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Background: Postoperative negative behavioral changes (NBCs) are common among children, but risk for this is thought to be reduced with premedication. Midazolam has for many years been a standard premedication for children. More recently, the alpha-2 adrenergic agonist clonidine has also become popular as a preanesthetic sedative. We hypothesized that clonidine was superior to midazolam for limiting new NBCs in children as assessed using the Post Hospital Behavior Questionnaire (PHBQ)., Methods: This was a prospective, randomized, controlled, blinded study, including 115 participants aged 24 to 95 months and their parents. The participants underwent ear, nose, or throat outpatient surgery and were randomly allocated to premedication with oral midazolam 0.5 mg/kg or oral clonidine 4 µg/kg. Participants were anesthetized by protocol. At home, later, parents were asked to complete the PHBQ assessment instrument for postoperative NBCs for the participants 1 week, 1 month, and 6 months after the surgery. A secondary outcome, preinduction anxiety, was assessed using modified Yale Preoperative Anxiety Scale (mYPAS)., Results: The primary outcome, more than 3 NBCs in an individual case at 1 week, showed no difference in proportions between treatment in the clonidine group compared to the midazolam group, (12/59 or 20% vs 7/56 or 13%, respectively, odds ratio 1.39, 95% confidence interval [CI], 0.75-2.58; P = .32). A secondary result showed a higher preinduction anxiety level in the clonidine compared to the midazolam group (mYPAS >30, 43/59 or 71% vs 12/56 or 21%, respectively; P < .001)., Conclusions: These results did not show a clinical or statistically significant difference, with respect to the primary outcome of behavior changes at 1 week, between the cohorts that received midazolam versus clonidine as a premedication., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 International Anesthesia Research Society.)

Background: Intrathecal clonidine prolongs spinal anesthesia. We evaluated the effects of the addition of intrathecal or intravenous clonidine (75 µg) to standard cesarean delivery spinal anesthesia on postoperative pain and neonatal outcomes., Methods: In a randomized, placebo-controlled, double-blind trial, 64 women scheduled for elective cesarean delivery under spinal anesthesia were randomly allocated and compared among 3 groups: intrathecal clonidine 75 µg, intravenous clonidine 75 µg, and placebo. The primary outcome was acute postoperative pain. A sample size of 26 individuals per group (N = 78) was planned., Results: From April 2015 to April 2016, 64 women were analyzed (14 excluded). No differences in postoperative pain scores were found (Numerical Verbal Scale for pain at movement at 24 hours of postcesarean delivery: 4.53 ± 3.0 vs 4.45 ± 2.73 vs 3.93 ± 3.07 for control, intrathecal, and intravenous, respectively, P = .771). Intrathecal and intravenous clonidine led to more sedation, in comparison to the control group, during the intraoperative period (Richmond Agitation and Sedation Scale: -0.3 ± 0.47 vs -1 ± 0.53 vs -0.73 ± 0.45 for control, intrathecal, and intravenous, respectively, overall P < .001; Dunn correction: P < .001 for intrathecal versus control; P = .021 for intravenous versus control; and P = .208 for intrathecal versus intravenous)., Conclusions: Intrathecal or intravenous clonidine had no effect on postoperative pain after cesarean delivery. Both intrathecal and intravenous clonidine caused more sedation.

Background: Clonidine, an α-2 agonist, has long been used as a local anesthetic adjunct with proven efficacy to prolong peripheral nerve block duration. Dexmedetomidine, a newer α-2 agonist, has a more favorable pharmacodynamic and safety profile; however, data comparing its efficacy as an adjunct to that of clonidine are inconsistent. We sought to compare the clinical efficacy of these 2 α-2 agonists by examining their effects on peripheral nerve block characteristics for upper extremity surgery., Methods: A preliminary search found that the overwhelming majority of randomized controlled trials comparing perineural dexmedetomidine to clonidine for upper extremity surgery were in the setting of supraclavicular brachial plexus block (SCB). Therefore, we performed a systematic review and meta-analysis of randomized controlled trials comparing dexmedetomidine with clonidine as perineural adjuncts to single-injection SCB. Sensory and motor block duration and onset, analgesic duration, α-2 agonist side effects, and block complications were analyzed. Sensory block duration was designated as a primary outcome. Data were combined using random-effects modeling, and ratio-of-means was used to analyze the results., Results: A total of 868 patients from 14 clinical studies were included in the analysis. Compared with clonidine, dexmedetomidine prolonged the duration (ratio of means [95% confidence interval {CI}]) of sensory block by an estimate of 1.2 (1.2-1.3; P< .00001). It also prolonged the duration (ratio of means [99% CI]) of motor block by an estimate of 1.2 (1.1-1.3; P < .00001), and analgesia by an estimate of 1.2 (1.1-1.3; P < .00001). It also hastened the onset of sensory block by an estimate of 0.9 (0.8-1.0; P < .00001) and motor block by an estimate of 0.9 (0.9-1.0; P = .002). Dexmedetomidine was associated with an increased odds ratio (99% CI) of transient bradycardia by an estimate of 7.4 (1.3-40.8; P = .003) and postoperative sedation by an estimate of 11.8 (1.9-73.6; P = .0005). There were no differences in other α-2 agonist-related side effects or block-related complications., Conclusions: Compared with clonidine as a local anesthetic adjunct for single-injection SCB, perineural dexmedetomidine enhances sensory, motor, and analgesic block characteristics. These benefits should be weighed against the increased risk of transient bradycardia.

Background and Objectives: Patient-controlled epidural analgesia (PCEA) with bupivacaine and hydromorphone provides high quality analgesia after orthopedic surgery but is associated with a frequent incidence of opioid-related side effects (15%-30%). Epidural clonidine has a different side effect profile, but there are no large surveys documenting its use. We performed this prospective survey to evaluate analgesia and the side effect profile in total hip replacement patients before and after a systematic change from PCEA with bupivacaine/hydromorphone to bupivacaine/clonidine., Methods: Five hundred consecutive patients received PCEA with 0.06% bupivacaine and hydromorphone (10 mcg/mL) as a previously described prechange control group. The standard analgesic regimen was then systematically changed to 0.06% bupivacaine and clonidine (1 mcg/mL) without changing the PCEA settings or other aspects of perioperative care, and 500 consecutive patients were included as a postchange group. All data were prospectively entered and then abstracted from the electronic medical record. Data collection included daily verbal pain scores (VPS), pruritus, nausea, hypotension, need for IV fluid boluses, sedation, and respiratory depression. An online survey to measure staff satisfaction with the changeover was sent to all participating surgeons, anesthesiologists, physical therapists, and physician's assistants., Results: Patient characteristics were similar between groups. Most patients received central neuraxial anesthesia (99%). The clonidine group had lower VPS at rest (2.3 vs 3.7, P<0.001 with 95% confidence interval [CI] of difference of 1.4 [1.1, 1.7]) on POD0. The incidence of nausea was 10%-11% for clonidine and 13%-15% for hydromorphone. The incidence of pruritus was less with clonidine (1 vs 10%, P<0.01 with 95% CI of difference of 9% [6, 12]). However, the incidence of hypotension (20 vs 11%, P<0.001 with 95% CI of differences 9% [5, 14]) and IV fluid boluses was more frequent with clonidine (36 vs 19%, P<0.001 with 95% CI of differences of 16 [11, 12]). Sixty-five percent of staff completed the online survey, and 70% considered clonidine worse than hydromorphone., Conclusion: The systematic changeover from epidural hydromorphone to clonidine produced mixed results without obvious superiority. The VPS at rest was reduced only on postoperative day 0; pruritus was reduced, but hypotension was increased. On the basis of medical staff preference, we discontinued the systematic change and returned to our previous standard solution of bupivacaine and hydromorphone for PCEA after total hip replacement.

Background: Clonidine is an alpha(2) adrenoreceptor and imidazoline receptor agonist, which has analgesic, sedative, and minimum alveolar anesthetic concentration-sparing effects. It has been used orally, IV, and epidurally. In spinal surgery, there is a reluctance to use local anesthetic-based epidural analgesia postoperatively because of fears of masking important signs of nerve root or spinal cord injury., Methods: We randomized 66 patients undergoing uncomplicated decompressive spinal surgery to receive an epidural infusion of either clonidine (Group C) or saline placebo (Group P) postoperatively. Morphine consumption by patient-controlled analgesia device was recorded for 36 h., Results: Morphine consumption was significantly lower in Group C. The mean consumption at 36 h was 35 mg (95% confidence interval 21-50 mg) in Group C, compared with 61 mg (95% confidence interval 48-74 mg) in the control group. Nausea was significantly reduced in Group C (6.5%), when compared with placebo (38.2%)., Conclusion: Low-dose epidural clonidine significantly reduced the demand for morphine and reduced postoperative nausea with few side effects.

Background: We tested the hypothesis that 100 microg clonidine added to 0.375% bupivacaine would prolong the duration of analgesia from popliteal fossa nerve blockade., Methods: Ninety-nine patients scheduled for hospital admission after foot or ankle surgery entered this randomized, double-blind, placebo-controlled trial. Patients received a popliteal fossa block (nerve stimulator technique, via the posterior approach) using 30 mL 0.375% bupivacaine, with epinephrine. Patients were randomized to receive no clonidine, 100 microg clonidine IM, or 100 microg clonidine with bupivacaine for the popliteal block. Patients also received a combined spinal-epidural anesthetic, a saphenous nerve block, and postoperative IV patient-controlled analgesia. The primary outcome was patient-reported duration of analgesia., Results: Duration of analgesia was statistically longer in the block clonidine group (18 +/- 6 h for clonidine with bupivacaine vs 14 +/- 7 h for IM clonidine and 15 +/- 7 h for control, P = 0.016 for control vs clonidine with bupivacaine). Pain scores, analgesic use, and side effects attributable to pain management were similar among groups., Conclusions: Clonidine significantly prolongs the analgesic duration after popliteal fossa nerve blockade with bupivacaine.

Background: Spinal anesthesia is increasingly used in adolescents. However, the anesthesia provided by bupivacaine alone may be too short for the planned surgery. The addition of clonidine 2 microg/kg to bupivacaine provides a prolonged anesthetic action but may be associated with hypotension. In the present study, we investigated the efficacy and safety of intrathecal clonidine 1 mug/kg in adjunction to bupivacaine in spinal anesthesia in adolescents., Methods: Eighty-three adolescents, 51 males, aged 10-15 yr, scheduled for orthopedic surgery were enrolled in this placebo-controlled, randomized study. Patients were given spinal anesthesia either with plain 0.5% isobaric bupivacaine 0.2-0.4 mg/kg or bupivacaine with clonidine 1 microg/kg. The duration of sensory block was the primary outcome measure., Results: Clonidine prolonged the duration of both the sensory and motor block. The time to regression of sensory block by two dermatomes was 136 (mean) (sd, 56) min in the adolescents with clonidine versus 107 min (sd, 42) in the controls (95% CI for diff: 5-53 min, P = 0.02). The time to full recovery of motor block was 251 min (sd, 79) in the adolescents with clonidine versus 181 min (sd, 59) in the controls (95% CI: 39-103 min, P = 0.001). Time to the first dose of rescue analgesia was longer in the adolescents with clonidine, 461 min (sd, 147) versus 330 min (sd, 138) in the controls (95% CI: 53-207 min, P = 0.01). There was no difference in the frequency of hypotension or bradycardia between the groups., Conclusion: In adolescents, clonidine 1 microg/kg prolonged the duration of sensory block achieved with bupivacaine by 30 min and postoperative analgesia by 120 min without severe adverse events.

The administration of epidural opioids, though effective for producing analgesia, has severe side effects in most patients. It is unknown whether clonidine can effectively replace opioids and cause fewer side effects. We compared, in this randomized trial, the incidence of vomiting and pruritus as well as the analgesic profile of three different combinations of bupivacaine, fentanyl, and clonidine administered epidurally in patients undergoing the Nuss procedure: bupivacaine + fentanyl, bupivacaine + clonidine, bupivacaine + fentanyl + clonidine. The incidence of side effects was significantly less in the bupivacaine + clonidine group (33%) compared with the bupivacaine + fentanyl (92%) and bupivacaine + fentanyl + clonidine (73%) groups (P = 0.004). Quality of postoperative analgesia was similar in the three groups. No significant complications were observed. In conclusion, clonidine is an effective and safe alternative to epidural opioids.

We hypothesized that combined femoral-sciatic nerve block (FSNB) offers better analgesia with fewer side effects than intraarticular infiltration (IA) in children undergoing anterior cruciate ligament (ACL) reconstruction. Thirty-six children undergoing ACL reconstruction were randomized to FSNB or IA. FSNB patients had FSNB with bupivacaine (0.125%)-clonidine (2 microg/kg), whereas IA patients received bupivacaine (0.25%)-clonidine (1 microg/kg)-morphine (5 mg). Postoperatively, analgesia was provided with patient-controlled analgesia and rescue morphine. Patient demographics were similar. FSNB patients required less intraoperative fentanyl (50 +/- 40 microg versus 80 +/- 50 microg; P = 0.04). Visual analog scale score for FSNB was smaller than IA in the recovery room (1.8 +/- 3 versus 5.4 +/- 3; P = 0.0002) and during the first 24 h (1.6 +/- 1 versus 2.9 +/- 2; P = 0.01)). FSNB morphine use in the first 18 h was less (7 +/- 13 mg versus 21 +/- 21 mg; P = 0.03). Fewer FSNB patients vomited (11% versus 50%; P = 0.03). IA patients required morphine patient-controlled analgesia sooner. After ACL reconstruction in children, FSNB with bupivacaine-clonidine provides better analgesia with fewer side effects than IA with bupivacaine-clonidine-morphine.

We evaluated the efficacy of local or systemic parecoxib combined with lidocaine/clonidine IV regional analgesia in complex regional pain syndrome (CRPS) type 1 in a dominant upper limb. Thirty patients with CRPS type 1 were divided into three groups. The control group (CG) received both IV saline in the healthy limb and IV loco-regional 1 mg/kg of lidocaine + 30 mug of clonidine, diluted to a 10-mL volume with saline. The systemic parecoxib group (SPG) received a regional block similar to that administered to the CG but with systemic 20 mg of parecoxib, whereas the IV regional anesthesia with parecoxib group (IVRAPG) received an extra IV 5 mg of loco-regional parecoxib compared with the CG. The block was performed once a week for 3 consecutive weeks. Analgesia was evaluated by the 10-cm visual analog scale (VAS) and rescue analgesic consumption. The IVRAPG showed less daily ketoprofen (milligrams) consumption in the second and third weeks compared with the other groups (P < 0.05). The IVRAPG also showed less ketoprofen consumption when comparing the first and second week with the third week (P < 0.05). The VAS score comparison among groups revealed that groups were similar during the first and second week observation, although the IVRAPG showed smaller VAS scores in the third week compared with both CG and SPG (P < 0.05). We conclude the IV 5 mg of parecoxib was an effective antiinflammatory drug combined with clonidine/lidocaine loco-regional block in CRPS type 1.

Unlabelled: In this study, we investigated the antihyperalgesic effect of clonidine after surgery. Sixty patients undergoing right colic resection were studied. Patients were randomized to receive prior to general anesthesia a 2-mL intrathecal (IT) injection of 300 microg of clonidine or saline, or 10 mg of bupivacaine. General anesthesia was achieved using a target concentration propofol infusion and monitored using bispectral index. Postoperative analgesia was provided by morphine IV given through a patient-controlled analgesia device. Postoperative analgesia was assessed by morphine requirements and visual analog scale pain scores at rest, cough, and movement during the first 72 h. Mechanical hyperalgesia was measured by von Frey filaments. Patients were questioned regarding residual pain at 2 wk,1, 6, and 12 mo. The patient-controlled analgesia morphine requirements were significantly smaller in the IT clonidine group (31.5 +/- 12 versus 91 +/- 25.5 and 43 +/- 15 mg, respectively, in groups clonidine, saline, and bupivacaine: P < 0.05 at 72 postoperative hours). The area of hyperalgesia at 72 h was 3 +/- 5 cm(2) in the clonidine group versus 90 +/- 30 and 35 +/- 20 cm(2) in the saline and bupivacaine groups (P < 0.05). At 6 mo, fewer patients in the clonidine group experienced residual pain than in the saline group (0 of 20 versus 6 of 20, P < 0.05). We conclude that both intraoperative spinal clonidine and bupivacaine improve immediate postoperative analgesia. IT clonidine was, however, more potent than IT bupivacaine to reduce postoperative secondary hyperalgesia., Implications: Spinal clonidine contributes to the reduction of secondary hyperalgesia in patients recovering from abdominal surgery.

Although clonidine has been shown to increase the duration of local anesthetic action and prolong postoperative analgesia when included in single-injection nerve blocks, the only controlled investigation of the efficacy of this practice to improve analgesia for continuous perineural local anesthetic infusion failed to discern any clinically relevant benefits. For this study, we used a larger dose of clonidine in an attempt to improve analgesia. Patients (n = 20) undergoing moderately painful orthopedic surgery of the shoulder received an interscalene brachial plexus block (40 mL of mepivacaine 1.5%, epinephrine 2.5 microg/mL, and clonidine 50 microg) and a perineural catheter before surgery. After surgery, ropivacaine 0.2% or ropivacaine 0.2% plus clonidine 2 microg/mL was delivered via the catheter for 3 days (basal rate, 5 mL/h; patient-controlled bolus, 5 mL; lockout, 1 h). Investigators and patients were blind to random group assignment. The primary outcome variable was designated as the most intense pain during the day after surgery. Secondary end-points included additional pain scores, patient-controlled bolus doses, oral analgesic use, sleep quality, and catheter- or infusion-related complications. There were no statistically significant differences between groups for any of the variables investigated. We conclude that adding clonidine 2 microg/mL to a ropivacaine interscalene perineural infusion does not decrease breakthrough pain intensity the day after surgery. For the additional end-points, our negative findings are only suggestive of a lack of effect and require further study for verification.

We hypothesized that onset of sensory block is delayed in infected versus healthy tissues within the same nerve distribution after axillary brachial plexus block (ABPB) and that clonidine added to mepivacaine would enhance anesthesia and postoperative analgesia. Forty-one outpatients undergoing thumb/index paronychia surgery under ABPB were randomly assigned to receive in a double-blind fashion 400 mg mepivacaine plus either 100 microg clonidine (clonidine group, n = 21) or 2 mL saline (placebo group, n = 20). Onset of sensory block in the infected area was delayed compared with healthy areas of the same nerve distribution (24.7 +/- 5.5 min versus 21.3 +/- 7.2; P = 0.02 for median and 21.6 +/- 7.8 min; P = 0.04 for radial) within the placebo group. In the clonidine group, when compared to placebo i) onset of sensory block in both the median and radial nerve territories was accelerated (11.1 +/- 5.6 and 10.5 +/- 5.2 versus 21.3 +/- 7.2 and 21.6 +/- 7.8 min, respectively; P < 0.001), ii) onset of sensory block in the region of infection was accelerated (9.1 +/- 1.9 versus 24.7 +/- 5.5 min; P < 0.001), iii) duration of anesthesia (275 +/- 75 versus 163 +/- 57; P = 0.04) and time to first analgesic requirement (279 +/- 87 versus 197 +/- 84 min; P = 0.002) were prolonged with decreased visual analog scale scores at this time (30 +/- 18 versus 70 +/- 24; P < 0.001), and iv) verbal numeric rating scores were decreased at 24 h (1.7 +/- 2.2 versus 4.1 +/- 3.0; P = 0.002) and 48 h (0.1 +/- 0.5 versus 1.5 +/- 2.4; P = 0.01) postoperatively. Our findings suggest that in the setting of distal infected tissue surgery under ABPB infected tissues are resistant to anesthesia compared with healthy areas within the same nerve distribution and clonidine added to mepivacaine enhances both anesthesia and postoperative analgesia.

We evaluated the systemic and local effects of clonidine as an analgesic adjunct to psoas compartment block (PCB) with levobupivacaine. In a randomized, prospective, double-blind trial, 36 patients requiring hip fracture surgery received PCB and general anesthesia. Patients were randomized into three groups. Each patient received PCB with 0.4 mL/kg of levobupivacaine 0.5%. The control group (group L) received IV saline, the systemic clonidine group (group IC) received IV clonidine 1 mug/kg, and the peripheral clonidine group (group C) received IV saline and PCB with clonidine 1 microg/kg. The interval from time of completion of block injection to first supplementary analgesic administration was longer in group IC compared with group L (mean +/- sd, 13.4 +/- 6.1 versus 7.3 +/- 3.6 h; P = 0.03). There was no difference between group C and group L (10.3 +/- 5.9 versus 7.3 +/- 3.6 h; P > 0.05). The groups were similar in terms of 24 h cumulative morphine and acetaminophen consumption. There were no significant differences among groups regarding postoperative adverse effects (bradycardia, hypotension, sedation, and nausea). We conclude that IV but not perineural clonidine (1 microg/kg) prolongs analgesia after PCB without increasing the incidence of adverse effects.

A 47-yr-old man with history of complex regional pain syndrome type 1 underwent an IV Bier block with a mixture of lidocaine and clonidine. The tourniquet was deflated after 60 min, and approximately 10 min later he presented with complex partial seizures. The possible mechanisms for this are discussed, and the effects of clonidine, lidocaine, and the mixture of both are reviewed, as are four additional published cases reporting seizures after the administration of clonidine.

Intrathecal (IT) clonidine is an effective analgesic, but it also produces hemodynamic depression and sedation which are likely to be related to IT clonidine's cephalad spread within the cerebrospinal fluid. We hypothesized that IT clonidine's side effects could be reduced without compromising the duration and quality of analgesia by injecting clonidine IT in a hyperbaric solution and elevating the patient's trunk. We prospectively randomized 30 elderly patients to receive IT 150 microg of either isobaric (ISO) or hyperbaric (HYPER) clonidine for postoperative analgesia after surgical repair of traumatic hip fracture. Hemodynamics, IV fluid administration, visual analog pain scores, sedation scores, and clonidine cerebrospinal fluid levels were recorded at fixed intervals. Patients in the ISO group required significantly more crystalloid fluid administration (median, 2500 mL; range, 1500-3000 mL) than those in the HYPER group (median, 1500; range, 500-3000 mL) to maintain adequate arterial blood pressure (P < 0.01). Also, the decrease in heart rate was significantly more pronounced in the ISO than in the HYPER group (P < 0.01). The duration of analgesia was significantly larger in the ISO (median, 400 min; range, 115-400 min) than in the HYPER (median, 265 min; range, 205-400 min) group (P < 0.05). Sedation scores did not differ between groups. We conclude that increasing the baricity of IT clonidine solution in the conditions of our experiment reduces hemodynamic side effects but also analgesia from IT administered clonidine.

Unlabelled: We investigated the interaction between spinally administered bupivacaine and clonidine using an animal model of acute and inflammatory pain. Rats implanted with lumbar intrathecal catheters were injected intrathecally with saline (control), bupivacaine (1 to 100 microg), or clonidine (0.1 to 3 microg) and tested for their responses to thermal stimulation to the tail (tail flick test) and subcutaneous formalin injection into the hindpaw (formalin test). The effects of the combination of bupivacaine and clonidine on both stimuli were tested by isobolographic analysis. General behavior and motor function were examined as side effects. The 50% effective doses of bupivacaine and clonidine were significantly smaller when combined compared with each single drug in both the tail flick test (2.82 and 0.11 microg versus 7.1 and 0.29 microg, respectively) and phase 1 (0.24 and 0.009 microg versus 5.7 and 0.15 microg) and phase 2 (0.31 and 0.012 microg versus 3.2 and 0.16 microg) of the formalin test. Side effects were decreased by the combination. These results suggest a favorable combination of intrathecal bupivacaine and clonidine in the management of acute and inflammatory pain., Implications: The analgesic interaction between intrathecally administered bupivacaine and clonidine was examined during acute thermal and inflammatory-induced pain in rats. The analgesia produced by the combination of these two drugs was synergistic in both acute thermal and inflammatory induced pain, with a decrease in behavioral side effects.

The use of intrathecal clonidine as an adjunct for the management of chronic pain, intra- and postoperative analgesia is gaining an increase in popularity. However, antinociceptive doses of intrathecal clonidine may produce pronounced hemodynamic side effects, including hypotension and bradycardia. In this report, we present a case of severe hypotension after cardiopulmonary bypass in a patient with intrathecal clonidine infusion. We postulate that the intrathecally administered alpha 2-agonist clonidine reduced our patient's ability to tolerate the hemodynamic lability that is present during the separation from cardiopulmonary bypass by potentially inhibiting sympathetic nervous system activity, renin-angiotensin system, or vasopressin release. The authors report a case of severe hypotension after cardiopulmonary bypass in a patient receiving intrathecal clonidine infusion for chronic neuropathic pain.

Unlabelled: Postoperative pain after total knee arthroplasty (TKA) is severe and can complicate early physical therapy. We tested the hypothesis that intrathecal clonidine would improve postoperative analgesia for TKA using a hyperbaric bupivacaine spinal anesthetic. In a double-blinded, placebo-controlled protocol, 81 ASA physical status I-III patients undergoing either a single or bilateral TKA were randomized into 4 groups with the following 2-mL solutions added to 15 mg of hyperbaric bupivacaine: 1) sterile saline, 2) morphine (250 microg), 3) morphine (250 microg) with clonidine (25 microg), and 4) morphine (250 microg) with clonidine (75 microg). At 1, 2, 4, 6, 12, and 24 h postoperatively, we measured visual analog scales (VAS), cumulative IV morphine consumption, hemodynamics, nausea, ancillary drugs, and side effects. Our primary comparison was between the clonidine with morphine groups versus the morphine group. We found that the combined administration of intrathecal clonidine and morphine decreased 24 h IV morphine consumption by 13 mg (P = 0.028) when compared with intrathecal morphine alone. This corresponded to a decrease in the VAS score of 1.3 cm at 24 h postoperatively (P = 0.047). Adverse side effects were similar among all groups with the exception of more relative hypotension in the clonidine groups through postoperative hour 6. We conclude that the coadministration of intrathecal clonidine and morphine decreases the 24-h IV morphine consumption and improves the 24-h VAS score when compared with intrathecal morphine alone., Implications: In this prospective, randomized, double-blinded, and placebo-controlled trial, we identify an effective postoperative analgesic approach in total knee replacement surgery. Intrathecal morphine (250 microg) combined with clonidine (25 or 75 microg) provided superior analgesia compared with intrathecal morphine alone.

Unlabelled: Spinal anesthesia has numerous advantages over general anesthesia for patients undergoing lumbar laminectomy and microdisk surgery. In this study, we evaluated the addition of epidural clonidine and/or bupivacaine, injected at the incision site, on postoperative outcome variables in patients undergoing lower spine procedures using spinal anesthesia. One hundred twenty patients having lumbar spine surgery received bupivacaine spinal anesthesia supplemented by 150 microg of epidural clonidine with or without incisional bupivacaine, epidural placebo plus incisional bupivacaine, or placebo with incisional saline. Demographic data, intraoperative hemodynamics, blood loss, pain, nausea, urinary retention, hospital discharge, and other variables were compared by using either analysis of variance or chi(2) analysis. Demographics were similar. IV fluids, blood loss, incidence of intraoperative bradycardia, and hypotension were not different among groups. Postanesthesia care unit pain scores were lower and demand for analgesics was less in patients who received both the clonidine and subcutaneous bupivacaine. Patients who received epidural clonidine also had improved postoperative hemodynamics. Hospital discharge, urinary retention, and other variables were not different. We conclude that epidural clonidine as a supplement to spinal anesthesia produced no perioperative complications and improved postoperative pain and hemodynamic stability in patients undergoing lower spine procedures., Implications: Spinal anesthesia with supplemental epidural clonidine in combination with incision site subcutaneous bupivacaine was evaluated both intra- and postoperatively and compared with spinal anesthesia alone for lower lumbar spine procedures. Both epidural clonidine and subcutaneous incisional bupivacaine, added to spinal anesthesia for lumbar spine surgery, improves pain relief and reduces the need for postoperative opioids with their associated side effects.

Unlabelled: Used as the sole analgesic, clonidine produces analgesia after central neural blockade and intraarticular injection but not after axillary block. In this study, we sought to determine whether interscalene clonidine induces analgesia for shoulder arthroscopy. Forty patients scheduled for shoulder arthroscopy were prospectively included in this double-blinded study. Using a nerve stimulator technique, an interscalene catheter was inserted. The patients were randomly divided into two groups. The interscalene group (n = 20) received clonidine 150 micro g in 15 mL of saline through the catheter and 1 mL of subcutaneous saline, and the systemic group (n = 20) received 15 mL of saline through the catheter and clonidine 150 micro g (1 mL) subcutaneously. All patients underwent general anesthesia for surgery. On completion of arthroscopy, all patients received, via a patient-controlled analgesia, on demand a bolus of 8 mL of ropivacaine 0.2% through the catheter with a 1-h lockout period. Postoperative pain was measured every 4 h using the visual analog scale (VAS) for 24 h. Additional postoperative analgesia was available with parenteral nalbuphine if required until VAS < 3. VAS scores in the recovery room were significantly higher in the systemic group compared with the interscalene group (P < 0.0001). Analgesic duration was significantly longer in the interscalene group (P < 0.00001), and ropivacaine consumption was significantly less than in the systemic group (P < 0.0001). No significant difference was observed between groups for nalbuphine consumption. Side effects were comparable in the two groups., Implications: Clonidine administered via an interscalene catheter enhanced analgesia compared with systemic administration. Nevertheless, the adverse effect of clonidine at this dose limits its use for routine management for postoperative analgesia.

Unlabelled: Although clonidine has both hypnotic and analgesic actions, the dose relationship for each actions is still unknown in a clinical setting when clonidine is used as a premedication in children. We studied 80 ASA physical status I children (age range, 3-8 yr). Subjects were randomly divided into two groups (minimum alveolar anesthetic concentration [MAC]-Awake group, n = 40; MAC-Tetanus group, n = 40). Each patient received one dose of clonidine from 1 to 5 microg/kg orally, 100 min before arrival at the operating room. Anesthesia was induced and maintained with sevoflurane in oxygen and air. Before tracheal intubation, end-tidal sevoflurane was decreased stepwise by 0.2% at the start of 1.2%, a verbal command was given to the patients, and MAC-awake was determined in each patient. We also investigated MAC-tetanus, determined with transcutaneous electric tetanic stimulations, after tracheal intubation in each patient by observing the motor response to a transcutaneous electric tetanic stimulus to the ulnar nerve at a sevoflurane concentration decreased stepwise by 0.25% at the start of 2.75%. The initial reduction in MAC-tetanus was not as steep as that in MAC-awake. Clonidine reduced MAC-tetanus by 40% at the maximal dose of 5 microg/kg, whereas MAC-awake was already reduced by 50% at 2 microg/kg. We conclude that separate dose-response relationships for oral clonidine are present regarding the hypnotic and analgesic effects in children undergoing sevoflurane anesthesia., Implications: Separate dose-response relationships for oral clonidine were found regarding the hypnotic and analgesic effects in children undergoing sevoflurane anesthesia.

Unlabelled: Clonidine prolongs anesthesia and analgesia of local anesthetics in various neural blocks as well as the duration of retrobulbar block. We assessed the dose-response relationship of clonidine added to lidocaine in peribulbar block. Sixty patients undergoing cataract surgery were given peribulbar block with 7 mL of 2% lidocaine and hyaluronidase with either saline (Control) or clonidine in 0.5-microg/kg (0.5 Clon), 1.0-microg/kg (1.0 Clon), or 1.5-microg/kg (1.5 Clon) doses. The onset and duration of lid and globe akinesia, globe anesthesia and analgesia, postoperative analgesic requirement, and adverse effects (hypotension, bradycardia, hypoxia, sedation, and dizziness) were recorded. The success rate and onset of block were comparable in all groups. The duration of lid and globe akinesia, globe anesthesia and analgesia was significantly (P < 0.01) prolonged in patients receiving 1.0 and 1.5 microg/kg clonidine as compared with the Control group. Perioperative pain scores and analgesic requirement were significantly less in these groups. 0.5 microg/kg clonidine did not increase the duration of anesthesia and analgesia significantly. Hypotension and dizziness were observed more in patients receiving 1.5 microg/kg clonidine as compared with other groups. We conclude that 1.0 microg/kg clonidine with a mixture of lidocaine (2%) significantly prolonged the duration of anesthesia and analgesia after peribulbar block with limited side effects., Implications: We studied the effect of the addition of 0.5, 1.0 and 1.5 microg/kg clonidine to a lidocaine-hyaluronidase mixture on the onset and duration of peribulbar block and perioperative analgesia. A dose of 1.0 microg/kg produced a significant increase in duration of anesthesia and analgesia with minimal side effects.

Unlabelled: Epidurally administered clonidine enhances the quality and duration of postoperative analgesia when it is used as an adjunct to local anesthetics in children. We investigated the dose-response relationship for epidural clonidine when added to a continuous postoperative epidural infusion of ropivacaine. By use of an observer-blinded design, 55 pediatric patients (1-4 yr old) were randomly given a postoperative epidural infusion of plain ropivacaine 0.1% 0.2 mg. kg(-1). h(-1) (Group R), ropivacaine 0.08% 0.16 mg. kg(-1). h(-1) plus clonidine 0.04 microg. kg(-1). h(-1) (Group RC1), ropivacaine 0.08% 0.16 mg. kg(-1). h(-1) plus clonidine 0.08 microg. kg(-1). h(-1) (Group RC2), or ropivacaine 0.08% 0.16 mg. kg(-1). h(-1) plus clonidine 0.12 microg. kg(-1). h(-1) (Group RC3). A clear dose-response relationship could be identified for a continuous infusion of epidural clonidine, with clonidine dosages in the 0.08-0.12 microg. kg(-1). h(-1) range providing improved postoperative analgesia (reduced Children's Hospital of Eastern Ontario pain score, increased time to first supplemental analgesic demand, and a reduced total number of doses of supplemental analgesics during the first 48 h after surgery). Analgesia was improved without any signs of increased sedation or other side effects. The adjunct use of epidural clonidine in the dosage range of 0.08-0.12 microg. kg(-1). h(-1) appears effective and safe for use in children., Implications: The addition of clonidine (0.08-0.12 microg.kg(-1).h(-1))to a continuous epidural infusion of ropivacaine was found to improve postoperative pain relief in children. No clinically significant signs of sedation or other side effects were observed.

Unlabelled: We sought to determine whether spinal clonidine 50 microg prolongs the analgesia from the spinal administration of sufentanil 7.5 microg and bupivacaine 2.5 mg early in the first stage of labor. Thirty patients were randomized to receive a 2-mL spinal injection of sufentanil 7.5 microg + bupivacaine 2.5 mg with or without clonidine 50 microg using a combined spinal-epidural (CSE) technique. Pain, nausea, pruritus, sedation, motor block, blood pressure, and heart rate were assessed until the patient requested additional analgesia. Analgesia was significantly prolonged in patients who received spinal sufentanil + bupivacaine + clonidine (197 +/- 70 vs 132 +/- 39 min; P = 0.004). Pain scores and side effects, including motor block, sedation, and hypotension, were similar between groups. Spinal clonidine significantly prolongs labor analgesia from spinal sufentanil and bupivacaine without producing serious adverse side effects., Implications: We studied the effects of spinal clonidine administered with spinal sufentanil and bupivacaine on labor analgesia using a combined spinal-epidural technique and conclude that spinal clonidine significantly prolongs labor analgesia from spinal sufentanil and bupivacaine without producing serious adverse effects.

Unlabelled: Clonidine premedication enhances the pressor effects of ephedrine in awake and anesthetized patients. To test the hypothesis that clonidine augments the pressor response to ephedrine during spinal anesthesia, 48 ASA physical status I or II patients were randomly assigned to either the clonidine group (n = 23), receiving oral clonidine approximately 5 microg/kg 90 min before spinal anesthesia, or the control group (n = 25), receiving no clonidine. Spinal anesthesia was performed at either the L2-3 or the L3-4 interspace using 0.5% hyperbaric tetracaine solution 1.4-3.0 mL. Blood pressure (BP), heart rate, and the upper dermatomal level of analgesia were determined at 1-min intervals with the patient in the supine position after tetracaine injections. When systolic BP decreased to <80% of the prespinal value or <100 mm Hg, IV ephedrine 0.2 mg/kg was administered as a bolus. There were no differences in the duration until the first dose of ephedrine after tetracaine injections, and the upper level of analgesia between groups (control group 8.5+/-3.7 min, T5; clonidine group 7.7+/-2.7 min, T6). Although prespinal and preephedrine BP values were higher in the control group, the magnitude of increases in mean BP after ephedrine was significantly greater in the clonidine group (P < 0.05). We conclude that oral clonidine premedication augments the pressor response to IV ephedrine during spinal anesthesia., Implications: The pressor effect of ephedrine is enhanced in patients given oral clonidine premedication during spinal anesthesia.

Unlabelled: We evaluated the analgesic efficacy and hemodynamic and respiratory safety of clonidine when added to bupivacaine for caudal blocks in 58 children aged 38 +/- 2 mo (mean +/- SEM). Patients scheduled for ambulatory hernia repair were randomly given a caudal injection (0.75 mL/kg) of either saline placebo (P group), bupivacaine, 0.25% (B group), bupivacaine plus epinephrine 1:200,000 (BE group), bupivacaine plus clonidine 1 microgram/kg (BC1 group), or bupivacaine plus clonidine 2 micrograms/kg (BC2 group). Postoperative measurements included duration of analgesia, hemodynamics, and respiratory monitoring for 6 h. Thereafter, parents assessed their child's analgesic requirements at home every 3 h for 18 h. The duration of analgesia (median [range]) was significantly longer (P < 0.05) in the BC1 and BC2 groups (360 [270-360] min and 360 [355-360] min, respectively) compared with the P (77[45-190]), B (346[105-360]), or BE group (300[75-360]). Similarly, the BC1 and BC2 groups required less additional analgesic within the first 24 h. All groups showed a significant decrease in mean arterial pressure compared with baseline values, but the differences among the groups were not significant. Bradycardia and respiratory depression were not observed. Clonidine 1 and 2 micrograms/kg can be safely added to bupivacaine caudal blockade in small children for ambulatory hernia repair to achieve an increased duration of analgesia compared with bupivacaine alone or bupivacaine plus epinephrine., Implications: The addition of clonidine, an antihypertensive drug with analgesic properties, to local anesthetics in caudal blocks prolongs postoperative pain relief and reduces the need for additional pain treatment in children after hernia operation.

This study assessed the minimum dose of clonidine required to prolong the duration of both anesthesia and analgesia after axillary brachial plexus blockade. Eighty patients scheduled for elective hand surgery were divided into eight groups in a randomized, double-blind fashion. An axillary brachial plexus block was performed with 40 mL 1% mepivacaine plus 1:200,000 epinephrine. The control group received no clonidine. In the other groups, increasing doses of clonidine (0.1, 0.2, 0.3, 0.4, 0.5, 1, and 1.5 micrograms/kg) were added to the local anesthetic solution. Onset time, duration of anesthesia and analgesia, postoperative pain score, intake of analgesics, and adverse effects were recorded. The eight groups were comparable in terms of onset time, postoperative pain score, and analgesic requirement. The minimum dose of clonidine required to significantly prolong the duration of analgesia and anesthesia was, respectively, 0.1 and 0.5 microgram/kg. No side effects (sedation, drowsiness, bradycardia, arterial hypotension) were reported. We conclude that the dose of clonidine required to prolong significantly the duration of both anesthesia and analgesia after axillary brachial plexus blockade is 0.5 microgram/kg and that, at this dose, clonidine may be used without important reported side effects even in outpatients.

Postoperative analgesia may be prolonged by the addition of clonidine to local anesthetic solutions used for regional anesthesia. The purpose of this study was to test this hypothesis in a clinical trial of patients undergoing podiatric surgery. The study design was prospective, double-blinded, and randomized. Ninety ASA physical status I or II patients scheduled for bunionectomy or hammer toe repair were randomized to receive ankle or metatarsal blocks with plain 1.73% lidocaine (Group L), 1.73% lidocaine with 10 micrograms/mL of clonidine added (Group C10), or 1.73% lidocaine with 20 micrograms/mL clonidine (Group C20). Time from the performance of the block to 1) loss of sensation to pinprick, 2) return of sensation to pinprick, 3) onset of postsurgical pain, and 4) time of first oral pain medication intake were recorded. Beginning at 1 h after the completion of the block, visual analog scale (VAS) and verbal pain scores were recorded every 30 min. Additional postoperative oral pain medication required in the first 9 h after the block was also recorded. Analysis of variance (ANOVA) was used to analyze intergroup differences in the VAS and verbal pain scores, the time to first reported pain, the time to first oral pain medication, and the total amount of oral pain medications required. Repeated-measures ANOVA was used to analyze the VAS and verbal pain scores overall and integrated assessment of pain scores and rescue medication was per-formed. Adverse events were also recorded for each group. There were no differences among the three groups with regard to overall VAS pain scores although Group C10 had significantly better verbal pain scores after the first 3 h (P < 0.05). There was also no difference in time to loss or return of pinprick sensation. Group C10 had a longer time to first reported pain (P < 0.01), a longer time to first oral pain medication (P < 0.01), a lower average total dose of oral pain medication required (P < 0.05), and a lower integrated assessment of pain and medication (P < 0.01) than Group L. More patients in Group C10 reported no pain postoperatively (P < 0.01) and no pain medication taken (P < 0.01) than Group L. Group C20 results suggested no statistically significant improvement over plain lidocaine. One patient in Group C20 experienced significant hypotension postoperatively. pH determinations and chemical analysis by capillary electrophoresis showed no significant change in composition of the solutions when clonidine was mixed with lidocaine and stored at 4 degrees C for 1 wk. Compared to 1.73% lidocaine, combining clonidine (10 micrograms/mL) with lidocaine for local anesthetic block for foot surgery significantly increases the duration and quality of postoperative analgesia.

This study contrasts the efficacy and side effects of epidural clonidine and sufentanil in the perioperative period. Using a randomized, prospective, double-blind study design, 40 patients undergoing abdominal surgery under propofol/nitrous oxide anesthesia were enrolled. Before anesthesia, an epidural catheter was inserted at the L1-L2 interspace. At induction of anesthesia, the patients received epidurally either clonidine (4 micrograms/kg in 10 mL) infused in 20 min followed by a 2-micrograms.kg-1.h-1 infusion (5 mL/h) during 12 h (Group 1) or sufentanil (0.5 microgram/kg in 10 mL) in 20 min followed by a 0.25-microgram.kg-1.h-1 infusion (5 mL/h) during 12 h (Group 2). Intraoperatively, increases in arterial blood pressure and heart rate not responding to propofol bolus (0.5 mg/kg) were treated with a bolus of intravenous (IV) sufentanil 0.035 microgram/kg. Postoperatively, IV sufentanil boluses (5 micrograms) were given through a patient-controlled analgesia (PCA) device. Postoperative analgesia was assessed by recording the IV PCA sufentanil requirements and the patients' visual analog scale (VAS) at 3, 6, 12, 18, 24, 36, and 48 h. Sedation analog scales and side effects were also recorded. Plasma clonidine and sufentanil concentrations were measured after 20 min and 6, 12, and 24 h. The number of reinjections of propofol (n = 1.6 +/- 1.6 in Group 1 vs 6.5 +/- 4.0 in Group 2) and of IV sufentanil (n = 0.6 +/- 0.8 in Group 1 vs 3.8 +/- 3.7 in Group 2) was significantly reduced (P < 0.001) in the epidural clonidine group. In the early postoperative period, pain scores and rescue analgesic requirements were very low in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Postoperative analgesia after intrathecal co-administration of clonidine hydrochloride (75 micrograms) and morphine sulfate (0.5 mg) was compared with analgesia produced after either intrathecal morphine (0.5 mg) or 0.9% sodium chloride in 90 patients undergoing total hip replacement under bupivacaine spinal anesthesia. Patient-controlled morphine requirements were significantly reduced (P < 0.001) postoperation by both clonidine/morphine (median 5 mg/24 h) and morphine (median 7 mg/24 h) compared with control (saline) (median 28 mg/24 h). However, no significant additional reduction in postoperative analgesic requirements was shown with the clonidine/morphine combination compared with morphine alone. Visual analog pain scores, although good in all groups at all times, were significantly poorer in the control group at 2 h (P < 0.04) and 4 h (P < 0.001) after operation compared with both treatment groups, and significantly poorer than the clonidine/morphine group at 6 h (P < 0.002) and 24 h (P < 0.009) postoperation. Mean arterial blood pressure was significantly lower in the clonidine/morphine group than in the two other groups (P < 0.001) between 2 and 5 h after operation. The incidence of emesis was similar in the clonidine/morphine and morphine groups and was significantly more than in the control group.

We studied 61 patients undergoing elective major non-cardiac surgery in a randomized, double-blind, placebo-control clinical trial to test the hypothesis that the addition of clonidine to a standardized general anesthetic could safely provide postoperative sympatholysis for patients with known or suspected coronary artery disease. Patients were allocated randomly to receive either placebo (n = 31) or clonidine (n = 30). The treatment group received premedication with a transdermal clonidine system (0.2 mg/d) the night prior to surgery, which was left in place for 72 h, and 0.3 mg oral clonidine 60-90 min before surgery. Clonidine reduced enflurane requirements, intraoperative tachycardia, and myocardial ischemia (1/28 clonidine patients vs 5/24 placebo, P = 0.05). However, clonidine decreased heart rates only during the first five postoperative hours; the incidence of postoperative myocardial ischemia (6/28 clonidine vs 5/26 placebo) did not differ between the two groups. Patients who experienced postoperative myocardial ischemia tended to have higher heart rates after surgery. Clonidine significantly reduced the plasma levels of epinephrine (P = 0.009) and norepinephrine (P = 0.026) measured on the first postoperative morning. There were no differences in the need for intravenous fluid therapy or antihypertensive therapy after surgery. The number of hours spent in an intensive care setting and the number of days spent in hospital were not different between the two groups. These results suggest that larger doses of clonidine should be investigated for their ability to decrease postoperative tachycardia and myocardial ischemia.

The prolonging effects of oral clonidine on sensory block during tetracaine spinal anesthesia were studied in 47 healthy patients scheduled for urologic or gynecologic surgery. All patients received 15 mg tetracaine intrathecally in isobaric saline. The patients were randomly allocated into four groups. Group 1 (n = 13) was administered 0.25 mg triazolam orally. Group 2 (n = 12), Group 3 (n = 12), and Group 4 (n = 10) received 75 micrograms, 150 micrograms, and 300 micrograms of oral clonidine, respectively. These drugs were administered 1 h before anesthesia. Sensory block was evaluated by pinprick. All regression times in Groups 2, 3, and 4 were significantly longer than those in Group 1. The prolonging effect of oral clonidine increased in a dose-dependent manner and reached a maximal effect at 150 micrograms. Four patients in Group 4 developed bradycardia (heart rate < 45 bpm), suggesting that the dose of 300 micrograms of oral clonidine may promote bradycardia during spinal anesthesia.

Agonist interactions in antinociceptive effects between clonidine and opioids can be used to reduce opioid requirements in surgical patients. However, clonidine can cause marked sedation and associated respiratory dysfunction. Thus, the benefit of using clonidine to reduce opioid use on respiration is questionable. This double-blind randomized study compared the analgesic efficacy, arterial blood gases, and pharmacokinetics of an intravenous (IV) infusion of fentanyl 75 micrograms/h and a mixture of fentanyl 25 micrograms/h plus clonidine 0.3 micrograms.kg-1.h-1 in 32 healthy young adults after surgery for scoliosis correction. Oxygen saturation (FIO2: 0.21) and respiratory rate were monitored as well as supplemental analgesia demands (IV ketoprofen via a patient-controlled device), pain, sedation, and hemodynamics. Oxygen and naloxone (5 micrograms.kg-1.min-1) were administered, respectively, if more than three episodes of oxygen saturation less than 90% were observed within 10 min and if PaCO2 was higher than 50 mm Hg. Pain relief, sedation, and ketoprofen requirements were similar in both groups. The number of episodes of arterial desaturation less than 90% (> 20 s) was 106 for four patients in the fentanyl group (versus none in the clonidine-fentanyl group). Naloxone was required in six patients and oxygen in two patients of the fentanyl group (versus none in the group receiving clonidine). Dopamine, 10 micrograms.kg-1.min-1, was required in one patient of the clonidine-fentanyl group to correct hypotension. Mean arterial blood pressure, plasma clearance, and the elimination rate constant of fentanyl were lower in the clonidine-fentanyl group than in the fentanyl group.(ABSTRACT TRUNCATED AT 250 WORDS)

Although the epidural administration of clonidine and fentanyl provides pain relief after surgery, the interaction between the two drugs has not been examined formally. This study used an isobolographic method to determine whether epidurally administered fentanyl and clonidine interact in an additive or synergistic manner. Ninety women with moderate to severe pain after elective cesarean section under epidural anesthesia were studied. Using a randomized, double-blind protocol, we assigned each patient to receive a single epidural injection of one of three doses of fentanyl, clonidine, or a fixed ratio combination. Pain relief, blood pressure (BP), heart rate (HR), and sedation were measured 15 min after injection. Each drug alone and in combination produced analgesia, as measured by pain relief scores, and reduced need for intravenous morphine. Although the effective dose producing analgesia in 50% of patients (ED50) for the mixture was only 52% of that predicted by an additive interaction, this did not differ significantly from additivity, likely due to large variability. Clonidine, alone or in combination with fentanyl, produced a minor reduction in BP, but did not affect HR or cause more sedation than fentanyl. Unlike studies in rodents, this clinical study did not demonstrate synergy between fentanyl and clonidine. This could reflect a true species difference or differences in methodologies used. Nonetheless, a reduced dose of fentanyl and clonidine can be combined for excellent analgesia.