Impact of Endovascular Intervention on Pain and Sensory Thresholds in Nondiabetic Patients With Intermittent Claudication: A Pilot Study

The Journal of Pain, Vol 10, No 3 (March), 2009: pp 264-273 Available online at www.sciencedirect.com

Impact of Endovascular Intervention on Pain and Sensory Thresholds in Nondiabetic Patients With Intermittent Claudication: A Pilot Study Philip M. Lang,* Gesa Vock,* Gabriel M. Schober,* Sybille Kramer,* Thomas Abahji,† Alexander Crispin,‡ Dominik Irnich,* and Ulrich Hoffmann† *Interdisciplinary Pain Center, Department of Anesthesiology, University of Munich, Germany. † Department of Angiology, University of Munich, Germany. ‡ Department of Biometry, Epidemiology, and Medical Informatics, University of Munich, Germany.

Abstract: Pain and sensory neuropathy are common in patients with peripheral arterial disease. So far it is unknown to what extent pain and sensory parameters can be ameliorated by endovascular intervention used to resolve the arterial obstruction. Seventeen nondiabetic patients with intermittent claudication were investigated in the present study. The patients had to undergo percutaneous transluminal angioplasty (PTA) to improve blood flow in the affected leg. To acquire detailed information of their sensory state quantitative sensory testing (QST) was performed before and 24 hours and 3 months after PTA. QST is a standardized clinical testing procedure for the detection of sensory changes that consists of multiple tests for thermal and mechanical detection and pain thresholds as well as vibratory thresholds and stimulus response functions. An age-matched control group was investigated with an interval of 3 months. Pain during exercise decreased by 60% (examined by numerical rating scale) after endovascular intervention, whereas the ankle/brachialindex—representing the peripheral hemodynamic situation—increased by 29%. Sensory function determined by QST did not change significantly following PTA over a 3-month period. Successfully performed PTA is highly effective in reducing exercise induced pain in patients with intermittent claudication. Perspective: The study demonstrates that successfully performed PTA is a highly effective tool in reducing exercise induced pain in patients with intermittent claudication. However, the pain reduction observed cannot be verified by evaluating sensory functions using standardized quantitative sensory testing. © 2009 by the American Pain Society Key words: Chronic ischemia, ischemic pain, neuropathic pain, QST, PTA, angioplasty, stenting.

P

ain in the lower extremity is often caused by peripheral arterial disease (PAD). About 1.5% of men under 50 years of age and 5% of men over 50 have symptomatic PAD,5 the prevalence of PAD in people aged 65 years and older is 20% for men and 17% for women.4 Ischemic pain in moderate PAD (stage II) presents during exercise as intermittent claudication (CI), whereas patients with severe PAD (stage III and IV) have Received April 30, 2008; Revised August 11, 2008; Accepted September 8, 2008. Address reprint requests to Dr P.M. Lang, Interdisciplinary Pain Center, Department of Anesthesiology, University of Munich, Pettenkoferstr 8a, Munich 80336, Germany. E-mail: [email protected] 1526-5900/$36.00 © 2009 by the American Pain Society doi:10.1016/j.jpain.2008.09.001

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pain at rest accompanied by ischemic lesions. There is increasing evidence that chronic ischemic pain has a neuropathic component, mainly in patients with severe PAD.19,25 Patients with ischemic pain develop sensory neuropathy,6,17,19 these sensory deficits seem to be independent of a frequently coexisting diabetes mellitus (DM).19 Therefore, ischemic pain can be considered as a mixed nociceptive-neuropathic pain condition. It is unknown what effect on pain and sensory function can be achieved by performing percutaneous transluminal angioplasty (PTA) to resolve the arterial obstruction in patients with PAD. It has been shown that PTA is able to improve quality of life in PAD patients.16,26 Kügler and Rudolfsky demonstrated a decrease in pain intensity specifically measured with a visual analogue scale (VAS).

Lang et al

265

Some efforts have been made to improve sensory changes in diabetics. Tight blood glucose control in diabetic patients could improve thermal thresholds.1 However, the improvement of the rheology of the blood by application of pentoxifylline did not have any impact on sensory findings in diabetic patients.3 This might indicate that it is necessary to ameliorate the basic condition of the particular underlying disease. The question is whether sensory deficits in patients with PAD are reversible in response to successful PTA. If chronic ischemic pain is considered to be a mixed nociceptive-neuropathic pain condition (mainly in patients with severe PAD, but detectable already in patients with moderate PAD19), then quantitative sensory testing (QST) seems suitable to evaluate these effects. We conducted the present study to evaluate whether re-instatement of arterial perfusion alter patients subjective pain complaints and are these improvements verifiable with a standardized QST. Although DM is common in patients with PAD and it is unclear to what extent a diabetic neuropathy might mask symptoms of ischemic pain during exercise or even changes in sensory thresholds. Therefore, we recruited nondiabetic patients undergoing minimal invasive angioplasty for their intermittent claudication.

Methods Study Design The study was initiated as a pilot trial to investigate the influence of an endovascular intervention on pain and sensory thresholds in nondiabetic patients with PAD. The patients underwent QST in addition to a complete vascular work-up (see below). After initial evaluation, the patients underwent PTA. One day and 3 months after endovascular intervention vascular examinations as well as QST were repeated. Control patients underwent 2 QST sessions with an interval of 3 months. Fig 1A illustrates the work-up of the 2 groups investigated.

Patients and Control Patients Seventeen patients with moderate PAD (Fontaine stage II) and claudication but without DM and 12 healthy age-matched control patients participated in this study (for characteristics see Table 1). Control patients were included if they had no signs of PAD (no claudication and normal ABI), no DM, and not more than 2 risk factors for PAD (arterial hypertension, hypercholesterolemia, smoking, and age over 65). All subjects participated voluntarily and gave written informed consent. The study was carried out according to the Helsinki Declaration, and was approved by the local Ethics Committee. Exclusion criteria were known or suspected neurological disease, chronic substance abuse, any pain medication and any surgical intervention on the leg investigated.

Figure 1. A, Study design. Patients with intermittent claudication entering the investigation received quantitative sensory testing (QST) and an assessment by the department of angiology. 24 hours after percutaneous transluminal angioplasty (PTA), a second QST was performed. After 3 months, a follow-up was done including QST and examination of the hemodynamic situation (angio assessment). Control patients were included in the study if a peripheral arterial disease was ruled out. QST was performed 2 times with an interval of 3 months. B, Hemodynamic state. The ankle-brachial-index (ABI) indicating the hemodynamic situation of the affected leg. Systolic pressures of the upper arm and the ankle were recorded by Doppler sonography. Patients with intermittent claudication demonstrated an increased ABI 3 months after PTA, reflecting improved hemodynamics. Data are presented as mean ⫾ SEM. (**P ⬍ .01). C, Pain rating at the maximal walking distance. Pain ratings were performed by using a numerical rating scale (NRS, 0 to 10). Patients with intermittent claudication were asked immediately after stopping the treadmill testing. Please note that exercise induced pain was significantly reduced 3 months after PTA. Data are presented as mean ⫾ SEM. (***P ⬍ .001).

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QST to Evaluate Pain Reduction After PTA

General Characteristics, Risk Factors, and Clinical Examination of the Subjects in the Control Group (CG) and the Patients With Claudication (CI)

Table 1.

Number of subjects (n) Age (year) mean ⫾ SEM Sex male (n) female (n) Risk factors Smoker Never (n) Ex-Smoker (n) Smoker (n) Arterial hypertension Yes/No (n) Hypercholesterinemia Yes/No (n) Family history of PAD Yes/No (n) History of cardiovascular disease Yes/No (n) History of cerebrovascular disease Yes/No (n) Clinical examination Ankle/Brachial-Index Treadmill (meters) initial claudication distance absolute walking distance Pain at absolute walking distance (numerical rating scale (NRS): 1-10)

CG

CI

12

17

61.5 ⫾ 1.9

62.1 ⫾ 3.1

9 3

14 3

8 2 2

1 7 9

1/11

12/5

3/9

13/4

1/10

3/8

0/12

5/11

2/9

1/11

1.22 ⫾ 0.05

0.69 ⫾ 0.05

— — 0

50 ⫾ 11 120 ⫾ 18 5,8 ⫾ 0.4

Data are number (n) per group respectively mean ⫾ SEM.

Diagnosis and Evaluation of Peripheral Arterial Disease All patients had a full clinical work-up, including a comprehensive history, physical examination, ABI measurement, pulse volume recordings, standardized treadmill exercise test (inclination of 12% and a speed of 3.2 km/h) and a duplex-ultrasound study. Angiography was performed before or at the time of intervention.

Quantitative Sensory Testing A comprehensive quantitative sensory testing (QST) protocol has been developed by the German Research Network on Neuropathic Pain (DFNS) to improve the diagnostic value of QST and to provide a broad basis of reproducible results.24 QST was performed under identical conditions for each subject, including standardized instructions. All subjects were tested in a comfortable position in a quiet room. Subjects were not permitted access to the QST computer screen and were not given visual or auditory cues to indicate the start of the stimulus. The dorsolateral skin of the foot (sensory region of the sural nerve: S1) on the side where the PTA was to be performed was tested first, followed by the skin of the

maxillary part of the face, innervated by the maxillary nerve (V2, only baseline measurement). Control subjects were tested on both sides of the body in an alternating sequence balanced across subjects. The QST procedure started with the determination of thermal followed by mechanical thresholds. The detailed QST protocol including reference data is reported elsewhere.24 In brief the following testing procedures were performed: Thermal Testing. Thermal tests were conducted by means of a Peltier-based computerized thermal stimulator (TSA II; Medoc Inc; Ramat Ishai, Israel), with a 3 ⫻ 3 cm contact probe. All thresholds were measured using ramped stimuli (1°C/s) until the subject pressed a stop button. Cut-off temperatures were 0°C and 50°C. First, cold and warm detection thresholds (CDT, WDT) were assessed. Then subjects were asked about the numbers of paradoxical heat sensations (PHS) during the thermal sensory limen procedure (TSL) of alternating warm and cold stimuli. Afterward, cold and heat pain thresholds (CPT, HPT) were investigated. Mechanical Testing. Mechanical detection thresholds (MDT) were measured with a set of von Frey filaments forming a geometric series, incrementing by a factor of 2 from 0.25 mN to 512 mN (Marstock-nervtest Ltd; Marburg, Germany). Using the method of limits, 5 ascending and 5 descending series of stimuli were applied (1-second duration per stimulus). Mechanical pain thresholds (MPT) were measured in a similar manner to the former test using punctate mechanical stimulators (blunt pinpricks) the intensity of which followed a geometric series, incrementing by a factor of 2 from 8 mN to 512 mN (Department of Physiology and Pathophysiology, University of Mainz, Germany). The pinpricks had a sharp noninjuring tip with a diameter of 0.2 mm.33 This time the subjects were asked to report whether they felt a prick or a blunt touch. In a separate test, a stimulus-response function for the mechanical pain sensitivity (MPS) was determined using the same pinpricks described above which activate A␦nociceptors.10,28,33 Pain in response to stroking light touch (dynamic mechanical allodynia; DMA) was tested by light stroking with a wisp of cotton (3 mN), a cotton wool tip fixed to an elastic strip (100 mN) and a brush (200 to 400 mN). Each of the 7 intensities of pinpricks and 3 intensities of light stroking was applied 5 times in a randomized sequence. The patients were asked to rate pain on a numerical rating scale (NRS; 0 ⫽ no pain, 100 ⫽ maximal imaginable pain). The mechanical pain sensitivity was calculated as the geometric mean of all pain ratings for pinprick stimuli. Dynamic mechanical allodynia was quantified as the geometric mean of all numerical pain ratings after light touch stimuli. The wind-up ratio (WUR) was examined using 10 repetitive pinprick stimuli (1 Hz) compared with a single pinprick stimulus. A pinprick with a force of 256 mN was used for testing over the foot. A force of 128 mN was chosen for the face due to the approximately 2-fold higher sensitivity of the face for this type of stimulus in comparison to the foot. Wind-up ratio was calculated as

Lang et al the mean pain rating of a series of 5 repetitive pinprick stimuli divided by the mean pain rating of 5 single stimuli. Vibration detection thresholds (VDT) were examined with a Rydel-Seiffer tuning fork (64 Hz) that has a graded readout of vibration amplitude (from 0 to 8). Vibration detection threshold was assessed with 3 series of descending stimulus intensities. Pressure pain thresholds (PPT) were measured using a pressure algometer (FDK20, Wagner Instruments; Greenwich, CT) with a range between 2 and 20 kg. The algometer had a rubber tip with a contact area of 1 cm2. The algometer was pressed to the skin with an increasing ramp of 0.5 kg/s and the patient was asked to respond verbally as soon as the pressure became painful.

Percutaneous Transluminal Angioplasty Catheter interventions in all patients were performed via an ipsilateral approach. After local anesthesia, an introducing sheath (5F or 6F) was inserted into the femoral artery in the antegrade direction using the Seldinger technique and a bolus of heparin (5000 IU) was given intra-arterially. Under fluoroscopic control, the lesion was crossed by use of a steerable guide wire. Before stent implantation dilatation of the superficial femoral artery lesion with a double-lumen balloon catheter was performed. If appropriate, catheter thrombectomy and/or thrombolysis by infiltrating urokinase into the occlusion were performed. The techniques have been described previously in detail.2 Stent implantation was performed if technically required. The technical result of the procedure was assessed by completion arteriography immediately after the intervention. Percutaneous transluminal angioplasty (PTA) was considered successful if the ABI improved by at least 0.15 and/or the absolute treadmill distance was doubled for the period of time investigated (3 months).

Data Analysis Primary outcome parameter was the subjective pain rating (NRS) of the patients investigated. Secondary, in order to verify these ratings sensory function was analyzed by using QST. Besides the numbers of the paradoxical heat sensations, cold and heat pain thresholds, and vibration detection thresholds all other QST data were log10 transformed because these data are log-normally distributed.24 All continuous variables were expressed as raw and log data and are given as the mean ⫾ SEM. Statistical inferences were based on mixed linear models for each QST parameter as dependent variable using the MIXED procedure of SAS 9.1 (SAS Institute; Cary, NC). The model included a random intercept for each participant and the fixed effects of time (baseline, 24 hours after PTA (only CI) and 3 months after PTA, respectively 3 months after baseline (for the control group, CG), group (CI ⫽ patients with intermittent claudication; CG), interaction of time and group, age (entered numerically), and sex. The Wilcoxon test for paired measurements was used to test for differences between baseline and 3 months

267 after PTA (ABI, pain score). Due to the exploratory nature of our analyses, no alpha adjustment for multiple testing was undertaken. Raw P values ⬍.05 were regarded as statistically significant. Therefore, the test results must not be taken as absolutely confirmatory. Data from the control group were used to normalize the test results of the individual patient by calculating the Z-transform: Z ⫽ (valuepatient ⫺ meancontrols)/ SDcontrols. This procedure will result in a QST profile where all parameters are presented as standard normal distributions (zero mean, unit variance). Z values above zero indicate a gain of function meaning that the patient is more sensitive to the test stimulus compared with control patients, whereas Z scores below zero indicate a loss of function referring to a diminished sensitivity of the patient. Results of the Z-transformation are illustrated in Fig 2.

Results Patients and Control Subjects Patients with intermittent claudication rated their pain during exercise at absolute walking distance with an average value of 5.8 on a numerical rating scale (NRS) from 0 to 10 (0 indicating no pain, 10 indicating worst imaginable pain). All 17 patients had severe claudication with significant arterial stenosis or occlusions located at the femoropopliteal level and were scheduled for endovascular intervention. The claudication reduced the maximal walking distance to a mean of 120 meters. The gender distribution in the patient and the control group are not equal, but similar. General characteristics, risk factors, and the results of the clinical examination of the subjects investigated are presented in Table 1. Endovascular intervention resulted in an improvement of the hemodynamic situation (improvement of ABI ⱖ0.15 and/or doubled treadmill distance) in 13 of the 17 patients investigated.

Ankle/Brachial Index Three months after PTA, an overall increase in ankle/ brachial index (ABI) of 28.8% could be observed (Fig 1B; P ⫽ .001) in all patients who underwent PTA. The 13 successfully treated patients showed an increase in ABI of 35.1% (0.70 ⫾ 0.05 to 0.94 ⫾ 0.04). Not surprisingly, the ABI remained almost unchanged (0.66 ⫾ 0.08 (mean ⫾ SEM, ⫹1.5% compared with baseline) in the 4 patients who revisited without hemodynamic improvement 3 months after endovascular intervention. The absolute walking distance was more than doubled in all patients 3 months after PTA (⫹123%; 120 ⫾ 18 to 267 ⫾ 86 m; NS).

Pain Fig 1C illustrates that in patients undergoing endovascular intervention exercise induced pain decreased by 60.2% [NRS 5.8 (⫾0.4) to 2.3 (⫾0.7) (mean ⫾ SEM.) P ⬍ .001] over the 3 months period between baseline and

268

Figure 2. Sensory profile at baseline and 3 months after endovascular intervention. A, The Z score profiles of patients with PAD before and 3 months after PTA are shown for all tested QST parameters (besides PHS and DMA, see B) over the affected leg. B, Numbers of paradoxical heat sensations (PHS) and pain rating of dynamic mechanical allodynia (DMA) are given as retransformed raw data. The sensory profile of the affected leg at baseline (unfilled circle) shows a loss of sensory function in terms of cold hypoesthesia (CDT), an increased number of paradoxical heat sensations (PHS), presence of dynamic mechanical allodynia (DMA), an increased wind-up phenomenon (WUR), and vibratory hypoesthesia (VDT). The sensory profile 3 months after PTA (filled circles) demonstrates some changes: reduction of CDT, reduced number of paradoxical heat sensations (PHS) as well as ratings of DMA, and a normalized WUR. However, no significant differences could be observed comparing the 2 time points of the patients for any QST parameter. Please note, the loss of function of mechanical detection threshold (MDT) is due to 1 outlier. Z score: numbers of standard deviations between patient data and group-specific mean values of the control subjects. Displayed data represent mean Z scores ⫾SEM.

follow-up testing. In patients (n ⫽ 13) who underwent successful intervention the pain decreased from 5.5 (⫾1.4) to 1.2 (⫾2.1), which represents a 78.9% reduction. The pain rating in the 4 patients undergoing PTA that was not hemodynamically successful did not change substantially [⫺11.1%; NRS 6.7 (⫾0.2) to 6.0 (⫾1.8)].

Quantitative Sensory Testing Data obtained from quantitative sensory testing (QST) are presented in Table 2. The Z profile illustrated in Fig 2 showed a “gain of function” for most of the sensory parameter investigated. Thresholds for thermal and mechanical detection and pain thresholds were shifted upward on the Z score (meaning less loss of function or increased gain of function). A gain of function could be shown for thermal detection thresholds—mainly for cold stimuli (CDT) and accordingly the thermal sensory limen (TSL). Both thermal pain thresholds (CPT and HPT) were more sensitive 3 months following endovascular intervention. Fig 2B illustrates the results obtained for paradoxical heat sensations (PHS) during the TSL procedure of alternating warm and cold stimuli. A patient report of heat during cold stimulation was considered as PHS. In patients with intermittent claudication following PTA, the PHS were reduced. For dynamic mechanical allodynia

QST to Evaluate Pain Reduction After PTA (DMA) a similar result could be observed: Brush-evoked allodynia demonstrated a decrease 3 months after endovascular intervention in patients with intermittent claudication (Fig 2B). DMA was almost undetectable in the CG. The wind-up ratio (WUR) determined after 5 series of pinprick stimuli was diminished 3 months after PTA compared with a normalized Z score. The Z score of the mechanical detection threshold (MDT) demonstrates a loss of function. However, this is due to 1 outlier. Vibratory detection thresholds (VDT) as well as the mechanical pain thresholds (MPT) tested with pinpricks were not changed much by endovascular intervention. Pressure pain threshold (PPT) and the mechanical pain sensitivity (MPS) demonstrate some increase in sensitivity following PTA (gain of function). Statistical analysis could not show any difference after PTA, neither in the treated group alone or in comparison to the control group. The only significant result was obtained for the difference in pressure pain threshold (PPT) between PAD patients and control patients. This difference was present at baseline and 3 months after PTA (P ⬍ .001 for both time points). The result of the statistical analysis is presented in Table 3. Therefore, there is no hard evidence for PTA-induced changes in sensory function determined by QST. Due to the clear changes observed in Fig 2, a post hoc power analysis (80%) was performed for the number of paradoxical heat sensations (PHS), pain rating of dynamic mechanical allodynia (DMA), and wind-up (WUR) to estimate the number of patients that would be necessary to obtain statistical significant results: PHS ⫽ 35, ALL ⫽ 170, and WUR ⫽ 30. In order to address the fact that 4 of 17 patients undergoing endovascular intervention had no improvement of their hemodynamic situation, we present the results of the QST grouped according to patients with and without hemodynamic benefit in Table 4. The relative changes (%) are displayed in Fig 3. Interestingly the most prominent changes observed in the Z score (PHS, DMA, and WUR) were similar in both treated subgroups (with and without hemodynamic benefit). Most strikingly, differences were obtained for detection and pain thresholds for cold stimuli (CDT, CPT). Hemodynamic improvement was associated with a gain of function; indicating that a smaller drop in temperatures is needed to evoke the perception of cold sensation and cold pain. The mechanical pain threshold (MPT) decreased in patients without hemodynamic benefit, suggesting mechanical stimuli of lower intensity cause pain. The vibration detection thresholds (VDT) remain unchanged after successful endovascular intervention, VDT declined further in patients without hemodynamic benefit.

Discussion Investigating the impact of endovascular intervention on pain and sensory thresholds the study demonstrated a remarkable decrease of exercise-induced pain in nondi-

CG

BASELINE Thermal thresholds Cold detection threshold CDT (°C from baseline 32°C) Warm detection threshold WDT (°C from baseline 32°C) Thermal sensory limen TSL (°C) Paradox heat sensation PHS (x/3) Cold pain threshold CPT (°C) Heat pain threshold HPT (°C) Mechanical thresholds Mechanical detection threshold MDT (mN) Mechanical pain threshold MPT (mN) Mechanical pain sensitivity MPS Dynamic mechanical allodynia DMA Wind-up

LOG

3 MONTHS LATER

5.6

affected leg

5.6

0.68 ⫾ 0.8

face

2.0

0.22 ⫾ 0.09

affected leg

9.7

0.96 ⫾ 0.05

face

2.9

0.31 ⫾ 0.14

affected leg face affected leg face affected leg face affected leg face

16.9 3.7 1.0 ⫾ 0.3 0.1 ⫾ 0.1 11.4 ⫾ 2.9 13.7 ⫾ 3.9 46.6 ⫾ 0.8 43.6 ⫾ 1.6

1.18 ⫾ 0.06 0.48 ⫾ 0.09

8.4

16.6

CI

LOG

⌬

0.62 ⫾ 0.11

0.85 ⫾ 0.10 ⫺13.4%

1.18 ⫾ 0.06

1.0 ⫾ 0.4 9.5 ⫾ 2.4 47.2 ⫾ 0.5

BASELINE

LOG

9.8

0.89 ⫾ 0.07

⫺2.5

0.27 ⫾ 0.08

10.0

0.96 ⫾ 0.05

3.4

0.42 ⫾ 0.07

⫺1.7%

21.7 4.8 1.5 ⫾ 0.3 0.0 ⫾ 0.0 ⫺8.4% 9.3 ⫾ 2.3 19.7 ⫾ 2.3 ⫹3.9% 46.1 ⫾ 0.7 40.6 ⫾ 1.0

1.22 ⫾ 0.09 0.52 ⫾ 0.09

24 HOURS LATER

LOG

3 MONTHS LATER

LOG

⌬

8.5

0.82 ⫾ 0.08

7.4

0.73 ⫾ 0.09 ⫺24.5%

9.0

0.92 ⫾ 0.04

8.4

0.88 ⫾ 0.05 ⫺16.7%

19.2

1.22 ⫾ 0.06

17.2

1.14 ⫾ 0.08 ⫺20.7%

1.1 ⫾ 0.3

0.8 ⫾ 0.2

⫺46.7%

12.2 ⫾ 2.0

12.0 ⫾ 2.6

⫹13.5%

45.6 ⫾ 0.8

45.6 ⫾ 0.7

⫺3.5%

affected leg

9.3

0.83 ⫾ 0.10

12.2

0.97 ⫾ 0.09 ⫹31.2%

42.6

1.15 ⫾ 0.14

58.4

0.95 ⫾ 0.18

53.4

0.97 ⫾ 0.17 ⫹25.3%

face affected leg

0.2 122.5

⫺0.67 ⫾ 0.03 1.84 ⫾ 0.14

141.8

1.93 ⫾ 0.13 ⫹15.8%

0.3 92.9

⫺0.59 ⫾ 0.06 1.54 ⫾ 0.15

100.5

1.50 ⫾ 0.16

66.3

1.44 ⫾ 0.13 ⫺28.6%

face affected leg

63.1 2.1

1.68 ⫾ 0.11 0.26 ⫾ 0.09

1.4

0.09 ⫾ 0.09 ⫺33.3%

22.5 4.0

1.11 ⫾ 0.10 0.31 ⫾ 0.13

4.5

0.49 ⫾ 0.10

3.6

0.32 ⫾ 0.12 ⫺10%

face affected leg

4.0 0.0

0.47 ⫾ 0.11 ⫺1.00 ⫾ 0.00

5.3 0.7

0.58 ⫾ 0.09 ⫺0.72 ⫾ 0.15

0.7

⫺0.73 ⫾ 0.15

0.1

⫺0.87 ⫾ 0.07 ⫺85.7%

2.8

0.37 ⫾ 0.06

2.2

0.30 ⫾ 0.05 ⫺24.1%

face affected leg face affected leg

Vibration detection threshold VDT (x/8) face Pressure pain threshold affected leg PPT (Pa) face

0.0 ⫺1.00 ⫾ 0.00 1.8 0.23 ⫾ 0.03 2.5 0.33 ⫾ 0.07 6.7 ⫾ 0.2 7.0 ⫾ 0.2 517 272

⫺1.00 ⫾ 0.00

2.5

0.34 ⫾ 0.07 ⫹38.9%

6.6

⫺1.5%

547

2.71 ⫾ 0.05

⫹5.8%

0.1 ⫺0.91 ⫾ 0.06 2.9 0.42 ⫾ 0.05 2.8 0.37 ⫾ 0.06 5.5 ⫾ 0.5 6.9 ⫾ 0.3 401 158

2.57 ⫾ 0.05 2.15 ⫾ 0.06

5.7 ⫾ 0.6

385

5.1 ⫾ 0.6

2.56 ⫾ 0.04

⌬: Changes in % from baseline to 3 months later (for HPT and CPT the difference from baseline was used). log data are presented for all QST parameters besides PHS, CPT, HPT and VDT.

338

⫺7.7%

2.50 ⫾ 0.04 ⫺15.7%

269

2.68 ⫾ 0.05 2.41 ⫾ 0.04

0.01

Lang et al

Quantitative Sensoric Testing (QST) of the Subjects in the Control Group (CG) and the Patients With Claudication (CI). Data are Presented as Raw and Log Data (Mean ⴞ SEM)

Table 2.

270

QST to Evaluate Pain Reduction After PTA

Statistical Analysis: P Values From the Type III Analyses of Effects From the Random Intercept Models. The Results are Adjusted for Age and Sex Table 3.

Temperature tests Cold detection threshold CDT Warm detection threshold WDT Thermal sensory limen TSL Paradoxical heat sensation PHS Cold pain threshold CPT Heat pain threshold HPT Mechanical tests Mechanical detection threshold MDT Mechanical pain threshold MPT Mechanical pain sensitivity MPS Allodynia ALL Wind-up WUR Vibration detection threshold VDT Pressure pain threshold PPT

TIME

GROUP

INTERACTION TIME BY GROUP

0.5124

0.1817

0.2155

0.1870

0.9771

0.9951

0.3732

0.5337

0.2191

0.4235

0.8566

0.1963

0.8999

0.8299

0.3974

0.9197

0.1767

0.6767

0.4923

0.4041

0.6887

0.4989

0.3604

0.1678

0.4724

0.1127

0.8602

0.2737

0.3579

0.2958

0.8147

0.3485

0.0952

0.3771

0.0670

0.6153

0.7864

0.0043

0.1693

abetic patients with PAD over a 3-month period. Some degree of gained sensory function could be observed that might be associated with an improved hemodynamic situation. However, no significant changes in sensory thresholds in response to PTA were found.

Pain Reduction A remarkable decrease in exercise-induced pain was observed 3 months after PTA. The data obtained in the present study is consistent with previous results from Kügler and Rudofsky showing a decrease in pain intensity by 62.8%16 (compared with 60.2% in our study). However, our follow-up data represents a 3-month period compared with the measurement after 1 week in the above mentioned study. In addition, we presented a highly selective group, that is, only nondiabetic patients with claudication. The patients investigated from Kügler and Rudofsky suffered from moderate and severe PAD and almost two thirds of them had coexisting DM.16 Therefore, the sensation of pain during exercise is fairly reliable and was exclusively caused by vascular obstruction and is unlikely to be due to other factors, for example, neurological reasons. Unfortunately, Kügler and Ru-

dofsky did not report the hemodynamic success of the PTA, whereas our trial focused on this issue additionally. Patients with a successful intervention showed a decrease in their pain score, whereas patients without a sufficient PTA result do not report considerable pain relief during exercise. It might be possible that the reduced pain intensity is due to a placebo effect. But this possibility is low, because the 4 patients with unsuccessful PTA did not show such a pain reduction. If we therefore consider them as an unplanned sham (or placebo) group, this study provides evidence for the efficacy of successful PTA for exercise induced pain reduction in patients with intermittent claudication. In comparison, patients who underwent femoropopliteal bypass surgery suffered from prolonged postoperative neuropathic pain which was attributed to the surgical incision.11 To our knowledge, there is no scientific comparison of the effectiveness in pain reduction from bypass surgery and percutaneous angioplasty. Usually, patients with intermittent claudication suffer from exercise induced pain which is related to an underlying ischemic muscle. Tissue distally to the stenosis undergoes ischemia, hypoxia and acidosis during exercise. Accumulating metabolites and an increased acidity might be responsible for ischemic pain in these patients. Therefore, it seems reasonable that a reparative intervention resulted in a reduced pain perception.

Changes in Sensory State After Endovascular Intervention The investigated patients showed no significant changes in sensory thresholds. This could be due to various reasons. Most likely, the patients had fairly normal sensory levels at the time of inclusion in the study, which did not differ much from the control group besides the pressure pain threshold (PPT), which was significantly higher in the control group compared with the treated patients at baseline and 3 months following endovascular intervention. The higher sensitivity to pressure in PAD patients might be due to sensitized nociceptors or axons in the periphery where pressure results easier in nociceptive perception. One has to take into account that even slightly changed sensory parameters might already be fixed in patients with moderate PAD. This theory is supported by the fact that vibration detection threshold (VDT) did not change after PTA, whereas in patients without successful endovascular intervention the VDT dropped further. Another possibility would be that temporary ischemic episodes lead to an ischemic preconditioning in peripheral nerves. Studies on human nerve biopsies of patients with chronic vasculitic neuropathy demonstrated that unmyelinated fibers were less vulnerable to ischemia than myelinated ones which were affected earlier.8 Again, this is underlined by the fact that the biggest fibers investigated (A␤ tested by VDT) did not show any improvement after successful PTA. Although A⌬-fibers seemed to be affected by hemodynamic improvement: Cold detection threshold (CDT) gained function 3 months

Lang et al

271

Quantitative Sensoric Testing (QST) of the Subjects Undergoing Endovascular Intervention. Subgroups were Formed for Patients who Hemodynamically Improve (n ⴝ 13) and Who Did Not Benefit From it (n ⴝ 4). Data are Presented as Raw and Log Data (Mean ⴞ SEM)

Table 4.

HEMODYNAMIC IMPROVEMENT BASELINE Thermal thresholds Cold detection threshold CDT (°C from baseline 32°C) Warm detection threshold WDT (°C from baseline 32°C) Thermal sensory limen TSL (°C) Paradox heat sensation PHS (x/3) Cold pain threshold CPT (°C) Heat pain threshold HPT (°C) Mechanical thresholds Mechanical detection threshold MDT (mN) Mechanical pain threshold MPT (mN) Mechanical pain sensitivity MPS Dynamic mechanical allodynia DMA Wind-up

affected leg

3 MONTHS LATER

affected leg

7.4 0.71 ⫾ 0.11 8.6 0.88 ⫾ 0.06 18.0 1.19 ⫾ 0.07 0.9 ⫾ 0.3

6.5 0.71 ⫾ 0.18 8.4 0.87 ⫾ 0.14 18.2 1.04 ⫾ 0.32 1.0 ⫾ 0.7

7.6 0.78 ⫾ 0.20 7.9 0.88 ⫾ 0.08 14.7 1.00 ⫾ 0.26 0.5 ⫾ 0.3

affected leg

7.5 ⫾ 2.3

12.9 ⫾ 3.2

14.9 ⫾ 6.2

9.3 ⫾ 3.7

affected leg

46.7 ⫾ 0.7

45.3 ⫾ 0.8

44.2 ⫾ 1.4

46.9 ⫾ 0.7

affected leg

50.3 1.15 ⫾ 0.17 88.5 1.49 ⫾ 0.17 4.6 0.37 ⫾ 0.15 0.4 ⫺0.79 ⫾ 0.15 2.8 0.40 ⫾ 0.06 5.7 ⫾ 0.5

64.8 1.00 ⫾ 0.19 77.1 1.44 ⫾ 0.17 4.1 0.36 ⫾ 0.15 0.1 ⫺0.84 ⫾ 0.10 2.2 0.31 ⫾ 0.06 5.7 ⫾ 0.6

17.6 1.15 ⫾ 0.17 107.4 1.71 ⫾ 0.37 2.2 0.12 ⫾ 0.30 1.4 ⫺0.48 ⫾ 0.43 3.2 0.49 ⫾ 0.05 5.1 ⫾ 1.6

16.2 0.90 ⫾ 0.41 31.2 1.41 ⫾ 0.15 1.8 0.19 ⫾ 0.16 0.0 ⫺1.00 ⫾ 0.00 2.2 0.29 ⫾ 0.11 3.4 ⫾ 2.0

360.7 2.52 ⫾ 0.05

338.2 2.50 ⫾ 0.05

530 2.71 ⫾ 0.07

336 2.50 ⫾ 0.09

affected leg log affected leg log

log affected leg log affected leg log affected leg log affected leg affected leg affected leg log

BASELINE

10.8 0.95 ⫾ 0.08 10.4 0.99 ⫾ 0.05 22.8 1.29 ⫾ 0.07 1.6 ⫾ 0.4

log

log Vibration detection threshold VDT (x/8) Pressure pain threshold PPT (Pa)

3 MONTHS LATER

NO HEMODYNAMIC BENEFIT

log data are presented for all QST parameters besides PHS, CPT, HPT and VDT

after successful PTA, whereas patients without hemodynamic benefit showed opposite results. Although CDT appeared to be influenced in both directions, therefore it is possible that CDT represents the most sensitive parameter in response to ischemia. The presence of paradoxical heat sensations (PHS) might indicate alterations in A␦-cold fiber function or even central mechanisms responsible for cold sensation.23 An increased wind-up ratio (WUR) represents temporal summation of the applied nociceptive stimulus (here pinpricks).23 Both PHS and WUR suggest disinhibition in the central processing of incoming C-fiber signals resulting from impaired C-fiber input.12,22 The reduction in WUR might be due to lower nociceptive activity following PTA. The presence of dynamic mechanical allodynia (DMA) usually indicates central sensitization.29 DMA was observed in the patients investigated and these rates decline after endovascular intervention (Fig 2B). This could be the result of an ongoing C-fiber input which leads to central sensitization, reorganization of spinal synaptic transmission and a loss of inhibitory control mechanisms.30,31 As a consequence, the hemody-

namic improvement after PTA could therefore lead to reduced liberation of mediators that activate peripheral nociceptors15 and axonal receptors14,18,20 expressed on human nerves. The fact that we could observe such changes might indicate that the exercise induced ischemic pain (intermittent claudication) may have already initiated some mechanisms of central plasticity as has been observed in patients with other chronic pain conditions. Considerably greater samples would have been necessary for effects of the observed magnitude to reach statistical significance. A gain of function in sensory thresholds following PTA could be interpreted in 2 directions. Given impaired detection thresholds, a gain of function implicated an improvement of sensory function (regained nerve function). However, pain thresholds demonstrating gain of function could be interpreted as hyperalgesia, that is, lowered pressure pain thresholds in patients with intermittent claudication compared with control patients as well as the mechanical pain threshold after successful hemodynamic intervention. Endovascular intervention might be not only an impor-

272

QST to Evaluate Pain Reduction After PTA could help to evaluate function of motor nerves in addition to the sensory function to accomplish a comprehensive work-up of all nerve qualities. However, nerve conduction studies would not help to find changes in nociceptive nerve fibers.

Technical Considerations

Figure 3. Comparison of changes after endovascular intervention in patients with and without hemodynamic improvement. For the number of paradoxical heat sensations (PHS), mechanical pain sensitivity (MPS), presence of dynamic mechanical allodynia (DMA), wind-up (WUR) similar changes were observed following PTA with and without hemodynamic benefit. However, there are sensory changes presenting inverse directions: Detection and pain thresholds for cold and mechanical stimuli (CDT, CPT, MDT, and MPT) improved with successful intervention, whereas patients without hemodynamic benefit demonstrate some loss in these parameters. Vibratory detection thresholds (VDT) remain unchanged after PTA with hemodynamic improvement, whereas the 4 patients who did not benefit from PTA lost vibratory function.

tant tool to improve blood flow, moreover it could inhibit the process of pain, sensory neuropathy and central sensitization.19 Nociceptive input and consecutive central sensitization as well as direct peripheral sensitization due to ischemia contribute to this multifaceted pain condition. However, QST cannot provide objective evidence supporting the subjective pain reduction.

Implication for Future Trials Due to some promising changes—albeit not of statistical significance (implicating a need for much greater sample sizes)—further investigations should be performed to elucidate sensory changes in chronic ischemic pain conditions. To clarify improvements in pain and sensory functions, it might be worthwhile to include PAD patients with significant sensory deficit. Therefore, it might be necessary to include patients with chronic critical limb ischemia. In this case, one might have to cope with the problem that this sensory deficit is already unchangeably fixed (as discussed above). Regarding sensory discrimination, it seems worthwhile to focus especially on cold detection and pain thresholds. Furthermore sensory function tests indicating a possible participation of central pain mechanisms should be emphasized. In addition, determination of the density of epidermal nerve fibers could bring a correlation between sensory function and morphology. Nerve conduction studies

References 1. Bertelsmann FW, Heimans JJ, Van Rooy JC, Dankmeijer HF, Visser SL, Van d V: Peripheral nerve function in patients

A control group was investigated to show that sensory thresholds did not change spontaneously in a 3 month period. An age-matched control group was chosen to control for a possible influence of age on risk for PAD21 and reported threshold shifts in QST according to the age of the investigated patients.9,13,32 Both the PAD and the control group had a higher proportion of male subjects, this fact reflects the gender distribution of risk factors like hypertension (relationship to development of distal symmetrical neuropathy7). The DFNS has developed a protocol for QST, which should minimize errors in carrying out QST.23,24 In the present study we performed QST according to these standardized guidelines. All sensory tests are well established and described in the literature. However, QST is a psychophysical test and therefore depends on patient cooperation.27 It cannot be completely excluded that this has affected our results. However, the fact that we could not find differences over a period of 3 months underlines the quality of the method used in the present study. The investigation of a control group which did not undergo any intervention provides data that show that QST is highly reproducible over a 3month period.

Conclusions Successful endovascular intervention is highly effective in reducing exercise induced pain in patients with intermittent claudication. Hemodynamic improvement over a 3-month period did not change sensory function in a significant manner. Sensory function tests associated with central processing derived from painful input appeared to be influenced by PTA, which resulted in reduced nociceptive input. Much greater sample sizes are necessary to obtain significant results. In addition, we could demonstrate that QST is highly reproducible over a 3-month period. Further studies are necessary to investigate the role of ischemic pain and altered sensory thresholds in the progression of PAD.

Acknowledgment Parts of the presented results are topics of the thesis of G. V. (in preparation; medical faculty of the University of Munich).

with painful diabetic neuropathy treated with continuous subcutaneous insulin infusion. J Neurol Neurosurg Psychiatry 50:1337-1341, 1987 2. Canova CR, Schneider E, Fischer L, Leu AJ, Hoffmann U:

Lang et al Long-term results of percutaneous thrombo-embolectomy in patients with infrainguinal embolic occlusions. Int Angiol 20:66-73, 2001 3. Cohen SM, Mathews T: Pentoxifylline in the treatment of distal diabetic neuropathy. Angiology 42:741-746, 1991 4. Diehm C, Schuster A, Allenberg JR, Darius H, Haberl R, Lange S, Pittrow D, von SB, Tepohl G, Trampisch HJ: High prevalence of peripheral arterial disease and co-morbidity in 6880 primary care patients: cross-sectional study. Atherosclerosis 172:95-105, 2004 5. Dormandy J, Mahir M, Ascady G, Balsano F, De Leeuw P, Blombery P, Bousser MG, Clement D, Coffman J, Deutshinoff A: Fate of the patient with chronic leg ischaemia: A review article. J Cardiovasc Surg (Torino) 30:50-57, 1989 6. England JD, Ferguson MA, Hiatt WR, Regensteiner JG: Progression of neuropathy in peripheral arterial disease. Muscle Nerve 18:380-387, 1995 7. Forrest KY, Maser RE, Pambianco G, Becker DJ, Orchard TJ: Hypertension as a risk factor for diabetic neuropathy: A prospective study. Diabetes 46:665-670, 1997 8. Fujimura H, Lacroix C, Said G: Vulnerability of nerve fibres to ischaemia: A quantitative light and electron microscope study. Brain 114(Pt 4):1929-1942, 1991 9. Gibson SJ, Farrell M: A review of age differences in the neurophysiology of nociception and the perceptual experience of pain. Clin J Pain 20:227-239, 2004 10. Greenspan JD, McGillis SL: Stimulus features relevant to the perception of sharpness and mechanically evoked cutaneous pain. Somatosens Mot Res 8:137-147, 1991 11. Greiner A, Rantner B, Greiner K, Kronenberg F, Schocke M, Neuhauser B, Bodner J, Fraedrich G, Schlager A: Neuropathic pain after femoropopliteal bypass surgery. J Vasc Surg 39:1284-1287, 2004 12. Hansen C, Hopf HC, Treede RD: Paradoxical heat sensation in patients with multiple sclerosis: Evidence for a supraspinal integration of temperature sensation. Brain 119(Pt 5):17291736, 1996 13. Heft MW, Cooper BY, O’Brien KK, Hemp E, O’Brien R: Aging effects on the perception of noxious and non-noxious thermal stimuli applied to the face. Aging (Milano) 8:35-41, 1996 14. Irnich D, Tracey DJ, Polten J, Burgstahler R, Grafe P: ATP stimulates peripheral axons in human, rat and mouse: Differential involvement of A(2B) adenosine and P2X purinergic receptors. Neuroscience 110:123-129, 2002 15. Julius D, Basbaum AI: Molecular mechanisms of nociception. Nature 413:203-210, 2001 16. Kügler CF, Rudofsky G: Do age and comorbidity affect quality of life or PTA-induced quality-of-life improvements in patients with symptomatic pad? J Endovasc Ther 12:387393, 2005 17. Laghi PF, Pastorelli M, Beermann U, de Candia S, Gallo S, Blardi P, Di Perri T: Peripheral neuropathy associated with ischemic vascular disease of the lower limbs. Angiology 47: 569-577, 1996 18. Lang PM, Burgstahler R, Sippel W, Irnich D, SchlotterWeigel B, Grafe P: Characterization of neuronal nicotinic acetylcholine receptors in the membrane of unmyelinated human C-fiber axons by in vitro studies. J Neurophysiol 90: 3295-3303, 2003

273 19. Lang PM, Schober GM, Rolke R, Wagner S, Hilge R, Offenbacher M, Treede RD, Hoffmann U, Irnich D: Sensory neuropathy and signs of central sensitization in patients with peripheral arterial disease. Pain 124:190-200, 2006 20. Lang PM, Tracey DJ, Irnich D, Sippel W, Grafe P: Activation of adenosine and P2Y receptors by ATP in human peripheral nerve. Naunyn Schmiedebergs Arch Pharmacol 366: 449-457, 2002 21. Ouriel K: Peripheral arterial disease. Lancet 358:12571264, 2001 22. Price DD, Hu JW, Dubner R, Gracely RH: Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses. Pain 3:57-68, 1977 23. Rolke R, Baron R, Maier C, Tolle TR, Treede RD, Beyer A, Binder A, Birbaumer N, Birklein F, Botefur IC, Braune S, Flor H, Huge V, Klug R, Landwehrmeyer GB, Magerl W, Maihofner C, Rolko C, Schaub C, Scherens A, Sprenger T, Valet M, Wasserka B: Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 123:231243, 2006 24. Rolke R, Magerl W, Campbell KA, Schalber C, Caspari S, Birklein F, Treede RD: Quantitative sensory testing: A comprehensive protocol for clinical trials. Eur J Pain 10:77-88, 2006 25. Rüger LJ, Irnich D, Abahji TN, Crispin A, Hoffmann U, Lang PM: Characteristics of chronic ischemic pain in patients with peripheral arterial disease. Pain 139:201-208, 2008. 26. Sabeti S, Czerwenka-Wenkstetten A, Dick P, Schlager O, Amighi J, Mlekusch I, Mlekusch W, Loewe C, Cejna M, Lammer J, Minar E, Schillinger M: Quality of life after balloon angioplasty versus stent implantation in the superficial femoral artery: Findings from a randomized controlled trial. J Endovasc Ther 14:431-437, 2007 27. Shy ME, Frohman EM, So YT, Arezzo JC, Cornblath DR, Giuliani MJ, Kincaid JC, Ochoa JL, Parry GJ, Weimer LH: Quantitative sensory testing: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 60:898-904, 2003 28. Slugg RM, Meyer RA, Campbell JN: Response of cutaneous A- and C-fiber nociceptors in the monkey to controlledforce stimuli. J Neurophysiol 83:2179-2191, 2000 29. Treede RD, Handwerker HO, Baumgartner U, Meyer RA, Magerl W: Hyperalgesia and allodynia: Taxonomy, assessment, and mechanisms, in Brune K, Handwerker HO (eds): Hyperalgesia: Molecular Mechanisms and Clinical Implications. Seattle, IASP Press, 2004, pp 1-15 30. Woolf CJ, Costigan M: Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci U S A 96:7723-7730, 1999 31. Woolf CJ, Wall PD: Relative effectiveness of C primary afferent fibers of different origins in evoking a prolonged facilitation of the flexor reflex in the rat. J Neurosci 6:14331442, 1986 32. Zaslansky R, Yarnitsky D: Clinical applications of quantitative sensory testing (QST). J Neurol Sci 153:215-238, 1998 33. Ziegler EA, Magerl W, Meyer RA, Treede RD: Secondary hyperalgesia to punctate mechanical stimuli: Central sensitization to A-fibre nociceptor input. Brain 122(Pt 12)22452257, 1999