The study was investigator initiated and Pfizer donated capsules of pregabalin and placebo. The authors have no conflict of interest regarding this manuscript.
Conceived and designed the experiments: SAWB SSO AMD HvG OHGW. Performed the experiments: SAWB SSO AMD HvG OHGW. Analyzed the data: SAWB OHG. Contributed reagents/materials/analysis tools: SAWB SSO AMD JWP HvG OHGW. Wrote the paper: SAWB SSO AMD JWP HvG OHGW. Inclusion of patients, acquisition of data: SAWB SSO AMD JWP HvG OHGW.
Intense abdominal pain is the dominant feature of chronic pancreatitis. During the disease changes in central pain processing, e.g. central sensitization manifest as spreading hyperalgesia, can result from ongoing nociceptive input. The aim of the present study is to evaluate the effect of pregabalin on pain processing in chronic pancreatitis as assessed by quantitative sensory testing (QST).
This randomized, double-blind, placebo-controlled trial evaluated effects of pregabalin on pain processing. QST was used to quantify pain processing by measuring thresholds to painful electrical and pressure stimulation in six body dermatomes. Descending endogenous pain modulation was quantified using the conditioned pain modulation (CPM) paradigm to elicit a DNIC (diffuse noxious inhibitory controls) response. The main effect parameter was the change in the sum of all body pain threshold values after three weeks of study treatment versus baseline values between both treatment groups.
64 patients were analyzed. No differences in change in sum of pain thresholds were present for pregabalin vs. placebo after three weeks of treatment. For individual dermatomes, change vs. baseline pain thresholds was significantly greater in pregabalin vs. placebo patients for electric pain detection threshold in C5 (P = 0.005), electric pain tolerance threshold in C5 (P = 0.04) and L1 (P = 0.05), and pressure pain tolerance threshold in T4 (P = 0.004). No differences were observed between pregabalin and placebo regarding conditioned pain modulation.
Our study provides first evidence that pregabalin has moderate inhibitory effects on central sensitization manifest as spreading hyperalgesia in chronic pancreatitis patients. These findings suggest that QST can be of clinical use for monitoring pain treatments in the context of chronic pain.
ClinicalTrials.gov
The treatment of chronic pancreatitis patients can be a major clinical challenge.
One of the main factors contributing to this problem is the lack of evidence regarding the origin of chronic pancreatitis pain.
Medication targeting altered central pain processing, e.g. gabapentinoids such as pregabalin, has been used successfully to treat other chronic pain disorders such as post-herpetic neuralgia and neuropathic pain of central origin.
The aim of the present study is to evaluate the effect of pregabalin as adjuvant pain treatment on pain processing, measured by somatic QST, in patients with chronic pancreatitis. We hypothesized that the hyperalgesia in chronic pancreatitis patients with pain will undergo reduction under pregabalin treatment, but not under placebo treatment.
The protocol for this trial and supporting CONSORT checklist are available as supporting information; see
This study was part of an investigator initiated double blind, placebo-controlled, parallel-group study of increasing doses of pregabalin conducted in the Netherlands (department of Surgery, Radboud University Nijmegen Medical Center) and Denmark (department of Gastroenterology & Hepatology, Aalborg Hospital, Aarhus University Hospital).
For trial inclusion, patients needed to have chronic abdominal pain typical for pancreatitis (i.e. dull epigastric pain more than 3 days per week for at least 3 months) and a diagnosis of chronic pancreatitis based on the Mayo Clinic diagnostic criteria.
Clinical endpoints i.e. pain scores and side-effects of the main study are presented in more detail in the original manuscript.
A control group was recruited in Denmark for comparison with our chronic pancreatitis group to confirm the presence of spreading hyperalgesia at the baseline pre-medication measurement in the pancreatitis group. The controls were completely healthy and had no history of a medical condition that could interfere with our pain measurements.
Eligible patients at our outpatient departments were randomly assigned in a one to one ratio to receive either pregabalin or placebo. A pseudo-random code was computer generated for the randomization blocks that had a size of six. Stratification of trial participants was based on the absence or presence of diabetes mellitus to minimize unbalance in distribution of undiagnosed diabetic polyneuropathy. Patients received increasing doses of either pregabalin or matching placebo for the study period of 3 weeks. Initial dose was 75 mg pregabalin twice a day (BID). After three days this was increased to 150 mg pregabalin BID, with a further increase to 300 mg BID after one week and for the rest of the study period. An equivalent regime was followed in the placebo arm. The same oral dosing schedule was prescribed to all patients. Daily dosages were split into two equivalent doses, one administered in the morning between 7 a.m. and 10 a.m. and one in the evening between 7 p.m. and 10 p.m. In the case of unacceptable side effects experienced by patients, a single downward dose titration was allowed. Patients had to stay on that final dosage for the remaining study period. Patients were instructed to taper their study medication after three weeks of treatment, by halving their dose for seven days, and then to stop medication. Patients and those administrating study medication, assessing outcomes, and analyzing data were blinded to group assignment.
Patients considered for participation in this trial were screened for eligibility and physical fitness. A systematic physical examination including a neurological examination was performed to assess for any relevant conditions and neurological disorders. If eligible, they were randomized by their treating physician for placebo or pregabalin on their second visit, one week after their screening visit. During their second visit all patients had a baseline QST measurement, followed by another QST measurement at the end of the study period of three weeks, i.e. before they were instructed to taper their medication. During the whole study period patients were instructed not to change their daily pain medication. They were only allowed to take extra pain medication in the case of a painful exacerbation of their chronic pancreatitis.
QST took place using a standard temporal test sequence.
After initial QST training per participating subject, pressure pain thresholds were obtained for muscles overlying bone using a pressure algometer with a 1.0 cm2 probe (Somedic Sales AB, Horby, Sweden), at each of the following sites on the dominant body side: clavicle (C5 dermatome), sternum (T4 dermatome), pancreatic site (dorsal and ventral T10 dermatome), hip region (L1 dermatome) and knee (L4 dermatome) (
Quantitative sensory testing was performed on the following sites on the dominant body side (black dots): clavicle (C5 dermatome), sternum (T4 dermatome), pancreatic site (dorsal and ventral T10 dermatome), hip region (L1 dermatome) and knee (L4 dermatome).
Thresholds to electric constant current skin stimulation (Digistim; Biometer A/S, Copenhagen, Denmark; tetanic stimulation at 100 Hz, 0.2-ms square waves, self-adhesive electrodes 3 cm apart) were measured on the dominant side of the body at the same sites as for pressure pain thresholds. Two thresholds were measured: electric pain detection threshold (ePDT) and electric pain tolerance threshold (ePTT). As the primary endpoint, the sum of all the thresholds was again calculated.
The conditioned pain modulation (CPM, previously known as DNIC (diffuse noxious inhibitory control)) paradigm was performed to test the ability of the patient to generate descending inhibitory modulation.
The primary effect parameter for the study was the between group difference (change) in sum of electric or pressure pain thresholds after three weeks of study medication vs. baseline values.
A
For this mechanistic study we performed an intention to treat analysis. We performed statistical analysis using the Statistica for Windows Software Package (Release 7.0, Statsoft Inc, Tulsa, OK, USA). All baseline characteristics and measurements are given as medians with interquartile ranges. In view of the non-Gaussian data distribution purely non-parametric analysis was performed. Statistical significance was set at P≤0.05.
The sum of all dermatomes for electric and pressure pain detection and tolerance thresholds and the conditioned pain modulation results were compared between the control and the study group using Mann Whitney U testing to confirm spreading hyperalgesia and pro-nociceptive pain modulation shift in the pancreatitis patients.
We calculated differences (change) in sum of thresholds or individual thresholds between values at pre-medication baseline and after three weeks’ medication. We then compared these differences between the groups using Mann Whitney U testing. Further analysis consisted of comparison of placebo vs. pregabalin groups at pre-medication baseline and after three weeks’ treatment for the sum of thresholds, for individual thresholds, or for conditioned pain modulation values using Mann Whitney U testing.
From October 2008 to May 2010 a total of 236 patients diagnosed with chronic pancreatitis in the last five years in one of both hospitals were screened and 64 patients were randomized; the study was completed without any incident. The majority of patients not meeting inclusion criteria were free of pain, had passed away or were no longer being treated in either of the hospitals. 64 patients completed the study and were finally analyzed in the intention to treat analysis (
The majority of patients not meeting inclusion criteria had passed away, were free of pain or were no longer being treated in either of the hospitals.
Pregabalin (n = 34) | Placebo (n = 30) | |
Age (years) | 52 (46–58) | 55 (42–65) |
Males - no. (%) | 20 (59) | 19 (63) |
Etiology - no. (%) | ||
- Toxic-metabolic | 16 (47) | 17 (57) |
- Idiopathic | 11 (32) | 11 (37) |
- Genetic | 2 (6) | 0 (0) |
- Autoimmune | 1 (3) | 0 (0) |
- Recurrent and severe acute pancreatitis | 2 (6) | 1 (3) |
- Obstructive | 2 (6) | 1 (3) |
Diary pain score (visual analogue scale 0–10) | ||
- Average pain | 4 (2–6) | 3 (2–5) |
- Maximal pain | 6 (4–8) | 5 (4–7) |
Concomitant analgesics - no. (%) |
||
- None | 3 (9) | 2 (7) |
- Weak analgesics | 7 (21) | 11 (37) |
- Strong analgesics | 24 (71) | 17 (57) |
MEQ/day | 80 (10–158) | 49 (13–128) |
Duration of chronic pancreatitis (months) | 92 (55–132) | 83 (60–147) |
Diabetes mellitus - no. (%) | 10 (29) | 10 (33) |
Previous interventions for chronic pancreatitis – no. (%) | ||
- Pancreas resection/drainage procedures | 6 (18) | 5 (17) |
- Thoracoscopic splanchnic denervation | 2 (6) | 4 (13) |
Patients treated with enzymes for pancreatic exocrine insufficiency - no. (%) | 18 (53) | 13 (43) |
Ongoing alcohol abuse - no. (%) |
7 (21) | 11 (37) |
Current smoker - no. (%) | 26 (76) | 22 (77) |
All values are medians with interquartile ranges unless mentioned otherwise. Percentages may not total 100 due to rounding.
Weak analgesics were defined as NSAIDS, paracetamol, codeine and tramadol. Strong analgesics were defined as opioid based therapies.
Alcohol abusing patients were defined as female patients drinking >14 units of alcohol per week or male patients drinking >21 units of alcohol per week.
‘MEQ’ is morphine equivalents, ‘pregabalin’ is pregabalin study group and ‘placebo’ is placebo study group.
No statistical differences between groups were observed.
The sum for pressure and electric pain detection and tolerance thresholds of all dermatomes was significantly lower for the pancreatitis group at baseline vs. healthy controls (
Pancreatitis | Control | P-value | |
SUM ePDT (mA) | 28 (21–41) | 47 (21–65) | 0.026 |
SUM ePTT (mA) | 44 (34–62) | 68 (48–92) | 0.017 |
SUM pPDT (kPa) | 1912 (951–2551) | 2285 (2018–3018) | 0.008 |
SUM pPTT (kPa) | 2694 (2110–3185) | 3234 (2785–4018) | 0.005 |
CPM (%) | 4.2 (0.0–22.4 ) | 32.6 (10.4–41.8) | 0.008 |
All values are medians with interquartile ranges. ‘Control’ is healthy control group and ‘Pancreatitis’ is chronic pancreatitis group. ‘ePDT’ is electric pain detection threshold, ‘ePTT’ is electric pain tolerance threshold, ‘pPDT’ is pressure pain detection threshold, ‘pPPT’ is pressure pain tolerance threshold and ‘CPM’ is conditioned pain modulation.
The sum of all dermatomes for pressure and electric pain detection and tolerance thresholds at baseline was similar for the pregabalin vs. placebo groups (
Before | After | |||
Pregabalin | Placebo | Pregabalin | Placebo | |
SUM ePDT (mA) | 33.4 (23.6–43.5) | 23.4 (18.9–33.8) | 37.3 (27.9–51.6) • | 26.1 (17.2–39.7) |
SUM ePTT (mA) | 53.4 (39.2–67.1) | 41.7 (32.6–51.6) | 52.3 (38.9–73.9) | 44.0 (34.9–55.2) |
SUM pPDT (kPa) | 1936 (1063–2574) | 1759 (902–2449) | 1817 (1109–3312) | 1817 (844–2585) |
SUM pPTT (kPa) | 2677 (2043–3136) | 2720 (2307–3230) | 2798 (2355–3945) | 2853 (2131–3264) |
All values are medians with interquartile ranges. • = Measurements after study treatment were significantly higher in the pregabalin group compared to the placebo group.
At baseline, patients in the placebo group tolerated the cold pressor task for 32 seconds (IQR 23–98) and in the pregabalin group for 40 seconds (IQR 23–60), this was not statistically different between groups. Also no significant difference was found in baseline CPM response between the placebo and pregabalin group (
There was no significant difference in differences (change) in
Before | After | |||
Pregabalin | Placebo | Pregabalin | Placebo | |
ePDT (mA) | ||||
- C5 | 3.9 (2.5–5.1) | 3.5 (2.4–6.0) | 4.5 (3.4–5.6) | 3.1 (2.1–6.0) |
- T4 | 5.0 (3.0–7.0) | 3.5 (2.7–6.3) | 6.2 (4.2–8.5) • | 3.9 (3.3–7.6) |
- T10 | 5.8 (4.3–8.1) | 3.7 (3.0–7.7) | 6.5 (4.7–9.2) | 4.9 (3.2–7.9) |
- L1 | 4.8 (3.6–6.4) | 4.3 (3.1–5.9) | 6.6 (4.4–8.9) | 4.7 (2.7–8.4) |
- L4 | 5.7 (4.0–8.5) | 4.1 (3.2–6.5) | 5.8 (4.1–9.1) • | 4.4 (3.2–6.6) |
- T10 BACK | 5.9 (3.8–7.2) | 4.8 (3.8–6.9) | 5.8 (4.3–10.3) • | 4.3 (2.8–7.8) |
ePTT (mA) | ||||
- C5 | 6.9 (5.4–10.7) | 5.4 (4.1–9.9) | 9.6 (5.4–14.4) • | 6.3 (5.0–10.7) |
- T4 | 8.9 (5.6–13.0) | 7.6 (5.1–10.7) | 10.9 (7.5–16.2) | 8.6 (5.6–11.6) |
- T10 | 10.6 (6.1–12.7) | 7.3 (3.7–10.7) | 8.8 (6.1–15.1) | 7.9 (5.6–12.6) |
- L1 | 9.5 (6.5–13.5) | 7.2 (5.2–11.1) | 9.5 (7.0–14.8) • | 7.1 (5.8–12.9) |
- L4 | 9.9 (6.7–13.3) | 7.4 (5.1–10.0) | 9.1 (6.6–14.9) | 7.2 (5.7–10.9) |
- T10 BACK | 11.7 (6.5–16.3) | 9.3 (6.4–12.6) | 9.1 (6.6–14.9) | 8.9 (6.9–12.5) |
pPDT (kPa) | ||||
- C5 | 263 (142–334) | 232 (106–380) | 228 (130–321) | 245 (115–398) |
- T4 | 281 (195–392) | 289 (139–409) | 277 (169–421) | 268 (147–359) |
- T10 | 166 (97–302) | 154 (85–264) | 129 (65–328) | 157 (61–306) |
- L1 | 376 (207–511) | 340 (197–571) | 292 (207–566) | 424 (168–528) |
- L4 | 406 (235–601) | 396 (176–613) | 447 (177–689) | 332 (204–641) |
- T10 BACK | 378 (211–474) | 276 (162–522) | 332 (132–549) | 313 (161–480) |
pPTT (kPa) | ||||
- C5 | 421 (313–523) | 378 (309–563) | 451 (310–614) | 459 (358–599) |
- T4 | 481 (307–555) | 422 (335–528) | 431 (352–691) | 371 (284–530) |
- T10 | 246 (165–493) | 257 (176–402) | 280 (173–570) | 236 (156–432) |
- L1 | 578 (454–675) | 548 (407–706) | 551 (437–716) | 581 (479–649) |
- L4 | 608 (530–776) | 614 (437–776) | 733 (526–933) | 700 (508–866) |
- T10 BACK | 574 (403–699) | 561 (476–731) | 612 (397–838) | 537 (395–635) |
CPM response (%) | 0.9 (0.0–22.0) | 8.9 (0.0–23.8) | 0.0 (0.0–22.4) | 0.0 (−4.0–19.8) |
All values are medians with interquartile ranges. • = Measurements after study treatment were significantly higher in the pregabalin group compared to the placebo group.
Pregabalin | Placebo | |||
Change | Percentage change (%) | Change | Percentage change (%) | |
ePDT (mA) | ||||
- C5 | 0.8 (0.2–1.9) • | 24 (5–55) | −0.1 (−0.9–0.5) | 2 (−25–16) |
- T4 | 1.5 (−0.7–3.0) | 39 (−13–83) | 0.7 (−1.1–1.5) | 17 (−16–49) |
- T10 | 0.8 (−0.7–3.1) | 12 (−11–52) | 0.4 (−0.7–1.4) | 8 (−9–40) |
- L1 | 1.2 (−0.2–3.8) | 25 (−6–71) | 0.3 (−0.5–2.3) | 11 (−11–51) |
- L4 | 0.9 (−0.8–2.3) | 14 (−16–46) | 0.7 (−0.9–1.7) | 18 (−22–37) |
- T10 BACK | 0.6 (−1.2–4.3) | 16 (−22–75) | −0.6 (−1.4–1.3) | −14 (−29–14) |
ePTT (mA) | ||||
- C5 | 2.0 (−0.1–3.7) • | 25 (−1–64) | 0.7 (−2.4–1.9) | 12 (−27–40) |
- T4 | 2.6 (−0.6–5.1) | 41 (−5–60) | 1.5 (−0.9–2.9) | 15 (−12–46) |
- T10 | 1.0 (−0.8–2.4) | 10 (−10–27) | 0.8 (−1.2–2.4) | 17 (−9–53) |
- L1 | 1.9 (−0.8–4.9) • | 29 (−7–59) | −0.2 (−2.3–2.1) | −3 (−28–38) |
- L4 | 1.5 (−2.0–5.2) | 22 (−20–53) | −0.3 (−1.2–3.0) | 0 (−14–83) |
- T10 BACK | 1.1 (−1.9–4.8) | 10 (−20–57) | −0.5 (−2.8–2.7) | −5 (−21–36) |
pPDT (kPa) | ||||
- C5 | 12 (−79–89) | 7 (−39–34) | −13 (−51–50) | −7 (−19–31) |
- T4 | 9 (−91–72) | 4 (−34–26) | −3 (−89–45) | −1 (−29–13) |
- T10 | 13 (−31–77) | 6 (−31–53) | −1 (−51–26) | 0 (−24–15) |
- L1 | 63 (−137–117) | 18 (−39–53) | 12 (−99–135) | 9 (−19–40) |
- L4 | 80 (−129–176) | 18 (−30–37) | 0 (−50–88) | 0 (−13–23) |
- T10 BACK | 41 (−63–89) | 9 (−7–31) | 34 (−73–90) | 9 (−24–24) |
pPTT (kPa) | ||||
- C5 | 19 (−65–152) | 3 (−17–40) | 17 (−32–103) | 5 (−9–31) |
- T4 | 83 (−24–169) • | 18 (−7–43) | −48 (−108–43) | −13 (−21–12) |
- T10 | 10 (−56–111) | 5 (−15–53) | 20 (−103–56) | 7 (−34–23) |
- L1 | −7 (−82–136) | −1 (−16–32) | 69 (−149–144) | 16 (−19–28) |
- L4 | 17 (−253–278) | 6 (−30–53) | 75 (15–225) | 12 (3–33) |
- T10 BACK | 41 (−74–194) | 5 (−15–40) | 14 (−165–81) | 3 (−27–21) |
SUM ePDT | 6.0 (−1.2–15.0) | 19 (−6–62) | 2.3 (−1.9–5.8) | 9 (−8–19) |
SUM ePTT | 7.6 (−7.1–13.5) | 13 (−14–25) | 2.7 (−7.1–10.9) | 7 (−15–28) |
SUM pPDT | 311 (−155–526) | 16 (−9–39) | 131 (−330–329) | 11 (−14–20) |
SUM pPTT | 226 (−265–593) | 10 (−14–20) | 193 (−192–380) | 8 (−6–17) |
CPM response (%) | 1 (−4–18) | −18 (−100–134) | −2 (−23–6) | −100 (−136–16) |
All values are medians with interquartile ranges. • = Measurements after study treatment were significantly higher in the pregabalin group compared to the placebo group.
For
For
There was no significant difference in differences (change) in
There was no significant difference in differences (change) in
For
The difference (change) in cold pressor task latency and CPM response was not significantly different between the study groups (
After 3 weeks’ study medication,
For
After three weeks of study medication patients in the placebo group tolerated the cold pressor task for 42 seconds (IQR 21–116) and in the pregabalin group for 46 seconds (IQR 27–77); this was not statistically significant. Also no significant difference could be found between groups for CPM response after study medication (
Our study is the first to demonstrate that a three-week treatment with pregabalin in chronic pancreatitis patients results in a moderate antihyperalgesic effect compatible with a reduction of central sensitization. A shift toward more anti-nociceptive pain modulation appears less likely as mechanism due to the unaltered conditioned pain modulation (CPM) response. Interestingly, this early treatment effect is 1) visible only in dermatomes distant from the referred pancreatic area, and 2) more pronounced for electric skin thresholds than for pressure muscle thresholds. This implies 1) better effects on distant as compared to segmental central sensitization and 2) more effective hyperalgesia reduction in skin compared to deeper tissues. These results suggest that measuring pain sensitivity using quantitative sensory testing (QST) may prove useful in monitoring the effects of pain treatment in chronic pancreatitis and help us to diagnose and manage altered pain processing in chronic pain disorders.
Nociceptive input from the pancreas spreads via ascending pathways to spinal and supraspinal central nervous system structures in chronic pancreatitis.
The treatment of pain in chronic pancreatitis patients is usually based on the WHO pain treatment ladder, which ends with opioid treatment. Opioids can provide effective analgesia in some pancreatitis patients, but may have considerable side effects or even induce hyperalgesia.
In this study we failed to show a significant difference between groups regarding our primary outcome measure (change in sum of thresholds). The significant result regarding secondary outcome measure (change in individual dermatomal thresholds) suggests a moderate effect on spreading hyperalgesia. Interestingly, antihyperalgesic treatment with pregabalin resulted in a greater increase of electric pain thresholds than of pressure pain thresholds after three weeks treatment. A possible explanation is that pregabalin is initially more effective in reducing skin sensitization, as reflected by electric thresholds, as compared to deep tissue sensitization, as reflected by pressure thresholds.
In this study no significant improvement in conditioned pain modulation (CPM) could be found, suggesting that the main effect of pregabalin is to directly target central sensitization reflected by hyperalgesia, rather than the pro/anti-nociceptive balance of endogenous modulation. We did, however, demonstrate that before treatment, pancreatitis patients showed less inhibitory pain modulation than healthy controls in accordance with other studies.
A limitation of this study is the relatively small size of the chronic pancreatitis group. A larger sample of chronic pancreatitis patients would appear necessary to provide more detailed and significant evidence of the relation between pregabalin treatment, changes in pain scores and changes in hyperalgesia. While we did find parallel, separate reductions in pain scores and pain sensitivity in our patient collective, the study was not adequately powered to formally study – or prove – correlations between clinical pain reduction and reduction in hyperalgesia. Definitive proof of such a relationship awaits future larger and longer-lasting trials. It should be noted that most chronic pancreatitis studies are small due to the difficulties in recruiting large groups of uniform chronic pancreatitis patients. Better and larger national and international collaborations are necessary to permit larger and longer population based trials in chronic pancreatitis.
In this study an intention to treat analysis was performed conform the international standard for randomized clinical trials. It can be argued that for the mechanistic endpoints an analysis including only patients fully compliant with the study protocol should be performed (per protocol analysis). We therefore also performed a per protocol analysis, but we did not present these data in this manuscript, because there were no major differences compared to the intention to treat analysis.
Another limitation of the study is the absence of a long-term follow-up. We only measured effects after a relatively short treatment period of three weeks. At this time, modest reductions in distant skin hyperalgesia were already noticeable and significant, albeit without return to normal values (i.e. as in healthy volunteers). This reduction in hyperalgesia occurred in a patient population with a long history of chronic pancreatitis, generally regarded as being particularly difficult to manage.
In conclusion our study provides first evidence that pregabalin modestly reduces the spreading hyperalgesia as manifestation of central sensitization associated with chronic pancreatitis pain. This effect was evident after three weeks of pregabalin treatment and was most evident for electric skin pain thresholds. However more research is needed to predict the long-term effects and define effective dosage schemes for pregabalin use in different stages of chronic pancreatitis.
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