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Pain Medicine 2014; ••: ••–•• Wiley Periodicals, Inc.

Increased Pain Sensitivity in Chronic Pain Subjects on Opioid Therapy: A Cross-Sectional Study Using Quantitative Sensory Testing

Yi Zhang, MD, PhD, Shihab Ahmed, MD, MPH, Trang Vo, BS, Kristin St. Hilaire, BS, Mary Houghton, BS, Abigail S. Cohen, BS, Jianren Mao, MD, PhD, and Lucy Chen, MD MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Reprint requests to: Lucy Chen, MD, Wang Ambulatory Care Center, MGH Center for Pain Medicine, 15 Parkman Street, Boston, MA 02114, USA. Tel: 617-724-3466; Fax: 617-724-4488; E-mail: [email protected]. Disclosure: This work was supported by NIH R01 grants DA036564 and DA022576.

Abstract Objective. The aim of this study was to compare the sensitivity to experimental pain of chronic pain patients on opioid therapy vs chronic pain patients on non-opioid therapy and healthy subjects by quantitative sensory testing (QST). Setting. There is a growing body of evidence demonstrating that chronic use of opioid drugs may alter pain sensitivity. Identifying the characteristic changes in thermal pain sensitivity in chronic opioid users will be helpful in diagnosing pain sensitivity alterations associated with chronic opioid use. Methods. Utilizing an office-based QST technique, we examined thermal pain threshold, tolerance, and temporal summation in 172 chronic pain subjects receiving opioid therapy, 121 chronic pain subjects receiving non-opioid therapy, and 129 healthy subjects. Results. In chronic pain subjects receiving opioid therapy, there were detectable differences in QST

characteristics compared with both chronic pain subjects receiving non-opioid therapy and healthy subjects. Specifically, in chronic pain subjects receiving opioid therapy, 1) sensitivity to heat pain was increased; threshold to heat pain was significantly lower; 2) tolerance to supra-threshold heat pain was significantly decreased; and 3) temporal pain summation was exacerbated, as compared with chronic pain subjects receiving non-opioid therapy. In a subgroup of chronic pain subjects receiving opioid therapy with increased heat pain sensitivity, their average opioid medication dosage was significantly higher than those who had an above-average heat pain threshold. Moreover, a subset of chronic pain subjects on opioid therapy exhibited a significant decrease in diffuse noxious inhibitory control (DNIC) compared with chronic pain subjects on nonopioid therapy. Conclusion. These findings suggest that a subset of QST parameters can reflect opioid-associated thermal pain sensitivity alteration, including decreased heat pain threshold, decreased cold and heat pain tolerance, diminished DNIC, and/or exacerbated temporal summation. Key Words. Opioids; Hyperalgesia; Chronic Pain

Introduction Opioid analgesics are commonly used for treatment of moderate to severe pain. In addition to the well-known side effects including sedation, nausea, constipation, dependence, and addiction, opioid-induced hyperalgesia (OIH), defined as a paradoxically increased sensitivity to noxious stimuli, has been increasingly recognized in patients receiving opioid therapy by clinicians [1–3]. Although there is no clinical diagnostic criteria of OIH and no consensus on how clinical OIH can be detected, there has been a growing body of evidence in preclinical and clinical studies demonstrating the existence of OIH. Many 1

Zhang et al. preclinical and clinical studies used alterations of thermal pain sensitivity as a surrogate of OIH, although a causal relationship between opioid-associated thermal pain sensitivity alteration and OIH has not been firmly established. Multiple animal studies have shown a reduction of baseline nociceptive threshold following repeated administration of opioid analgesics. For instance, decreased mechanical allodynia and thermal hyperalgesia have been shown in animals after acute administration of morphine [4], fentanyl [5], heroin [6], chronic administration of intrathecal morphine [7,8], and systemic opioid analgesics [9–11]. Clinically, intraoperative remifentanil infusion has been shown to increase postoperative pain and morphine consumption [12]. Patients undergoing detoxification from high-dose opioids have decreased pain after detoxification [13]. The same outcome has been reported in patients with cancer pain [14]. In human studies, OIH has been observed in heroin-dependent subjects [15], former opioid addicts on opioid maintenance [16,17], as well as chronic pain subjects receiving opioid therapy [18,19]. Thus, recognizing and detecting OIH in patients receiving opioid therapy are critical to the success of opioid therapy. Clinical diagnosis of OIH remains difficult due to the lack of evidence for clinical characteristics of OIH [1,2]. Human experimental pain models may be utilized for assessing the characteristics of OIH with standard protocols. In this regard, quantitative sensory testing (QST) has been used as a tool to detect OIH. However, most studies on the QST outcome of OIH have been carried out in opioid addicts or former opioid addicts maintained on methadone or buprenorphine [15–17]. In this patient population, lowered threshold and tolerance for cold pressor pain have been observed [15–17,20], whereas threshold to mechanical pressure-induced pain seems to be not affected [21]. On the other hand, chronic pain patients receiving prescribed opioid medication may have different QST characteristics. We have previously reported in our interim analysis at an earlier stage of this study in a small number of subjects that decreased heat pain threshold and exacerbated temporal pain summation may be characteristic QST changes in chronic pain subjects with opioid therapy [18]. A recent study in chronic back pain patients receiving opioid therapy also showed significantly reduced heat pain thresholds than healthy subjects [22]. Other studies have reported no change in thermal pain sensitivity in chronic low back pain patients receiving opioid therapy [23–25]. The discrepancy in QST characteristics in chronic opioid users may be secondary to differences in patient populations, investigator techniques, and sample size. In order to better identify the characteristic changes in thermal pain sensitivity associated with opioid therapy, we examined a variety of responses to innocuous or noxious heat and cold stimulation using an office-based QST in a large cohort of subjects consisting of chronic pain subjects with or without opioid therapy, as well as healthy control subjects. 2

Materials and Methods Study Subjects This study was approved through our institutional research board. Study subjects were recruited from the Massachusetts General Hospital (MGH) and local community through advertisement and physician referrals. Three groups of subjects were recruited: those with neither pain nor opioid therapy (healthy control), with chronic pain but not on opioid therapy (pain non-opioid), and with chronic pain and on opioid therapy (pain opioid). A total of 485 subjects consented to this study. These 485 subjects include the 140 subjects (41 healthy control subjects, 41 pain non-opioid subjects, and 58 pain opioid subjects) in our previous interim analysis and report [18]. All subjects were between ages 18 and 65 years. The following inclusion criteria were used: 1) Healthy control subjects have had no pain and no opioid treatment for at least 6 months (healthy controls). 2) Pain non-opioid subjects have had a stable pain condition (e.g., low back pain) but without opioid treatment for at least 3 months. 3) Pain opioid subjects have had a stable pain condition for at least 3 months and also have been on opioid therapy for at least the past 3 months. 4) Chronic opioid therapy (methadone excluded) was defined as taking at least 30 mg daily morphine equivalent dose for at least 6 weeks, without opioid dose changes during the past month. For standardized data analysis, we used the following conversion ratios between an oral dose of morphine and other opioid analgesics (1 mg morphine = 0.33 mg oxycodone, 0.25 mg hydromorphone, 0.33 mg hydrocodone, 4 mg codeine, or 0.21 μg transdermal fentanyl) (Washington State Agency Medical Group Guideline on Opioid Dosing, http://www.agencymeddirectors .wa.gov/opoiddosing.asp). 5) Because it is difficult to recruit subjects with pain but not on any pain medications, pain non-opioid and pain opioid subjects may have been taking non-opioid pain medications but without recent (within 1 month) dose changes. The following exclusion criteria were used in all groups: 1) Subject has sensory deficits at a QST site resulting from such medical conditions as diabetes, alcoholic neuropathy, AIDS neuropathy, severe thyroid, and liver or kidney diseases; 2) Subject has scar tissue, infection, or acute injury at a QST site; 3) Subject has had interventional pain management procedures that may alter QST responses including neuraxial or local anesthetic block within the last 8 weeks; 4) Subject has a major psychiatric disorder requiring a recent (within 1 month) hospitalization, such as major depression, bipolar disorder, schizophrenia, anxiety disorder, and psychosis; and 5) Subject is taking illicit drug detected through a urine toxicology screen. Study Procedure Potential subjects were first screened through a phone interview according to the inclusion and exclusion criteria. Those subjects who passed the phone interview were

Quantitative Sensory Testing, Pain, and Opioid-Induced Hyperalgesia scheduled to visit the MGH Center for Translational Pain Research. Pain opioid subjects were asked to take their routine opioid dose between 4 and 6 hours before the scheduled visit to minimize variation and avoid potential opioid withdrawal. Upon arrival, the informed consent was obtained and cosigned by an investigator. Each subject filled out a modified McGill Pain Questionnaire containing information on demographic data, clinical pain inventory (pain location, pain intensity on visual analog scale (VAS), pain pattern, pain duration, clinical diagnosis), and medications including non-opioid and opioid analgesics. A urine sample was collected for urine toxicology screen. The urine toxicology screen was used to detect illicit drug use and opioid analgesics. To verify that sensory deficits did not exist, each subject underwent a focused physical examination, which included vital signs and sensory examination at the site of QST (one of the two forearms unrelated to the dermatome distribution of the subject’s preexisting pain). Sensory examination included responses to alcohol swab and cotton swab. QST Parameters QST responses to thermal stimulation were examined using Medoc Thermal Sensory (Medoc Advanced Medical Systems, Durham, NC, USA) described previously [26]. The QST experimenter was blinded to the group membership of subjects being tested. Each QST session was carried out in a quiet room maintained at 25 ± 2°C. A contact thermode (3 × 3 cm) was gently attached and secured with a band onto the ventromedial part of a forearm in each subject. For cold and warm sensation, temperature at the thermode changed at 1°C/s from a neutral temperature of 32°C to a temperature that the subject indicated as cold or warm. For heat pain and cold pain threshold and tolerance, temperature at the thermode changed at 1.5°C/s from a neutral temperature of 32°C to a cutoff temperature of either 53°C (heat stimulation) or 0°C (cold stimulation). By pressing a computer mouse button, each subject was able to stop stimulation at any time during a session. Four categories of thermal QST parameters were examined in the following sequence: cold and warm sensation, cold and heat pain threshold, cold and heat pain tolerance, and temporal summation of pain to heat stimulation. Each test was repeated for three times with a 3-minute interval. To test cold and warm sensation, subjects were instructed to stop stimulation when they first perceived cold or warm sensation as temperature changed from the neutral temperature (32°C). To detect cold and heat pain threshold, subjects were instructed to stop stimulation when they first perceived painful sensation, as temperature descended (cold pain) or ascended (heat pain) from the neutral temperature of 32°C. The temperature at which the subject stopped

the stimulation was recorded as threshold temperature (°C). To examine pain tolerance, two protocols were used. 1) To detect the maximal tolerable temperature (°C) for cold or heat pain, subjects were asked to tolerate the stimulation beyond their cold or heat pain threshold until it reached the maximal tolerable level. The maximum temperature was preset at 53°C and 0°C for heat pain and cold pain, respectively, to avoid tissue injury. 2) To detect the duration (seconds) of tolerance to supra-threshold heat pain stimulation, subjects were asked to tolerate, as long as he or she could, heat stimulation preset at 47°C for a maximum of 60 seconds. Because the heat pain threshold in normal subjects is about 45°C and subjects on opioid therapy were expected to have a lower than normal heat pain threshold, this preset supra-threshold heat stimulation was above the heat pain threshold for subjects in all three groups. Temporal pain summation is a characteristic psychophysical response in human subjects correlating with the electrophysiological response of nociceptive neurons in the spinal cord dorsal horn (windup) [27]. To examine temporal pain summation, a train of four identical stimuli at 47°C, separated by a 2.2-second interval between stimuli, was applied to the subject’s forearm. Subjects were asked to rate their pain by VAS at the peak of each stimulus. Diffuse noxious inhibitory control (DNIC), alternatively referred to as conditioned pain modulation, is a measure of endogenous pain modulatory system, which may be altered in subjects with opioid therapy [28]. As this test was included later into this study, only a small subset of subjects in this study was subjected to this test. To assess DNIC, heat stimulation was used as “test stimulation,” whereas cold stimulation was used as “conditioning stimulation.” Heat stimulation (47°C, 4 seconds) was delivered via a contact thermode (3 × 3 cm) attached and secured with a band onto the ventromedial part of a forearm in each subject. Cold stimulation was delivered by immersing the non-tested arm in cold water for 30 seconds. The DNIC test paradigm was depicted in Figure 1: The first heat stimulus was delivered to the ventromedial part of left arm and the subject was asked to report the numeric pain score (0–10). This was recorded as “baseline pain score.” Subject was then asked to immerse the right hand in a water bath with temperature controlled at 12°C. Following 15 seconds of immersion, while the right hand was still in the cold water bath, the second test stimulation was delivered to the left arm and pain intensity was recorded again (Test 1). Fifteen seconds later, subjects were asked to remove their right hand from the cold water bath (with the total time of hand immersion in the cold water bath being 30 seconds). Two additional heat stimuli to the left arm were conducted 15 and 30 seconds subsequent to the removal of the right hand from the cold water bath, designated as Test 2 and Test 3, respectively. Following the delivery of each test stimulus, subjects were asked to report the numeric pain scores (0–10). 3

Zhang et al. Water-bath 30s

B

47C

12s

15s

30s

T1

11s

15s

T2

11s

T3

37C 1s

4s

4s

4s

4s

Figure 1 Diffuse noxious inhibitory control (DNIC) testing paradigm. B = heat stimulation before cold water bath immersion; T1 = test stimulation 1; T2 = test stimulation 2; T3 = test stimulation 3.

Statistical Analysis

Results

We used the statistical package Stata Version 12 (StataCorp LP, College Station, TX, USA) for data analysis. The following statistical analyses were performed. 1) For discrete data, such as gender, the Fisher’s exact test was used for between-group comparisons. 2) The Shapiro–Wilk test is used to test the normality of data. For quantitative data that follow normal distribution, the parametric one-way analysis of variance (ANOVA) was used to examine differences among groups, when a main effect was detected; the post hoc Bonferroni test was used for pairwise comparison to determine the source of differences. For data that do not follow normal distribution, nonparametric Kruskal–Wallis equality-ofpopulations rank test was used to examine differences among groups. When a main effect was detected, a Stata add-on module kwallis2 was used for post hoc pairwise comparison to determine the source of difference. 3) For analysis of QST measurements, the data from each QST test in a subject were first averaged to yield a mean response. One-way ANOVA was then used to examine differences among groups. When a main effect was detected, the post hoc Bonferroni test was used to determine the source(s) of differences. 4) Pearson’s correlation analysis was used to examine the relationship between a clinical factor (e.g., opioid dose) and a QST response. 5) To compare the degree of temporal pain summation among groups, the percent change in the response to the second, third, and fourth stimulation over the response to the first (baseline) stimulation was calculated and analyzed using repeated one-way ANOVA followed by the post hoc Bonferroni test. 6) The magnitude of DNIC was calculated as the percentage decrease from the baseline heat pain score from each of the subsequent pain score reported during and after the conditioning stimulation (Tests 1, 2, and 3). For each statistical test, the significance level was set at P < 0.05. For effect size calculation, we used an online Cohen’s d effect size calculator (http://www.danielsoper.com/ statcalc3/calc.aspx?id=48).

Demographic Data

4

A total of 485 subjects were consented, of which 422 subjects completed QST including 129 healthy subjects (Group 1), 172 pain subjects on non-opioid therapy (Group 2), and 121 pain subjects on chronic opioid therapy (Group 3). Sixty-three subjects did not complete the study mainly due to a positive urine drug test. Please refer to Figure 2 for detailed flow chart of subject enrolment. There was no difference in gender among the three groups by Fisher’s exact test (P = 0.33). There was no difference in age between Group 2 and Group 3; however, the average age on healthy subjects is younger than Group 2 and Group 3 (35.0 ± 14.2 years vs 45.6 ± 134 years vs 46.6 ± 9.5 years, respectively). There were no statistical differences among groups in other demographic data recorded in the study such as type and duration of pain as well as non-opioid pain medications (Table 1). Warm and Cold Sensation There were no differences in the threshold to warm and cold sensation among all three groups. Threshold to Cold Pain There were no differences in the cold pain threshold among all three groups (Figure 3). Lowest Tolerated Temperature Both pain opioid and pain non-opioid subjects showed a decreased tolerance to painful cold temperature. While healthy subjects could tolerate the lowest temperature of 0.56 ± 0.15°C, pain non-opioid subjects could only tolerate the lowest temperature of 2.46 ± 0.41°C (P = 0.01 compared with healthy group, Cohen’s d effect size 0.49). Pain opioid subjects showed an even further decreased cold pain tolerance with the lowest tolerated temperature

Quantitative Sensory Testing, Pain, and Opioid-Induced Hyperalgesia 2786 Contacted

1286 Phone Screened

1158 Excluded

770 Excluded

498 Enrolled

131 Healthy - no pain

2 Withdraw

196 Pain non opioid

24 Withdraw

129 Completed

Figure 2 Recruitment and enrollment flow diagram. being 3.88 ± 0.62°C (P = 0.05, Cohen’s d effect size 0.23) compared with pain non-opioid group (Figure 4). Threshold to Heat Pain Pain opioid group subjects showed a lower threshold (43.7 ± 0.36°C) for heat pain as compared with pain non-opioid group subjects (44.7 ± 0.27°C; P = 0.04, Cohen’s d effect size 1.26), as well as healthy control subjects (44.7 ± 0.28°C; P = 0.05, Cohen’s d effect size 1.25) (Figure 5). Maximal Tolerated Heat Temperature The maximal tolerated heat temperature was lower in pain opioid group subjects (48.8 ± 0.25°C) as compared with either healthy subjects (49.9 ± 0.14°C; P = 0.01, Cohen’s d effect size 0.49) or pain non-opioid group subjects (49.4 ± 0.16°C; P = 0.04, Cohen’s d effect size 0.25) (Figure 6). Tolerance to Supra-Threshold Heat Stimulus A Shapiro–Wilk test for distribution showed that the values of maximal tolerated time for supra-threshold heat stimu-

171 Pain opioid

50 Withdraw

172 Completed

121 Completed

422 Completed study

lation do not follow normal distribution. Accordingly, we used nonparametric Kruskal–Wallis equality-ofpopulations rank test to examine differences among groups. The Kruskal–Wallis showed statistical difference exists among the three groups (P < 0.01). Pain opioid group subjects also showed a markedly decreased tolerance to supra-threshold heat pain stimulation, reflected by a shorter duration of sustained supra-threshold heat stimulation (47°C) before a subject terminated the stimulation, as compared with pain nonopioid group subjects (37.1 ± 2.2 seconds vs 43.5 ± 1.7 seconds, P = 0.02, Cohen’s d effect size 0.29) as well as healthy subjects (37.1 ± 2.2 seconds vs 46.7 ± 1.8 seconds, P < 0.01, Cohen’s d effect size 0.43) (Figure 7). Temporal Pain Summation A train of four identical supra-threshold heat stimuli (47°C) resulted in a progressive increase in pain intensity (VAS) in subjects from all three groups, a known phenomenon of temporal pain summation. However, the magnitude of temporal summation was higher in pain opioid group subjects as compared with healthy and pain non-opioid subjects (334 ± 35.5% vs 250 ± 21.2%, 240 ± 25.4%, 5

Zhang et al.

Table 1

Baseline demographics and pain conditions Healthy Control (N = 129)

Pain Non-Opioid (N = 172)

Pain Opioid (N = 121)

Age (year)* Gender (M/F) DOP (year) DOM(year) VAS Disability† Depression Anxiety Pain condition

35.0 ± 14.2 54/75 N/A N/A N/A 0/129 0/129 0/129 N/A

Adjuvants

N/A

45.6 ± 13.4 78/93 9.7 ± 9.5 N/A 5.4 ± 1.6 43/172 41/172 36/172 Spine-related pain (35%) Injury (39%) Joint osteoarthritis (9%) Persistent postsurgical pain (4%) Peripheral neuropathy (3%) Fibromyalgia (5%) CRPS (2%) Cancer pain (2%) Other (1%) Tylenol (4%) NSAIDs (7%) Tramadol (2%) Anticonvulsants (22%) Muscle relaxants (8%) Antidepressants (10%)

46.6 ± 9.5 63/58 9.5 ± 9.6 8.9 ± 9.6 5.8 ± 1.7 71/121 39/121 27/121 Spine-related pain (39%) Injury (33%) Joint osteoarthritis (11%) Persistent postsurgical pain (4%) Peripheral neuropathy (3%) Fibromyalgia (4%) CRPS (3%) Cancer pain (1%) Other (2%) Tylenol (3%) NSAIDs (6%) Tramadol (1%) Anticonvulsants (26%) Muscle relaxants (6%) Antidepressants (14%)

* Age of healthy control group is younger than both pain non-opioid and pain opioid groups. † Percentage of disability is higher in pain opioid group than in pain non-opioid group. CRPS = complex regional pain syndrome; DOP = duration of pain; DOM = duration of medication (opioid); M/F = male/female; N/A = not applicable; NSAID = nonsteroidal anti-inflammatory drug; VAS = visual analog scale.

P = 0.03, Cohen’s d effect size 0.39, pain opioid group compared with pain non-opioid group). There were no differences in the magnitude of temporal summation between healthy subjects and pain non-opioid group (Figure 8).

Correlation between Different Thermal Pain Measurements A correlation existed between different measurements of thermal pain sensitivity and tolerance in pain opioid subjects, suggesting a global change of thermal pain perception and modulation. The Pearson correlation analysis showed a correlation between cold and heat pain tolerance, as well as different measurements of heat pain sensitivity and tolerance. However, there was no correlation between temporal summation of pain and other modalities of QST such as heat/cold pain sensitivity and tolerance (Table 2, values represent Pearson correlation co-efficiency; values in parentheses represent P values). Correlation between Opioid Dose and Heat Pain Tolerance

Figure 3 Cold pain threshold. 6

We divided pain opioid group subjects into two subgroups: subjects with a heat pain threshold above the group mean (Subgroup A) and those below the group mean (Subgroup B) to examine whether the duration and dose of opioid therapy in each subgroup would correlate with their respective QST changes. Subgroup B subjects showed a higher average dose of opioid medications (A: 75 ± 13 mg; B: 162 ± 55 mg; P = 0.03). This subgroup of

Quantitative Sensory Testing, Pain, and Opioid-Induced Hyperalgesia

Lowest Tolerated Cold Pain Temperature

Maximal Tolerated Temperature

6

50.5

50

* Temperature (Celsius Degree)

Temperature (Celsius Degree)

5 4 3

**

2

49.5

*

49

48.5

1

48 0

47.5

Group

Group

Figure 4 Lowest tolerated cold pain temperature. Blue: healthy control; red: pain non-opioid; yellow: pain opioid. *P ≤ 0.05 pain opioid group compared with pain non-opioid group; **P ≤ 0.01, pain non-opioid group compared with healthy group.

Heat Pain Threshold 45.5

Temperature (Celsius Degree)

45

Figure 6 Maximal tolerated heat temperature. Blue: healthy control; red: pain non-opioid; yellow: pain opioid. *P ≤ 0.01 pain opioid group compared with healthy group; P ≤ 0.05 pain opioid group compared with pain non-opioid group. subjects also had lower maximal tolerated heat temperature (49.6 ± 0.27°C vs 47.6 ± 0.63°C, P = 0.01, Cohen’s d effect size 0.91) as well as a shorter duration of suprathreshold heat pain tolerance (41.2 ± 3.6 seconds vs 22.9 ± 4.6 seconds) as compared with that of Subgroup A (P = 0.01, Cohen’s d effect size 0.92) (Figure 9A–C). In contrast, the duration of opioid therapy in Subgroups A and B was not statistically different. DNIC Testing

44.5

*

44 43.5 43 42.5 42

Group

Figure 5 Heat pain threshold. Blue: healthy control; red: pain non-opioid; yellow: pain opioid. *P ≤ 0.05 pain opioid group compared with pain non-opioid group; P ≤ 0.05 pain opioid group compared with healthy group.

We further tested DNIC in a subset of 16 subjects with chronic pain on opioid therapy and 12 chronic pain subjects on non-opioid therapy. Chronic pain subjects on opioid therapy showed a decreased magnitude of DNIC, manifested as less reduction in heat pain intensity by a second noxious stimulus (cold pain). The DNIC magnitude was reduced at all three time points tested and reached statistical significance at the third time point (40.8 ± 6.1% in non-opioid group vs 26.6 ± 4.6%, P = 0.03, Cohen’s d effect size 0.59) (Figure 10). Discussion We showed that in chronic pain subjects receiving opioid therapy, there were detectable differences in QST characteristics compared with chronic pain subjects receiving non-opioid therapy as well as healthy control subjects. In chronic pain subjects receiving opioid therapy, there was a global increase of sensitivity to noxious thermal stimuli, 7

Zhang et al.

Supra-threshold Heat Pain Tolerance 50

Seconds

45

*

40 35 30 25 20

Group Figure 7 Supra-threshold heat pain tolerance duration. Blue: healthy control; red: pain non-opioid; yellow: pain opioid. *P ≤ 0.01 pain opioid group compared with healthy group; P ≤ 0.05 pain opioid group compared with pain non-opioid group.

Figure 8 Temporal pain summation. BL = baseline stimulus; S1/BL = stimulus 1 over baseline; S1/BL = stimulus 2 over baseline; S1/BL = stimulus 3 over baseline; VAS = visual analog scale. *P ≤ 0.05 pain opioid group compared with pain non-opioid group as well as healthy group. 8

while sensation to non-noxious cold/warm was unchanged. Threshold to cold pain was slightly lower in chronic pain subjects receiving opioid therapy than the other two groups, but was statistically insignificant. However, in Group 3 subjects, 1) threshold to heat pain was lower; 2) tolerance to supra-threshold cold and heat pain was decreased; and 3) temporal pain summation was exacerbated as compared with Group 2 and Group 1 subjects. In a subgroup of chronic pain subjects receiving opioid therapy who displayed a below-average heat pain threshold, their average opioid medication dosage was higher (>twofold) than the remaining Group 3 subjects who had an above-average heat pain threshold. Moreover, chronic pain subjects on opioid therapy exhibited a decrease in DNIC compared with chronic pain subjects on non-opioid therapy, suggesting that diminished DNIC may be a possible underlying mechanism of altered thermal pain response associated with opioid use. Comparison with Other Studies of Opioid-Associated Pain Sensitivity Alteration Our finding of decreased cold pain tolerance is consistent with several previous studies in patients maintained on chronic methadone or buprenorphine using a cold pressor test [15–17,20], confirming the existence of cold pain intolerance in chronic opioid users. Our data also showed a decreased heat pain threshold and decreased heat pain tolerance in chronic pain patients receiving opioid therapy. This is consistent with our previous study with a smaller sample size [18]. Wang et al. [23] also reported a reduced heat pain threshold in opioid-treated chronic low back pain patients compared with healthy subjects. However, our results are different from theirs in that there was a statistically significant difference in heat pain threshold between pain subjects on opioid vs non-opioid therapy, whereas in their study there was no difference between pain subjects on opioid vs non-opioid therapy, although both groups had reduced heat pain threshold compared with healthy controls. Wang et al. showed a higher thermal detection threshold to warm stimuli in opioid-treated pain patients as compared with both non-opioid-treated patients and healthy subjects, whereas our results showed no differences in cold or heat detection threshold in pain subjects with or without opioid compared with healthy subjects. Reznikov et al. [25] examined pain threshold to von Frey filament stimulation, mechanical pressure, heat stimuli, as well as supra-threshold tonic heat pain intensity in chronic pain patients receiving opioid vs nonopioid therapy. Different from our findings, they showed no differences between the two groups in all abovementioned measurements. Several factors might explain the discrepancy between our results and those from Wang et al. [22] and Reznikov et al. [25]. Firstly, there are methodological differences in QST. In this study, we only measured thermal pain response, as our previous study showed no differences in mechanical pain in opioid-treated vs non-opioid-treated

Quantitative Sensory Testing, Pain, and Opioid-Induced Hyperalgesia

Table 2

Correlation between different modalities of quantitative sensory testing (QST) HPT

HPT MTHT LTCT SHT Summation*

1.00 0.7077 (0.001) −0.4004 (0.001) 0.4621 (0.001) −0.1343 (0.0723)

MTHT

LTCT

SHT

Summation*

1.00 −0.5526 (0.001) 0.6166 (0.001) −0.1284 (0.0859)

1.00 −0.4558 (0.001) −0.0862 (0.2527)

1.00 −0.0164 (0.8267)

1.00

* Percentage change of VAS at third stimulus over VAS at baseline stimulus was used to compute correlation of summation and other QST modalities. HPT = heat pain threshold; MTHT = maximal tolerated heat temperature; SHT = supra-threshold heat tolerance; LTCT = lowest tolerated cold temperature.

chronic pain patients [18], which is similar to the findings from Reznikov et al. Reznikov et al. used VAS scores at different time points while subjects were exposed to supra-threshold heat stimulus to measure heat pain threshold and tolerance. We used three different measurements to evaluate heat pain responses: heat pain threshold, the maximal temperature a subject was able to tolerate, and the maximal duration by which a subject could tolerate a supra-threshold heat pain stimulus. Although widely used as a measurement of pain, VAS score could be readily influenced by subjects’ psychosocial background and previous pain experience. Thus, significant within-group variations in VAS score may be expected, which could mask a relatively small betweengroup differences. Indeed, in their study, although statistically not significant, opioid group subjects reported higher VAS scores than non-opioid subjects at all time points during supra-threshold heat pain stimulation. In contrast, we used perhaps more objective measurements (temperature point and time duration) to assess heat pain threshold and tolerance, which may be less affected by subjects’ psychosocial background and previous pain experience, thus enabling us to detect between-group differences. Secondly, sample size may influence the detection of differences between groups. To our best knowledge, our current study has the largest sample size to date, thus providing more statistical power to detect differences in cold and pain responses in opioid-treated subjects. Thirdly, difference in patient population may also account for the difference in results. The chronic pain conditions in our study groups are predominantly noncancer pain, whereas Reznikov et al.’s study included both caner and noncancer pain. The average duration of opioid treatment in our group was 2.7 years vs 32 weeks in Reznikov et al.’s study. It is possible that changes in thermal pain sensitivity may become more detectable with prolonged opioid treatment.

Furthermore, it is well known that concurrent use of illicit drugs may influence subjects’ perception and response to noxious stimuli. In this study, we excluded all subjects who had a detectable illicit drug on urine test, whereas the other studies did not explicitly exclude these subjects. Lastly, the heterogeneity of opioid medication use may also contribute to the difference between our results and those of others. Pharmacologically, methadone is distinctly different from other opioid medications in that it possesses the NMDA receptor antagonism activity. It has been well established that the NMDA receptormediated pathway plays an important role in the development and maintenance of OIH [1]. Indeed, it has been shown that methadone may be used to prevent OIH in a study involving cancer patients [29]. Previous studies examining effects of opioids on thermal responses appeared to have included all opioid medications. However, in our study, to avoid such implication, we excluded subjects using methadone as their opioid therapy. It is possible that the inclusion vs exclusion of methadone in these studies may have contributed, at least partially, to the difference between our results and those of others. Possible Impact of Opioid Dose on Opioid-Associated Pain Sensitivity Alteration We also showed that in chronic pain subjects receiving opioid therapy who displayed low threshold to heat pain, the average dose of daily morphine equivalent dosage is higher than those who had less reduction in heat pain threshold, although the duration of opioid therapy was not statistically different between these two subgroups. This result is consistent with our previous finding in a small group of subjects [18]. A study by Hooten et al. [30] also showed a similar result. They evaluated associations between heat pain perception using a standardized QST method and opioid dose among 109 patients with chronic

9

Zhang et al. A

Magnitude of DNIC

Opioid Medication Dose 50

*

200

150

100

50

45

Percentage Pain Reduction

Daily Morphine Equivalent Dose (mg)

250

40 35

*

30 25 20 15 10 5

0

0

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1

B Maximal Tolerated Heat Temperature

Maximal Tolerated Heat Temperature (Celsius Degree)

52

50

*

48

3

Heat Stimulus

Figure 10 Diffuse noxious inhibitory control (DNIC) in chronic pain subjects on opioid and non-opioid therapy. Blue: pain opioid; red: pain non-opioid. *P ≤ 0.05 pain opioid group compared with pain non-opioid group.

51

49

2

47 46 45 44

Subgroup

C Tolerance Duration to'Suprethreshold Heat Temperature 50 45 40

Seconds

35

*

30 25 20 15 10

Group 3 were considered, although the subgroup analysis showed higher morphine equivalent dose in those Group 3 subjects with a lower (than group mean) heat pain threshold. Therefore, although a higher dose of opioid is more likely to induce such changes, opioid dose alone may not be the only determinant in the development of these changes but rather is one of the multiple factors leading to them. For example, a recent study by Edwards et al. [24] showed that chronic spinal pain patients with a high risk for misuse of prescription opioids are more sensitive to pain than low risk patients as measured by QST.

5 0

subgroup

Figure 9 Subgroup analysis in chronic pain subjects with opioid therapy. (A) Daily morphine equivalent dose. (B) Maximal tolerated heat pain temperature. (C) Tolerance duration to suprathreshold heat temperature. Blue: subgroup A; red: subgroup B. *P ≤ 0.05.

pain undergoing opioid tapering in an outpatient multidisciplinary rehabilitation program. Their results showed that a greater baseline morphine equivalent dose was associated with more hyperalgesic values [30]. In our study, a Pearson correlation analysis did not reveal a direct relationship between opioid dosage and the degree of heat pain threshold or tolerance deduction when all subjects in 10

Opioid-Associated Pain Sensitivity Alteration and DNIC Our data showed an overall decreased tolerance to both cold and heat pain in patients treated with chronic opioids, suggesting that cold pain and heat pain are similarly affected in these patients. A strong correlation between cold pain and heat pain tolerance in pain opioid group subjects in this study lends further support to this notion. Temporal summation of pain, which reflects the central modulation of pain perception, is also exacerbated in pain opioid group compared with pain non-opioid group. Taken together, our data suggest that the mechanism of opioidassociated pain sensitivity alteration may involve the central modulation of global pain processing instead of modulation of individual pathways for different sensory modalities. Consistent with this notion, our data showed that chronic pain subjects on opioid therapy have a diminished diffuse

Quantitative Sensory Testing, Pain, and Opioid-Induced Hyperalgesia inhibitory noxious control. Similarly altered DNIC in patients with chronic pain and opioid therapy has also been shown by Ram et al. [26]. Our findings and those of Ram et al. suggest that chronic opioid use may downregulate DNIC, which, in turn, contributes to the alteration in thermal pain sensitivity. Limitations The cross-sectional nature of this study may limit the interpretation of the observed difference in QST measurements between pain opioid group and pain non-opioid group. We cannot exclude the possibility that certain physiological, psychosocial, or unknown factors may render subjects more sensitive to pain and also predispose them to the need of opioid therapy. To establish the causal relationship of opioid use and altered QST response, a randomized controlled study where pain subjects are randomly assigned to opioid or non-opioid treatment is needed. The average age of healthy subjects is younger than pain opioid and pain non-opioid groups. We cannot exclude the possibility that age may account for some of the difference in QST between healthy and pain subjects. However, there is no difference in age, as well as other demographics between pain opioid and pain nonopioid groups, suggesting that the difference we observed between these two groups is not influenced by the demographics of these two groups.

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Clinical Implications It has been suggested that certain pain response may predict OIH. For example, Cohen et al. [28] evaluated 355 patients on analgesic medications who were scheduled for interventional procedures. They showed that a standard subcutaneous injection of lidocaine provoked higher pain intensity and unpleasantness scores (in response to needle insertion) in patients receiving opioid treatment compared with patients receiving non-opioid treatment. Hooten et al. have shown that heat pain threshold measured by QST correlates with the severity of pain in chronic pain patients including those on opioid therapy [31]. Consistent with those findings, the present data showed that chronic pain patients on opioid therapy displayed altered thermal pain response compared with patients treated with non-opioid therapy; this altered response can be detected by a subset of standard QST parameters. However, the Cohen’s d effect sizes of these QST parameters are in the range of 0.2–0.5, which is considered small to medium [32], with the exception of the heat pain threshold parameter, which has an effect size of 1.26. Although this difference can be detected with a large sample size in a research setting, whether QST is sensitive enough to be used as a clinical diagnostic tool still needs further investigation. Threshold to heat pain may be a more sensitive measurement to detect changes in thermal pain sensitivities in chronic pain patients receiving opioid therapy.

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