoff CE: Use of the lidocaine fmri data, MC and EP participated in collecting data. TJS participated in patch 5% in reducing intensity of various pain qualities reported by study coordination and AVA conceived the study and participated in its patients with low-back pain. Curr Med Res Opin 2004, 20(Suppl 2):S5–S12. design and coordination. All authors have read and approved the final 20. Baliki MN, Geha PY, Jabakhanji R, Harden N, Schnitzer TJ, Apkarian AV: A manuscript. preliminary fMRI study of analgesic treatment in chronic back pain and knee osteoarthritis. Mol Pain 2008, 4:47. Received: 28 February 2012 Accepted: 24 April 2012 21. Herrmann DN, Barbano RL, Hart-Gouleau S, Pennella-Vaughan J, Dworkin RH: Published: 24 April 2012 An open-label study of the lidocaine patch 5% in painful idiopathic sensory polyneuropathy. Pain Med 2005, 6:379–384. References 22. Geha PY, Baliki MN, Chialvo DR, Harden RN, Paice JA, Apkarian AV: Brain 1. Devor M, Wall PD, Catalan N: Systemic lidocaine silences ectopic neuroma activity for spontaneous pain of postherpetic neuralgia and its and DRG discharge without blocking nerve conduction. Pain 1992, modulation by lidocaine patch therapy. Pain 2007, 128:88–100. 48:261–268. 23. Galer BS, Sheldon E, Patel N, Codding C, Burch F, Gammaitoni AR: Topical 2. Attal N, Gaude V, Brasseur L, Dupuy M, Guirimand F, Parker F, Bouhassira D: lidocaine patch 5% may target a novel underlying pain mechanism in Intravenous lidocaine in central pain: a double-blind, placebo-controlled, osteoarthritis. Curr Med Res Opin 2004, 20:1455–1458. psychophysical study. Neurology 2000, 54:564–574. 24. Gimbel J, Linn R, Hale M, Nicholson B: Lidocaine patch treatment in 3. Koppert W, Dern SK, Sittl R, Albrecht S, Schuttler J, Schmelz M: A new patients with low back pain: results of an open-label, nonrandomized model of electrically evoked pain and hyperalgesia in human skin: the pilot study. 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Dworkin RH, Jensen MP, Gould E, Jones BA, Xiang Q, Galer BS, Gammaitoni AR: Treatment Satisfaction in Osteoarthritis and Chronic Low Back Pain: The Role of Pain, Physical and Emotional Functioning, Sleep, and Adverse Events. J Pain 2010, 12:416-424. 30. Benedetti F, Carlino E, Pollo A: How placebos change the patient's brain. Neuropsychopharmacology 2011, 36:339–354. 31. Wager TD, Atlas LY, Leotti LA, Rilling JK: Predicting individual differences in placebo analgesia: contributions of brain activity during anticipation and pain experience. J Neurosci 2011, 31:439–452. 32. Zubieta JK, Stohler CS: Neurobiological mechanisms of placebo responses. Ann N Y Acad Sci 2009, 1156:198–210. 33. Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK: Individual differences in reward responding explain placebo-induced expectations and effects. Neuron 2007, 55:325–336. 34. 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Friston KJ, Frith CD, Turner R, Frackowiak RS: Characterizing evoked Submit your next manuscript to BioMed Central hemodynamics with fMRI. Neuroimage 1995, 2:157–165. and take full advantage of: doi:10.1186/1744-8069-8-29 Cite this article as: Hashmi et al.: Lidocaine patch (5%) is no more • Convenient online submission potent than placebo in treating chronic back pain when tested in a • Thorough peer review randomised double blind placebo controlled brain imaging study. Molecular Pain 2012 8:29. • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molecular Pain Springer Journals

Lidocaine patch (5%) is no more potent than placebo in treating chronic back pain when tested in a randomised double blind placebo controlled brain imaging study

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Springer Journals
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Copyright © 2012 by Hashmi et al.; licensee BioMed Central Ltd.
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Medicine & Public Health; Pain Medicine; Molecular Medicine; Neurobiology; Neurosciences; Neurology
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1744-8069
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10.1186/1744-8069-8-29
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22531485
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Abstract

Background: The 5% Lidocaine patch is used for treating chronic neuropathic pain conditions such as chronic back pain (CBP), diabetic neuropathy and complex regional pain syndrome, but is effective in a variable proportion of patients. Our lab has reported that this treatment reduces CBP intensity and associated brain activations when tested in an open labelled preliminary study. Notably, effectiveness of the 5% Lidocaine patch has not been tested against placebo for treating CBP. In this study, effectiveness of the 5% Lidocaine patch was compared with placebo in 30 CBP patients in a randomised double-blind study where 15 patients received 5% Lidocaine patches and the remaining patients received placebo patches. Functional MRI was used to identify brain activity for fluctuations of spontaneous pain, at baseline and at two time points after start of treatment (6 hours and 2 weeks). Results: There was no significant difference between the treatment groups in either pain intensity, sensory and affective qualities of pain or in pain related brain activation at any time point. However, 50% patients in both the Lidocaine and placebo arms reported a greater than 50% decrease in pain suggesting a marked placebo effect. When tested against an untreated CBP group at similar time points, the patch treated subjects showed significantly greater decrease in pain compared to the untreated group (n = 15). Conclusions: These findings suggest that although the 5% Lidocaine is not better than placebo in its effectiveness for treating pain, the patch itself induces a potent placebo effect in a significant proportion of CBP patients. Keywords: Chronic pain, fmri, Clinical trial, Placebo, Lidocaine, Topical analgesic Background central analgesic effect of Lidocaine has also been sug- Multiple lines of evidence suggest that aberrant activity in gested [5,8]. sodium channels contributes to chronic pain conditions The most advocated mode of Lidocaine administration that involve neuropathy. Blocking sodium channels such is with 5% Lidocaine adhesive patches that are applied to as with systemic Lidocaine reduces evoked intensity of the affected area and act by local absorption [9,10]. The acute pain [1-5] and also relieves pain in some patient systemic absorption is minimal; hence the chances of ad- populations such as in chronic post herpetic neuralgia verse side effects are low. However, the effectiveness of [2,6,7]. The main mechanism through which Lidocaine is patches medicated with Lidocaine (5%) in reducing pain is said to act is by inhibition of ectopic discharge in sensi- less clearly understood. Some recent studies reported that tized and hyperactive cutaneous nociceptors. In addition, a 5% Lidocaine patches either have variable effects or no effects in acute pain models of pain in healthy subjects * Correspondence: a-apkarian@northwestern.edu suggesting a partial and inconsistent block of nociceptors Department of Physiology [11-13]. These findings raised important questions regard- Departments of Anesthesia, Surgery, Northwestern University, Feinberg ing the mechanisms and potential efficacy of Lidocaine School of Medicine, Chicago, Illinois, ,60611, USA Full list of author information is available at the end of the article © 2012 Hashmi et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hashmi et al. Molecular Pain 2012, 8:29 Page 2 of 10 http://www.molecularpain.com/8/1/29 patches in reducing pain and led to the speculation that There was a significant decrease in back pain magni- Lidocaine patches may be more effective in reducing tude with treatment duration (F = 7.8, p< 0.001) but 2,89 pathological pain related with an abnormally increased ex- no treatment type effect (F = 0.72, p = 0.4), and no 1,89 pression of sodium channels [14]. This assumption is significant interaction between type and duration of based on the fact that chronic pain patients with neuro- treatment (F = 0.03, p = 0.99). At baseline, the lidocaine 2,89 pathic pain conditions such as low back pain, painful dia- treated group did not show a significant difference in back betic neuropathy and complex regional pain syndrome pain magnitude from the placebo group (Figure 1A). benefit from treatment with topical Lidocaine, but even Similarly, there was no treatment type effects at the 6 in these conditions, the effects of Lidocaine on pain are hour (F = 0.18, p = 0.89) and 2 week period 1,29 variable between subjects and can range from 29% to (F = 1.06, p = 0.31). 1,29 80% of the studied cases [2,11,14-18]. Whether Lidocaine For both Lidocaine and placebo treated groups, there patches are effective in treating chronic back pain is par- was a decrease in the sensory and affective MPQ scores ticularly unclear since the purported effectiveness of the for treatment duration (Sensory: F =11.6, p< 0.0001; 2,84 treatment is derived from open labelled clinical trials affective F = 22.66, p = 0.0001), but there was no 2,84 [18-21]. fMRI studies have also shown central analgesic treatment type effect at 6 hours (sensory p> 0.5; effects of 5% Lidocaine, but again these studies were not affective p> 0.3) or at 2 weeks (sensory p> 0.1; controlled for a placebo effect [18,20,22-25]. affective p> 0.4) (Figure 1B-E). Overall, the effects of It is not known whether the 5% Lidocaine patch has a Lidocaine patch on CBP pain could not be distin- true pharmacological effect on chronic back pain or if it guished from that of placebo. Yet, we observe decreased is a potent placebo. Here we aimed to study how the 5% pain of CBP with continued treatment for both treat- Lidocaine patch compares with a placebo patch in redu- ment groups. Note that there were no harmful or unin- cing pain of CBP and to investigate brain activity that tended effects reported by subjects in either group. can differentiate between the treatments. We hypothe- sised that pain and related brain activity will diminish more in participants in the active treatment arm. In a Effects of Lidocaine vs. placebo on CBP pain related brain randomised double-blind, placebo controlled clinical activity trial, 30 CBP patients received drug or placebo treatment Average group activity map was generated for 30 CBP and underwent brain imaging to identify activity for fluc- patients to determine brain regions reflecting spontan- tuations of spontaneous pain, at baseline and at two time eous back pain. The spontaneous pain ratings corre- points (6 hours and 2 weeks) after start of treatment. lated significantly with BOLD response in the medial Moreover, we investigated inter-individual differences in prefrontal cortex, extending from the medial frontal pain responses to test whether a subset of patients is pole to the genual anterior cingulate cortex (Figure 2A, more responsive to Lidocaine treatment than placebo Table 1). To correct for task related brain activity con- treatment. founds we subtracted the visual rating activity maps from the pain rating activity maps (whole-brain paired Results t-test). The resultant map showed essentially the same Effects of Lidocaine vs. placebo on CBP pain pattern as the uncorrected map (Figure 2B) (opposite The chronic back pain intensity (peak pain in spontan- contrast was null). Furthermore, contrasting between eous pain ratings on numerical 0-100 scale and visual the Lidocaine and the placebo treated groups (un- analog 0-10 scale values) and back pain properties (sen- paired t-tests, n = 15 subjects per group) at baseline, at sory, 0-33 scale, and affective, 0-12 scale, pain qualities 6 hours, and at 2 weeks of treatment showed no sig- from MPQ) were compared between the two treatment nificant brain activity. The mean activation maps for groups at baseline, 6 hours, and 2 weeks post treatment Lidocaine treated and placebo treated groups (n = 15 using a repeated-measures two-way (drug and placebo subjects per group) at baseline again showed spontan- treatment arms by sessions) repeated-measures analysis eous pain related statistically significant activation in of variance (2-RM-ANOVA). The peak rating of spon- the medial prefrontal and the genual anterior cingulate cortices (Figure 2C & 2D). However, there was no sig- taneous pain and the VAS scores were strongly corre- nificant mean activation at 6 hrs or at 2 weeks of lated with each other (R = 0.53, p< 0.002, n = 30), and treatment in either the Lidocaine treated group, or the since the spontaneous pain was collected during fMRI placebo treated group. Overall, we observe a consistent acquisition, we designated its peak pain rating as the brain activity at baseline for spontaneous pain of CBP. pain intensity criterion for brain activity. Also note that However, as back pain magnitude decreases with treat- at baseline, there was no significant difference (p> 0.05) ment the related brain activity also decreases in both between the two groups in depression scores (BDI), anx- groups. iety scores (BAI) or neuropathic pain scores (NPS). Hashmi et al. Molecular Pain 2012, 8:29 Page 3 of 10 http://www.molecularpain.com/8/1/29 Figure 1 Pain did not differ between chronic back pain (CBP) patients treated with 5% lidocaine patches or with patches containing no active drug (placebo). A. Variation of CBP pain with treatment type and treatment duration. Treatment duration, but not type, significantly decreased CBP pain. B-E. Effect of treatment type and duration on sensory (range 0-33) and affective scores (range 0-12) obtained on the McGill pain Questionnaire (MPQ). Sensory and affective scores decreased with treatment duration for both types of treatment. Error bars represent SEMs. *p< 0.05, ** p< 0.01 differences from baseline. Inter individual differences in patch induced analgesia groups based on a median split. The median of the abso- As a next step, we tested the hypothesis that a subset of lute change in pain in all subjects was 29.4. Thus, all susceptible CBP patients benefits more from Lidocaine subjects that showed more than median change in pain treatment than the placebo treatment. For this analysis, were designated to the CBP decreasing and those less first all subjects were separated objectively into two than median pain change were assigned to the CBP Hashmi et al. Molecular Pain 2012, 8:29 Page 4 of 10 http://www.molecularpain.com/8/1/29 Figure 3 Pain for treated and observed groups, and pain when treated group was subdivided based on pain of CBP decreasing (CBPd) or persisting (CBPp) after 2 weeks. A. Pain at baseline and after 2-weeks (visual analog score, VAS, 0-10 score) in CBP patients who received no interventions or treatment instructions, CBP observed (n = 15), in contrast to the patients who participated in the clinical Figure 2 Different groupings for brain activity for spontaneous trial for an ineffective treatment, CBP (n = 30). The two treatment fluctuations of pain of CBP calculated for brain scans collected groups started at a similar intensity of back pain but only the CBP at baseline. Coordinates x = 8, y = 56, z = 20 for A-D (top row are group showed decrease in back pain after two weeks. Error treatment sagittal, middle horizontal, and bottom coronal slices; middle and bars represent SEMs. * p< 0.05. B. Back pain intensity, in CBPd and bottom rows: left side is left hemisphere). A. Whole-group average CBPp groups, as a function of treatment duration. A median split brain activity for rating spontaneous pain of CBP patients (n = 30 shows that on average the group that showed absolute pain change subjects). Brain activity was limited to medial prefrontal cortex (BA 9) more than the median had significantly lower pain at the 2 week and the genual anterior cingulate cortex (BA 32). B. Contrast time point. between activity for rating spontaneous pain of CBP and rating length of a bar varying in time (control for visual, motor, and task demands; paired t-statistic n = 30 subjects) identifies the same brain activity as in A. C and D. Brain activity was similar between placebo of subjects that showed a more than median decrease in (C) and lidocaine (D) treated groups for spontaneous pain of CBP at pain i.e. the CBP decreasing group. The mean percent baseline (n = 15 subjects per group), and closely matched whole- change in pain in the Lidocaine treated group (54.7%, group activity shown in activity and contrast maps were generated SEM = 9.81) was not significantly different (t = 0.25, using random-effects statistics with z score> 2.3 and cluster p = 0.8) from the placebo treated group (59.7% SEM = threshold p< 0.01, corrected for multiple comparisons. 10.316). Moreover, pain related brain activity was not significantly different between the placebo and Lidocaine persisting groups. Next, we investigated whether the per- treated subjects within the CBPd subset with a less strin- cent change in pain differed between Lidocaine and pla- gent fixed-effects contrast. Using the same technique, cebo treated subjects within a subset of patients. There contrasting brain activity between the Lidocaine and pla- were eight placebo and 7 Lidocaine treated CBP subjects cebo treated subjects within the CBPp group showed no that had reported a more than median (median = 29.4) significant difference between the two groups. decrease in pain after 2 weeks of treatment and the mean percent change = 61.4%, SEM = 2.04. In the remaining subjects (below the median value) there were 7 placebo Is the patch a potent placebo? and 8 Lidocaine treated subjects and the mean percent The effects of 5% Lidocaine patch were indistinguishable change in this group was 3.9%, SEM = 0.13 (Figure 3B). from the placebo patch, but one remaining question was Note that with this grouping, there was no difference in the marked reduction in pain observed in both Lidocaine pain between the groups at the 6 hour time point and placebo treated groups. A greater than 50% reduction (F = 2.7, p = 0.11). in clinical pain in a large proportion of subjects represents 1,29 Next, we compared the change in pain between the a marked effect and this analgesia could have been caused Lidocaine and placebo treated groups within the subset by a number of factors associated with the experiment. For Table 1 Patient clinical characteristics Age Duration Sex BDI BAI NPS Sensory MPQ Affective MPQ MQS Pain Mean 51.36 14.2 14 F 6.6 12.3 55.0 16.5 5.5 4.8 71.6 SD 9.08 12 16 M 4.2 8.8 15.5 7 3.6 6.1 24.1 Scale/Range years years 20 0-63 0-100 0-33 0-12 0-21 0-100 BDI, Beck Depression Inventory; BAI, Beck Anxiety Inventory; NPS, neuropathic pain scale; MPQ, McGill Pain Questionnaire; MQS, Medication Quantification Scale. Hashmi et al. Molecular Pain 2012, 8:29 Page 5 of 10 http://www.molecularpain.com/8/1/29 instance, the clinical trial setting, expectation of pain relief and complex regional pain syndrome, the drug showed from a treatment and the twice daily application of the greater benefit than placebo, but the effectiveness was patch for two weeks may have acted as a potent placebo. variable ranging from 29% to 80% of studied cases Alternatively, the reduction in pain in the CBPd group [11,16-19]. may have been due to other disease related factors such as The mode of action of topical Lidocaine is not clear due to natural fluctuations in pain intensity. Therefore, we and clearly shows inter individual variability in respon- compared back pain between the observational group siveness between patients with neuropathic pain syn- (CBP , n =15) and the treatment group (CBP observed treat- dromes and also in evoked pain responses in healthy , n = 30), at baseline and after two weeks. Within this ment subject after treatment. In one study, several patients time period, VAS rating for back pain significantly with complete loss of electric nerve function and marked decreased for the CBP but not for the CBP treatment observed subepidermal nerve-fiber plexus denervation in the per- group (2-RM-ANOVA for the two groups and visits F ipheral limb showed a response to the Lidocaine patch = 8.33, p = 0.03; post-hoc comparisons show 1. no dif- 2,43 [21]. An important implication of this study was that ference between groups at baseline, p> 0.1, 2. no differ- electric nerve function is not an essential for the ence between baseline and 2-weeks for CBP observed mechanisms of 5% Lidocaine therapeutic action. Even in group p> 0.6, 3. a significant decrease in VAS pain for healthy subjects, 5% Lidocaine was not more effective CBP group between baseline, 6.6 ± 0.07, and 2- treatment than placebo in treating experimental pain and innocu- weeks, 3.8 ± 0.09, t =4.3, p< 0.001) (Figure 3A). Note ous sensation including heat evoked pain, mechanical that between the two groups there was no difference in 1) pain and capsaicin induced pain [11-13]. These negative back pain duration (CBP 14.2 ± 0.39 years, in con- treatment findings led to the speculation that the 5% Lidocaine is trast to CBP 14.5 ± 0.5, t-test p> 0.9), 2) a border- observed too low a dose to effectively block healthy nociceptors, line difference in age (t-test, p = 0.06), 3) no difference in but may block pathological activity associated with upre- gender (Mann Whitney rank sum test, p = 0.4), and 4) no gulated sodium channels that result in neuropathic pain difference in depression (t-test, p> 0.4), attesting to the [11,14]. The Lidocaine patch has been suggested to affect close match between the treatment and observed CBP neuropathic pain by a local non selective stabilization of groups. Therefore, we conclude that the presence of the sodium channels on cutaneous afferents at or near the potential analgesic treatment within the clinical trial set- site of application [1,9]. The findings of the present study ting was critical for the decrease in back pain intensity corroborated by other studies raise some questions in observed after two weeks in the CBP group. treatment this regard and show that Lidocaine was not more effect- ive than placebo in treating chronic back pain that does have a significant contribution from neuropathic sources. Discussion The 5% Lidocaine patch is an off label treatment for Here we demonstrate that 5% Lidocaine patch reduces chronic back pain. This treatment has been increasingly the magnitude of CBP through a mechanism that cannot be distinguished from the effects of the placebo patch. advocated due to its purported effectiveness and is However, pain intensity was reduced in a significant pro- recommended over other treatments due to fewer side portion of subjects in the 5% Lidocaine and placebo trea- effects [19,28,29]. The confidence in the efficacy of the ted groups. These findings indicate that the therapeutic 5% Lidocaine patch especially for treating CBP is based effectiveness of 5% Lidocaine observed in other back mainly on open labelled trials and the role of placebo an- pain studies was due to the potent placebo properties of algesia in mediating the actions of the 5% Lidocaine the patch itself and not due to a pharmacological action patch had not been tested before. Our findings suggest of the drug. that the 5% Lidocaine patch acts as potent placebo and Placebo controlled clinical trials have shown that sys- has no detectable pharmacological effect in either pain temic or topical Lidocaine reduces severity of chronic report or in brain activity. The fact that a nearly equal post-herpetic neuropathy, neuropathic pain, and for pain number of subjects in the Lidocaine and placebo arm associated with inflammatory bowel disease [4,26,27]. reported a marked decrease in pain indicates that the This is the first placebo controlled clinical trial for 5% effects of just the patch itself irrespective of the presence Lidocaine in chronic back pain and our findings indicate of drug can produce analgesia through endogenous pain that the analgesic effects of 5% Lidocaine patch on CBP regulatory mechanisms associated with placebos [30-32]. could not be distinguished from the placebo patch. In A putative placebo mechanism in reducing pain is addition, there was a generalized decrease in sensory and reflected by the fact that only the patch treated group as affective pain qualities after treatment, but even in these a whole showed a significant reduction in pain intensity measurements, the 5% Lidocaine treated group was not when compared to a group of CBP patients that were not given any treatment. This observation explains the significantly different from the placebo group. In other positive findings we had reported in a previous report clinical conditions such as painful diabetic neuropathy Hashmi et al. Molecular Pain 2012, 8:29 Page 6 of 10 http://www.molecularpain.com/8/1/29 where in an open labelled trial, the 5% Lidocaine patch clinical use of the Lidocaine patch in CBP is warranted. was effective in reducing pain intensity on average ac- Overall, based on these findings, we conclude that the companied with related changes in pain related brain ac- 5% Lidocaine patch has no drug mediated action on in- tivation patterns after treatment [20]. However, in the tensity of CBP; however, it does reduce pain intensity in present and in the preliminary study, we observed a more than 50% of subjects that is most likely due to a marked reduction in clinical pain after treatment that placebo effect. Our findings suggest that the patch is a suggests that the patch induces a potent placebo potent agent for inducing placebo analgesia. analgesia. However, the present study also demonstrates that not Methods all subjects responded with analgesia to the patch, and Subjects the percent change in pain was negligible in half of the A sample size of 30 subjects was predetermined based on subjects. Thus, the placebo effect induced by the patches a a review of literature [4,38]. A total of 38 patients were is subject to a prominent inter-individual variability and recruited for the brain imaging and treatment study. As this extent of variability has not been observed in previ- shown in the consort flow chart shown in Figure 4, data ous placebo studies [31,33-35]. This could be because from 7 subjects was not analyzed due to failure to attend most placebo studies have studied healthy subjects and the repeat sessions for non specific reasons and data from placebo responses in clinical populations may be affected 1 subject was excluded from analysis due to technical by disease chronicity. Another prominent factor is that faults. Thus, data from a total of 30 subjects (16 males, unlike most placebo studies where a group of subjects is 14 females, age 51.36 ± 0.30 years, mean ± SEM) was conditioned to believe in the benefits of the treatment included in the brain imaging analysis. An additional 15 [36,37], here all patch treated subjects were given similar patients (10 males, 5 females, age 46.3 ± 0.38 years) were open ended instructions that the treatment may or may recruited and their pain was measured at intervals similar not reduce their pain. Thus the psychobiological to the patch treated groups. Brain imaging data was not mechanisms that lead to reduction or no reduction in collected in this group. pain would be reflective of each individuals own expecta- All subjects were right-handed and gave informed con- tions, belief in the treatment and anxiety about the treat- sent to procedures approved by the Northwestern Uni- ments potential benefits. versity Institutional Review Board. Participants were compensated financially for their time. All patients, One limitation of this study is that the number of sub- recruited by newspaper ads in Chicago area, were diag- jects is lower than what would be required for a clinical nosed with CBP by a clinician and had to fulfill a specific trial. However, corroborated by other studies, these find- list of inclusion/exclusion criteria. Patients were included ings indicate that a large sample size would result in a if they had CBP for >1 year, and a pain score> 4/10 VAS similar outcome. A calculation for the required sample at the baseline visit. Subjects were excluded if they suf- size to achieve a clinically relevant change in pain of 20 fered from co-morbidities, major psychiatric conditions % combined with the present findings required 536 sub- or other medical conditions (Table 2). Patients who jects to achieve a desired power of 0.85 (large effect size). entered the brain imaging and treatment group were Such a large number of chronic back pain subjects would given specific instructions regarding the potential pain be extremely difficult if not unachievable to recruit for relief by the patch and were also told that they had a an fMRI study. Nevertheless, additional studies are 50% chance of receiving either patches containing drug needed that test the effects of the 5% Lidocaine patch or placebo. During the 2 weeks of treatment period, they against a placebo to arrive at a solid conclusion regard- could take up to 2 regular strength acetaminophen ing the efficacy of this treatment in chronic back pain. tablets (325 mg) per day, if needed. All patients were Recently, the 5% Lidocaine patch has emerged as first asked to refrain from taking analgesic medications for line therapy and since side effects are lower than oral or 72 hours prior to the imaging session. Patients who systemic doses, its use has become popular especially in entered the observational group were not given any geriatric populations. Our findings raise some important instructions, were not administered any treatments, and considerations since even though the 5% Lidocaine had were instructed that they can manage their pain by any no direct effect; the patch itself induces analgesia that is means they deemed necessary. two to three folds higher than the accepted clinical level of 20% , but a discussion about the ethics of using place- bos that produce strong analgesic effects is beyond the Subject groups and experimental sessions for brain scope of the objectives of this study. This study brings to imaging with treatment bear “the elephant in the room” issue relating to the ever Efficacy for pain relief by 5% Lidocaine patch was tested in present placebo effect in analgesic trials. This study also a randomised, double blind, placebo controlled longitudinal raises the need for more consideration into whether the study. Of the patients recruited to this part of the study, Hashmi et al. Molecular Pain 2012, 8:29 Page 7 of 10 http://www.molecularpain.com/8/1/29 Figure 4 Consort 2012 flowchart. data from 15 CBP patients that received the patches con- Experimental tasks and fMRI data acquisition taining 5% Lidocaine and 15 age and sex matched CBP Each volunteer in this group participated in three experi- patients that received a patch containing the vehicle and no mental sessions. The first session was conducted imme- Lidocaine (placebo arm) were included in the analysis. Par- diately before start of treatment (baseline), the second ticipants were randomly selected to receive drug or pla- session was performed 6 hours after application of the cebo. The Northwestern University Clinical Unit personnel first set of patches and the third session was after 2 generated the random allocation sequence using a random weeks of using the patches. At baseline, the patients number generator, and held its key to the end of the study. filled out questionnaires related to their pain that All patients and experimenters (while delivering treat- included the McGill pain questionnaire (MPQ), neuro- ments, scanning and analyzing data) were blinded to type pathic pain scale (NPS), Beck depression inventory (BDI) of treatment. The first application of the unlabeled patch and Beck anxiety inventory (BAI). Before scanning, parti- was carried out by a clinician (blinded to type of treatment) cipants were trained on a finger-span device that was whoalsoexplained theproperuse of the patch. The patient later used for acquiring continuous ratings of the fluc- was supplied with a measured number of unlabeled patches tuations of spontaneous pain of CBP, on a numerical (identical between drug and placebo arms) and specific scale ranging from 0-100 during functional scans. This instructions were given to self administer the patch twice device was composed of a potentiometer the voltage of daily at 12 hour intervals for a period of two weeks. There which was digitized and time-stamped in reference to was no difference in the appearance of the patches that fMRI image acquisition and connected to a computer contained Lidocaine or no drug. providing visual feedback of the ratings [39,40]. In Table 2 Coordinates of brain regions activated in relation to spontaneous ratings of CBP Brain Region Z-VALUE co-ordinatesx y z P - values CBP baseline activitypain task r MPFC/gACC 5.29 12 56 22 0.001 (BA 9, 32) CBP baseline activity r MPFC/gACC 4.61 12 42 24 0.004 pain task> visual control (BA 9, 32) Lidocaine: CBP baseline activity r MPFC/gACC 3.66 16 36 20 0.004 pain task (BA 9, 32) 3.25 6 42 18 0.040 Placebo: CBP baseline activity r MPFC/gACC 3.95 12 38 18 0.0003 pain task (BA 9, 32) Hashmi et al. Molecular Pain 2012, 8:29 Page 8 of 10 http://www.molecularpain.com/8/1/29 addition to the pain-rating task, subjects were trained to (FMRIB) Expert Analysis Tool [(FEAT; [41]; http://www. perform a visual rating task [39] during which subjects fmrib.ox.ac.uk/fsl)]. The data pre processing were con- rated the changes in the length of a bar on the 0-100 nu- ducted using the FSL 4.1 [41] and MATLAB 7.9. First, merical rating scale projected on a screen. The length of the skull of brain was extracted and the first 4 volumes the bar varied over time to match the pain ratings were removed to compensate for scanner drifts. More- obtained from the subject in the preceding scan. Thus over, typical FSL preprocessing was implemented which this task serves as a control for task-related activations includes slice-time correction spatial smoothing with such as visual inputs, motor performance, magnitude es- 5mm kernel, intensity normalization, and high-pass fil- timation, attention, and anticipation. tering (150 sec). The mean BOLD signal from white mat- After training, the subjects were placed in the scanner, ter, cerebrospinal fluid, and whole brain without skull T1-weighted structural images and fMRI data were col- and the 6 motion components from motion correction, lected while subjects performed pain or visual rating and motion outlier vectors were regarded as covariates tasks In addition to the pain rating scan, a visual rating of no interest and regressed out from the BOLD signal. task scan was acquired in which the subject rated the In addition, probabilistic Independent Component Ana- length of the bar as it varied over time in conjunction lysis was then implemented in MELODIC (Multivariate with the subjects own pain ratings obtained in one of the Exploratory Linear Decomposition into Independent preceding spontaneous pain rating scans. Components) to select artefact components, using an fMRI data were acquired with a 3-T Siemens Trio automated procedure that identified and removed edge whole body scanner with echo-planar imaging (EPI) cap- components and signal dropout components. The fMRI ability using the standard radio-frequency head coil. signal was then linearly modeled on a voxel by voxel Multislice T2*-weighted echoplanar images were basis using FMRIB’s Improved Linear Model (FILM) with obtained with the following parameters: repetition time local autocorrelation correction [42,43]. (TR) = 2.5 s; echo time (TE) = 30 ms; flip angle = 90°, slice thickness = 3 mm, in-plane resolution = 64 × 64. The 36 Analysis of effects of Lidocaine vs. placebo slices covered the whole brain from the cerebellum to For this step, the experimenter was given a code that the vertex. A total of 244 volumes were acquired per separated the subjects into two groups. However, the ex- condition in all participants and the first 4 volumes were perimenter was not informed about the type of treat- discarded during the preprocessing step. A T1-weighted ment (5% Lidocaine or placebo). The chronic back pain anatomical MRI image was also acquired for each subject intensity (peak pain in spontaneous pain ratings on nu- using the following parameters: TR = 2.1 s, TE = 4.38 ms, merical scale and visual analog scale values) and back flip angle = 8°, field of view = 220 mm, slice thickness = 1 pain properties (sensory and affective pain qualities) mm, in-plane resolution = 0.86 × 0.86 mm , and number were compared between the two groups at all three scan of sagittal slices = 160. sessions using a repeated measures analysis of variance. Session 2 (6 hrs) and 3 (2 weeks) procedures were Brain function in the two groups was assessed for similar to session 1, patients filled out MPQ at all three each session for ratings of spontaneous pain and for vis- time points. Some subjects had missing values in sensory ual control ratings. Ratings were binarized relative to and affective scores (n = 3 at 6 hour and n = 2 at 2 weeks) the mean rating of spontaneous fluctuations of back scores in the MPQ and were not included in correspond- pain [39] and convolved with a canonical hemodynamic ing statistical testing. This was followed by scanning pro- response function (gamma function: lag, 6 s; SD, 3 s). cedures identical to those used at baseline. The significance of the model fit to each voxel time The CBP patients in the observational group received series was calculated, yielding statistical parametric no treatment. They filled out the McGill Pain Question- maps for each subject and condition. All group level naire at baseline and after a two-week period. They too analyses were carried out using FEAT in a random were trained on the finger span device and had fMRI effects analysis after the co-registration of individual scan at their second visit (not analyzed for the present scans to standard space [152 subject average Montreal study). For this group, change in back pain was assessed Neurological Institute (MNI) space, http://www.bic.mni. between baseline and the second visit, using the visual mcgill.ca/cgi/icbm_view/]. Average group activity map analog scale (VAS) of the MPQ questionnaire. was generated for 30 subjects to ascertain the region that corresponds significantly with spontaneous pain Image pre-processing and GLM analysis ratings. 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Wehrfritz A, Namer B, Ihmsen H, Mueller C, Filitz J, Koppert W, Leffler A: Competing interests Differential effects on sensory functions and measures of epidermal The author(s) declare that they have no competing interests. nerve fiber density after application of a lidocaine patch (5%) on healthy human skin. Eur J Pain 2011, 15:907–912. Acknowledgments 14. Campbell JN: How does topical lidocaine relieve pain. Pain 2012, We thank Judy L. Paice for help in instructing participants for proper use of 153:255–256. therapy. We thank all participants in the study, and Apkarian lab personnel 15. Baron R, Mayoral V, Leijon G, Binder A, Steigerwald I, Serpell M: 5% for help in various aspects of the study and insightful discussions. The study lidocaine medicated plaster versus pregabalin in post-herpetic neuralgia was funded by Endo Pharmaceuticals and in part by National Institutes of and diabetic polyneuropathy: an open-label, non-inferiority two-stage Health R01 NS35115. 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Friston KJ, Frith CD, Turner R, Frackowiak RS: Characterizing evoked Submit your next manuscript to BioMed Central hemodynamics with fMRI. Neuroimage 1995, 2:157–165. and take full advantage of: doi:10.1186/1744-8069-8-29 Cite this article as: Hashmi et al.: Lidocaine patch (5%) is no more • Convenient online submission potent than placebo in treating chronic back pain when tested in a • Thorough peer review randomised double blind placebo controlled brain imaging study. Molecular Pain 2012 8:29. • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit

Journal

Molecular Pain – Springer Journals

Published: Apr 24, 2012

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