JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (27)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Li, X.
Right arrow Articles by Clark, J. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Li, X.
Right arrow Articles by Clark, J. D.
Anesth Analg 2001;93:204-209
© 2001 International Anesthesia Research Society

REGIONAL ANESTHESIA

Opioid-Induced Hyperalgesia and Incisional Pain

Xiangqi Li, MD, Martin S. Angst, MD, and J. David Clark, MD, PhD

Veterans Affairs, Palo Alto Health Care System and Department of Anesthesiology, Stanford University, Palo Alto, California

Address correspondence and reprint requests to J. David Clark, MD, PhD, VAPAHCS, Anesthesiology, 112A, 3801 Miranda Avenue, Palo Alto, CA 94304. Address e-mail to djclark{at}stanford.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Opioids occupy a position of unsurpassed clinical utility in the treatment of pain of many etiologies. However, recent reports in laboratory animals and humans have documented the occurrence of hyperalgesia when the administration of opioids is abruptly tapered or discontinued, a condition known as opioid-induced hyperalgesia (OIH). In these studies we documented that rats administered morphine (40 mg · kg-1 · day-1 for 6 days) via subcutaneous osmotic minipumps demonstrated thermal hyperalgesia and mechanical allodynia for several days after the cessation of morphine administration. Additional experiments using a rat model of incisional pain showed that that attributable to OIH were additive with the hyperalgesia and allodynia that resulted from incision. In our final experiments we observed that if naloxone is administered chronically before incision then discontinued (20 mg · kg-1 · day-1 for 6 days), the hyperalgesia and allodynia that result from hind paw incision was markedly reduced. In contrast, naloxone 1 mg/kg administered acutely after hind paw incision increased hyperalgesia and allodynia. We conclude that the chronic administration of exogenous opioid receptor agonists and antagonists before incision can alter the hyperalgesia and allodynia observed in this pain model, perhaps by altering intrinsic opioidergic systems involved in setting thermal and mechanical nociceptive thresholds.

Implications: The chronic administration of opioids followed by abrupt cessation can lead toa state of hyperalgesia. In these studies we demonstrate that the hyperalgesiafrom opioid cessation and from hind paw incision are additive in rats. Wesuggest that failure to take into consideration preoperative opioid use canlead to excessive postoperative pain.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Though opioids occupy a position of unsurpassed clinical utility for the treatment of many types of pain, some practitioners harbor concerns about the long-term consequences of their use. These consequences can generally be classified as either psychological (e.g., psychological dependence and addiction) or physiological (e.g., analgesic tolerance and constipation). Another complication that may be observed with the use of opioids is opioid-induced hyperalgesia (OIH). One setting in which OIH has been observed is with the use of very large doses of either IV or intrathecal opioids such as morphine (1–4). A second setting in which OIH has been observed is with the chronic use of opioids followed by abrupt reductions in dosage. This manifestation of OIH is not limited to the well-described pain complaints of those who abuse drugs and subsequently undergo opioid withdrawal. There are now reports documenting spontaneous pain, allodynia, and thermal hyperalgesia in humans after reductions in dosage or abrupt cessation of opioids administered for therapeutic purposes (5,6). Likewise, sudden cessation of intrathecal morphine delivery because of catheter malfunction can lead to a state of allodynia to mechanical stimuli (light touch) that resolves on resumption of opioid administration (7).

With more attention being focused on opioid pharmacology over the last decade paralleling increased clinical enthusiasm for this class of drugs, OIH has become a focus of laboratory investigations, some of the more important of which have noted a gradual onset of thermal hyperalgesia in rats treated with intermittent daily injections of morphine and other opioids (8–10), and have documented brief periods of opioid abstinence during continuous opioid administration hastens the onset and increases the magnitude of OIH (11). The mechanistic basis for OIH is unclear, but N-methyl-D-aspartate (NMDA) receptor activation seems to be a critical step (12–14).

Many patients present for surgical procedures with histories of chronic opioid use for medically indicated or illicit purposes. Furthermore, chronically administered opioids are often mismanaged in the perioperative setting because of unrecognized patient usage, fear of overdose, or temporary unavailability of the oral route of administration. Significant reductions in opioid dosage from preprocedural levels may therefore lead to hyperalgesia in the perioperative period. Potentially worsening this problem is the presence of pain caused by the surgical procedure itself.

In the studies described below, we test the hypothesis that abrupt cessation of opioid administration at the time of hind paw incision in a rat model of incisional pain leads to a heightened manifestation of the thermal hyperalgesia and mechanical allodynia observed after incision in control animals. We also explore the role of intrinsic opioid systems in the regulation of nociceptive thresholds. We conclude that exogenous opioid administration or manipulation of endogenous opioid activity strongly regulates thermal hyperalgesia and mechanical allodynia in the rat incisional model of pain.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All protocols used in these studies were approved by our local Animal Use Committee. Male Sprague-Dawley rats were obtained from B&K (Freemont, CA) at a weight of approximately 200 g and used in experiments at approximately 250 g. Animals were kept under standard husbandry conditions two per cage, 12 h:12 h light:dark cycle with food and water ad libitum. These conditions were maintained throughout the course of chronic treatments. Each animal was used for a single group of studies.

After weighing rats, 2 mL osmotic minipumps (Alza, Palo Alto, CA) capable of delivering a steady infusion of 10 µL/h were implanted subcutaneously. For this, induction of isoflurane anesthesia was followed by shearing of a patch of hair on the back. After skin sterilization a 1.5 cm skin incision was made followed by creation of a pocket of sufficient size to fit the pump. The pump was inserted and the incision was closed with surgical staples followed by application of antibiotic ointment. The pumps had been filled with morphine sulfate (Sigma, St Louis, MO) dissolved in 0.9% NaCl at sufficient concentration to deliver 40 mg · kg-1 · day-1. This infusion rate and duration has previously been demonstrated to lead to morphine tolerance and dependence in rats (15). Control animals were subjected to anesthesia, creation of the skin pocket, and closure. Preliminary experiments established that implantation of saline-containing pumps for periods of up to 2 wk did not alter thermal withdrawal latencies when compared with animals having creation of a skin pocket alone. After 6 days the animals were again anesthetized, and the pumps were removed, or, in some groups of animals, replaced with a new morphine-containing pump.

Some animals, having had morphine-containing osmotic minipumps implanted, were injected subcutaneously with naloxone 1 mg/kg (Sigma) dissolved in 0.9% NaCl on days 2, 4, and 6 after pump implantation. In other experiments animals received naloxone as an infusion via an osmotic minipump at the rate of 20 mg · kg-1 · day-1 before hind paw incision. In the postincisional period, one group of animals received a subcutaneous bolus of naloxone 1 mg/kg 30 min before testing.

For some experiments, rats underwent hind paw incision as originally described by Brennan et al. (16) and as we have previously used (17). In this model a 1-cm incision was made on the plantar surface of right hind paw with the animal under isoflurane anesthesia using a #15 scalpel blade. The incision was started immediately distal to the heel, and extended to a point just proximal to the first set of tori (footpads). Care was taken to identify and divide the plantaris muscle. After hemostasis was obtained, two 4-0 silk sutures were placed in mattress fashion along the wound. Antibiotic ointment was then applied. Animals in the control groups underwent anesthesia without incision. Wounds were checked for evidence of dehiscence before behavioral testing.

We used the method of Hargreaves et al. (18) as we have done previously (17) to measure thermal withdrawal latencies in our rats. In this assay, animals were placed on a 27°C temperature-controlled glass surface inside a cylindrical (20 cm diameter) clear enclosure. After a 20-min period of acclimation, a focused beam of light was directed to the plantar surface of the hind paw immediately distal to the proximal set of footpads. Preliminary experiments established the current needed from the power source to obtain a paw flick latency of 10–12 s in control rats. Two latency measurements were made per animal approximately 5 min apart. A 20-s stimulation limit (cutoff) was used to avoid tissue damage. The observer was kept blinded as to pretreatment protocol.

We used the method of Chaplan et al. (19) as we have done previously (17) to measure mechanical allodynia. In this type of experiment rats were placed on raised wire mesh platforms in cylindrical clear enclosures, allowed to acclimate 20 min, and calibrated nylon von Frey filaments were applied for 5 s to the same area of the footpad as described for the Hargreaves et al. (18) assay. The observer watched for purposeful withdrawal of the hind paw from the stimulus. Typically, a range of fibers from 0.4 to 21 g force (7 fibers) was used.

Analysis of repeated measures was accomplished by using a two-way analysis of variance for repeated measures followed by post hoc testing. For parametric data obtained from thermal hyperalgesia testing, Dunnett’s test was used to detect differences between groups at specific time points. For the nonparametric data obtained from mechanical allodynia testing, a Mann-Whitney U-test was used to detect differences between groups.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Rats having undergone the implantation of osmotic minipumps containing morphine (40 mg · kg-1 · day-1) demonstrated transient analgesia to thermal stimuli as assessed by using the Hargreaves et al. (18) method (Fig. 1). No analgesia was detectable by the third day postminipump implantation, and withdrawal latency was unaffected by the injection of naloxone 1 mg/kg after testing on days 2, 4, and 6 in combination with morphine infusion (Group 3 versus Group 4). These combination morphine/naloxone treated rats commonly exhibited signs of withdrawal such as shaking, paw paddling, and diarrhea after the injection of naloxone. Rats administered naloxone 1 mg/kg intermittently (no other drugs) on days 2, 4, and 6 did not have thermal withdrawal latencies statistically different from control rats, nor did they exhibit any signs of withdrawal after naloxone injection (Group 2 versus Group 1). The continuous infusion of naloxone at the rate of 20 mg · kg-1 · day-1 did not alter thermal responses over the 6 days of infusion (Group 5).



View larger version (52K):
[in this window]
[in a new window]
  		Figure 1. Thermal paw withdrawal latencies in rats during the period of pretreatment. Group 1: control rats; Group 2: rats administered naloxone boluses on days 2,4,6 (after testing); Group 3: rats with morphine pumps (placed after testing on day 1); Group 4: rats with morphine pumps also given naloxone boluses on days 2, 4, and 6; Group 5: rats with naloxone pumps (placed after testing on day 1). For Groups 1–4 n = 6 rats; for Group 5, n = 8 rats. Statistical analysis performed to detect differences between control and treatment group withdrawal latencies on indicated days, *P < 0.05; **P < 0.01.

 
Rats treated with morphine for 6 days using osmotic minipumps demonstrated thermal hyperalgesia and mechanical allodynia after pump removal (Fig. 2). These effects were greatest on days 1–3 after pump removal. The degree of thermal hyperalgesia observed after pump removal tended to be more and of longer duration if naloxone was administered intermittently during the period of morphine infusion, though differences were not statistically significant (Group 4 versus Group 3). Animals treated with naloxone boluses alone on days 2, 4, and 6 before testing displayed no hyperalgesia or allodynia relative to control animals (Group 2 versus Group 1). Animals having received a naloxone infusion for 6 days followed by pump removal had thermal and mechanical latencies indistinguishable from controls (Group 5). In no group of animals were shaking, paw paddling or diarrhea (signs of withdrawal) noted during testing in the 7-day period after the cessation of morphine administration.



View larger version (19K):
[in this window]
[in a new window]
  		Figure 2. Thermal hyperalgesia (A) and mechanical allodynia (B) after various pretreatments. In this figure day 0 represents the day of osmotic pump removal corresponding to day 6 of the pretreatment period. Group 1: control rats; Group 2: rats administered naloxone boluses on days 2, 4, and 6 (after testing); Group 3: rats with morphine pumps (placed after testing on day 1); Group 4: rats with morphine pumps also given naloxone boluses on days 2, 4, and 6; Group 5: rats with naloxone pumps (placed after testing on day 1). For Groups 1–4 n = 6 rats. For Group 5, n = 10. Statistical analysis performed to detect differences between control and treatment group withdrawal latencies on indicated days, *P < 0.05; **P < 0.01.

 
Hind paw incision according to the method of Brennan et al. (16) led to the transient changes in thermal and mechanical withdrawal thresholds, as we have previously reported (17) (Fig. 3). Additional data demonstrate that rats pretreated with morphine infusion combined with intermittent naloxone administration then hind paw incision displayed hyperalgesia and allodynia of increased intensity and of longer duration than control animals (Group 3 versus Group 1). However, if instead of simply removing the morphine pumps from the morphine/naloxone treated animals the pumps were replaced at the time of hind paw incision, the resulting hyperalgesia and allodynia were indistinguishable from those variables in control incised animals (Group 2 versus Group 1).



View larger version (15K):
[in this window]
[in a new window]
  		Figure 3. Thermal hyperalgesia (A) and mechanical allodynia (B) after various pretreatments followed by hind paw incision. In this figure day 0 is considered to be the day of osmotic pump removal and hind paw incision. Group 1: control (incision only); Group 2: rats treated with a morphine pump/intermittent naloxone boluses before incision, morphine pump replaced at time of hind paw incision; Group 3: rats treated with a morphine pump/intermittent naloxone boluses before incision, morphine pump removed at time of hind paw incision. For all groups n = 6–8 rats. Statistical analysis performed to detect differences between control and treatment group withdrawal latencies on indicated days, *P < 0.05; **P < 0.01.

 
In a separate set of experiments rats were pretreated with either saline (Group 1) or naloxone by continuous infusion (20 mg · kg-1 · day-1, Group 2) then subjected to hind paw incision. This dose and duration of naloxone infusion enhances the analgesic potency of morphine in rats (20). The data are presented in Figure 4. Less thermal hyperalgesia and mechanical allodynia were demonstrable after hind paw incision in animals pretreated with naloxone infusion. A separate group of rats had 1 mg/kg naloxone administered 30 min before thermal and mechanical testing at the indicated times after having undergone hind paw incision (Group 3). Thermal and mechanical thresholds were significantly lower in these animals at some time points as compared with animals having incision alone.



View larger version (15K):
[in this window]
[in a new window]
  		Figure 4. Thermal hyperalgesia (A) and mechanical allodynia (B) after various pretreatments followed by hind paw incision. Group 1: control (incision only); Group 2: rats treated with a naloxone pump before incision (pump removed at time of hind paw incision); Group 3: control rats injected with naloxone 1 mg/kg 30 min before behavioral testing. For all groups n = 6 rats. Statistical analysis performed to detect differences between control and treatment group withdrawal latencies on indicated days, *P < 0.05; **P < 0.01.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The studies described above were designed to explore the influence of the chronic administration of the opioid agonist morphine and the opioid antagonist naloxone on the thermal hyperalgesia and mechanical allodynia observed after hind paw incision in rats. Our data are consistent with the related hypotheses that chronic administration of morphine or naloxone can alter thermal hyperalgesia and mechanical allodynia after hind paw incision, and that intrinsic opioidergic mechanisms influence the degree of hyperalgesia and allodynia measurable after hind paw incision. The fundamental observations supporting these hypotheses are as follows: 1) pretreatment of rats with morphine followed by abrupt cessation led to hyperalgesia and allodynia; 2) pretreatment with morphine/abstinence followed by hind paw incision led to an increase in the degree of hyperalgesia and allodynia caused by incision of the hind paw; 3) this excess hyperalgesia and allodynia could be eliminated by the continuation of morphine infusion in the postincisional period, even though animals appeared tolerant to morphine; 4) pretreatment with naloxone for 6 days greatly reduced the hyperalgesia and allodynia measured after hind paw incision; and 5) naloxone administered acutely after hind paw incision increased hyperalgesia and allodynia; this was particularly prominent several days after incision.

A portion of the first hypothesis—that chronic exposure to opioids can lead to hyperalgesia—is not a new one. In fact, the observation that hyperalgesia could be demonstrated after abrupt cessation of opioids is nearly three decades old and was mentioned in early studies directed at understanding addiction and dependence (21). OIH has more recently been recognized as a matter that may be of some clinical significance and has also been recognized as a phenomenon that could shed some light on mechanisms of hyperalgesia resulting from other etiologies. We now understand that this may be a centrally mediated phenomenon because intrathecal administration of morphine, particularly if intermittent, leads to thermal hyperalgesia in rats. Thus, in protocols where opioid infusions were intermittently stopped or in protocols where naloxone was used to induce abstinence, the degree of hyperalgesia produced was more than in animals receiving continuous infusions (11,14). In the present studies we failed to demonstrate robust increases in hyperalgesia or allodynia in rats treated with morphine infusion/intermittent naloxone when compared with rats treated with morphine infusion alone. We did not, however, investigate the possibilities that increased doses of naloxone or more frequent administration of the opioid receptor antagonist would have reproduced the results observed by others.

Additional studies demonstrated that systemic administration of the relatively µ-opioid receptor selective agonist, fentanyl, could cause OIH in rats (13), thus implicating the µ-opioid receptor in OIH but not excluding other classes of opioid receptors. Finally, although relatively little is known about the mechanism of induction of OIH, NMDA receptors have been implicated by experiments documenting that both analgesic tolerance and OIH were reduced if NMDA receptor antagonists were administered along with opioids (12–14). In this regard some distinction might be made between OIH and the hyperalgesia resulting from hind paw incision. It appears the cutaneous hyperalgesia observed in the rat incisional model is not sensitive to NMDA antagonists, at least when administered after the incision is made (22).

These studies go beyond previously published reports in several ways. One new set of observations relates to the effects of chronic naloxone exposure on the thermal hyperalgesia and mechanical allodynia seen after hind paw incision. Relatively chronic (5–7 days) exposure of rats to the opioid antagonists naloxone or naltrexone does not alter baseline sensitivity to thermal stimuli, but does shift the morphine dose response curve to the left, implying heightened sensitivity of the rats to morphine’s analgesic effects (20). We also failed to observe any effect on baseline thermal and mechanical withdrawal thresholds, but we were able to demonstrate that animals treated for 6 days with a continuous subcutaneous infusion of naloxone at 20 mg · kg-1 · day-1 showed much less thermal hyperalgesia and mechanical allodynia after hind paw incision. The observations of pretreatment with extrinsically supplied opioid agonists and antagonists altering thermal and mechanical nociceptive thresholds in our pain model lead us to hypothesize that intrinsic opioidergic mechanisms might be partly responsible for controlling thermal and mechanical thresholds after hind paw incision. Indeed, we were able to demonstrate that the acute administration of naloxone in rats having undergone hind paw incision markedly increased thermal hyperalgesia and mechanical allodynia for days after incision. This is consistent with intrinsic opioids playing the hypothesized regulatory role.

A second contribution of the present studies relates to the increased hyperalgesia and allodynia observed in the incised hind paws of rats if those animals had been pretreated with morphine. Our data suggest that although this effect is not evident within the first 24 hrs after incision, an additive effect of incision and opioid pretreatment can be demonstrated at later time points. One interpretation would be that nociceptive mechanisms are nearly fully activated in the initial period after hind paw incision, which makes observation of additional hyperalgesia or allodynia difficult to document. However, as recovery from the surgical insult occurs, the additional effect of the opioid-induced hyperalgesia becomes evident. We are unaware of reports examining the interaction between OIH and other types of pain, such as neuropathic or inflammatory pain. In one study where rats were rendered tolerant to morphine it was observed that formalin-induced pain behaviors were unaltered (23). However, the animals continued to receive morphine treatment during the formalin testing and were not hyperalgesic.

Though direct extrapolation of animal behavioral data to clinical practice is fraught with peril, the continued pursuit of issues surrounding OIH may lead to clinical investigations directed at evaluating the impact of chronic opioid administration, dosing schedules, and perioperative opioid management on patient’s pain experiences. We are particularly concerned with the apparent additive effects of OIH with incisional hyperalgesia and allodynia. Patients often present for procedures with histories of opioid use for medically indicated or illicit purposes. It is also not uncommon for there to be significant impediments to maintaining preoperative opioid administration rates in the perioperative period because of confusion over preoperative dose, the temporary unavailability of the oral route of administration in some patients, or rational or irrational fears of overdose. It could be that rapid decreases in opioid doses combined with procedural pain leads to excess pain in the perioperative period. Our animal data indicate that the excess hyperalgesia and allodynia resulting from OIH can be eliminated simply by maintaining preincisional opioid levels. Given that OIH can occur in humans (5,6,24), it would seem prudent to remain cognizant of the potential consequences of rapid downward changes in opioid doses in the perioperative setting.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Sjogren P, Jonsson T, Jensen NH, et al. Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine. Pain 1993; 55: 93–7.[ISI][Medline]
  2. De Conno F, Caraceni A, Martini C, et al. Hyperalgesia and myoclonus with intrathecal infusion of high-dose morphine. Pain 1991; 47: 337–9.[ISI][Medline]
  3. Potter JM, Reid DB, Shaw RJ, et al. Myoclonus associated with treatment with high doses of morphine: the role of supplemental drugs. BMJ 1989; 299: 150–3.
  4. Ali NM. Hyperalgesic response in a patient receiving high concentrations of spinal morphine. Anesthesiology 1986; 65: 449.[ISI][Medline]
  5. Lipman JJ, Blumenkopf B. Comparison of subjective and objective analgesic effects of intravenous and intrathecal morphine in chronic pain patients by heat beam dolorimetry. Pain 1989; 39: 249–56.[ISI][Medline]
  6. Miser AW, Chayt KJ, Sandlund JT, et al. Narcotic withdrawal syndrome in young adults after the therapeutic use of opiates. Am J Dis Child 1986; 140: 603–4.[Abstract]
  7. Devulder J, Bohyn P, Castille F, et al. A case of uncommon withdrawal symptoms after a short period of spinal morphine administration. Pain 1996; 64: 589–91.[ISI][Medline]
  8. Mayer DJ, Mao J, Holt J, et al. Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions. Proc Natl Acad Sci U S A 1999; 96: 7731–6.[Abstract/Free Full Text]
  9. Laulin JP, Celerier E, Larcher A, et al. Opiate tolerance to daily heroin administration: an apparent phenomenon associated with enhanced pain sensitivity. Neuroscience 1999; 89: 631–6.[ISI][Medline]
  10. Hoffmann O, Plesan A, Wiesenfeld-Hallin Z. Genetic differences in morphine sensitivity, tolerance and withdrawal in rats. Brain Res 1998; 806: 232–7.[ISI][Medline]
  11. Ibuki T, Dunbar SA, Yaksh TL. Effect of transient naloxone antagonism on tolerance development in rats receiving continuous spinal morphine infusion. Pain 1997; 70: 125–32.[ISI][Medline]
  12. Celerier E, Laulin J, Larcher A, et al. Evidence for opiate-activated NMDA processes masking opiate analgesia in rats. Brain Res 1999; 847: 18–25.[ISI][Medline]
  13. Celerier E, Rivat C, Jun Y, et al. Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology 2000; 92: 465–72.[ISI][Medline]
  14. Dunbar SA, Pulai IJ. Repetitive opioid abstinence causes progressive hyperalgesia sensitive to N-methyl-D-aspartate receptor blockade in the rat. J Pharmacol Exp Ther 1998; 284: 678–86.[Abstract/Free Full Text]
  15. Noble F, Cox BM. Differential desensitization of mu- and delta- opioid receptors in selected neural pathways following chronic morphine treatment. Br J Pharmacol 1996; 117: 161–9.[ISI][Medline]
  16. Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain 1996; 64: 493–501.[ISI][Medline]
  17. Li X, Clark JD. The role of heme oxygenase in neuropathic and incisional pain. Anesth Analg 2000; 90: 677–82.[Abstract/Free Full Text]
  18. Hargreaves K, Dubner R, Brown F, et al. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988; 32: 77–88.[ISI][Medline]
  19. Chaplan SR, Bach FW, Pogrel JW, et al. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994; 53: 55–63.[ISI][Medline]
  20. Paronis CA, Holtzman SG. Increased analgesic potency of mu agonists after continuous naloxone infusion in rats. J Pharmacol Exp Ther 1991; 259: 582–9.[Abstract/Free Full Text]
  21. Tilson HA, Rech RH, Stolman S. Hyperalgesia during withdrawal as a means of measuring the degree of dependence in morphine dependent rats. Psychopharmacologia 1973; 28: 287–300.[ISI][Medline]
  22. Zahn PK, Brennan TJ. Lack of effect of intrathecally administered N-methyl-D-aspartate receptor antagonists in a rat model for postoperative pain. Anesthesiology 1998; 88: 143–56.[ISI][Medline]
  23. Rohde DS, Detweiler DJ, Basbaum AI. Formalin-evoked Fos expression in spinal cord is enhanced in morphine- tolerant rats. Brain Res 1997; 766: 93–100.[ISI][Medline]
  24. Devulder J. Hyperalgesia induced by high-dose intrathecal sufentanil in neuropathic pain. J Neurosurg Anesthesiol 1997; 9: 146–8.[ISI][Medline]
Accepted for publication March 28, 2001.




This article has been cited by other articles:


Home page
 Br J AnaesthHome page
M. D. Larson, P. D. Berry, J. May, A. Bjorksten, and D. I. Sessler
Autonomic effects of epidural and intravenous fentanyl
Br. J. Anaesth., February 1, 2007; 98(2): 263 - 269.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
J.-K. Cheng, R. C.-C. Chou, L.-L. Hwang, and L.-C. Chiou
Antiallodynic Effects of Intrathecal Orexins in a Rat Model of Postoperative Pain
J. Pharmacol. Exp. Ther., December 1, 2003; 307(3): 1065 - 1071.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
M. F. Davies, F. Haimor, G. Lighthall, and J. D. Clark
Dexmedetomidine Fails to Cause Hyperalgesia After Cessation of Chronic Administration
Anesth. Analg., January 1, 2003; 96(1): 195 - 200.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
V. Raghavendra, M. D. Rutkowski, and J. A. DeLeo
The Role of Spinal Neuroimmune Activation in Morphine Tolerance/Hyperalgesia in Neuropathic and Sham-Operated Rats
J. Neurosci., November 15, 2002; 22(22): 9980 - 9989.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
X. Li and J. D. Clark
Hyperalgesia During Opioid Abstinence: Mediation by Glutamate and Substance P
Anesth. Analg., October 1, 2002; 95(4): 979 - 984.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
R. Schmid, G. Koren, J. Klein, and J. Katz
The Stability of a Ketamine-Morphine Solution
Anesth. Analg., April 1, 2002; 94(4): 898 - 900.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (27)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Li, X.
Right arrow Articles by Clark, J. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Li, X.
Right arrow Articles by Clark, J. D.

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press