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OBSTETRIC ANESTHESIOLOGY

An Evaluation of the Postoperative Antihyperalgesic and Analgesic Effects of Intrathecal Clonidine Administered During Elective Cesarean Delivery

From the Department of Anesthesiology, St Luc Hospital Medical School, Université Catholique de Louvain, Brussels, Belgium.

Address correspondence and reprint requests to P. Lavand’homme, Department of Anesthesiology, St Luc Hospital, Université Catholique de Louvain, Av Hippocrate 10–1821, 1200 Brussels, Belgium. Address e-mail to lavandhomme{at}anes.ucl.ac.be.

Abstract

BACKGROUND: Intrathecal clonidine improves intraoperative anesthesia and postoperative analgesia after cesarean delivery. Clonidine also possesses antihyperalgesic properties. Hyperalgesia contributes to postoperative pain and may be associated with increased risk of chronic pain after surgery. In this study, we evaluated the postoperative antihyperalgesic effect of intrathecal clonidine after caesarean delivery.

METHODS: Ninety-six parturients undergoing elective cesarean delivery were randomly assigned to receive intrathecal bupivacaine-sufentanil (BS group), bupivacaine-sufentanil-clonidine 75 µg (BSC group), or bupivacaine-clonidine 150 µg (BC group). The primary outcome was the extent and the incidence of periincisional punctate mechanical hyperalgesia as assessed by response to application of a von Frey filament at 24 and 48 h after cesarean delivery. Postoperative morphine requirements and pain scores, as well as residual pain at 1, 3, and 6 mo, were also assessed.

RESULTS: The BC group had a significantly reduced area of periincisional hyperalgesia at 48 h (median, 25th–75th percentiles): 1.0 (1.0 – 3.3) cm² vs 9.5 (5.0–14.0) cm² in the BS group vs 5.0 (2.5–12.3) cm² in the BSC group (P = 0.02 with the BS group). The incidence of hyperalgesia at 48 h was also lower in the BC group: 16% vs 41% in the BS group vs 34% in the BSC group (P = 0.03 with BS group). Postoperative morphine consumption, pain scores, and incidence and intensity of residual pain did not differ among groups.

CONCLUSIONS: Intrathecal clonidine 150 µg combined with bupivacaine had a postoperative antihyperalgesic effect expressed as a significant reduction in the extent and incidence of periincisional punctate mechanical hyperalgesia at 48 h after elective cesarean delivery compared with intrathecal bupivacaine-sufentanil and intrathecal clonidine 75 µg-bupivacaine-sufentanil.

Cesarean delivery is a common surgical procedure. The rate is currently increasing, reaching more than 25% of the deliveries in many Western countries.1,2 One survey performed among pregnant women has clearly shown that pain during and after cesarean delivery is the greatest concern of the parturients.3 Most cesarean procedures are done under spinal anesthesia involving various combinations of intrathecal anesthetics/analgesics. In particular, the addition of clonidine, an 2-adrenoceptor agonist, to spinal bupivacaine and a µ-opioid agonist, has been shown to improve both intraoperative analgesia4 and postoperative pain.5,6 Beyond their analgesic properties,7 2-adrenoceptor agonists also possess antihyperalgesic properties.8–10 Hyperalgesia is the physiological expression of central nervous system sensitization induced by nociceptive inputs from the surgical wound.11 This antihyperalgesic effect deserves further attention because the hyperalgesia which occurs after tissue incision may contribute to postoperative pain.11,12 Furthermore, both severe postoperative pain and central sensitization have been associated with an increased risk of developing persistent, long-term pain after surgery.13,14

Clinical trials have demonstrated that perioperative drug therapy may increase or decrease the area of mechanical hyperalgesia surrounding the surgical incision in the postoperative period, reflecting hyperalgesic15 or antihyperalgesic properties, respectively.10,16 We hypothetized that intrathecal clonidine administered during cesarean delivery would have a postoperative antihyperalgesic effect, i.e., reduce the incidence and area of periincisional punctate mechanical hyperalgesia at 48 h after delivery. Secondary outcomes included the postoperative analgesic effect of intrathecal clonidine, as assessed by clinical pain scores and morphine consumption, and the presence of residual pain up to 6 mo after the surgical procedure.

METHODS

After institutional Human Ethical Committee approval and written informed consent, healthy parturients, ASA Physical Status 1 and 2, scheduled for elective cesarean delivery, were included in this prospective study. Exclusion criteria included preterm pregnancy (<37 wks gestation), multiple gestation, asthma or cardiovascular disease (e.g., preeclampsia, hypertension), allergy to nonsteroidal antiinflammatory drugs, more than one previous cesarean delivery, and conversion to general anesthesia because of failed spinal anesthesia. A history of established chronic pain, i.e., low back pain, fibromyalgia or headaches (defined as requiring regular medical follow-up with pain specialists, as well as recent use (within the year preceding pregnancy) of opioid analgesics or antidepressant drugs), was also an exclusion criteria.

Patients were instructed on the use of the patient-controlled analgesia (PCA) pump, as well as how to use the Visual Analog Scale (VAS: 10-cm unmarked line, 0 = none and 10 = maximal score). They also received instructions on answering a postoperative pain questionnaire during follow-up phone interviews.

Study group allocation was generated by a computer-generated random number table and was sealed in opaque envelopes that were opened by an anesthesiologist not involved in the intra- or postoperative care of the patient. This anesthesiologist prepared the study spinal solution in an unlabeled syringe. The patient, the anesthesiologist responsible for intraoperative care, and the individual who performed the postoperative evaluations were blinded to group assignment.

Intraoperative Procedure
All parturients were premedicated with IV ranitidine 50 mg, metoclopramide 10 mg and oral sodium citrate 0.3 M 30 mL. After a 500-mL IV preload with balanced salt solution, spinal anesthesia was initiated in the sitting position using a 25-gauge pencil-point spinal needle inserted at the L3–4 interspace. The following intrathecal solutions were administered according to group assignment: hyperbaric bupivacaine with sufentanil 2 µg (BS group), hyperbaric bupivacaine with sufentanil 2 µg and clonidine 75 µg (BSC group), or hyperbaric bupivacaine and clonidine 150 µg (BC group). The bupivacaine dose was adjusted based on patient height: 9 mg when <160 cm, 10 mg for height between 160 and 175 cm and 11 mg when >175 cm. The intrathecal drugs were provided by the following manufacturers: bupivacaine (0.5% Marcaine hyperbare, Astra-Zeneca, Sweden), sufentanil (Sufenta, Janssen-Cilag, Belgium) and clonidine (Catapressan, Boehringer Ingelheim, Germany) and were adjusted to a total volume of 3.2 mL with normal saline. All the cesarean procedures were performed through a Pfannenstiel incision with peritoneal closure. In the recovery room, the regression of spinal analgesia was assessed by application of a cold stimulus (ether test) every 15 min. When the sensory level reached the Th10 dermatome, IV morphine PCA analgesia was initiated (demand bolus: 1 mg, lockout time: 5 min, maximum allowable dose: 25 mg in 4 h). All the parturients received IV postoperative diclofenac 150 mg daily (started in the recovery room) and were allowed to receive IV acetaminophen 1 g every 6 h as needed. The study protocol analgesic regimen was continued for 48 postoperative hours after delivery.

Intraoperative Assessments
The time of intrathecal injection was considered time zero (T0). The following variables were recorded from T0 until 45 min (T45) after injection: blood pressure and heart rate were assessed every 2 min from T0 until T10, every 5 min from T11 until T45. Hypotension was defined as a 20% reduction from the preanesthetic baseline systolic blood pressure and bradycardia was defined as heart rate <45 bpm. The level of sedation was assessed at 5-min intervals after delivery by using the following scale: one = awake; two = mild sedation: drowsy but arouses to verbal stimulus; three = moderate sedation: arouses to light touch; four = severe sedation: arouses to firm touch. The highest score recorded for each patient was used for data analysis. The following were also recorded: the level of sensory blockade (assessed to cold [ether test] every 5 min for 20 min), the highest sensory level attained, duration of surgical procedure, and the dose of vasopressor (ephedrine plus phenylephrine combination: 2.5 mg ephedrine and 15 µg phenylephrine per mL). In the recovery room, the duration of spinal analgesia (defined interval from T0 until sensory level regressed to Th10), as well as the time of administration of the first demand PCA dose were noted.

Outcome Assessment
The presence and the area of hyperalgesia for punctate mechanical stimuli around the surgical incision was measured at 24 and 48 h according to the method previously described.16,17 Stimulation with a von Frey hair (396 m Newton) was started from outside the hyperalgesic area where no pain sensation was experienced and moved toward the incision by 1-cm steps until the patient reported a distinct change in perception. The first point where a painful, sore or sharper feeling appeared was marked, and the distance to the incision was measured. The area of hyperalgesia was determined by testing along radial lines separated by 5 cm around the incision. The observations were transcribed onto graph paper and the total surface area was calculated. The incidence of periincisional mechanical hyperalgesia (defined as the presence of hyperalgesia, no matter the degree) was calculated.

Acute postoperative pain was assessed using the following variables: cumulative dose of morphine consumption (PCA use) and acetaminophen at 12, 24, and 48 h; VAS pain scores for wound pain at rest and with movement (assessed by asking the parturient to sit on the edge of her bed), as well as scores for uterine contraction pain at 12, 24, and 48 h.

The incidence of postoperative residual pain or discomfort was evaluated at 1, 3, and 6 mo after completion of surgery. Patients where asked by a research nurse to answer a standard series of questions (Appendix 1) by telephone.

Statistical Analysis
Statistical analysis was performed with Statistica for Windows (version 5; Statsoft, Tulsa, OK). The primary outcome variable was the area of punctate mechanical hyperalgesia surrounding the wound at 48 h. The analgesic effects of clonidine on postoperative VAS scores and PCA morphine requirements were considered secondary outcomes.

Preliminary observations involving 20 parturients who underwent elective cesarean delivery under spinal anesthesia with 0.5% hyperbaric bupivacaine and sufentanil demonstrated that the mean (± sd) area of punctate hyperalgesia surrounding the wound was 7.5 cm² (±5.0). Sample size calculations based on these data suggested that a group size of 30 patients would detect a difference of 50% in the extent of periincisional punctate hyperalgesia (power = 80%, two-tailed = 0.05). Therefore, we prospectively decided to enroll 32 patients per group.

The normal distribution of the data was assessed using the Kolmogorov-Smirnov test. Data were analyzed using analysis of variance and analysis of variance for repeated measures (demographic data, VAS scores, analgesic use) or Kruskal-Wallis analysis of variance on ranks (area of hyperalgesia, residual pain intensity scores). Post hoc comparisons were made using the Tukey honestly significant difference test. Comparisons of the observed proportions were performed using ² analysis and the Fisher’s exact test. Results are expressed as mean ± sd or otherwise specified. A probability (P) value of <0.05 was considered to be statistically significant.

RESULTS

Ninety-six patients completed the postoperative follow-up at 24 and 48 h and 90 patients (30 in the BS group, 31 in the BSC group and 29 in the BC group) completed the follow-up at 1, 3, and 6 mo after the procedure. Demographic data did not differ among the groups (Table 1). No patient was excluded because of failed spinal anesthesia. Intraoperative supplementary analgesia, i.e., inhalation of nitrous oxide, was required in two patients (one in the BS group and one in the BC group) at the time of skin closure.

Wound Hyperalgesia and Acute Postoperative Pain
The postoperative extent of the area of punctate mechanical hyperalgesia surrounding the wound at 24 h and 48 h was smaller in the BC group than in the BS group (P = 0.02) (Fig. 1). The incidence of punctate mechanical hyperalgesia at 48 h was also lower in the BC group than in the BS group (P = 0.03). VAS scores for incision pain at rest and at movement did not differ among the groups (Figs. 2a and b) nor did uterine cramping pain scores (data not shown). Postoperative PCA morphine requirements did not differ among the groups (Fig. 3). Acetaminophen use was similar among the groups at the different time points and the total dose at 48 h did not differ: 2 ± 2 g in the BS group, 2 ± 1 g in the BSC group and 2 ± 2 g in the BC group (P = 0.126).

View larger version (16K): [in this window] [in a new window]   Figure 1. Postoperative mechanical hyperalgesia. Area of punctate mechanical hyperalgesia surrounding the surgical incision (median, 25th and 75th percentiles and extreme values) Percentage of patients (numbers in brackets) presenting with hyperalgesia at 24 h and 48 h after surgery is also reported for the different groups. *P < 0.05 with BS group for both the area and the prevalence of mechanical hyperalgesia. Treatment groups: BS: intrathecal bupivacaine-sufentanil, BSC: intrathecal bupivacaine-sufentanil with clonidine 75 µg, BC: intrathecal bupivacaine with clonidine 150 µg.

View larger version (20K): [in this window] [in a new window]   Figure 2. Postoperative pain. Evaluation of postoperative incisional pain scores (Visual Analog Scale score: 0–10) at rest (a) and with movement (b) at 12, 24, and 48 h after cesarean delivery. Data are expressed as median, 25th and 75th percentile and extreme values. There were no differences among groups. Treatment groups: BS: intrathecal bupivacaine-sufentanil, BSC: intrathecal bupivacaine-sufentanil with clonidine 75 µg, BC: intrathecal bupivacaine with clonidine 150 µg.

View larger version (15K): [in this window] [in a new window]   Figure 3. Postoperative IV patient-controlled analgesia (PCA). Cumulative doses of morphine (mean ± sd) delivered by a PCA device at 12, 24, and 48 h after surgery (after intrathecal dose). There were no differences among groups. Treatment groups: BS: intrathecal bupivacaine-sufentanil, BSC: intrathecal bupivacaine-sufentanil with clonidine 75 µg, BC: intrathecal bupivacaine with clonidine 150 µg.

Residual Pain
The overall incidence of persistent pain at 1, 3, and 6 mo was 28%, 14%, and 7% and no significant differences were found among groups (Table 2). Analgesic intake was limited to acetaminophen and other nonsteroidal antiinflammatory drugs. At 1 mo after surgery, 10% of patients in the BS group, 13% of patients in the BSC group and 13% patients in the BC group reported discomfort surrounding the scar, but no pain. These unpleasant feelings disappeared within 3 mo in all patients.

Spinal Analgesia and Side Effects
No major side effect (i.e., hemodynamic event which did not respond to vasopressor treatment or atropine) was associated with the intrathecal injection of clonidine 75 or 150 µg (Table 3). The incidence of hypotension was not different among groups for T0–15 min and T16–30 min, but was higher in the BC group than in the BS group at T31–45 min. Mild sedation was more frequently observed in patients from the BC group. Although the duration of intrathecal anesthesia did not differ among the groups, the first use of PCA morphine was significantly delayed in the BSC group compared to the other groups (Table 3).

DISCUSSION

The present study demonstrates that intraoperative administration of intrathecal clonidine 150 µg with bupivacaine reduces the incidence and extent of periincisional punctate mechanical hyperalgesia at 48 h after elective cesarean delivery compared to bupivacaine with sufentanil and bupivacaine with sufentanil and clonidine 75 µg.

In contrast to the analgesic effects, the antihyperalgesic properties of the 2-adrenoceptor agonists have not been extensively studied, at least in the clinical setting of perioperative pain.

Tissue injuries induce a central neuronal sensitization, a state of hyperexcitability in pain processing, which contributes to and enhances pain.18,19 Hyperalgesia, the enhancement of pain for a given stimulus, is the expression of this phenomenon in clinical practice, and periincisional punctate mechanical hyperalgesia can be used to measure postoperative central nervous system sensitization.16,17 Intrathecal 2-adrenergic agonists effectively relieve postoperative mechanical hyperalgesia after plantar incision in animal models.20,21 In volunteers, intrathecal, but not IV, clonidine reduces the area of mechanical hyperalgesia secondary to intradermal capsaicin injection.9 A dose of 150 µg is required to observe this antihyperalgesic effect, while 50 µg is ineffective.8 In a clinical trial, intrathecal clonidine 300 µg was effective in blunting the development of mechanical wound hyperalgesia after major abdominal surgery.10

The analgesic effect of clonidine is greater after neuraxial compared to systemic administration7 and intrathecal clonidine displays an analgesic plateau effect at 75 µg. Further dose increases only serve to enhance the duration, but not the intensity, of analgesia.8,22

The present study sought to assess the antihyperalgesic effect of intrathecal clonidine administered during cesarean delivery. Intrathecal clonidine should be used cautiously for cesarean delivery because of the risk of adverse intraoperative hemodynamic effects and the risk of prolonged motor/sensory blockade leading a delayed postoperative recovery. For these reasons, we elected to limit the dose of intrathecal clonidine to 150 µg combined with bupivacaine, and we reduced the dose to 75 µg when combined with sufentanil and bupivacaine. This lack of sufentanil in the group with the highest dose of clonidine, however, precludes us from making any conclusions regarding a dose-response effect of clonidine’s antihyperalgesic properties in this setting.

In addition, the possibility that the presence of sufentanil masked the antihyperalgesic effect of clonidine 75 µg cannot be excluded. Systemic opioids, in a dose-related manner, promote the development of postoperative hyperalgesia.15 Although there is little evidence for a similar effect of intrathecal opioids in humans, the phenomenon has been observed in rats after a single dose of intrathecal morphine.23

Very few trials have considered the impact of postoperative hyperalgesia on postoperative pain.11 Two observations deserve further comments. First, although hyperalgesia may be involved in postoperative pain and may enhance the amount of pain experienced by the patient,11 its reduction was not associated with a significant reduction of clinical pain measured by VAS scoring, both in patients in the current study and in patients undergoing abdominal surgery.10 Similar observations have been reported with systemic ketamine and other antihyperalgesic drugs.16,24 These findings question the relationship between the extent of postoperative punctate hyperalgesia, a quantitative measure, and clinical pain, a subjective experience subject to multifactorial modulation.13

The second observation which should be emphasized is that the duration of the antihyperalgesic effect from a single dose of intrathecal clonidine (at least 48 h) outlasted the duration of the analgesic effect, as assessed by the first request for postoperative analgesics, both in the current study and a previous study.10 In clinical trials, the additional analgesic effect of intrathecal clonidine combined with a local anesthetic and opioid agonist usually does not extend more than 6 to 12 h after cesarean delivery.4–6,25

This finding questions the mechanisms that underly postoperative hyperalgesia and central sensitization, as well as those underlying clonidine’s antihyperalgesic effect. Exogenous clonidine mimics the effects of endogenous norepinephrine and activates descending inhibitory pathways.26 Clonidine’s antihyperalgesic mechanisms partly rely on reinforcement of noradrenergic inhibitory controls in the dorsal horn of the spinal cord. Norepinephrine is a mixed 2- and 1-adrenoceptor agonist and 2-adrenoceptor binding mediates presynaptic inhibition of glutamatergic excitatory transmission,27 whereas binding to 1-adrenoceptors on inhibitory interneurons promotes the release of -aminobutyric acid and glycine neurotransmitters.28 Experimental data support a major role of descending noradrenergic activity on persistent pain in the perioperative period. In a model of surgical incision, noradrenergic inhibitory systems are quickly activated during, and immediately after surgery, and preemptive intrathecal administration of norepinephrine transporter inhibitors reduces postincisional mechanical hyperalgesia in a dose-dependent manner for several days.29 Whether the single preoperative administration of analgesic drugs affords a preemptive effect on postoperative analgesia in clinical practice is controversial,30,31 as is the question of whether the intraoperative administration of an intrathecal drug exerts a preemptive effect on the development of postoperative hyperalgesia.

Beyond the question of whether hyperalgesia contributes to postoperative pain, the abnormal persistence of central nervous system sensitization may induce permanent modifications and promote the development of persistent pain after surgery.11 Furthermore, the extent of postoperative hyperalgesia may positively correlate with an increased risk of persistent pain.13,32 Periincisional mechanical hyperalgesia may last for more than 3 mo after abdominal hysterectomy17 and has been observed in 5% to 9% of women 6 wks after elective cesarean delivery.33 In the same study,33 16% of women reported wound or abdominal pain persisting at 6 wks. Nikolajsen et al.34 reported an incidence of persistent pain more than 18% at 3 mo and 12% at 10 mo after cesarean delivery. Spinal anesthesia may have a protective effect for residual pain34 and we have speculated that noxious inputs reaching the central nervous system are less during spinal anesthesia than during general anesthesia. In patients undergoing abdominal surgery,10 intrathecal bupivacaine reduced the incidence of residual pain in comparison with saline. Intrathecal clonidine 300 µg afforded an even greater protective effect than bupivacaine. In the present study, although intrathecal clonidine 150 µg reduced both the extent and the incidence of postoperative mechanical hyperalgesia, this effect was not associated with a significant reduction in the incidence of persistent pain. It is possible that the dose of intrathecal clonidine was inadequate. Alternatively, the incidence and the severity of residual pain after cesarean delivery is low and the study may have been under-powered to find a difference in residual pain incidence. Finally, the use of a nonvalidated tool to assess persistent pain might also account for the lack of correlation between the reduction of postoperative periincisional hyperalgesia and chronic pain after the procedure.

In conclusion, intrathecal bupivacaine-clonidine 150 µg demonstrates postoperative antihyperalgesic properties after cesarean delivery, compared with intrathecal bupivacaine-sufentanil, or bupivacaine-sufentanil-clonidine 75 µg. The duration of the antihyperalgesic effect outlasts that of the analgesic effect as assessed by the first analgesic request. A long-term benefit on residual pain requires further study. Although we did not identify significant side effects of clonidine at the doses we administered, potential benefits of intrathecal clonidine administration during cesarean delivery need to be balanced with well-known side effects such as sedation, and prolonged motor and sensory block which are undesirable in this patient population.

APPENDIX

1. Do you still feel pain today? Yes/no. If you presently experience pain, where is your pain located? At the level of the scar? Yes/No. Elsewhere? Yes/No. Please describe where. Please, quantify the level of pain that you feel using a scale from One to Five as following: One = slight pain; Two = mild pain; Three = moderate pain; Four = high pain; Five = very high pain.
   
2. Do you experience discomfort, but no pain, around the scar? (for example: loss of sensitivity? Unpleasant feeling related to touch or wearing clothes?) Yes/No.
   
3. If you presently experience pain, how frequent is your pain: Constant? More than 2 days per week? <2 days per wk?
   
4. Does pain interfere with your daily life, i.e., does pain interfere with the following tasks: Caring of your baby? Carrying your baby? Performing your daily work? Does the pain interfere with your sleep? Yes/No.
   
5. Do you take any analgesics to relieve your pain? Yes/no. Please provide the name and doses. Do you need daily analgesics? Yes/No.
   

Footnotes

Accepted for publication April 29, 2008.

Supported by the Department of Anesthesiology of St Luc Hospital, Université Catholique de Louvain.

Presented at the ASA Annual Meeting (October 14–18, 2006, Chicago, IL) during the SOAP/Journal Abstract Session: Basic mechanisms underlying our routine daily practices of obstetric anesthesia.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lavand’homme, P. M. Articles by De Kock, M. F. Search for Related Content PubMed PubMed Citation Articles by Lavand’homme, P. M. Articles by De Kock, M. F. Related Collections Obstetrics Pain Mechanisms Pain Medicine Regional Anesthesia Pain Pharmacology