Pain Medicine 2011; 12: 17201726 Wiley Periodicals, Inc.

OPIOIDS, SUBSTANCE ABUSE & ADDICTIONS SECTION Original Research Article Longitudinal Observation of Changes in Pain Sensitivity during Opioid Tapering in Patients with Chronic Low-Back Pain
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Haili Wang, MD, Michael Akbar, MD, Nina Weinsheimer, MD, Simone Gantz, Dipl-Soz Wiss, and Marcus Schiltenwolf, MD Department of Orthopedics, Trauma Surgery and Paraplegiology, University Hospital of Heidelberg, Heidelberg, Germany Reprint requests to: Haili Wang, MD, Division of Pain Management, Department of Orthopedic Surgery, University of Heidelberg, Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany. Tel: +49-6221-966505; Fax: +49-6221-966230; E-mail: haili.wang@ok.uni-heidelberg.de. There are no nancial or other relationships that might lead to a conict of interest. The rst two authors contributed equally to this project.

and 6 months after the start of opioid tapering (T3) in 35 patients with both cLBP and opioid medication (OP), 35 opioid-nave cLBP patients (ON), and 28 individuals with neither pain nor opioid intake (HC). Results. Signicant differences in heat pain thresholds were found among the three groups at all three time points (T1: P = 0.001, T2: P = 0.015, T3: P = 0.008), but not between the two patient groups. OP patients showed lower cold pain thresholds at T2 than ON patients and HC. At T3, the heat pain thresholds of OP patients still remained lower than HC (P = 0.017), while those of ON patients were normalized. Conclusions. Our ndings suggest that long-term use of opioids does not reduce pain sensitivity in cLBP patients; opioid tapering may induce brief hyperalgesia that can be normalized over a longer period. Key Words. Opioid Tapering; Pain Sensitivity; Chronic Low-back Pain; Quantitative Sensory Testing Introduction To date, evidence of long-term amelioration of pain and improvements in function attributable to opioid therapy is lacking. Meta-analyses and systemic reviews of randomized, double-blind, placebo-controlled trials of opioids for chronic noncancer pain found these trials were of brief duration (average 5 weeks), subject to publication bias from pharmaceutical company sponsorship, and limited by eligibility criteria that excluded subjects with a history of substance abuse [14]. Furthermore, patients on longterm opioid treatment often complain of symptoms such as agitation, sleep disturbance, nausea, emesis, constipation, and cognitive disturbance, even hyperalgesia [510]. These studies showed that exposure to opioids alters pain sensitivity. Angst et al. showed direct evidence in humans that short-term administration of an

Abstract Objective. Several studies have shown that exposure to opioids for short or long periods alters pain sensitivity. Little is known about changes in pain sensitivity during and after tapering of long-term prescribed opioid treatment in chronic low-back pain (cLBP) patients. Design. The goal of this prospective longitudinal study was to investigate pain sensitivity in a homogeneous patient population (cLBP patients only) after tapering of long-term (17 months) opioid use and to monitor the changes in pain sensitivity for 6 months. Methods. Pain sensitivity (thermal sensation and thermal pain thresholds in low back and nondominant hand) was measured by quantitative sensory testing (QST) at 1 day before (T1), 3 weeks after (T2), 1720

Pain Sensitivity under Opioid Therapy opioid can enhance hyperalgesia, as observed during withdrawal, and they pointed to a potential role of the N-methyl-D-aspartate (NMDA)-receptor system in mediating such a hyperalgesic response. Compton et al. conrmed the presence of hyperalgesia in four healthy non-opioid-dependent men using the acute opioid physical dependence (APD) model and showed that pain thresholds and tolerance to the cold pressor uniformly decreased across all APD induction methods. These ndings provide initial support for the existence of opioid-induced hyperalgesia, which has been conceptualized as a coexisting opponent process to opioidinduced analgesia and proposed to be an alternative explanation for the development of analgesic tolerance to opioids. To date, however, little is known about changes in pain sensitivity during and after opioid tapering in chronic lowback pain (cLBP) patients treated with long-term opioids. A previous study by our group compared the intensity of pain before and after multidisciplinary pain therapy in patients with cLBP who underwent opioid withdrawal. The pain intensity via visual analog scale was signicantly decreased at discharge [11]. Another study of hyperalgesia under opioid withdrawal demonstrated that 714 days after withdrawal 12 patients showed decreased tolerance for cold in the cold pressor task, although their quality of life had signicantly improved [12]. A study using quantitative sensory testing (QST) suggested that the pain thresholds of pre-heroindependent addicts were still different several months after detoxication [13]. In contrast, some studies indicate that the pain threshold values of chronic pain patients treated with opioids do not differ signicantly from those of chronic pain patients treated with non-opioid analgesics [14]. Therefore, longitudinal studies are needed to resolve the question of whether long-term opioid therapy and opioid tapering causes the increase in pain sensitivity reported in chronic pain patients. The goal of this prospective longitudinal study was to investigate in a homogeneous patient population (cLBP patients only) the long-term (17 months) effects of opioid analgesics on pain sensitivity and to follow for 6 months the changes in pain sensitivity during opioid tapering and withdrawal. We used the QST technique to assess pain sensitivity over a period of 6 months. To our knowledge, this is the rst longitudinal study of 6 months duration regarding pain sensitivity during and after opioid tapering. from the Department of Orthopedic Surgery, and all gave informed consent. Three groups of subjects were studied: patients with both cLBP and opioid therapy (group 1, N = 35); those who had cLBP but had not been on opioid therapy for at least 3 months (group 2, N = 35); and healthy controls with neither pain nor opioid therapy (group 3, N = 28). The inclusion criteria for patients with cLBP were as follows: 1) age between 20 and 70 years; 2) a history of at least 6 months of chronic myofascial low-back pain without radicular sensory or motor decits or radicular pain symptoms (herniation or disc protrusion excluded by magnetic resonance imaging), but sick leave amounting to less than 6 months within the 12 months immediately before enrolment in this study (grade II chronication according to von Korff [15]); 3) opioid therapy was dened as intake of a morphine equivalent dose of at least 30 mg per day every day for more than 3 months. For the standardized data analysis, we used the following conversion ratios between an oral dose of morphine and other opioid analgesics: 1 mg morphine = 0.65 mg oxycodone, 0.25 mg methane, 5 mg tilidine, 0.01 mg fentanyl, 0.13 mg hydromorphone, 5 mg tramadol [16,17]; and 4) non-opioid pain medication in the group of opioid-nave patients was allowed. The exclusion criteria for both groups were: 1) sensory decits because of diabetes, alcoholic neuropathy, spinal stenosis, or severe thyroid, liver, or kidney disease; 2) interventional pain management procedures that might alter QST responses, including neuraxial or local anesthetic block, within the previous 3 months; 3) major psychiatric disorders requiring recent hospitalization, such as schizophrenia or psychosis; and 4) infection or acute injury at the QST site. Study Procedure The study lasted 6 months (Figure 1). Before admission into the study, each patient lled in a questionnaire giving information on demographic data, pain location, pain intensity on a numeric rating scale (NRS: 0 = no pain, 10 = worst pain imaginable), pain pattern, pain duration, clinical diagnosis, and medications, including opioid and non-opioid analgesics. During the whole study, all patients kept records of the medications they used. Opioid Tapering Procedure Upon admission to the study, the dosage of opioid preparation was halved every 3 days until the patients became opioid clean. In the rst week, patients usually complained of symptoms such as nausea, weakness, increased sweating, or sleep disturbance. During the opioid tapering, doxepine was applied for damping of withdrawal symptoms until 2 weeks after the patient had become opioid clean. All patients had stopped the use of opioids by T2, and 85% of them remained opioid clean 6 months after opioid withdrawal. Only data from these 85% were 1721

Methods Study Subjects The study was approved by the ethics committee of the University of Heidelberg, Germany and was funded by the research fund of the Department of Orthopedic Surgery of the University of Heidelberg. The subjects were recruited

Wang et al.
Intention-to-treat 99 patients

1 patient refused participation

98 patients recruited

35 opioid-positive (Group 1)

35 opioid-nave (Group 2)

28 healthy controls (HC) (Group 3)

1 patient excluded (spinal claudication)

2 patients dropped out (invalid QST values)

6 subjects dropped out (invalid QST values)

T1: 34 patients

T1: 33 patients

T1: 22 HC

2 patients dropped out

4 patients dropped out

T2: 32 patients

T2: 29 patients

12 patients dropped out

10 patients dropped out

T3: 20 patients

T3: 19 patients

Figure 1 Flow diagram of study participants during 6-month follow-up. T1 = day 0; T2 = day 21; T3 = day 180; HC = healthy controls; QST = quantitative sensory testing.
used for statistical analysis (group 1, N = 17; group 2, N = 22, group 3, N = 18); the remaining 15% of patients who continued to use opioids at the 6-month time point were considered as dropouts. QST QST was performed using the Thermal Sensory Analyzer (TSA) II (Medoc Inc., Ramat Ishai, Israel) and was carried out at three time pointsat admission into the study (T1) and at 3 weeks (T2) and 6 months (T3) thereafterin a quiet room maintained at 2025C. A contact thermode (3 3 cm) was gently attached and secured with a band onto the lower back (bilaterally) and the nondominant hand in each subject. The baseline temperature was 32C. The cutoff temperatures were 0C and 50C. Each subject was told to stop stimulation as soon as he/she felt 1722 Subjects were instructed to stop stimulation as soon as they perceived an increase or decrease in temperature from the baseline (32C). The testing was performed four times in each patient. Testing of CP and WP Subjects were instructed to stop stimulation as soon as they perceived a painful sensation as temperature decreased (CP) or increased (WP) from the baseline temperature of 32C. The testing was performed three times a change in temperature. The measured parameters were: cold sensation (CS), warm sensation (WS), cold pain threshold (CP), and heat pain threshold (WP). Testing of CS and WS

Pain Sensitivity under Opioid Therapy in each patient. The temperature at which the subject stopped the stimulation was recorded as threshold temperature (C). Statistical Analysis According to the ShapiroWilk test, the values of QST were not normally distributed, so nonparametric tests were used. As an overall test the Friedman test was used for comparisons of the differences among the QST results among three time points. The Wilcoxon test was used to compare differences of the QST results between two time points. The overall KruskalWallis test was used to compare the three unpaired groups, the MannWhitney U-test for two groups. Spearmans rho and Pearsons correlation coefcients were used to examine the relationships between QST value and depression, duration of pain, duration of opioid medication, dose of opioids, and subjective pain intensity. Only complete datasets are included. All tests were performed with Statistical Package for the Social Sciences (SPSS) 17.0 software for Windows (SPSS Inc., Chicago, IL, USA). For each statistical test, the signicance level was set at P 0.05. Bonferroni correction was used to correct for multiple testing. Results Table 1 shows characteristics of the subjects in all three groups. Overall, there were no statistically signicant differences in age and sex among the groups. The depression rate, the mean duration of pain, and pain medication with nonsteroidal anti-inammatory drugs and antidepressants were comparable between OP and ON patients. The only differentiating characteristic between these two groups was the intake of opioids. There were signicant differences in heat pain thresholds at all three time points (KruskalWallis test: T1, P = 0.001; T2, P = 0.015; T3, P = 0.008) among all three groups. However, this difference was conrmed only between group 1 and group 3 at all time points (MannWhitney test: T1, P = 0.007; T2, P = 0.007; T3, P = 0.017) and between groups 2 and 3 at T1 (P = 0.001) and at T2 (0.002); there was no difference between the two patient groups at any time point (Figure 2A). At T2, signicant differences in CPs were found among all three groups (KruskalWallis test: P = 0.003 for hand, P = 0.023 for left low back). The opioid-positive patients of group 1 had a signicant lower threshold to cold stimuli than patients in group 2 (P = 0.004 for hand) and healthy controls (P = 0.001 for hand, P = 0.021 for left low back). Opioid-nave patients had a pain threshold similar to that of healthy controls (Figure 2B). Compared with T1, group 1 patients reacted to warm stimuli signicantly faster at T2 (P = 0.029), while group 2 patients did not change their pain prole. At T3, group 1 patients showed a further increase in speed of reaction to warm stimuli (P = 0.01) and a further lowering of CP (P = 0.026) relative to T2. Group 2 patients showed signicant changes in heat pain thresholds (P = 0.028) at T3 compared with T1. No correlations between QST values and depression, pain duration, opioid dose, or opioid duration were found. NRS scores showed moderately signicant correlations with thermal sensation, but not with pain thresholds. Statistically signicant correlations were found between sensation of warmth in the hand and both age (r = 0.308, P = 0.015) and sex (r = 0.271, P = 0.003). Discussion and Conclusions This prospective study is the rst to demonstrate the changes of pain sensitivity in patients with cLBP under long-term opioid use and opioid tapering in a longitudinal

Table 1

Characteristics of study subjects before therapy

Group 1 (N = 20) Group 2 (N = 19) 46.6 8.9 (2865) 63.2% 436.8% cLBP 42.5% 18.2% 7.3 5.6 5.3 2.3 0 0 NSAIDs (17.1%) Antidepressants (3%) Group 3 (N = 22) 47.1 10.3 (3366) 59.1% 40.9% No pain 5% 0 0 0 0 0 0 P-value P > 0.05 P > 0.05 P > 0.05* P > 0.05* P > 0.05* P > 0.05* P > 0.05*

Age (year) Female Male Diagnosis Depression Other psychic comorbidity Duration of pain (years) Pain intensity (NRS) Duration of opioid intake (months) Morphine equivalent dose (mg/d) Other pain medications

49.3 12.4 (3169) 40.0% 60.0% cLBP 45.5% 20.5% 10.3 10.5 6.23 1.9 16.9 21.6 107.3 77 NSAIDs (20%) Antidepressants (17.1%)

* Comparison between patient groups. cLBP = chronic low-back pain; NSAIDs = nonsteroidal anti-inammatory drugs; NRS = numeric rating scale.

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A 47 46 Temperature C 45 44 43 42 41 40 T1 T2 Time B 18 16 14 12 10 8 6 4 2 0 T1 CP ** ** * group 1 group 2 group 3 T3 * group 1 group 2 group 3 ** ** WP ** ** *

tapering, but this effect is no longer present 6 months later. To our knowledge, this is the rst longitudinal documentation of opioid tapering-induced hyperalgesia in a homogeneous patient population with cLBP under chronic opioid medication with such a long observation period (mean 17 months). This nding correlates with those of Prosser et al. [13] and indicates opioid-induced enhancement of hyperalgesia after opioid cessation. The mechanisms of opioid tapering-induced hyperalgesia are poorly described, especially in humans. One possible mechanism of opioid tapering-induced hyperalgesia is the activation of central neuroimmune responses as described by Raghavendra et al. [18], who demonstrated that chronic administration of morphine to sham-operated rats activated spinal glia and upregulated proinammatory cytokines (interleukin [IL]-1b, IL-6, and tumor necrosis factor-a), which could mediate hyperalgesia. This neuroimmune activation was further enhanced in nerve-injured rats after chronic morphine treatment. Spinal inhibition of proinammatory cytokines restored acute morphine antinociception in nerve-injured rats and also signicantly reversed the development of morphine tolerance and withdrawalinduced hyperalgesia and allodynia in nerve-injured or sham-operated rats. Two years later, the same research group investigated the effect of propentofylline, a glial modulator, on the expression of analgesic tolerance and withdrawal-induced hyperalgesia in chronic morphinetreated rats. They found that chronic morphine administration through repeated subcutaneous injections induced glial activation and enhanced pro-inammatory cytokine levels in the lumbar spinal cord [19]. Another study showed that during opioid abstinenceinduced withdrawal, administration of glutamate receptor antagonists and the kappa agonist to the nucleus raphe magnus suppressed the withdrawal-induced hyperalgesia, which is thought to be mediated by activation of those pain-facilitating neurons during opioid withdrawal [20]. Finally, the withdrawal of chronic opioid use could induce sensitization of spinal NMDA receptors, presynaptic/ central glutamate receptors, and peripheral a2adrenergic/adenosine receptors, thus decreasing the pain thresholds to stimuli and causing the hyperalgesia. Our results showed that the pain thresholds of opioidpositive and opioid-nave patients did not differ from each other at T1. Compared with healthy subjects, both opioidpositive and opioid-nave patients had signicantly decreased pain thresholds to heat stimuli. This indicates that low-back pain itself might induce peripheral sensitization [21], which seems not to be counteracted by opioid medication, as shown in our study and by other authors [22,23]. In contrast, long-term opioid therapy (in our study the mean duration of opioid use was 17 months) intensied the peripheral sensitization rather than reducing it. Potential confounding factors were considered in this study. We tested both healthy controls and opioid-nave

Temperature C

T2 Time

T3

Figure 2 Pain thresholds as measured by quantitative sensory testing in patients with chronic low-back pain. * P < 0.05; ** P < 0.01; T1 = day 0; T2 = day 21; T3 = day 180. Group 1: Patients with chronic low-back pain and under opioid therapy before study; group 2: patients with chronic low-back pain without opioid therapy before study; group 3: healthy controls. (A) Heat pain thresholds (WP). Both patient groups showed signicantly lower WP than healthy controls at T1 and T2. At T3, group 1 still had lower WP than group 3 but in group 2 pain sensitivity had improved signicantly after 6 months. (B) Cold pain thresholds (CP). At T2 but not at T1 or T3, the CP were signicantly different between groups 1 and 2 and between groups 1 and 3. Group1 patients were more sensitive to cold stimuli, and perceived the same cold stimuli as pain earlier, than those in group 3.
setting. We found 1) that long-term (average 17 months) opioid use did not cause increased or reduced pain sensitivity and 2) that opioid tapering leads to signicantly decreased pain thresholds as early as 3 weeks after opioid 1724

Pain Sensitivity under Opioid Therapy patients and used their baseline QST responses to ensure differentiation of QST ndings because of opioid usage or to preexisting low-back pain. The palm of the hand was additionally chosen as a control region to enable detection of any opioid-induced hyperalgesia independent of preexisting low-back pain [24]. To rule out any inuence of uctuations in ambient temperature on QST results, the temperature of the room where QST was carried out was kept stable at 2025C during testing [25,26]. Age and sex inuenced the perception of warmth in our study, so we considered both as potential confounding factors. All three groups turned out to be comparable for age and sex. Both of the two persons conducting the tests were female, excluding sex of the test person as confounding factor [27,28]. Duration of pain, pain intensity, comorbidity with depression, and use of antidepressants were all similar in both patient groups. We found no correlation between depression score and QST parameters at any time point. We found in this study that subjective pain intensity correlated with objective thermal perception, in agreement with our previous results [11] Correspondingly, we observed that heat pain thresholds of opioid-positive patients did not change over the whole study, even at the end of the follow-up period when patients were already opioid clean. This indicates that it is not pain thresholds with QST but rather thermal sensation that determines patients subjective pain intensity, as previous studies have reported [19,29]. In conclusion, this study makes two important observations. First, it conrms that cLBP patients demonstrate heat hyperalgesia when nociception is measured using QST. Opioid exposure additionally changes the thermal sensation in this patient population. Second, it shows that opioid tapering may induce cold hyperalgesia shortly after dose reduction but that this effect disappears after longterm (6 months in our study) abstinence from opioids. Acknowledgments We would like to acknowledge nancial support from the Orthopedic University Hospital, University of Heidelberg, Germany. References 1 Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: Systematic review of efcacy and safety. Pain 2004;112(3):37280. 2 Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. Opioids for chronic noncancer pain: A meta-analysis of effectiveness and side effects. CMAJ 2006; 174(11):158994. 3 Martell BA, OConnor PG, Kerns RD, et al. Systematic review: Opioid treatment for chronic back pain: Preva12 Younger J, Barelka P, Carrol I, et al. Reduced cold pain tolerance in chronic pain patients following opioid detoxication. Pain Med 2008;9(8):115863. 13 Prosser JM, Steinfeld M, Cohen LJ, et al. Abnormal heat and pain perception in remitted heroin dependence months after detoxication from methadonemaintenance. Drug Alcohol Depend 2008;95(3): 23744. 14 Fillingim RB, Doleys DM, Edwards RR, Lowery D. Clinical characteristics of chronic back pain as a function of gender and oral opioid use. Spine (Phila Pa 1976) 2003;28(2):14350. 15 Von Korff M, Ormel J, Keefe FJ, Dworkin SF. Grading the severity of chronic pain. Pain 1992;50(2):13349. 1725 lence, efcacy, and association with addiction. Ann Intern Med 2007;146(2):11627. 4 Moore RA, McQuay HJ. Prevalence of opioid adverse events in chronic non-malignant pain: Systematic review of randomised trials of oral opioids. Arthritis Res Ther 2005;7(5):R104651. 5 Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M. Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 2003;106(12):4957. 6 Compton P, Athanasos P, Elashoff D. Withdrawal hyperalgesia after acute opioid physical dependence in nonaddicted humans: A preliminary study. J Pain 2003;4(9):5119. 7 Celerier E, Rivat C, Jun Y, et al. Long-lasting hyperalgesia induced by fentanyl in rats: Preventive effect of ketamine. Anesthesiology 2000;92(2):46572. 8 Rivat C, Laulin JP, Corcuff JB, et al. Fentanyl enhancement of carrageenan-induced long-lasting hyperalgesia in rats: Prevention by the N-methyl-D-aspartate receptor antagonist ketamine. Anesthesiology 2002; 96(2):38191. 9 Koppert W, Sittl R, Scheuber K, et al. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology 2003;99(1):1529. 10 Chou R, Fanciullo GJ, Fine PG, et al. Opioids for chronic noncancer pain: Prediction and identication of aberrant drug-related behaviors: A review of the evidence for an American Pain Society and American Academy of Pain Medicine clinical practice guideline. J Pain 2009;10(2):13146. 11 Gartner CM, Schiltenwolf M. [Limited efcacy of opioids in chronic musculoskeletal pain]. Schmerz 2004;18(6):50614.

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