- Email: [email protected]
The Effect of Opioid Dose and Treatment Duration on the Perception of a Painful Standardized Clinical Stimulus
Original Articles
The Effect of Opioid Dose and Treatment Duration on the Perception of a Painful Standardized Clinical Stimulus Steven P. Cohen, M.D., Paul J. Christo, M.D., M.B.A., Shuxing Wang, M.D., Ph.D., Lucy Chen, M.D., Milan P. Stojanovic, M.D., Cynthia H. Shields, M.D., Chad Brummett, M.D., and Jianren Mao, M.D., Ph.D. Background and Objectives: The concept of opioid-induced hyperalgesia has recently gained prominence as a contributing factor for opioid tolerance and long-term treatment failure. But whereas the preclinical data for this phenomenon are strong, the mixed clinical data derive primarily from experimental pain models conducted in volunteers and heroin addicts, and nonstandardized clinical stimuli, e.g., surgery. The primary objective of this study is to delineate the effect of opioid dose and treatment duration on pain intensity and unpleasantness ratings following a standardized clinical pain stimulus. Methods: Three hundred and fifty-five patients, on a steady regimen of analgesic medications and scheduled for an interventional procedure, received a standardized subcutaneous injection of lidocaine prior to a full dose of local anesthetic. Before and immediately following the injection, subjects were asked to rate pain and unpleasantness intensity on a 0 to 10 numerical rating scale. Subjects were stratified into 6 groups based on opioid dosage. A control group of 27 volunteers who had no pain and were taking no analgesics were also injected. Results: Both opioid dose and duration of treatment directly correlated with pain intensity and unpleasantness scores. Baseline pain intensity was also positively associated with both outcome variables. Gender was found to be associated with pain intensity and unpleasantness, with females scoring higher in both categories than males. Compared with patients not receiving opioid treatment, patients receiving opioid therapy were more likely to rate the standardized pain stimulus as being more unpleasant than painful. Conclusions: The results of this study bolster preclinical and experimental pain models demonstrating enhanced pain perception in subjects receiving opioid therapy. This simple clinical model may provide a useful tool in examining opioid-induced hyperalgesia. Reg Anesth Pain Med 2008;33:199-206. Key Words:
Hyperalgesia, Nerve block, Opioid, Pain perception, Tolerance.
irst described over 100 years ago,1 the concept of opioid-induced hyperalgesia (OIH) suffuses nearly all aspects of pain management. Directly or indirectly, one’s perspective on this phenomenon affects the drugs we prescribe and the doses we feel comfortable dispensing. Our position on this con-
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troversial subject affects whether or not we prescribe opioids to patients suffering with noncancer pain, how we combat tolerance, and our likelihood to stay the course (i.e., escalate dosing) in patients who are already receiving opioid therapy. With respect to opioid therapy, this topic is equivalent in
From the Department of Anesthesiology & Critical Care Medicine (S.P.C., P.J.C.), Johns Hopkins School of Medicine, Baltimore, MD; Department of Surgery (S.P.C., C.H.S.), Walter Reed Army Medical Center, Washington, DC; Department of Anesthesiology & Critical Care (S.W., L.C., M.P.S., J.M.), Massachusetts General Hospital, Department of Anesthesiology & Critical Care (M.P.S.), Harvard Medical School, Boston, MA; and the Department of Anesthesiology (C.B.), University of Michigan School of Medicine, Ann Arbor, MI. Accepted for publication October 10, 2007. Funded in part by the John P. Murtha Neuroscience and Pain
Institute, Johnstown, PA, and the Army Regional Anesthesia & Pain Medicine Initiative, Washington, DC. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Reprint requests: Steven P. Cohen, M.D., 550 North Broadway, Suite 301, Baltimore, MD 21029. E-mail: [email protected] © 2008 Published by Elsevier Inc. on behalf of the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/08/3303-0001$34.00/0 doi:10.1016/j.rapm.2007.10.009
Regional Anesthesia and Pain Medicine, Vol 33, No 3 (May–June), 2008: pp 199 –206
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stature to, and influences how we contend with, other compelling issues such as addiction, dependence, abuse, diversion, and side effect management. Opioids are the second most frequently prescribed drug class for chronic pain, surpassed only by nonsteroidal anti-inflammatory drugs.2 Yet in recent years, the pendulum on prescribing opioids for chronic noncancer pain has swung back toward restraint, driven partly over concerns regarding OIH.3 In animal studies, the evidence supporting OIH is compelling, albeit mostly limited to rodents.4 In humans, the evidence is strong but conflicting. Among former heroin addicts in methadone maintenance programs, pain tolerance appears to be a more sensitive indicator of OIH than pain threshold, and cold pain a more reliable measure than electrical pain.5-7 The ability to demonstrate a relationship between intraoperative opioid dose and postoperative pain in surgical patients has been decidedly mixed, with some but not all studies demonstrating increased pain and analgesic use with higher opioid doses.8,9 For clinical trials, whereas 1 study found regular opioid use to be independently correlated with treatment failure in patients undergoing cervical facet denervation for chronic neck pain,10 in another study by the same group evaluating lumbar facet denervation, the association disappeared after controlling for confounding variables such as prior surgery, and duration of symptoms.11 There are several limitations to the existing human data. First, most clinical studies involved either short term opioid administration, or patients involved in methadone maintenance programs. In addition to agonist properties, methadone also acts as an antagonist at N-methyl-D-aspartate receptors, which may attenuate nociceptor sensitization.12 Second, most clinical studies used experimental stimuli to assess OIH, which may not simulate real life conditions. Finally, most studies that have sought to quantify OIH based on real life events used surgery, which can never be standardized, as the pain stimulus. The majority of these studies also started using narcotics in opioid-naïve patients at or just before surgical incision, which is dramatically different from the context in which most physicians encounter OIH. In clinical practice, the most common scenario whereby OIH is encountered involves chronic pain patients who have been maintained on opioids for months or even years, presenting with worsening symptoms. In an attempt to address some of these shortcomings, we evaluated the effect of opioid dose and duration of therapy on a standardized, clinical pain stimulus— the subcutaneous administration of local anesthetic
(LA) before an interventional pain management procedure.
Methods Permission to conduct this study was granted by the Internal Review Board at Johns Hopkins School of Medicine and all patients who consented to the procedures. The subjects were 355 patients scheduled for an interventional pain management procedure at the Johns Hopkins Hospital, plus 27 volunteers, without pain or receiving analgesic therapy, who underwent an identical standardized subcutaneous injection without a subsequent procedure. The inclusion criteria for the 355 patients were any acute or chronic pain condition amenable to a diagnostic/therapeutic nerve block or neuromodulation, and a regular analgesic regimen. Aside from control patients, all procedures were done as part of standard clinical care. Exclusion criteria included any change in opioid or other analgesic medications less than 14 days prior to the scheduled procedure, and an inability to understand English or adequately respond to the relevant questions. In addition, no patient took any analgesic the day of their procedure, or received any intravenous sedation or opioid prior to the clinical stimulus. Standardized Clinical Stimulus Under either fluoroscopic guidance or anatomic landmarks for nonfluoroscopically-guided procedures, the needle entry point was marked on the skin, and prepared and draped in an aseptic manner. Subjects were then informed that they were going to receive “a little numbing medication.” The standardized subcutaneous LA injection was performed by an unblinded pain management specialist using a 25-gauge needle and 1 mL of 1% lidocaine to raise a small skin wheal. Before the injection, subjects were asked to rate their pain score using a 0 to 10 numeric pain rating scale. Immediately after the injection, subjects were asked the following 2 questions: 1. On a 0 to 10 pain scale, with 0 being no pain and 10 being the worst pain you can imagine, how would you rate the injection you just received? 2. On a 0 to 10 unpleasantness scale, with 0 being not unpleasant and 10 being the most unpleasant experience you can imagine, how would you rate the injection you just received? All data were recorded by either the injecting physician or an unblinded assistant. Following the standardized LA injection, subjects were given as
Opioid Hyperalgesia Table 1. Equianalgesic Opioid Conversion Chart Medication Morphine Oxycodone Hydrocodone Hydromorphone Methadone Meperidine Codeine Propoxyphene Oxymorphone Transdermal fentanyl* Oral transmucosal fentanyl citrate* Intrathecal morphine*
Equianalgesic Dose 30 mg 20 mg 30 mg 6 mg 4 mg 300 mg 200 mg 200 mg 10 mg (12.5 mcg/h) 800 mcg 0.1 mg
*All medications per os unless otherwise specified.
much LA as deemed necessary to complete the scheduled procedure. In addition to patients who received the standardized lidocaine injection, 27 volunteers who reported no pain conditions within the past year and were using no analgesics received the same injections in either their neck or low back. Data Collection and Statistical Analysis In addition to pain intensity and unpleasantness scores, a number of other clinical and demographic data were collected for analysis. These included age, sex, procedure, location of pain, procedure location (e.g., low back for lumbar epidural steroid injections or facet blocks), duration of pain, duration of opioid therapy, opioid regimen, and preprocedure numerical pain rating score. For those patients taking opioids, their regular dose was converted to oral morphine equivalents according to standard accepted guidelines (Table 1).13,14 The oral morphine equivalent dose (MED) was then converted to a number on an escalating 6-point scale predetermined by a review of 100 medical records designed to stratify “high” and “low” dose opioid therapy for our pain clinic (Table 2). Categorical data are reported both by number of patients and percentage. Continuous data are reported as mean and standard deviation (SD) unless Table 2. Scaled Conversion of Daily Opioid Dose Oral Morphine Equivalents (mg/d)
Conversion Number
Control patients with no pain and taking no opioids 0 1-29 30-89 90-179 180-299 ⱖ300
0 1 2 3 4 5 6
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Table 3. Medications and Dosages Used by Study Participants Medication Oxycodone (n ⫽ 118) Hydrocodone (n ⫽ 35) Morphine (n ⫽ 27) Transdermal fentanyl (n ⫽ 22) Hydromorphone (n ⫽ 14) Methadone (n ⫽ 13) Codeine (n ⫽ 8) Oral transmucosal fentanyl (n ⫽ 4) Propoxyphene (n ⫽ 3) Intrathecal morphine (n ⫽ 2) Meperidine (n ⫽ 2) Oxymorphone (n ⫽ 1)
Median Dose (Range) 25 (2.5-300) 17 (5-70) 110 (15-400) 75 mcg/h (25-200) 12 (2-120) 60 (5-300) 53 (30-90) 1,200 mcg (800-2400) 195 (195-195) 10.3 (9.3-11.3) 50 (50-50) 40
NOTE. All doses in mg/day unless otherwise specified. Approximately twenty percent of subjects were taking more than 1 type of opioid.
otherwise indicated. Statistical analysis of the raw data was performed using software SPSS (SPSS Inc., Chicago, IL). By designating one variant as a factor and the other variants as dependents, 1-way analysis of variance was used to detect overall differences between means. When significant main effects were observed, post hoc Tukey HSD (Honestly Significant Difference) or Dunnett t tests were performed to determine the source(s) of differences. This analysis was repeated for each factor analyzed (e.g., age, sex, opioid dose, opioid treatment duration). Differences were considered statistically significant at the level of P ⬍ .05.
Results Demographic Data and Opioid Dosage A total of 382 patients participated in this study, among which 27 subjects with no pain and no opioid treatment served as a control group. The mean age of patients on opioid therapy was 51 years (SD 16, range 19-89), which was slightly younger than the age of patients not taking opioids (mean 53 years, SD 17, range 16-89, P ⫽ .003). The daily MED ranged from 7.5 mg to over 3,000 mg among the subjects on opioid therapy (Table 3). There were no differences in the average daily MED or duration of pain between male and female subjects. Subjects enrolled in this study underwent a wide variety of interventional procedures including interlaminar epidural steroid injection (n ⫽ 96), transforaminal epidural steroid injection (n ⫽ 63), facet block (n ⫽ 52), sacroiliac joint injection (n ⫽ 32), discography/intradiscal procedures (n ⫽ 13), sympathetic block (e.g., celiac plexus, lumbar sym-
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pathetic, ganglion impar, superior hypogastric plexus; n ⫽ 46), greater trochanteric bursa injection (n ⫽ 17), shoulder block (n ⫽ 2), spinal cord stimulator, or intrathecal pump implantation (n ⫽ 4), intercostal nerve block (n ⫽ 2), trigger point injection (n ⫽ 7), and others (n ⫽ 16). Baseline Differences Between Groups Subjects using intermediate or high doses of opioids (ⱖ 30 MED) were found to have higher preinjection pain scores than patients using no opioids (P ⫽ .0001). Between patients on low-dose (⬍ 30 MED) and intermediate or high doses of opioids, a trend toward statistical significance was noted for those in the latter group to have higher baseline pain scores (P ⫽ .24). However, the duration of symptoms in subjects using ⱖ30 MED was not statistically different than other groups (P ⫽ .13). Excluding control subjects, neither the location of pain nor the injection location differed between treatment groups (Table 4; P ⬎ .05). Pain Intensity and Unpleasantness Based on Procedure When only patients receiving opioids were considered, neither the type (P ⫽ .194 for both pain and unpleasantness), nor the location (P ⫽ .076 for pain and P ⫽ .233 for unpleasantness) of injection was associated with any outcome variable. However, when data from all study subjects were analyzed, differences in pain and unpleasantness scores were noted for both type (P ⫽ .007 and P ⫽.035 for pain and unpleasantness scores, respectively), and location (P ⫽ .024 and P ⫽ .134 for pain and unpleasantness scores, respectively). With regard to location, injections performed in the thorax region (mean 6.2, SD 3.3) were more likely to be perceived as painful or unpleasant than those in the pelvis (mean 2.6, SD 2.3). With respect to type of injection, in descending order, the 3 highest pain scores were noted for trigger point injections (mean 7.3, SD 3.1), “others” (e.g., extremity peripheral nerve blocks; mean 5.5, SD 3.2), and epidural steroid injections (mean 4.9, SD 2.8). Pain Intensity and Unpleasantness Based on Opioid Dose Overall differences in pain intensity (F ⫽ 4.22, P ⫽ .0001) and unpleasantness (F ⫽ 4.54, P ⫽ .0001) scores in response to standardized injections were noted between subjects receiving opioid therapy and those not taking opioids. Both mean postinjection pain intensity and unpleasantness scores (P ⬍ .001) were significantly higher in opioid therapy
patients than in patients treated exclusively with nonopioid analgesics, or in control subjects. These differences were independent of the type of procedure, location of procedure, pain duration, pain location, and gender (each P ⬎ .05). When opioid use was categorized by dose (Figs 1 and 2), both pain intensity and unpleasantness scores were significantly higher in subjects receiving daily MEDs of 90 mg-179 mg (group 4; n ⫽ 27), 180 mg-299 mg (group 5; n ⫽ 28), or more than 300 mg (group 6; n ⫽ 30), compared with subjects receiving low dose opioids (⬍90 MED; n ⫽ 123), no opioid treatment (group 1; n ⫽ 147), or control subjects (n ⫽ 27) (P ⬍ .001). Similarly, the duration of opioid treatment was positively correlated with both pain and unpleasantness scores (P ⫽ .001; Table 5, Figs 3 and 4). When gender was treated as an independent variable, significant differences in both pain intensity (F ⫽ 5.56, P ⫽ .019) and pain unpleasantness (F ⫽ 6.33, P ⫽ .012) were noted. Specifically, females responded to LA injection with higher pain and unpleasantness scores than male subjects irrespective of opioid dose. Preinjection pain scores were found to be associated with both outcome measures, such that patients with higher baseline pain were more likely to rate the subcutaneous LA injection as being more painful and unpleasant (P ⫽ .001). When control patients were excluded from analysis, the duration of pain had no significant impact on pain or unpleasantness ratings (Table 5). A significant difference was noted in the ratio of pain intensity:unpleasantness scores between patients receiving opioid therapy and those treated solely with nonopioid analgesics. The 147 patients not taking opioids reported slightly higher pain intensity scores than unpleasantness scores (ratio 1.05), which is in contrast with the ratio of 0.95 found in the 208 subjects who were receiving opioids (P ⫽ .033).
Discussion This is a simple prospective study with 1 defined objective: to examine the influence of opioid dose and duration of therapy on pain intensity and unpleasantness in response to a standardized subcutaneous injection before an interventional pain management procedure. The overall analysis demonstrated that both pain intensity and unpleasantness scores were significantly higher in subjects receiving opioid therapy compared with those patients using nonopioid pharmacotherapy. Although the design of this study is straightforward, the data interpretation requires further analysis. A number of issues could potentially influence
Table 4. Demographic and Clinical Variables as a Function of Daily Opioid Dose Patients, According to Daily Opioid Dose*
1-29 mg (n ⫽ 68)
30-89 mg (n ⫽ 55)
90-179 mg (n ⫽ 28)
180-299 mg (n ⫽ 27)
ⱖ300 mg (n ⫽ 30)
41.2 (13.2) Control
52.5 (16.9) P ⫽ .012
52.2 (16.2) P ⫽ .012
50.5 (16.1) P ⫽ .057
49.1 (15.2) P ⫽ .237
52.2 (12.6) P ⫽ .05
48.8 (16.5) P ⫽ .248
13 14
52 95
23 45
30 25
13 15
11 16
10 20
4.8 (6.2) P ⫽ .027
4.5 (5.0) P ⫽ .029
5.2 (6.4) P ⫽ .114
8.2 (10.9) P ⫽ 1.0
4.5 (5.0) P ⫽ .094
8.4 (8.1) Control
102 (70) 13 (9) 3 (2) 20 (14) 4 (3) 1 (1) 2 (1) 1 (1)
42 (62) 8 (12) 1 (1) 13 (19) 0 (0) 0 (0) 4 (6)
37 (67) 4 (7) 2 (4) 8 (15) 0 (0) 1 (2) 3 (5)
19 (68) 2 (3) 2 (7) 3 (11) 0 (0) 0 (0) 2 (7)
13 (48) 4 (15) 3 (11) 0 (0) 1 (4) 4 (15) 2 (7)
21 (70) 2 (7) 0 (0) 4 (13) 1 (3) 0 (0) 2 (7)
17 (63) 10 (37)
112 (76) 19 (13) 4 (3) 10 (7) 0 (0) 0 (0) 2 (1)
45 (66) 10 (15) 1 (1) 10 (15) 0 (0) 0 (0) 2 (3)
44 (80) 3 (5) 2 (4) 5 (9) 0 (0) 0 (0) 1 (2)
22 (79) 2 (7) 2 (7) 2 (7) 0 (0) 0 (0) 0 (0)
19 (70) 3 (11) 3 (1) 0 (0) 1 (4) 0 (0) 1 (4)
20 (69) 3 (10) 1 (3) 2 (7) 0 (0) 2 (7) 1 (3)
0 (0)
5.7 (2.6)
6.3 (2.1)
6.9 (2.2)
6.7 (2.2)
6.4 (2.1)
6.9 (2.4)
2.7 (2.1) Control
4.3 (2.8) P ⫽ .027
4.6 (2.9) P ⫽ .01
4.7 (2.9) P ⫽ .009
5.6 (2.9) P ⫽ .001
5.4 (2.9) P ⫽ .002
5.8 (3.0) P ⫽ .001
3.2 (2.2) Control
4.1 (3.0) P ⫽ .48
4.7 (3.1) P ⫽ .109
5.2 (3.3) P ⫽ .022
5.7 (3.2) P ⫽ .014
5.9 (3.3) P ⫽ .006
6.1 (3.0) P ⫽ .002
Cohen et al.
NOTE. P values are the results of post-hoc Dunnett t tests. Abbreviation: SD, standard deviation. Control group value is the reference for statistical comparison. *Opioid doses are in daily morphine equivalents.
•
0 mg (n ⫽147)
Opioid Hyperalgesia
Age in years, mean (SD) Sex, n Male Female Duration of pain in years, mean (SD) Location of pain, n (%) Low back Neck Thorax Extremity Head Abdomen Pelvis None Injection location, n (%) Low back Neck Thorax Extremity Head Abdomen Pelvis Baseline pain score, mean (SD) Standardized injection pain score, mean (SD) Standardized injection unpleasantness score, mean (SD)
Control Subjects With No Pain or Opioid Therapy (n ⫽ 27)
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Fig 1. Standardized injection pain scores as a function of opioid dose. Doses are given in daily oral morphine equivalents: 0, control patients with no pain and taking no opioids; 1, no opioids; 2, 1 mg to 29 mg; 3, 30 mg to 89 mg; 4, 90 mg to 179 mg; 5, 180 mg to 299 mg; 6, ⱖ300 mg. Error bars indicate standard deviation. * P ⬍ .05 compared with group 0. **P ⫽ .027 compared with group 0.
the response to LA injection. For instance, the intensity and/or duration of a subject’s pre-existing pain might conceivably affect their perception of the standardized LA injection. These factors can influence pain processing, and hence pain and unpleasantness scores, by fermenting the complex phenomena of peripheral and central sensitization, which in turn affects the 4 main components of pain experience: transduction, transmission, modulation, and perception.15,16 Similar confounding factors could be related to the site of injection and the type of interventional procedure the patient received. As borne out by our own and other observations,17 gender differences can account for differences in pain perception. Yet each of these potential confounding factors were analyzed, and except for gender and baseline pain scores, there were no clear associations between any of these factors and pain intensity and unpleasantness scores. A direct correlation was observed between opioid treatment and pain intensity and unpleasantness scores after LA injection. Moreover, a high opioid dose (designated as ⱖ90 mg MED) was found by multivariate analysis to be an independent predictor of painful response to LA injection. Of note, pain rating was conducted immediately after the injection, indicating that reported pain intensity and unpleasantness scores reflected the response to stimulation, rather than an attenuated effect of the LA. Distinctions were not made in this study between long- and short-acting opioids, nor was the time of day of the procedure recorded. It is therefore possible that patients taking solely short-acting
opioids (mostly group 2; 1-29 MED) who had procedures done later in the day experienced more pain than those taking the bulk of their opioids in long-acting preparations due to a hypersensitive “withdrawal-like” state. However, our data do not support the hypothesis that differences in pain and unpleasantness scores stemmed from subliminal opioid withdrawal because baseline pain scores were not statistically different between subjects using opioids. Collectively, these data suggest opioid treatment to be an important contributing factor to the perception of pain accompanying a clinical stimulus. An interesting observation was that unpleasantness scores tended to be higher than pain scores in patients taking ⱖ30 MED per day of opioids. One possible explanation for this unexpected finding is that the phenomenon of OIH may exert a greater effect on pain processing (e.g., cognitive and emotional components), and modulation pathways, than it does on nociceptive transduction and transmission. A second plausible reason is that unpleasantness scores may be more reliable indicators of pain tolerance, whereas pain scores better reflect nociceptive threshold. As alluded to earlier, the former has been shown in experimental studies to be a more reliable measure of OIH than the latter.6,7 One important caveat regarding our data interpretation is that psychological factors such as depression and anxiety were not independently considered in this study. Other factors, not controlled for, that might potentially influence pain experi-
Fig 2. Standardized injection unpleasantness scores as a function of opioid dose. Doses are given in daily oral morphine equivalents: 0, control patients with no pain and taking no opioids; 1, no opioids; 2, 1 mg to 29 mg; 3, 30 mg to 89 mg; 4, 90 mg to 179 mg; 5, 180 mg to 299 mg; 6, ⱖ300 mg. Error bars indicate standard deviation. *P ⬍ .05 compared with group 0.
Opioid Hyperalgesia
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Table 5. Pain and Unpleasantness Scores as a Function of Clinical and Treatment Variables Standardized Injection Pain Score, Mean (SD) Duration of pain (control group included as ⬍1 year) ⬍1 year 1-5 years ⬎5 years Duration of pain (control group excluded) ⬍1 year 1-5 years ⬎5 years Duration of opioid use None ⬍1 year ⱖ1 year Baseline pain score (0-10) 0 1-5 6-10
One-way ANOVA Tukey HSD 4.0 (3.0) Control 5.0 (2.8) P ⫽ .019 4.4 (2.8) P ⫽ .65 One-way ANOVA Tukey HSD 4.6 (3.2) Control 5.0 (2.8) P ⫽ .682 4.4 (2.8) P ⫽ .840 One-way ANOVA Tukey HSD 4.0 (2.7) Control 4.7 (2.9) P ⫽ .195 5.4 (3.0) P ⫽ .001 One-way ANOVA Tukey HSD 2.6 (2.0) Control 4.2 (2.8) P ⫽ .021 5.1 (2.9) P ⫽ .001
P ⫽ .018 Dunnett t test P ⫽ .569 P ⫽ .144 Control P ⫽ .213 Dunnett t test P ⫽ .796 P ⫽ .151 Control P ⫽ .001 Dunnett t test P ⬍ .001 P ⫽ .147 Control P ⫽ .001 Dunnett t test P ⫽ .001 P ⫽ .004 Control
Standardized Injection Unpleasantness Score, Mean (SD) One-way ANOVA P ⫽ .319 Tukey HSD Dunnett t test 4.3 (3.2) Control P ⫽ .629 4.9 (3.2) P ⫽ .288 P ⫽ .761 4.7 (3.1) P ⫽ .704 Control One-way ANOVA P ⫽ .83 Tukey HSD Dunnett t test 4.9 (3.4) Control P ⫽ .883 4.9 (3.2) P ⫽ .999 P ⫽ .774 4.7 (3.1) P ⫽ .910 Control One-way ANOVA P ⫽ .001 Tukey HSD Dunnett t test 4.0 (2.9) Control P ⬍ .001 5.0 (3.1) P ⫽ .021 P ⫽ .293 5.6 (3.3) P ⫽ .001 Control One-way ANOVA P ⫽ .001 Tukey HSD Dunnett t test 3.0 (2.2) Control P ⫽ .001 4.4 (3.1) P ⫽ .075 P ⫽ .044 5.2 (3.2) P ⫽ .001 Control
NOTE. P values listed in the columns are the results of 1-way ANOVA with post-hoc Tukey HSD (Honestly Significant Difference) and Dunnett t tests. Abbreviations: ANOVA, analysis of variance; SD, standard deviation. Control group value is the reference for statistical comparison.
ence include prior injections, distractions (e.g., the lumbar spine patients were able to look at the fluoroscopy machine during prone procedures, which was not the case during computed tomographyguided or cervical procedures), patient expectations, the timing of the procedure (i.e., procedures done in the afternoon might be associated with higher scores than those done in the morning), variations in the speed and placement of the injection, and the use of adjuvant and other nonopioid analgesics. In addition, not blinding the investigators could have inadvertently biased our results by subtly influencing patient perception or even the
Fig 3. Standardized pain scores as a function of duration of opioid use. Error bars indicate standard deviation. *P ⬍ .001 compared with “none.”
procedure itself. In future studies, attempts should be made to control for, and standardize, these variables, and enhance objectivity by blinding the investigators. One relationship not analyzed in this study was the effect drug type had on outcome measures. We elected not to examine this variable because doing so might result in misleading findings. First, a significant percentage of patients were taking more than 1 type of opioid medication, and many were taking several. Second, the results of such an anal-
Fig 4. Standardized unpleasantness scores as a function of opioid dose. Error bars indicate standard deviation. *P ⫽ .02 compared with “none.” **P ⬍ .001 compared with “none.”
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ysis would likely be biased against drugs that are available only in short-acting formulations, and in favor of drugs that are long acting (e.g., methadone), or predominantly used in sustained release preparations (e.g., fentanyl). Third, because opioid treatment was not standardized, it would prejudice the findings against drugs preferred by our referring doctors, because these providers tend not to be as adept at managing opioids as our pain clinic doctors, who tend to prefer long-acting drugs. Finally, there is a lot of controversy and variation surrounding opioid conversion, especially in high dose ranges. The results observed in this study are generally consistent with those demonstrated in previous studies involving heroin addicts in methadone maintenance programs5-7 and in surgical patients.8,9 It is important to note that the nociceptive stimulation in this study derived from an inescapable clinical stimulus. To the best of our knowledge, this is the first OIH study that utilized a standardized clinical stimulus as the nociceptive stimulus rather than experimental (e.g., cold pressor or electrical) stimulation. Two potential advantages of this model are that the medications patients were taking more closely reflected those prescribed in clinical practice, and the context is more realistic. But while this approach enabled us to evaluate OIH in a more clinically relevant setting, 1 potential confounding factor is that the control patients used as a comparison group were not subject to the same anxiety as those anticipating an imminent interventional procedure. In conclusion, the present data are consistent with the proposed clinical implications of OIH.18 Our findings provide yet another piece of evidence supporting the possible presence of OIH in subjects using opioid therapy, and may complement the data generated using experimental pain conditions on this topic.5-7 Pending future refinements, this simple model of transient pain may provide a standardized tool useful to examine the instant response to a painful stimulus in a clinical setting.
References 1. Rossbach MJ. Ueber die Gewoehnung an Gifte. Pflugers Archieve Gesamte. Physiologie des Menschen 1880;21:213-225. 2. Clark JD. Chronic pain prevalence and analgesic prescribing in a general medical population. J Pain Symptom Manage 2002;23:131-137.
3. Cohen SP, Raja SN. The middle way: A practical approach to prescribing opioids. Nat Clin Pract Neurol 2006;2:580-581. 4. Angst MS, Clark JD. Opioid-induced hyperalgesia. A qualitative systematic review. Anesthesiology 2006; 104:570-587. 5. Doverty M, Somogyi AA, White JM, Bochner F, Beare CH, Menelaou A, Ling W. Methadone maintenance patients are cross-tolerant to the antinociceptive effects of morphine. Pain 2001;93:155-163. 6. Doverty M, White JM, Somogyi AA, Bochner F, Ali R, Ling W. Hyperalgesic responses in methadone maintenance patients. Pain 2001;90:91-96. 7. Pud D, Cohen D, Lawental E, Eisenberg E. Opioids and abnormal pain perception: New evidence from a study of chronic opioid addicts and healthy subjects. Drug Alcohol Depend 2006;82:218-223. 8. Guignard B, Bossard AE, Coste C, Sessler DI, Lebrault C, Alfonsi P, Fletcher D, Chauvin M. Acute opioid tolerance: Intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 2000;93:409-417. 9. Cortinez LI, Brandes V, Munoz HR, Guerrero ME, Mur M. No clinical evidence of acute opioid tolerance after remifentanil-based anesthesia. Br J Anaesth 2001;87:866-869. 10. Cohen SP, Bajwa Z, Kraemer J, Dragovich A, Williams K, Hurley RW. Factors predicting success and failure for cervical facet radiofrequency denervation: A multi-center analysis. Reg Anesth Pain Med 2007;32: 495-503. 11. Cohen SP, Hurley RW, Christo PJ, Winkley J, Mohiuddin MM, Stojanovic MP. Clinical predictors of success and failure for lumbar facet radiofrequency denervation. Clin J Pain 2007;23:45-52. 12. Price DD, Mayer DJ, Mao J, Caruso FS. NMDAreceptor antagonists and opioid receptor interactions as related to analgesia and tolerance. J Pain Symptom Manage 2000;19:S7-S11. 13. Patanwala AE, Duby J, Waters D, Erstad BL. Opioid conversions in acute care [Erratum in: 2007;41:531]. Ann Pharmacother 2007;41:255-266. 14. Berdine HJ, Nesbit SA. Equianalgesic dosing of opioids. J Pain Palliat Care Pharmacother 2006;20:79-84. 15. Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron 2006;52:77-92. 16. Giordano J. The neurobiology of nociceptive and antinociceptive systems. Pain Physician 2005;8:277-290. 17. Arendt-Nielsen L, Bajaj P, Drewes AM. Visceral pain: Gender differences in response to experimental and clinical pain. Eur J Pain 2004;8:465-472. 18. Mao J. Opioid-induced abnormal pain sensitivity: Implications in clinical opioid therapy. Pain 2002; 100:213-217.
The Effect of Opioid Dose and Treatment Duration on the Perception of a Painful Standardized Clinical Stimulus Steven P. Cohen, M.D., Paul J. Christo, M.D., M.B.A., Shuxing Wang, M.D., Ph.D., Lucy Chen, M.D., Milan P. Stojanovic, M.D., Cynthia H. Shields, M.D., Chad Brummett, M.D., and Jianren Mao, M.D., Ph.D. Background and Objectives: The concept of opioid-induced hyperalgesia has recently gained prominence as a contributing factor for opioid tolerance and long-term treatment failure. But whereas the preclinical data for this phenomenon are strong, the mixed clinical data derive primarily from experimental pain models conducted in volunteers and heroin addicts, and nonstandardized clinical stimuli, e.g., surgery. The primary objective of this study is to delineate the effect of opioid dose and treatment duration on pain intensity and unpleasantness ratings following a standardized clinical pain stimulus. Methods: Three hundred and fifty-five patients, on a steady regimen of analgesic medications and scheduled for an interventional procedure, received a standardized subcutaneous injection of lidocaine prior to a full dose of local anesthetic. Before and immediately following the injection, subjects were asked to rate pain and unpleasantness intensity on a 0 to 10 numerical rating scale. Subjects were stratified into 6 groups based on opioid dosage. A control group of 27 volunteers who had no pain and were taking no analgesics were also injected. Results: Both opioid dose and duration of treatment directly correlated with pain intensity and unpleasantness scores. Baseline pain intensity was also positively associated with both outcome variables. Gender was found to be associated with pain intensity and unpleasantness, with females scoring higher in both categories than males. Compared with patients not receiving opioid treatment, patients receiving opioid therapy were more likely to rate the standardized pain stimulus as being more unpleasant than painful. Conclusions: The results of this study bolster preclinical and experimental pain models demonstrating enhanced pain perception in subjects receiving opioid therapy. This simple clinical model may provide a useful tool in examining opioid-induced hyperalgesia. Reg Anesth Pain Med 2008;33:199-206. Key Words:
Hyperalgesia, Nerve block, Opioid, Pain perception, Tolerance.
irst described over 100 years ago,1 the concept of opioid-induced hyperalgesia (OIH) suffuses nearly all aspects of pain management. Directly or indirectly, one’s perspective on this phenomenon affects the drugs we prescribe and the doses we feel comfortable dispensing. Our position on this con-
F
troversial subject affects whether or not we prescribe opioids to patients suffering with noncancer pain, how we combat tolerance, and our likelihood to stay the course (i.e., escalate dosing) in patients who are already receiving opioid therapy. With respect to opioid therapy, this topic is equivalent in
From the Department of Anesthesiology & Critical Care Medicine (S.P.C., P.J.C.), Johns Hopkins School of Medicine, Baltimore, MD; Department of Surgery (S.P.C., C.H.S.), Walter Reed Army Medical Center, Washington, DC; Department of Anesthesiology & Critical Care (S.W., L.C., M.P.S., J.M.), Massachusetts General Hospital, Department of Anesthesiology & Critical Care (M.P.S.), Harvard Medical School, Boston, MA; and the Department of Anesthesiology (C.B.), University of Michigan School of Medicine, Ann Arbor, MI. Accepted for publication October 10, 2007. Funded in part by the John P. Murtha Neuroscience and Pain
Institute, Johnstown, PA, and the Army Regional Anesthesia & Pain Medicine Initiative, Washington, DC. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Reprint requests: Steven P. Cohen, M.D., 550 North Broadway, Suite 301, Baltimore, MD 21029. E-mail: [email protected] © 2008 Published by Elsevier Inc. on behalf of the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/08/3303-0001$34.00/0 doi:10.1016/j.rapm.2007.10.009
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stature to, and influences how we contend with, other compelling issues such as addiction, dependence, abuse, diversion, and side effect management. Opioids are the second most frequently prescribed drug class for chronic pain, surpassed only by nonsteroidal anti-inflammatory drugs.2 Yet in recent years, the pendulum on prescribing opioids for chronic noncancer pain has swung back toward restraint, driven partly over concerns regarding OIH.3 In animal studies, the evidence supporting OIH is compelling, albeit mostly limited to rodents.4 In humans, the evidence is strong but conflicting. Among former heroin addicts in methadone maintenance programs, pain tolerance appears to be a more sensitive indicator of OIH than pain threshold, and cold pain a more reliable measure than electrical pain.5-7 The ability to demonstrate a relationship between intraoperative opioid dose and postoperative pain in surgical patients has been decidedly mixed, with some but not all studies demonstrating increased pain and analgesic use with higher opioid doses.8,9 For clinical trials, whereas 1 study found regular opioid use to be independently correlated with treatment failure in patients undergoing cervical facet denervation for chronic neck pain,10 in another study by the same group evaluating lumbar facet denervation, the association disappeared after controlling for confounding variables such as prior surgery, and duration of symptoms.11 There are several limitations to the existing human data. First, most clinical studies involved either short term opioid administration, or patients involved in methadone maintenance programs. In addition to agonist properties, methadone also acts as an antagonist at N-methyl-D-aspartate receptors, which may attenuate nociceptor sensitization.12 Second, most clinical studies used experimental stimuli to assess OIH, which may not simulate real life conditions. Finally, most studies that have sought to quantify OIH based on real life events used surgery, which can never be standardized, as the pain stimulus. The majority of these studies also started using narcotics in opioid-naïve patients at or just before surgical incision, which is dramatically different from the context in which most physicians encounter OIH. In clinical practice, the most common scenario whereby OIH is encountered involves chronic pain patients who have been maintained on opioids for months or even years, presenting with worsening symptoms. In an attempt to address some of these shortcomings, we evaluated the effect of opioid dose and duration of therapy on a standardized, clinical pain stimulus— the subcutaneous administration of local anesthetic
(LA) before an interventional pain management procedure.
Methods Permission to conduct this study was granted by the Internal Review Board at Johns Hopkins School of Medicine and all patients who consented to the procedures. The subjects were 355 patients scheduled for an interventional pain management procedure at the Johns Hopkins Hospital, plus 27 volunteers, without pain or receiving analgesic therapy, who underwent an identical standardized subcutaneous injection without a subsequent procedure. The inclusion criteria for the 355 patients were any acute or chronic pain condition amenable to a diagnostic/therapeutic nerve block or neuromodulation, and a regular analgesic regimen. Aside from control patients, all procedures were done as part of standard clinical care. Exclusion criteria included any change in opioid or other analgesic medications less than 14 days prior to the scheduled procedure, and an inability to understand English or adequately respond to the relevant questions. In addition, no patient took any analgesic the day of their procedure, or received any intravenous sedation or opioid prior to the clinical stimulus. Standardized Clinical Stimulus Under either fluoroscopic guidance or anatomic landmarks for nonfluoroscopically-guided procedures, the needle entry point was marked on the skin, and prepared and draped in an aseptic manner. Subjects were then informed that they were going to receive “a little numbing medication.” The standardized subcutaneous LA injection was performed by an unblinded pain management specialist using a 25-gauge needle and 1 mL of 1% lidocaine to raise a small skin wheal. Before the injection, subjects were asked to rate their pain score using a 0 to 10 numeric pain rating scale. Immediately after the injection, subjects were asked the following 2 questions: 1. On a 0 to 10 pain scale, with 0 being no pain and 10 being the worst pain you can imagine, how would you rate the injection you just received? 2. On a 0 to 10 unpleasantness scale, with 0 being not unpleasant and 10 being the most unpleasant experience you can imagine, how would you rate the injection you just received? All data were recorded by either the injecting physician or an unblinded assistant. Following the standardized LA injection, subjects were given as
Opioid Hyperalgesia Table 1. Equianalgesic Opioid Conversion Chart Medication Morphine Oxycodone Hydrocodone Hydromorphone Methadone Meperidine Codeine Propoxyphene Oxymorphone Transdermal fentanyl* Oral transmucosal fentanyl citrate* Intrathecal morphine*
Equianalgesic Dose 30 mg 20 mg 30 mg 6 mg 4 mg 300 mg 200 mg 200 mg 10 mg (12.5 mcg/h) 800 mcg 0.1 mg
*All medications per os unless otherwise specified.
much LA as deemed necessary to complete the scheduled procedure. In addition to patients who received the standardized lidocaine injection, 27 volunteers who reported no pain conditions within the past year and were using no analgesics received the same injections in either their neck or low back. Data Collection and Statistical Analysis In addition to pain intensity and unpleasantness scores, a number of other clinical and demographic data were collected for analysis. These included age, sex, procedure, location of pain, procedure location (e.g., low back for lumbar epidural steroid injections or facet blocks), duration of pain, duration of opioid therapy, opioid regimen, and preprocedure numerical pain rating score. For those patients taking opioids, their regular dose was converted to oral morphine equivalents according to standard accepted guidelines (Table 1).13,14 The oral morphine equivalent dose (MED) was then converted to a number on an escalating 6-point scale predetermined by a review of 100 medical records designed to stratify “high” and “low” dose opioid therapy for our pain clinic (Table 2). Categorical data are reported both by number of patients and percentage. Continuous data are reported as mean and standard deviation (SD) unless Table 2. Scaled Conversion of Daily Opioid Dose Oral Morphine Equivalents (mg/d)
Conversion Number
Control patients with no pain and taking no opioids 0 1-29 30-89 90-179 180-299 ⱖ300
0 1 2 3 4 5 6
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Table 3. Medications and Dosages Used by Study Participants Medication Oxycodone (n ⫽ 118) Hydrocodone (n ⫽ 35) Morphine (n ⫽ 27) Transdermal fentanyl (n ⫽ 22) Hydromorphone (n ⫽ 14) Methadone (n ⫽ 13) Codeine (n ⫽ 8) Oral transmucosal fentanyl (n ⫽ 4) Propoxyphene (n ⫽ 3) Intrathecal morphine (n ⫽ 2) Meperidine (n ⫽ 2) Oxymorphone (n ⫽ 1)
Median Dose (Range) 25 (2.5-300) 17 (5-70) 110 (15-400) 75 mcg/h (25-200) 12 (2-120) 60 (5-300) 53 (30-90) 1,200 mcg (800-2400) 195 (195-195) 10.3 (9.3-11.3) 50 (50-50) 40
NOTE. All doses in mg/day unless otherwise specified. Approximately twenty percent of subjects were taking more than 1 type of opioid.
otherwise indicated. Statistical analysis of the raw data was performed using software SPSS (SPSS Inc., Chicago, IL). By designating one variant as a factor and the other variants as dependents, 1-way analysis of variance was used to detect overall differences between means. When significant main effects were observed, post hoc Tukey HSD (Honestly Significant Difference) or Dunnett t tests were performed to determine the source(s) of differences. This analysis was repeated for each factor analyzed (e.g., age, sex, opioid dose, opioid treatment duration). Differences were considered statistically significant at the level of P ⬍ .05.
Results Demographic Data and Opioid Dosage A total of 382 patients participated in this study, among which 27 subjects with no pain and no opioid treatment served as a control group. The mean age of patients on opioid therapy was 51 years (SD 16, range 19-89), which was slightly younger than the age of patients not taking opioids (mean 53 years, SD 17, range 16-89, P ⫽ .003). The daily MED ranged from 7.5 mg to over 3,000 mg among the subjects on opioid therapy (Table 3). There were no differences in the average daily MED or duration of pain between male and female subjects. Subjects enrolled in this study underwent a wide variety of interventional procedures including interlaminar epidural steroid injection (n ⫽ 96), transforaminal epidural steroid injection (n ⫽ 63), facet block (n ⫽ 52), sacroiliac joint injection (n ⫽ 32), discography/intradiscal procedures (n ⫽ 13), sympathetic block (e.g., celiac plexus, lumbar sym-
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pathetic, ganglion impar, superior hypogastric plexus; n ⫽ 46), greater trochanteric bursa injection (n ⫽ 17), shoulder block (n ⫽ 2), spinal cord stimulator, or intrathecal pump implantation (n ⫽ 4), intercostal nerve block (n ⫽ 2), trigger point injection (n ⫽ 7), and others (n ⫽ 16). Baseline Differences Between Groups Subjects using intermediate or high doses of opioids (ⱖ 30 MED) were found to have higher preinjection pain scores than patients using no opioids (P ⫽ .0001). Between patients on low-dose (⬍ 30 MED) and intermediate or high doses of opioids, a trend toward statistical significance was noted for those in the latter group to have higher baseline pain scores (P ⫽ .24). However, the duration of symptoms in subjects using ⱖ30 MED was not statistically different than other groups (P ⫽ .13). Excluding control subjects, neither the location of pain nor the injection location differed between treatment groups (Table 4; P ⬎ .05). Pain Intensity and Unpleasantness Based on Procedure When only patients receiving opioids were considered, neither the type (P ⫽ .194 for both pain and unpleasantness), nor the location (P ⫽ .076 for pain and P ⫽ .233 for unpleasantness) of injection was associated with any outcome variable. However, when data from all study subjects were analyzed, differences in pain and unpleasantness scores were noted for both type (P ⫽ .007 and P ⫽.035 for pain and unpleasantness scores, respectively), and location (P ⫽ .024 and P ⫽ .134 for pain and unpleasantness scores, respectively). With regard to location, injections performed in the thorax region (mean 6.2, SD 3.3) were more likely to be perceived as painful or unpleasant than those in the pelvis (mean 2.6, SD 2.3). With respect to type of injection, in descending order, the 3 highest pain scores were noted for trigger point injections (mean 7.3, SD 3.1), “others” (e.g., extremity peripheral nerve blocks; mean 5.5, SD 3.2), and epidural steroid injections (mean 4.9, SD 2.8). Pain Intensity and Unpleasantness Based on Opioid Dose Overall differences in pain intensity (F ⫽ 4.22, P ⫽ .0001) and unpleasantness (F ⫽ 4.54, P ⫽ .0001) scores in response to standardized injections were noted between subjects receiving opioid therapy and those not taking opioids. Both mean postinjection pain intensity and unpleasantness scores (P ⬍ .001) were significantly higher in opioid therapy
patients than in patients treated exclusively with nonopioid analgesics, or in control subjects. These differences were independent of the type of procedure, location of procedure, pain duration, pain location, and gender (each P ⬎ .05). When opioid use was categorized by dose (Figs 1 and 2), both pain intensity and unpleasantness scores were significantly higher in subjects receiving daily MEDs of 90 mg-179 mg (group 4; n ⫽ 27), 180 mg-299 mg (group 5; n ⫽ 28), or more than 300 mg (group 6; n ⫽ 30), compared with subjects receiving low dose opioids (⬍90 MED; n ⫽ 123), no opioid treatment (group 1; n ⫽ 147), or control subjects (n ⫽ 27) (P ⬍ .001). Similarly, the duration of opioid treatment was positively correlated with both pain and unpleasantness scores (P ⫽ .001; Table 5, Figs 3 and 4). When gender was treated as an independent variable, significant differences in both pain intensity (F ⫽ 5.56, P ⫽ .019) and pain unpleasantness (F ⫽ 6.33, P ⫽ .012) were noted. Specifically, females responded to LA injection with higher pain and unpleasantness scores than male subjects irrespective of opioid dose. Preinjection pain scores were found to be associated with both outcome measures, such that patients with higher baseline pain were more likely to rate the subcutaneous LA injection as being more painful and unpleasant (P ⫽ .001). When control patients were excluded from analysis, the duration of pain had no significant impact on pain or unpleasantness ratings (Table 5). A significant difference was noted in the ratio of pain intensity:unpleasantness scores between patients receiving opioid therapy and those treated solely with nonopioid analgesics. The 147 patients not taking opioids reported slightly higher pain intensity scores than unpleasantness scores (ratio 1.05), which is in contrast with the ratio of 0.95 found in the 208 subjects who were receiving opioids (P ⫽ .033).
Discussion This is a simple prospective study with 1 defined objective: to examine the influence of opioid dose and duration of therapy on pain intensity and unpleasantness in response to a standardized subcutaneous injection before an interventional pain management procedure. The overall analysis demonstrated that both pain intensity and unpleasantness scores were significantly higher in subjects receiving opioid therapy compared with those patients using nonopioid pharmacotherapy. Although the design of this study is straightforward, the data interpretation requires further analysis. A number of issues could potentially influence
Table 4. Demographic and Clinical Variables as a Function of Daily Opioid Dose Patients, According to Daily Opioid Dose*
1-29 mg (n ⫽ 68)
30-89 mg (n ⫽ 55)
90-179 mg (n ⫽ 28)
180-299 mg (n ⫽ 27)
ⱖ300 mg (n ⫽ 30)
41.2 (13.2) Control
52.5 (16.9) P ⫽ .012
52.2 (16.2) P ⫽ .012
50.5 (16.1) P ⫽ .057
49.1 (15.2) P ⫽ .237
52.2 (12.6) P ⫽ .05
48.8 (16.5) P ⫽ .248
13 14
52 95
23 45
30 25
13 15
11 16
10 20
4.8 (6.2) P ⫽ .027
4.5 (5.0) P ⫽ .029
5.2 (6.4) P ⫽ .114
8.2 (10.9) P ⫽ 1.0
4.5 (5.0) P ⫽ .094
8.4 (8.1) Control
102 (70) 13 (9) 3 (2) 20 (14) 4 (3) 1 (1) 2 (1) 1 (1)
42 (62) 8 (12) 1 (1) 13 (19) 0 (0) 0 (0) 4 (6)
37 (67) 4 (7) 2 (4) 8 (15) 0 (0) 1 (2) 3 (5)
19 (68) 2 (3) 2 (7) 3 (11) 0 (0) 0 (0) 2 (7)
13 (48) 4 (15) 3 (11) 0 (0) 1 (4) 4 (15) 2 (7)
21 (70) 2 (7) 0 (0) 4 (13) 1 (3) 0 (0) 2 (7)
17 (63) 10 (37)
112 (76) 19 (13) 4 (3) 10 (7) 0 (0) 0 (0) 2 (1)
45 (66) 10 (15) 1 (1) 10 (15) 0 (0) 0 (0) 2 (3)
44 (80) 3 (5) 2 (4) 5 (9) 0 (0) 0 (0) 1 (2)
22 (79) 2 (7) 2 (7) 2 (7) 0 (0) 0 (0) 0 (0)
19 (70) 3 (11) 3 (1) 0 (0) 1 (4) 0 (0) 1 (4)
20 (69) 3 (10) 1 (3) 2 (7) 0 (0) 2 (7) 1 (3)
0 (0)
5.7 (2.6)
6.3 (2.1)
6.9 (2.2)
6.7 (2.2)
6.4 (2.1)
6.9 (2.4)
2.7 (2.1) Control
4.3 (2.8) P ⫽ .027
4.6 (2.9) P ⫽ .01
4.7 (2.9) P ⫽ .009
5.6 (2.9) P ⫽ .001
5.4 (2.9) P ⫽ .002
5.8 (3.0) P ⫽ .001
3.2 (2.2) Control
4.1 (3.0) P ⫽ .48
4.7 (3.1) P ⫽ .109
5.2 (3.3) P ⫽ .022
5.7 (3.2) P ⫽ .014
5.9 (3.3) P ⫽ .006
6.1 (3.0) P ⫽ .002
Cohen et al.
NOTE. P values are the results of post-hoc Dunnett t tests. Abbreviation: SD, standard deviation. Control group value is the reference for statistical comparison. *Opioid doses are in daily morphine equivalents.
•
0 mg (n ⫽147)
Opioid Hyperalgesia
Age in years, mean (SD) Sex, n Male Female Duration of pain in years, mean (SD) Location of pain, n (%) Low back Neck Thorax Extremity Head Abdomen Pelvis None Injection location, n (%) Low back Neck Thorax Extremity Head Abdomen Pelvis Baseline pain score, mean (SD) Standardized injection pain score, mean (SD) Standardized injection unpleasantness score, mean (SD)
Control Subjects With No Pain or Opioid Therapy (n ⫽ 27)
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Fig 1. Standardized injection pain scores as a function of opioid dose. Doses are given in daily oral morphine equivalents: 0, control patients with no pain and taking no opioids; 1, no opioids; 2, 1 mg to 29 mg; 3, 30 mg to 89 mg; 4, 90 mg to 179 mg; 5, 180 mg to 299 mg; 6, ⱖ300 mg. Error bars indicate standard deviation. * P ⬍ .05 compared with group 0. **P ⫽ .027 compared with group 0.
the response to LA injection. For instance, the intensity and/or duration of a subject’s pre-existing pain might conceivably affect their perception of the standardized LA injection. These factors can influence pain processing, and hence pain and unpleasantness scores, by fermenting the complex phenomena of peripheral and central sensitization, which in turn affects the 4 main components of pain experience: transduction, transmission, modulation, and perception.15,16 Similar confounding factors could be related to the site of injection and the type of interventional procedure the patient received. As borne out by our own and other observations,17 gender differences can account for differences in pain perception. Yet each of these potential confounding factors were analyzed, and except for gender and baseline pain scores, there were no clear associations between any of these factors and pain intensity and unpleasantness scores. A direct correlation was observed between opioid treatment and pain intensity and unpleasantness scores after LA injection. Moreover, a high opioid dose (designated as ⱖ90 mg MED) was found by multivariate analysis to be an independent predictor of painful response to LA injection. Of note, pain rating was conducted immediately after the injection, indicating that reported pain intensity and unpleasantness scores reflected the response to stimulation, rather than an attenuated effect of the LA. Distinctions were not made in this study between long- and short-acting opioids, nor was the time of day of the procedure recorded. It is therefore possible that patients taking solely short-acting
opioids (mostly group 2; 1-29 MED) who had procedures done later in the day experienced more pain than those taking the bulk of their opioids in long-acting preparations due to a hypersensitive “withdrawal-like” state. However, our data do not support the hypothesis that differences in pain and unpleasantness scores stemmed from subliminal opioid withdrawal because baseline pain scores were not statistically different between subjects using opioids. Collectively, these data suggest opioid treatment to be an important contributing factor to the perception of pain accompanying a clinical stimulus. An interesting observation was that unpleasantness scores tended to be higher than pain scores in patients taking ⱖ30 MED per day of opioids. One possible explanation for this unexpected finding is that the phenomenon of OIH may exert a greater effect on pain processing (e.g., cognitive and emotional components), and modulation pathways, than it does on nociceptive transduction and transmission. A second plausible reason is that unpleasantness scores may be more reliable indicators of pain tolerance, whereas pain scores better reflect nociceptive threshold. As alluded to earlier, the former has been shown in experimental studies to be a more reliable measure of OIH than the latter.6,7 One important caveat regarding our data interpretation is that psychological factors such as depression and anxiety were not independently considered in this study. Other factors, not controlled for, that might potentially influence pain experi-
Fig 2. Standardized injection unpleasantness scores as a function of opioid dose. Doses are given in daily oral morphine equivalents: 0, control patients with no pain and taking no opioids; 1, no opioids; 2, 1 mg to 29 mg; 3, 30 mg to 89 mg; 4, 90 mg to 179 mg; 5, 180 mg to 299 mg; 6, ⱖ300 mg. Error bars indicate standard deviation. *P ⬍ .05 compared with group 0.
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Table 5. Pain and Unpleasantness Scores as a Function of Clinical and Treatment Variables Standardized Injection Pain Score, Mean (SD) Duration of pain (control group included as ⬍1 year) ⬍1 year 1-5 years ⬎5 years Duration of pain (control group excluded) ⬍1 year 1-5 years ⬎5 years Duration of opioid use None ⬍1 year ⱖ1 year Baseline pain score (0-10) 0 1-5 6-10
One-way ANOVA Tukey HSD 4.0 (3.0) Control 5.0 (2.8) P ⫽ .019 4.4 (2.8) P ⫽ .65 One-way ANOVA Tukey HSD 4.6 (3.2) Control 5.0 (2.8) P ⫽ .682 4.4 (2.8) P ⫽ .840 One-way ANOVA Tukey HSD 4.0 (2.7) Control 4.7 (2.9) P ⫽ .195 5.4 (3.0) P ⫽ .001 One-way ANOVA Tukey HSD 2.6 (2.0) Control 4.2 (2.8) P ⫽ .021 5.1 (2.9) P ⫽ .001
P ⫽ .018 Dunnett t test P ⫽ .569 P ⫽ .144 Control P ⫽ .213 Dunnett t test P ⫽ .796 P ⫽ .151 Control P ⫽ .001 Dunnett t test P ⬍ .001 P ⫽ .147 Control P ⫽ .001 Dunnett t test P ⫽ .001 P ⫽ .004 Control
Standardized Injection Unpleasantness Score, Mean (SD) One-way ANOVA P ⫽ .319 Tukey HSD Dunnett t test 4.3 (3.2) Control P ⫽ .629 4.9 (3.2) P ⫽ .288 P ⫽ .761 4.7 (3.1) P ⫽ .704 Control One-way ANOVA P ⫽ .83 Tukey HSD Dunnett t test 4.9 (3.4) Control P ⫽ .883 4.9 (3.2) P ⫽ .999 P ⫽ .774 4.7 (3.1) P ⫽ .910 Control One-way ANOVA P ⫽ .001 Tukey HSD Dunnett t test 4.0 (2.9) Control P ⬍ .001 5.0 (3.1) P ⫽ .021 P ⫽ .293 5.6 (3.3) P ⫽ .001 Control One-way ANOVA P ⫽ .001 Tukey HSD Dunnett t test 3.0 (2.2) Control P ⫽ .001 4.4 (3.1) P ⫽ .075 P ⫽ .044 5.2 (3.2) P ⫽ .001 Control
NOTE. P values listed in the columns are the results of 1-way ANOVA with post-hoc Tukey HSD (Honestly Significant Difference) and Dunnett t tests. Abbreviations: ANOVA, analysis of variance; SD, standard deviation. Control group value is the reference for statistical comparison.
ence include prior injections, distractions (e.g., the lumbar spine patients were able to look at the fluoroscopy machine during prone procedures, which was not the case during computed tomographyguided or cervical procedures), patient expectations, the timing of the procedure (i.e., procedures done in the afternoon might be associated with higher scores than those done in the morning), variations in the speed and placement of the injection, and the use of adjuvant and other nonopioid analgesics. In addition, not blinding the investigators could have inadvertently biased our results by subtly influencing patient perception or even the
Fig 3. Standardized pain scores as a function of duration of opioid use. Error bars indicate standard deviation. *P ⬍ .001 compared with “none.”
procedure itself. In future studies, attempts should be made to control for, and standardize, these variables, and enhance objectivity by blinding the investigators. One relationship not analyzed in this study was the effect drug type had on outcome measures. We elected not to examine this variable because doing so might result in misleading findings. First, a significant percentage of patients were taking more than 1 type of opioid medication, and many were taking several. Second, the results of such an anal-
Fig 4. Standardized unpleasantness scores as a function of opioid dose. Error bars indicate standard deviation. *P ⫽ .02 compared with “none.” **P ⬍ .001 compared with “none.”
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Regional Anesthesia and Pain Medicine Vol. 33 No. 3 May–June 2008
ysis would likely be biased against drugs that are available only in short-acting formulations, and in favor of drugs that are long acting (e.g., methadone), or predominantly used in sustained release preparations (e.g., fentanyl). Third, because opioid treatment was not standardized, it would prejudice the findings against drugs preferred by our referring doctors, because these providers tend not to be as adept at managing opioids as our pain clinic doctors, who tend to prefer long-acting drugs. Finally, there is a lot of controversy and variation surrounding opioid conversion, especially in high dose ranges. The results observed in this study are generally consistent with those demonstrated in previous studies involving heroin addicts in methadone maintenance programs5-7 and in surgical patients.8,9 It is important to note that the nociceptive stimulation in this study derived from an inescapable clinical stimulus. To the best of our knowledge, this is the first OIH study that utilized a standardized clinical stimulus as the nociceptive stimulus rather than experimental (e.g., cold pressor or electrical) stimulation. Two potential advantages of this model are that the medications patients were taking more closely reflected those prescribed in clinical practice, and the context is more realistic. But while this approach enabled us to evaluate OIH in a more clinically relevant setting, 1 potential confounding factor is that the control patients used as a comparison group were not subject to the same anxiety as those anticipating an imminent interventional procedure. In conclusion, the present data are consistent with the proposed clinical implications of OIH.18 Our findings provide yet another piece of evidence supporting the possible presence of OIH in subjects using opioid therapy, and may complement the data generated using experimental pain conditions on this topic.5-7 Pending future refinements, this simple model of transient pain may provide a standardized tool useful to examine the instant response to a painful stimulus in a clinical setting.
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