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Anesth Analg 2003;96:195-200
© 2003 International Anesthesia Research Society

PAIN MEDICINE

Dexmedetomidine Fails to Cause Hyperalgesia After Cessation of Chronic Administration

M. Frances Davies, PhD, Fawzi Haimor, Geoffrey Lighthall, MD, PhD, and J. David Clark, MD, PhD

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

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


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Hyperalgesia occurring after the cessation of chronic opioid administration occurs in humans and has been modeled in rodents with chronic systemic and intrathecal administration paradigms. It is, however, unclear if this type of postanalgesic hyperalgesia is unique to opioids. The {alpha}2-adrenergic receptor agonist, dexmedetomidine (Dex), is similar to opioids in that it is an analgesic that interacts with cell-surface receptors linked to the inhibition of adenylate cyclase and the modulation of ion channel activity. In these studies, we first constructed antinociceptive dose-response curves for Dex and morphine (MSO4). The 50% effective doses for Dex and MSO4 administered intraperitoneally to C57Bl/6 mice were 75 µg/kg and 5.2 mg/kg, respectively. Using equally effective doses, we treated separate groups of mice with twice-daily injections of Dex or MSO4 for 5 days. Tolerance to these drugs was documented after this period. In the 16–72 h after cessation of administration, MSO4-treated mice demonstrated both thermal hyperalgesia and mechanical allodynia. However, the Dex-treated mice showed no changes in their thermal or mechanical withdrawal thresholds. We conclude that using this experimental paradigm, opioids but not an {alpha}2-adrenergic agonist, cause hyperalgesia and allodynia after cessation of chronic administration.

IMPLICATIONS: The cessation of the administration of opioids is associated with hyperalgesia in both humans and other animals. However, antinociceptive dexmedetomidine does not seem to be associated with this type of hyperalgesia syndrome during periods of abstinence.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Hyperalgesia in humans can occur in two distinct clinical settings. The first setting is one in which very large doses of opioids are administered such as in the setting of aggressive cancer pain management or management of sickle cell crisis. This hyperalgesia resolves with reduction of opioid dosage. Several opioids have been observed to cause this phenomenon (1–4). A second syndrome of hyperalgesia can be observed when serum levels of chronically given opioids are decreased. This has been observed in humans after purposeful or inadvertent discontinuation of opioids (5–7). Pain symptoms are, in fact, one of the diagnostic criteria for opioid withdrawal listed in the Diagnostic and Statistical Manual IV. Additional observations have been made in patients maintained on methadone for the treatment of opioid addiction. In this setting, former addicts maintained on methadone were found to be significantly hyperalgesic, as assessed by using cold pressor and electrical stimuli between doses of that opioid (8–10). These observations have raised the question of whether opioids given chronically for the treatment of pain cause some degree of unwanted hyperalgesia. It is not clear whether hyperalgesia in the setting of declining serum levels of opioids is unique to this class of compounds or if hyperalgesia is seen with other analgesics given under similar circumstances.

There are several models of opioid-abstinence hyperalgesia (OAH). These involve the chronic systemic or intrathecal administration of morphine (MSO4), fentanyl, and other opioids to rodents followed by abrupt cessation of administration (11–14). Whereas activation of spinal N-methyl-D-aspartic acid (NMDA) receptors and increased descending pain facilitation from supraspinal structures have been postulated to account for the development of OAH (14,15), persistent involvement of NMDA receptors and the closely related nitric oxide synthase (NOS) and heme oxygenase enzyme systems seem to be involved in maintaining this state of hyperalgesia (11).

Determining whether hyperalgesia is an opioid-specific versus a generic analgesic phenomenon is important for two reasons: First, the identification of analgesics not tending to cause hyperalgesia with prolonged use may have clinical utility in the field of chronic pain management. Second, it would help in our mechanistic understanding of OAH to determine whether this is an opioid-specific or generalized analgesic phenomenon. In the studies presented below, we attempted to determine whether the analgesic/sedative dexmedetomidine (Dex) is associated with hyperalgesia in mice as we have previously shown is the case for MSO4 and fentanyl (11). Dex was chosen for comparison because of the continuing interest in {alpha}2-adrenergic receptor agonists as analgesic compounds, and because {alpha}2-adrenergic receptor agonists are linked to the inhibition of adenylate cyclase and modulation of ion channel activity as are opioids. Finally, like MSO4, Dex reverses mechanical allodynia (16) and reduces sensitivity to noxious thermal stimuli (17) in experimental models of pain.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All experimental protocols were reviewed and approved by the Veterans Affairs Palo Alto Health Care System Subcommittee for Animal Studies before the initiation of work. All protocols conformed to the guidelines for the study of pain in awake animals as established by the International Association for the Study of Pain. Every effort was made to minimize animal suffering and to use only the number of animals necessary to produce reliable scientific data. The C57BL/6J mouse strain was used for these experiments (Charles River, Hollister, CA). Male mice between 10 and 14 wk (21–25 g) were used. All animals were kept 6–8 per cage with a 12 h/12 h light/dark cycle and food and water ad libitum. The specific numbers of mice used for each experiment are stated in the figure legends.

Behavioral Testing
Mechanical Withdrawal Thresholds.
Mechanical allodynia was assayed by using nylon von Frey filaments according to the "up-down" algorithm described by Chaplan et al. (18) as we have used previously (11). Allodynia here was defined as a response indicating that the stimulation was painful at a stimulus intensity less than that normally experienced as painful in the naïve animals. In these experiments, mice were placed on wire mesh platforms in clear cylindrical plastic enclosures of 10-cm diameter. After 20 min of acclimation, fibers of sequentially increasing stiffness (0.2–2 g, 7 fibers) were applied to the center of the plantar surface of a hindpaw just distal to the first set of foot pads and left in place 5 s. Withdrawal of the hindpaw from the fiber was scored as a response. When no response was obtained, the next stiffest fiber in the series was applied to the same paw; if a response was obtained, a less stiff fiber was next applied. Testing proceeded in this manner until four fibers had been applied after the first one causing a withdrawal response allowing the estimation of the mechanical withdrawal threshold.

Thermal Withdrawal Latency.
Response latencies to noxious thermal stimulation were measured by using the method of Hargreaves et al. (19) as we have modified for use with mice (11). Thermal hyperalgesia was defined here as a response indicating pain was experienced at a time point less than that at which pain was normally experienced in control animals when the same stimulus intensity was used. In this assay, mice were placed on a glass platform thermostatically controlled at 29°C in a plastic enclosure as described above. After 20 min of acclimation, a beam of focused light was directed toward the same area of the hindpaw as described for the von Frey assay. The time to withdrawal of the foot from the beam of light was measured. A 20-s cutoff was used to prevent tissue damage. For experiments in which antinociception was being measured, the light beam intensity was initially adjusted to provide a relatively short 3–4 s baseline, thus facilitating the quantification of antinociception (4.90 V). When using large doses of MSO4 in dose-response studies, occasionally it was necessary to surround the animal with a gloved hand because of excessive stereotypic movement (walking in circles within the enclosure). Preliminary experiments demonstrated that this sort of minimal restraint did not lead to alteration of baseline thermal withdrawal responses. In experiments in which we sought to quantify thermal hyperalgesia, the light beam intensity was adjusted to provide a somewhat longer (10–11 s) baseline in control animals thus facilitating the detection of thermal hyperalgesia (3.70 V). Two measurements were made per animal per test session.

Drug Administration
Dose-Response Studies.
Cumulative dose-response curves for MSO4 and Dex were constructed by measuring thermal paw withdrawal latency. After establishing baseline latencies, groups of mice were injected with analgesics followed in 20 min by repeated determination of thermal withdrawal latency. Preliminary experiments established 20 min to be a time at which peak effect for the chosen analgesics was achieved. For MSO4, the cumulative doses used were 0, 1, 2, 4, 8, 16, and 32 mg/kg. For Dex, the cumulative doses were 0, 12, 25, 50, 100, 200, and 400 µg/kg. Thus, each group of mice received a series of seven injections total with each incremental injection having the indicated mass of drug. Different groups of mice were used so that mice received only MSO4 or Dex, but not both. All drugs were injected in a 50-µL total volume of 0.9% NaCl in the intraperitoneal space by using a 27-gauge needle. MSO4 (morphine sulfate) was obtained from Sigma Chemical Co. (St. Louis, MO), and Dex was obtained from Abbott Laboratories (Abbott Park, IL). The parameter percent maximal possible effect (%MPE) was determined according to the following formula:

equation


The 50% effective dose (ED50) values, 95% confidence intervals (CIs), and areas under the curves (AUC, calculated by trapezoidal integration) were derived by using Prism 3.0 (GraphPad Software, San Diego, CA).

Chronic Exposure.
Some groups of mice were injected intraperitoneally with a 50-µL solution containing MSO4 16 mg/kg, Dex 200 µg/kg, or saline at 08:00 and 17:00 each day for 5 days before reassessment of thermal and mechanical withdrawal thresholds.

Time Course Studies.
Both drug-naïve and chronically treated mice were tested for the time course of antinociception caused by MSO4 16 mg/kg, Dex 200 µg/kg, or saline. In these experiments, mice were acclimated for thermal withdrawal latency testing as described above. After the injection of test drugs, thermal latencies were measured every 20 min for a total of 140 min.

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 withdrawal latency 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. For simple comparisons of two means such as those obtained for AUC data, a Student’s t-test was used. Data were displayed as ±SEM.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Cumulative dose-response curves for MSO4 and Dex were constructed by using the thermal paw withdrawal latency assay. Figure 1 displays the results. For Dex, the ED50 was 75 µg/kg, 95% CI 54–106 µg/kg. For MSO4, the ED50 was 5.2 mg/kg, 95% CI 4.5–6.0 mg/kg. From these curves, we estimated that the "just-maximal" doses for Dex and MSO4 were 200 µg/kg and 16 mg/kg, respectively, for these mice under these conditions. The "just maximal" dose was the dose estimated to provide 95%–100% MPE.



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  		Figure 1. Cumulative dose-response curves for morphine and dexmedetomidine. By using the thermal paw withdrawal assay, cumulative dose-response curves were constructed. (A) Data for morphine, (B) data for dexmedetomidine. Data are presented as percent maximal possible effect (%MPE) ± SEM, n = 6–8 mice in each experiment.

 
To confirm the approximate analgesic equivalence both in terms of peak analgesic effect and duration of action, Dex 200 µg/kg and MSO4 16 mg/kg were given to mice. The resulting antinociception was followed for 140 min after injection. As can be seen in Figure 2, peak antinociception for both Dex and MSO4 occurred within about 20 min, and gradually decreased to baseline levels over the ensuing 2 h. These antinociception duration profiles were nearly identical for the two drugs. Analysis of area under the time-antinociception curves (AUC) for MSO4 and Dex demonstrated that the difference was <2% (8053 ± 209 for MSO4, 8212 ± 198 for Dex, P > 0.05). Saline-injected animals had no changes in their thermal latencies over the course of the experiment. Thus, both with respect to peak effect and duration of action, the chosen doses of the two analgesics were indistinguishable.



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  		Figure 2. Antinociception time course for morphine, dexmedetomidine, and saline. In these experiments, groups of mice were injected with morphine 16 mg/kg, dexmedetomidine 200 µg/kg intraperitoneally, or 0.9% NaCl, and the time course of antinociception was followed by using the paw withdrawal assay. (A) Data are presented for drug-naïve mice, (B) the experiment was repeated for mice after 5 days of treatment with either morphine or dexmedetomidine. For all groups, n = 8–10 mice. Data are presented as percent maximal possible effect (%MPE) ± SEM.

 
After 5 days of twice-daily injections, the time courses of antinociception were again assessed, as shown in Figure 2B. For both MSO4 16 mg/kg and Dex 200 µg/kg, the analgesic effects were diminished from those observed in naïve animals (Fig. 2A). At no time point was the difference between MSO4 and Dex statistically significant. Analysis of AUC revealed that the AUC for MSO4 was approximately 12% less than that for Dex (3335 ± 195 for MSO4 and 3820 ± 254 for Dex, P > 0.05).

At various times after the cessation of analgesic administration, mechanical allodynia and thermal hyperalgesia were assessed. As can be seen in Figure 3, A and B, the thermal and mechanical withdrawal thresholds were significantly diminished for mice treated with MSO4 at 16, 24 h after the last dose of analgesic. These changes had largely resolved by 72 h, consistent with our previous observations (11). However, Dex-treated mice had thermal and mechanical thresholds indistinguishable from control at all of these time points. Thus, we were unable to demonstrate {alpha}2-adrenergic agonist-mediated hyperalgesia under these conditions.



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  		Figure 3. Thermal hyperalgesia and mechanical allodynia after cessation of analgesic administration. In (A) and (B), mechanical and thermal withdrawal thresholds were determined for control, morphine-, and dexmedetomidine-treated mice at various time points after the last dose of analgesic. Note that the thermal stimulation intensity was reduced when collecting these data as compared with the data in Figure 1. For all groups, n = 7–8 mice. Data are presented as maximal possible effect (%MPE) ± SEM; *P < 0.05, **P < 0.01.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Although the use of opioids for chronic pain is becoming more popular, this practice faces several challenges. Concerns have been voiced related to the infrequent but finite incidence of dose-limiting side effects, tolerance, and abuse. Recently added to this list of concerns is hyperalgesia. Although pain and hyperalgesia during withdrawal have long been recognized in humans and rodents (5,6,20,21), data demonstrating hyperalgesia during the chronic administration of opioids in the absence of overt withdrawal have added additional concern. Evidence as cited above has implicated various receptors and enzyme systems in this process, which has been interpreted as an example of opponent process theory (11,22). This theory holds that the chronic exposure of an organism to a given stimulus tends to be counterbalanced by an opposing set of adaptive forces. This theory would predict that chronic exposure to an analgesic would cause a compensatory sensitization to noxious stimuli (hyperalgesia). The data presented above, however, suggest that not all analgesics cause the same degree of sensitization to noxious stimuli, even when administered under reasonably carefully matched circumstances.

Our studies do not support the contention that the degree of tolerance obtained is an important factor in predicting hyperalgesia after cessation of administration for all analgesics, at least at the pair of MSO4 and Dex doses used in the present studies. Figure 2 demonstrates that tolerance to the doses of MSO4 and Dex chosen for these studies was comparable. Although it may be the case that sensitization to noxious stimuli accompanies or even partially underlies the manifestation of tolerance to opioids, we were unable to confirm that this sort of process accompanies tolerance to {alpha}2-adrenergic drugs. The chronic administration of {alpha}2-adrenergic agonists and opioids agonists has been reported by some (23,24), but not all (25,26), investigators not to cause cross tolerance, indicating that different mechanisms for analgesic tolerance may be involved.

Other data support the possibility that the neuroplastic changes accompanying exposure to the {alpha}2-adrenergic receptor agonist Dex are fundamentally different from those accompanying exposure to opioids. Whereas several reports demonstrated that blockade of NMDA receptors or inhibition of NOS reduces opioid tolerance (14,27–29), these systems were not demonstrated to have roles in tolerance to the analgesic effects of Dex in rats (30). Both NMDA receptors and NOS do seem to have roles in the induction and maintenance of OAH in animals (11). Other investigators have reported internalization of µ-opioid receptors after exposure to agonists (31), but this may not be the case for {alpha}2A-adrenergic receptors (32). Finally, the specific location of receptor expression might influence whether or not chronic exposure to an agonist leads to hyperalgesia. No study co-localizes {alpha}2-adrenergic and opioid receptors to the same neurons in the spinal cord. Furthermore, the patterns of expression of these receptors in higher central nervous system centers are clearly distinct (33,34).

One might consider the clinical implications of these findings. If one accepts that OAH could reduce the clinical utility of opioids, analgesics not tending to cause this phenomenon might constitute attractive alternatives. Whereas systemically administered {alpha}2-adrenergic drugs are seldom used in the management of chronic pain, one such drug, clonidine, is frequently used for epidural and intrathecal infusion in the management of chronic pain. Although untested in these studies, nonsteroidal antiinflammatory drugs and acetaminophen are neither associated with significant tolerance, nor have they been associated with hyperalgesia after chronic use. Another approach would be to attempt to limit OAH by the co-administration of, for example, an NMDA receptor antagonist. Dextromethorphan is one such drug. A combination dextromethorphan/MSO4 preparation (MorphiDex®) is currently under evaluation and seems to somewhat limit both the required daily dose of MSO4 to control chronic pain and perhaps the onset of tolerance (35). However, not all studies demonstrate an advantage to combining opioids with NMDA antagonists (36,37).


   Acknowledgments
 
This work was supported by the Veterans Affairs Merit Review and National Institutes of Health Grant RO-1 GM61260.


   References
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 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication September 9, 2002.




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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