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Anesth Analg 2003;97:810-815 © 2003 International Anesthesia Research Society
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Abstract |
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Opioids administered during surgery may be beneficial by preempting postoperative pain or detrimental by causing acute tolerance. We used a stable model of hyperalgesia in volunteers to test whether acute opioid exposure also results in such pain sensitization over a period of hours in humans. Ten healthy volunteers were studied. Areas of mechanical hyperalgesia and allodynia were induced by topical capsaicin application plus intermittent heating. Computer-controlled IV remifentanil infusion was titrated to a targeted plasma concentration that reduced pain report to noxious heat by 70% and was maintained at this level for 60–100 min. Areas of hyperalgesia and allodynia were measured during and after remifentanil infusion. Remifentanil (targeted concentration of 3.1 ± 1.2 ng/mL) reduced areas of hyperalgesia and allodynia by 33% ± 31% and 65% ± 28%, respectively, during infusion (P < 0.05). Areas of hyperalgesia and allodynia continuously enlarged 4 h after remifentanil was stopped, to 180% ± 47% and 180% ± 86%, respectively. This study demonstrates that acute opioid exposure enhances hypersensitivity for hours after exposure. If applicable to the surgical setting, this could increase the dose of opioid required for postoperative analgesia and enhance, rather than inhibit, postoperative pain.
IMPLICATIONS: Remifentanil infusion in normal volunteers acutely reduces hypersensitivity induced by capsaicin, but after cessation of remifentanil infusion, hypersensitivity increases beyond baseline, consistent with growing animal and human literature suggesting that acute exposure to opioids, such as during surgery, can exacerbate subsequent pain.
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Introduction |
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Animal studies of opioid analgesia suggest that hyperalgesia to noxious mechanical or heat stimulation may develop even after a single exposure to potent opioids (1,2). Evidence in humans also suggests that short-term infusion of potent opioids may exacerbate postoperative pain or experimental mechanical hyperalgesia on withdrawal of the opioid (3,4). This withdrawal hyperalgesia may be relatively long-lasting and may be associated with increased pain and analgesia requirements.
A human experimental pain model produced a stable area of mechanical hyperalgesia that was maintained for several hours without producing skin injury (3,5). This model used heat and capsaicin cream to sensitize the skin to produce an area of secondary hyperalgesia outside of the primary stimulus zone. This secondary area of hypersensitization can be maintained for hours by reinforcing, or "rekindling," the primary area; this was accomplished by applying a 40°C heat stimulus for 5 min every 40 min. This pain model may be useful for studying the effects of various treatment modalities on an established area of hyperalgesia over time.
The potent, ultra-short-acting µ-opioid remifentanil is suitable for rapid titration of plasma concentrations and maintenance of plasma concentrations to produce stable analgesia. It is often used as an adjunct to general anesthesia. Petersen et al. (3) demonstrated that remifentanil significantly reduced the area of secondary cutaneous hyperalgesia during an IV remifentanil infusion. They also reported that the area of secondary hyperalgesia rapidly returned to the baseline size within 30 min of remifentanil discontinuation. This study is the first to determine whether areas of hyperalgesia and allodynia from capsaicin were affected beyond this 30-min period after discontinuation of remifentanil, because studies in animals suggest that such hypersensitivity phenomena require a few hours to develop.
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Methods |
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This protocol was reviewed and approved by the Wake Forest University School of Medicine IRB and the General Clinical Research Center (GCRC) protocol committee (Winston-Salem, NC). Ten healthy (ASA physical status I) adult volunteers taking no prescription medications were recruited by advertising within the community with IRB-approved wording. Women were studied only after a negative pregnancy test and confirmation that they were not breast-feeding were obtained. Written, informed consent was obtained from all patients; this included a discussion of risks, including remifentanil side effects such as nausea/vomiting and respiratory depression, as well as discomfort and possible mild skin redness after the application of the Peltier thermode probe and/or topical capsaicin.
The volunteers were paid for study participation. The payment amount was determined according to a previously established schedule of procedures approved by the IRB. Partial payment was available in the event of dropout, depending on the protocol segments completed. Volunteers completing the study were paid US$400.
On Day 1, the volunteer reported to the GCRC and underwent a training session to learn to consistently rate pain from a Peltier thermode applied to the skin of the arm. For this training, each volunteer was exposed to random thermode temperatures for 5 s between 39°C and 51°C separated by 25-s intervals, and the volunteer was asked to report the perceived pain with a numerical scoring system of his or her choice. Scores were normalized to the 49°C stimulus. After training using the Peltier device, we induced mechanical hyperalgesia in the forearm with heat and capsaicin cream as described briefly below and previously (3,5). This training period both trained the subject to be very consistent in assessing the degree of pain and allowed the volunteer to experience and rate the hyperalgesia and allodynia from the capsaicin treatment in advance of remifentanil treatment. During this training period, we also measured the volunteer’s baseline blood pressure, heart rate, end-tidal CO2, and peripheral oxyhemoglobin saturation.
On Day 2, the volunteer reported (at least 24 h after the initial training session) to the GCRC in the morning after having had nothing to eat or drink since midnight. A peripheral IV catheter was inserted into a vein in an upper extremity, and lactated Ringer’s solution was infused at 1.5 mL · kg-1 · h-1 for the duration of the study. The Peltier thermode was then applied to the calf contralateral to that to be exposed to capsaicin, and the volunteer was asked to report the perceived pain to random thermode temperatures as described elsewhere (6).
A 4-cm2 Peltier controlled thermode was placed on the midlateral calf skin (contralateral calf to the calf exposed to the heat probe alone) and maintained at 45°C for 5 min. During that period, volunteers were asked to rate pain, if present, on a 0–10 verbal scale at 1-min intervals. Areas of mechanical hyperalgesia to von Frey stimulation and allodynia to cotton wisp stroking were determined, and capsaicin cream (0.075% capsaicin cream; Bioglan Pharma Inc., Malvern, PA) was placed on the same area with an occlusive dressing. After 30 min, the capsaicin dressing was removed, and areas of hyperalgesia to 225 mN of von Frey stimulation and allodynia to cotton wisp stroking were determined as described elsewhere (6).
Areas of hyperalgesia and allodynia were maintained constant by application, at 40, 80, 120, 160, 200, 240, 300, and 360 min after topical capsaicin, of the Peltier controlled thermode to the same area of original stimulation and maintained at 40°C for 5 min. Areas of hyperalgesia to von Frey stimulation and allodynia to cotton wisp stroking were determined immediately before and after each application of the thermode.
All monitoring and documentation met or exceeded GCRC conscious-sedation standards. Remifentanil plasma levels were titrated by using the STANPUMP algorithm (7) to run the computer-controlled infusion. During remifentanil infusion, continuous oxyhemoglobin saturation was monitored and recorded every 5 min. The goal of the remifentanil infusion was to establish a target plasma concentration that would produce at least a 70% reduction in pain rating of a 49°C skin thermode stimulus.
The initial plasma remifentanil target concentration was 1.0 ng/mL. After 8 min of infusion, the volunteer rated his or her pain to a randomly presented 39°C, 45°C, and 49°C skin thermode stimulus on the contralateral calf from the leg receiving the heat-capsaicin stimulus. Blood pressure, heart rate, and end-tidal CO2 were also recorded. If the reduction in pain magnitude at 49°C was not at least 70% and if the safety criteria were met (see below), the target plasma concentration was increased by 0.5 ng/mL, and the infusion was continued for a minimum of 8 min. This cycle of increasing the target plasma remifentanil concentration was repeated until the pain magnitude score for a 49°C thermode stimulus reflected a reduction of at least 70% from baseline or end-tidal CO2 was 
15 torr above baseline.
On reaching the desired degree of analgesia or the maximum end-tidal CO2, the computer-controlled infusion was continued at the final target plasma remifentanil concentration for a minimum of 60 min and a maximum of 100 min and was discontinued immediately after thermode probe reinforcement of the capsaicin and measurement of the areas of hyperalgesia and allodynia. The range of remifentanil steady-state infusion times was the result of requiring at least 60 min of exposure to steady-state remifentanil plasma concentrations and the need to terminate the infusion after thermode reinforcement of capsaicin (every 40 min).
Every 15–20 min during this final steady-state infusion, the volunteer’s response to a series of three random thermode temperatures of 39°C, 45°C, and 49°C was recorded, and end-tidal CO2 was measured. On discontinuation of the remifentanil infusion, the volunteer was monitored with continuous peripheral oxyhemoglobin saturation measurements until at least 30 min of measurement indicated sustained oxyhemoglobin saturation >90% without supplemental oxygenation or verbal stimulation. Volunteers were side-effect free for 1 h before discharge from the GCRC.
At the end of the 60- to 100-min steady-state remifentanil infusion, the areas of capsaicin-induced allodynia/hyperalgesia were mapped, and the remifentanil infusion was discontinued. Heat stimulus assessment with the thermode probe in the contralateral leg (noncapsaicin-treated leg) was accomplished by using the random 39°C, 45°C, and 49°C every 5 min for 15 min, then at 30 min, and then every 30 min for 360 min after the remifentanil infusion was stopped. The heat-probe reinforcement of capsaicin was continued every 40 min for approximately 240 min after discontinuation of remifentanil. Areas of allodynia and hyperalgesia were mapped according to the previously described methods immediately after the capsaicin was reinforced.
On Day 3, volunteers returned to the GCRC approximately 24 h after the initial application of capsaicin cream. At this time, we attempted to reactivate the capsaicin area from the previous day by using heat as described previously and screen for residual secondary allodynia/hyperalgesia. In addition, the heat-probe testing from 39°C to 51°C was also performed in the contralateral leg.
Volunteers received continuous peripheral oxyhemoglobin saturation monitoring during the remifentanil infusion. End-tidal CO2 was measured at the end of each titration period and every 15–20 min during the 60- to 100-min steady-state remifentanil infusion. The initial protocol indicated that supplemental oxygen via nasal cannula was to be administered if peripheral oxyhemoglobin saturation decreased to <90%. After four volunteers were studied, the protocol was amended to routinely administer supplemental oxygen via supplemental nasal cannula. The protocol also provided for provision of supplemental oxygen via nonrebreathing face mask or discontinuation of the remifentanil infusion if oxyhemoglobin saturation remained less than 90% despite oxygen supplementation and verbal stimulation. Provision for IV naloxone per physician investigator was also allowed. End-tidal CO2 values 15 torr more than baseline were treated by incrementally reducing the remifentanil infusion rate target by 0.5 ng/mL (as long as oxygen saturation was >90%) until the end-tidal CO2 was 
15 torr above baseline values. The infusion was then continued at this new, reduced rate. In these cases, the steady-state target remifentanil concentration might have been less than that needed for a 70% reduction in baseline pain to heat thermode stimulus. Finally, there were provisions for treatment of blood pressure reductions of more than 35% from baseline and of heart rates <45 bpm.
Nausea was treated, if requested by the volunteer, with metoclopramide 10 mg IV and was repeated once as necessary. If nausea continued, ondansetron 2–4 mg IV was administered. Severe nausea, if it compromised the volunteer’s ability to participate in the study, necessitated study discontinuation. Volunteers were contacted 48 h after study completion and questioned about any concerns or problems.
Unless otherwise indicated, data are presented mean ± SD. Continuous variables were tested over time by one-way repeated-measures analysis of variance followed by Dunnett’s test to the control, baseline values as indicated. P < 0.05 was considered statistically significant.
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Results |
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Five men and five women were studied. Their average age was 37 ± 4 yr, average height was 171 ± 4 cm, and average weight was 70 ± 4 kg. The average targeted concentration of remifentanil achieved for analgesia or side-effect limitations was 3.1 ± 1.2 ng/mL. During the titration period, there was a significant linear relationship (r = 0.51; P < 0.0001) between targeted plasma remifentanil concentration and reduction in pain report to the 49°C stimulus (Fig. 1). Three of 10 subjects did not achieve a 70% reduction in pain from this heat stimulus: 2 because of side effects (at 1.0 and 4.5 ng/mL targeted remifentanil concentration) and 1 because of reaching the maximum infusion rate (5.0 ng/mL targeted remifentanil concentration). Blood pressure and heart rate changes associated with remifentanil infusion were mild, and no volunteer required treatment. All volunteers maintained oxyhemoglobin saturation values more than 90% (9 of 10 volunteers received oxygen supplementation at 2 L/min via nasal cannula). Two volunteers requested treatment for nausea: one received metoclopramide only, and one received both metoclopramide and ondansetron. No studies were discontinued for any reason, and there were no persistent problems or questions identified at the 48-h follow-up.
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Pain with the 49°C thermode stimulus was 5.7 ± 2.5 at baseline (all pain scores were normalized to the response to 49°C = 10) and was significantly reduced to 2.6 ± 2.5 at the end of the steady-state remifentanil infusion (P < 0.001). This average reduction of >50% was less than the planned titration to >70% reduction, because 3 individuals did not achieve this level of analgesia, as noted previously. Pain report to all 3 levels of thermal stimulation (39°C, 43°C, and 49°C) was reduced during remifentanil infusion and then returned to baseline levels for the remainder of the study (Fig. 2). Pain report to this stimulus returned to baseline levels by the 30-min postremifentanil infusion measurement and at the 24-h follow-up (data not shown).
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The primary outcome variables of hyperalgesia (von Frey stimulation) and allodynia (cotton wisp stroking) were significantly affected by the remifentanil infusion. Areas of hyperalgesia and allodynia before remifentanil infusion were 64 ± 5.4 cm2 and 42 ± 4.1 cm2, respectively. Figure 3 illustrates the time course of changes in the mapped area of secondary hyperalgesia on the leg. The remifentanil infusion significantly reduced the areas of secondary hyperalgesia and allodynia (P < 0.001). The area of hyperalgesia progressively enlarged after termination of the remifentanil infusion and was significantly larger compared with the baseline measurement at the 200- and 240-min postinfusion assessments (Fig. 3; P < 0.05). After termination of the remifentanil infusion, the area of allodynia also progressively increased over time and was significantly larger 240 min postinfusion termination (Fig. 3; P < 0.05). Secondary cutaneous hyperalgesia to both the von Frey and cotton wisp stimulation was still present at the 24-h assessment, although the area was smaller than the baseline area after thermode reinforcement (Fig. 3).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Previously, we reported that a computer-controlled alfentanil infusion reduced the area of hyperalgesia to von Frey stimulation and allodynia to cotton wisp stroking produced by intradermal capsaicin injection, although there was no way to assess the effects of alfentanil withdrawal over time (8). In contrast, using the topical capsaicin with intermittent heat method, we were able to assess the opioid-withdrawal effects on hyperalgesia and allodynia over a several-hour postwithdrawal period. This method of producing a stable secondary hyperalgesia over a period of hours has proven to be useful in evaluating other treatments of hypersensitization (9–11).
This study is the first to assess, over a period of hours, hypersensitization after acute opioid withdrawal in volunteers. This study design, in which each volunteer was tested before, during, and after remifentanil infusion, assumes stability of areas of hyperalgesia and allodynia in the absence of drug treatment. Both the original description of the capsaicin/heat method (5) and our own work (12) justify this approach, because coefficients of variation in areas of hyperalgesia and allodynia over this time period (20%–30%) were clearly less than the increase in area to 180% of control observed four hours after remifentanil cessation in this study. In addition, others (3) observed a similar reduction in areas of hyperalgesia and allodynia during remifentanil infusion with this method; the areas returned to baseline within 30 minutes of remifentanil discontinuation. Thus, we believe that in this study, as in previous studies with capsaicin, it is a fair assumption that areas of hyperalgesia and allodynia remain stable over this time period. Neither we nor others have previously rekindled areas of hyperalgesia and allodynia 24 hours after capsaicin application, so we cannot comment on whether the areas observed in this study are larger than one would expect in the absence of remifentanil.
It is interesting that we failed to observe hypersensitivity to noxious heat after cessation of remifentanil infusion (Fig. 2), whereas areas of tactile hyperalgesia and allodynia progressively enlarged after remifentanil (Fig. 3). Although this could reflect differing effects on thermal versus mechanical sensory modalities, this is not supported by previous work in animals, which demonstrated increased thermal sensitivity after opioid exposure (1,2). More likely, this represents the difference between normal sensation (thermal testing) and central sensitization (capsaicin plus heat induced). The latter is important, because central sensitization may well be present during periods of opioid exposure, such as inflammation, surgery, or neuropathy-induced pain.
Several observations in preclinical models suggest that acute exposure to large doses of opioids results, after the resolution of the antinociceptive effect, in prolonged periods of a decreased withdrawal threshold to mechanical or thermal stimuli, which are interpreted as allodynia and hyperalgesia. For example, single doses of the highly potent and effective µ-opioid receptor agonist heroin (1) or the clinically used drug fentanyl (2) result in hyperalgesia and allodynia for days in rats. Similarly, some clinical studies (4,13), but not all (14), indicate that large intraoperative doses of opioids induce either tolerance or a state that results in increased opioid requirements and increased pain in the postoperative period. This led us to suggest that such a practice may be inducing preemptive hyperalgesia rather than analgesia (15).
We did not observe acute tolerance to remifentanil in this study, in contrast to a previous report in volunteers (16). The time course of acute tolerance to opioids varies across studies and probably reflects differences in the intensity or modality of pain stimulus in volunteers or differences between controlled stimuli in volunteers and the more complex setting of chronic or postoperative pain.
In summary, volunteers receiving a stimulus method that produced a constant area of mechanical hyperalgesia and allodynia in the absence of drug treatment demonstrated a reduction in these areas during remifentanil infusion at analgesic doses. Areas returned to baseline and then gradually increased, achieving areas 180% larger than baseline by four hours after cessation of the infusion. These data agree with previous studies in animals that even acute exposure to opioids may induce a long-lasting period of hyperalgesia and provide a convenient model to study interventions to reduce this unwanted effect.
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Acknowledgments |
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Supported in part by Grants GM48085, NS41386, and RR07122 from the National Institutes of Health (Bethesda, MD).
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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- 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.[Web of Science][Medline]
- 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.[Web of Science][Medline]
- Petersen KL, Jones B, Segredo V, et al. Effect of remifentanil on pain and secondary hyperalgesia associated with the heat-capsaicin sensitization model in healthy volunteers. Anesthesiology 2001; 94: 15–20.[Web of Science][Medline]
- Guignard B, Bossard AE, Coste C, et al. Interoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 2000; 93: 409–17.[Web of Science][Medline]
- Petersen KL, Rowbotham MC. A new human experimental pain model: the heat/capsaicin sensitization model. Neuroreport 1999; 10: 1511–6.[Web of Science][Medline]
- Eisenach JC, Hood DD, Curry R. Preliminary efficacy assessment of intrathecal injection of an American formulation of adenosine in humans. Anesthesiology 2002; 96: 29–34.[Web of Science][Medline]
- Gustafsson LL, Ebling WF, Osaki E, et al. Plasma concentration clamping in the rat using a computer-controlled infusion pump. Pharm Res 1992; 9: 800–7.[Web of Science][Medline]
- Eisenach JC, Hood DD, Curry R, Tong C. Alfentanil, but not amitriptyline, reduces pain, hyperalgesia, and allodynia from intradermal injection of capsaicin in humans. Anesthesiology 1997; 86: 1279–87.[Web of Science][Medline]
- Dirks J, Fabricius P, Petersen KL, et al. The effect of systemic lidocaine on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers. Anesth Analg 2000; 91: 967–72.
[Abstract/Free Full Text] - Dirks J, Petersen KL, Rowbotham MC, Dahl JB. Effect of systemic adenosine on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers. Reg Anesth Pain Med 2001; 26: 414–9.[Web of Science][Medline]
- Mikkelsen S, Dirks J, Fabricius P, et al. Effect of intravenous magnesium on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers. Br J Anaesth 2001; 86: 871–3.
[Abstract/Free Full Text] - Eisenach JC, Curry R, Hood DD. Dose response of intrathecal adenosine in experimental pain and allodynia. Anesthesiology 2002; 97: 938–42.[Web of Science][Medline]
- Chia YY, Liu K, Wang JJ, et al. Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anaesth 1999; 46: 872–7.[Web of Science][Medline]
- Cortinez LI, Brandes V, Munoz HR, et al. No clinical evidence of acute opioid tolerance after remifentanil-based anaesthesia. Br J Anaesth 2001; 87: 866–9.
[Abstract/Free Full Text] - Eisenach JC. Preemptive hyperalgesia, not analgesia? Anesthesiology 2000; 92: 308–9.[Web of Science][Medline]
- Vinik HR, Kissin I. Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg 1998; 86: 1307–11.[Abstract]
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