Clonidine as an Adjuvant to Local Anesthetics for Peripheral Nerve and Plexus Blocks: A Meta-analysis of Randomized Trials

A wide search strategy was used to retrieve relevant reports. We searched in MEDLINE, EMBASE, CENTRAL, BIOSIS, and CINAHL. Key words (nerve, plexus, block, blockade, clonidine) were combined using the Boolean meanings of or and and. The last electronic search was in June 2008. Bibliographies of retrieved articles were checked for additional references. There was no language restriction.

The following inclusion criteria were applied: (1) randomized treatment allocation; (2) comparison of clonidine added to a LA (experimental intervention) with the same LA regimen without clonidine (control intervention); (3) peripheral single-injection nerve or plexus block; (4) adults undergoing surgery without general anesthesia; (5) reporting on intraoperative and/or postoperative pain outcomes and/or drug-related adverse effects. When further adjuvants were used (for instance, epinephrine), the data were considered if the comparison was strictly controlled (i.e. , both experimental and control groups received the same regimen except for the clonidine).

Noninclusion criteria were: (1) patients undergoing general anesthesia or having an additional neuraxial block; (2) continuous LA administration or repeated injections; (3) intravenous regional anesthesia (Bier's block); (4) Children (younger than 18 yr); (5) peribulbar block. To overcome random play of chance on estimation of treatment effects, we excluded studies with fewer than 10 participants per group.5,6Retrieved articles were reviewed for inclusion by one author (Dr. Pöpping); queries were resolved through discussion with two other authors (Drs. Elia and Marret).

One author (Dr. Pöpping) extracted relevant information from original reports. Quality of data reporting was assessed using a modified three-items, seven-points Oxford scale taking into account method of randomization, concealment of treatment allocation, degree of blinding, and reporting of dropouts.7Two authors (Drs. Wenk and Marret) checked all extracted data. Discrepancies were resolved by discussion with two further authors (Drs. Elia and Tramèr). When continuous data were not reported as means with SD, we computed them whenever feasible as previously proposed.8,9We contacted the primary investigator of 23 retrieved reports to obtain additional information; seven answered, and additional data could be included in our analyses from three of those.10–12 

We first performed analyses that did not distinguish between different nerve and plexus blocks or LAs. For dichotomous data, we calculated Peto-odds ratios (OR) with 95% confidence intervals (CI). When the 95% CI around the OR did not include 1, results were considered statistically significant. To estimate the clinical relevance of a harmful effect, we computed numbers needed to harm (NNH) as numbers needed to treat with 95% CI using OR and control event rate. Confidence intervals around NNH point estimates were computed when the results were statistically significant.13 

For continuous data, weighted mean differences (WMD) with 95% CI were first calculated. When the data were heterogeneous (P < 0.1), we searched for the source of heterogeneity. There was an intention to investigate whether differences in effects could be explained by differences in the doses of clonidine using a linear regression model that was adapted for the analysis of correlated data.1We extrapolated variable doses to fixed doses using average body weights of the patient populations as reported in the trials. When no body weight was reported, we assumed that it was 70 kg. When there was no evidence of linear dose-responsiveness, a summary estimate was computed. From dose-finding studies, we selected the group of patients who received a dose of clonidine that was closest to all other doses in that analysis. We were using a random effects model when the test for heterogeneity was significant (P < 0.1). Alternatively, a fixed effect model was used.

In sensitivity analyses, we compared the degree of efficacy of clonidine in combination with intermediate and long-acting LAs. To minimize clinical heterogeneity in these sensitivity analyses, we exclusively considered data from trials that tested clonidine in patients receiving an axillary plexus block because this was the largest, clinically homogenous group of studies.

Analyses were performed using RevMan (Computer Program, version 4.3.2; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark), Microsoft Excel 11.3. for Mac, Maple 9.5 (University of Geneva, Geneva, Switzerland), and STATA 9 (STATA Corp, College Station, TX).

Of 280 retrieved titles, 38 were potentially relevant (fig. 1). Of those, we excluded 18 for various reasons. Data from one study were published twice14,15; we considered the first published report.14We eventually analyzed data from 20 randomized controlled trials (1,054 patients, 573 received clonidine) (table 1).10–12,14,16–31Fifteen studies tested clonidine for plexus blocks (14 axillary, 1 cervical), and five for nerve blocks (2 sciatic-femoral, 1 midhumeral, 1 ilio-inguinal-hypogastric, 1 ankle). All regimens were given as single injections in patients undergoing surgery without general anesthesia.

Clonidine was combined with intermediate-acting LAs (mepivacaine, 6 studies; lidocaine, 5 studies; prilocaine, 1 study) and with long-acting LAs (ropivacaine, 9 studies; bupivacaine, 3 studies; levo-bupivacaine, 1 study) (table 1).

Seventeen trials tested one dose of clonidine, two trials tested two doses,11,31and one trial tested three doses.18Three trials compared clonidine with other adjuvants.17,19,30In three, the effect of clonidine in combination with different LAs was tested.12,25,26Two studies had an additional active control group in which patients received clonidine systemically.14,27Sixteen trials tested a fixed dose, and four tested a variable dose. Twelve doses, ranging from 30 to 300 μg, were tested (fig. 2); 150 μg was tested in 271 patients (47% of all patients receiving clonidine) in 14 trials (70% of all trials).

The median quality score of data reporting was 4 (range, 1 to 6). Twelve studies (60%) were double-blind, the procedure of randomization was adequately described in seven (35%), and concealment of treatment allocation was described in four (20%).

Duration of postoperative analgesia, defined as time until first analgesic request, was reported in 13 trials testing 17 comparisons11,12,14,18–22,24,26,28,30,31; 13 comparisons were significant in favor of clonidine.||Clonidine doses that were considered for analysis ranged from 90 to 150 μg. In controls, duration of postoperative analgesia was on average 461 min (range, 128 to 1,151 min). Clonidine significantly increased the duration; WMD 123 min (95% CI 74–169; P < 0.001). The data were heterogeneous (P < 0.001); however, there was a lack of evidence of dose-responsiveness.

Time to onset of sensory block, determined by pinprick, was reported in 8 trials testing 11 comparisons;14,16,17,22,23,26,28,305 comparisons were significant in favor of clonidine.#Clonidine doses ranged from 90 to 150 μg. In controls, average time to onset of sensory block was 15 min (range, 4–26). Clonidine significantly shortened that time; WMD –2.2 min (95% CI –4.1 to –0.4; P = 0.02). The data were heterogeneous (P < 0.001); however, there was a lack of evidence of dose-responsiveness.

Duration of sensory block, determined by pinprick, was reported in 10 trials that tested 13 comparisons11,14,16,17,19,22,24,26,28,31; 10 comparisons were significant in favor of clonidine.**Clonidine doses that were considered for analysis ranged from 90 to 150 μg. In controls, the average duration of sensory block was 269 min (range, 87–596). Clonidine significantly prolonged the duration; WMD 74 min (95% CI 37–111; P < 0.001). The data were heterogeneous (P < 0.001); however, there was a lack of evidence of dose-responsiveness.

Time to onset of motor block, quantified using the Bromage scale or defined as a reduction of at least 50% in muscle strength, was reported in four trials that tested seven comparisons12,16,24,26; two comparisons were significant in favor of clonidine.††Clonidine dose was 150 μg in all four trials. In controls, average onset time of motor block was 18.3 min (range, 6.4–25.3). Clonidine had no significant impact on onset time; WMD –0.38 min (95% CI –3.14 to 2.38; P = 0.79).

Duration of motor block, quantified using the Bromage scale or defined as a reduction of at least 50% in muscle strength, was reported in seven trials that tested eleven comparisons11,16,19,21,24–26; nine comparisons were significantly longer with clonidine.‡‡Clonidine doses that were considered for analysis ranged from 115 to 150 μg. In controls, average duration of motor block was 405 min (range, 122–728). Clonidine significantly prolonged the duration; WMD 141 min (95% CI 82–199) (P < 0.001). The data were heterogeneous (P = 0.001); however, there was a lack of evidence of dose-responsiveness.

Incomplete block, or block failure, defined as the need for additional intravenous sedative or analgesic medication, additional nerve block, or wound infiltration during surgery, was reported in 16 trials.10–12,14,16–21,23,24,27–29,31Clonidine doses ranged from 30 to 300 μg. In controls, the average incidence of incomplete block was 8%, and with clonidine it was 7.3%, a difference that was not statistically significant; (OR 0.72; 95% CI 0.40–1.30).§§

Sensitivity analyses were performed to test the impact of adding clonidine to intermediate-acting and long-acting LAs. Duration of analgesia was on average 200 min with intermediate-acting and 850 min with long-acting LAs alone (fig. 3). Clonidine prolonged the duration of analgesia in combination with all tested LAs. All 95% CI overlapped, except when clonidine was added to the intermediate-acting prilocaine (additional duration of analgesia, average 48 min) or the long-acting bupivacaine (additional duration of analgesia, average 178 min). When combined data of clonidine added to intermediate-acting LAs were compared with combined data of clonidine added to long-acting LAs, there was no evidence of a difference; clonidine prolonged the duration of postoperative analgesia by about 2 to 2.5 h.

Average duration of sensory block was 174 min with intermediate-acting and 467 min with long-acting LAs alone (fig. 4). Clonidine prolonged the duration of sensory block in combination with all tested LAs. Prolongation was shortest when clonidine was added to the intermediate-acting prilocaine (average, 51 min) and was longest with the long-acting ropivacaine (average, 113 min). However, 95% CIs of all LAs overlapped. When combined data of clonidine added to intermediate-acting LAs were compared with combined data of clonidine added to long-acting LAs, there was no evidence of a difference; clonidine prolonged the sensory block by about 1.5 h.

Average duration of motor block was 181 min with intermediate-acting and 625 min with long-acting LAs alone (fig. 5). Clonidine prolonged the duration of motor block in combination with all tested LAs, except for mepivacaine (which had a wide 95% CI). All 95% CIs overlapped, except for the long-acting bupivacaine, which prolonged the motor block significantly more than the long-acting ropivacaine or the intermediate-acting prilocaine and lidocaine. With the intermediate-acting LAs and the long-acting ropivacaine, clonidine prolonged the duration of motor block by about 1.5 to 2 h. When clonidine was added to bupivacaine, the motor block was prolonged by about 4 h. The 95% CIs of ropivacaine (WMD, 106 min) and bupivacaine (WMD, 244 min) did not overlap.

Dichotomous data on arterial hypotension, fainting, bradycardia, or sedation could be analyzed (table 2).

Seven studies reported on presence or absence of episodes of arterial hypotension using specific definitions (i.e. , decrease in mean arterial pressure less than 55 mmHg, decrease in systolic blood pressure more than 20% or more than 30%, need for ephedrine).10,16–18,20,27,30Of those, five reported on at least one event.||||Clonidine doses ranged from 30 to 300 μg. In controls, the average incidence of arterial hypotension was 4.1%, and with clonidine it was 13.1% (OR 3.61; 95% CI 1.52–8.55; NNH 11).

Seven studies reported on presence or absence of episodes of bradycardia using specific definitions (i.e. , heart rate less than 45 beats/min or less than 50 beats/min, more than 20% decrease in heart rate, need for atropine).10,16–18,20,27,30Of those, three reported on at least one event.##Clonidine doses ranged from 30 to 300 μg. In controls, the average incidence of bradycardia was 4.1%, and with clonidine it was 8.5% (OR 3.09; 95% CI 1.10–8.64; NNH 13).

Four studies reported on at least one episode of sedation during surgery using specific definitions (i.e. , at least 2 points on a 4- or 5-point scale or no more than 4 points on a 5-point scale).10,17,18,20Clonidine doses ranged from 30 to 300 μg. In controls, the average incidence of sedation was 32.4%, and with clonidine it was 55.8% (OR 2.28; 95% CI 1.15–4.51; NNH 5).***

Two studies reported on orthostatic hypotension or fainting postoperatively.10,18Clonidine doses ranged from 30 to 300 μg. In controls, the average incidence of orthostatic hypotension or fainting was 2.9%, and with clonidine it was 12.9% (OR 5.07; 95% CI, 1.20–21.4; NNH 10).†††

All combined data were homogenous except for sedation (P = 0.04). There was a lack of evidence of dose-responsiveness for all drug-related adverse effects.

Postoperative pain intensity at 12 and 24 h, incidence of dry mouth, desaturation intraoperatively or postoperatively, postoperative nausea and vomiting, respiratory depression, symptoms of LA toxicity, or tourniquet pain were infrequently reported and were, therefore, not further analyzed.

This meta-analysis of 20 randomized controlled trials suggests that clonidine may be a useful adjuvant to LAs for peripheral nerve and plexus blocks. The duration of the analgesic and sensory block is prolonged by about 2 h. However, clonidine increases the risk of arterial hypotension, fainting, bradycardia, and sedation, and it prolongs the duration of the motor block.

Clonidine, an α²adrenergic agonist, was initially used for its antihypertensive properties. The large expression of α²receptors in the central nervous system, i.e., loecus coeruleus  and dorsal horn of the spinal cord, has eventually focused the interest of that drug on centrally mediated sedation and analgesia. Specific peripheral effects of clonidine appear less obvious because α²adrenoreceptors are not present on the axon of the normal peripheral nerve.2In one study, clonidine without LA given through an interscalene catheter provided better analgesia compared with the systemic administration of the same dose.32Similarly, in healthy volunteers, sensory and motor block were significantly prolonged when clonidine alone was administered into the axillary plexus sheath.33However, in another clinical study, clonidine alone failed to produce analgesia when injected into the axillary brachial plexus sheath.34Thus, data from clinical and experimental trials testing the effect of peripheral clonidine alone have remained inconclusive.

Laboratory and clinical data on clonidine as an adjuvant to LAs for peripheral nerve blocks are more convincing. On the isolated vagus nerve, clonidine intensified the conduction block induced by LAs.35When injected concomitantly with lidocaine for intravenous regional anesthesia, clonidine decreased the incidence of tourniquet pain.36In our analysis, a majority of comparisons reported on a significantly prolonged duration of postoperative analgesia with clonidine. Perhaps unexpectedly, this well documented analgesic effect did not translate into a decreased risk of block failure. This discrepancy may suggest that clonidine added to LAs primarily enhances the analgesic and less so the anesthetic properties of the peripheral nerve block. However, one major problem with all these studies was their limited size. Small trials are likely to report on results by random chance. For instance, more than 40% of control patients in one study were reported to have an incomplete block.18This unusually high baseline risk may have been related to the limited number of patients (n = 14), and it may have led to an overestimation of the rate of successful blocks with clonidine. One strength of meta-analysis is to combine inconclusive data from independent trials.

It has been postulated that clonidine improved the duration of postoperative analgesia only when used as an adjuvant to intermediate-acting LAs and that it was not worthwhile to combine it with long-acting LAs.3We performed sensitivity analyses to test this assumption. Interestingly, the beneficial effect of clonidine on the duration of analgesia was observed with all tested LAs. There were individual differences in as much as the benefit was minimal when clonidine was combined with prilocaine (less than 1 h prolongation of analgesia) and was maximal when combined with levo-bupivacaine (more than 4 h prolongation). This indirect comparison should not be overinterpreted because a limited number of patients received these two LAs. Also, 95% CIs of LAs overlapped. The similarity of the combined estimates of intermediate-acting and long-acting LAs suggested that there was actually no substantial differential effect of clonidine on postoperative analgesia that depended on the type of the LA. Those who are using clonidine as an adjuvant to LAs for peripheral nerve or plexus blocks should be aware that the clonidine-related prolongation of postoperative analgesia will last an average of about 2 h and independently of whether an intermediate-acting or long-acting LA is used. In contrast, the relative increase in duration of postoperative analgesia due to clonidine will largely depend on the nature of the LA. For instance, with intermediate-acting LAs alone, average duration of postoperative analgesia was 200 min. When clonidine was added, the duration increased by 112 min, i.e. , an increase of 56%. With long-acting LAs alone, average duration of postoperative analgesia was 850 min. When clonidine was added, the duration increased by 152 min, i.e. , an increase of 18% only. Thus, although clonidine prolongs duration of postoperative analgesia in association with any LA, the clinical relevance of adding clonidine to a long-acting LA may be questioned because the relative gain will be minimal. The same is true for duration of sensory and motor block.

It cannot be excluded that perineurally injected clonidine has an analgesic effect through systemic reabsorption. Only two studies compared clonidine across routes. In one, patients received 150 μg of clonidine subcutaneously or added to mepivacaine for brachial plexus block.14The duration of postoperative analgesia was longer in patients receiving clonidine into the plexus sheet. In the second, 140 μg of clonidine was added to ropivacaine for sciatic-femoral nerve block or was injected intramuscularly.27In that trial, clonidine had no impact on quality or duration of postoperative analgesia through either route.

Further new knowledge that emerged from our analysis related to the effect of clonidine on the duration of motor block. When added to intermediate-acting LAs, clonidine prolonged motor block by about 1.5 to 2 h. As with postoperative analgesia, the least effect was with prilocaine (average, 70 min). Interestingly, the motor block prolonging effect that was seen when clonidine was added to ropivacaine (106 min) was very similar to the intermediate-acting LAs. In contrast, when clonidine was added to bupivacaine, prolongation of motor block was more than twice as long (244 min). This may have practical implications, for instance, when an appropriate LA is to be chosen for a patient undergoing ambulatory surgery. Long-lasting postoperative analgesia may be regarded as a beneficial outcome because it implies prolonged pain-free recovery. Prolonged motor block, however, may not always be warranted. For instance, ambulation may be delayed in patients undergoing surgery of a lower extremity.

Clonidine increased the risk of bradycardia, arterial hypotension, and sedation. This was not unexpected, and it is most likely the result of systemic reabsorption. For rational decision-making it is important to know how often these adverse effects happen, whether they depend on the dose of clonidine, and whether they are clinically relevant. The NNH for sedation was about 5, and it was about 10 for hypotension and bradycardia. These typical, clonidine-related, adverse effects may be considered as minor harm. However, they all have the potential to interfere with early mobilization. There was limited evidence that the risk of orthostatic hypotension and fainting was significantly associated with clonidine. Although rare, these adverse effects cannot be classified as minor harm. In one study, two patients who had received 300 μg of clonidine could not be discharged after day case surgery because they fainted on ambulation or because systolic blood pressure was less than 80 mmHg.18In another study, one patient who had received 300 μg of clonidine developed severe hypotension for several hours and needed to be monitored.31These observations indicate that 300 μg of clonidine is too high a dose. Today, this dose is likely to be obsolete. However, we were unable to find evidence of dose-responsiveness for harm. Consequently, the safe dose that still has adequate analgesic properties remains unknown.

Our meta-analysis has limitations. First, all patients underwent surgery without general anesthesia. Drugs used for general anesthesia, such as opioids, may have effects that last into the postoperative period and may interfere with, for instance, the delay until first analgesic request. In patients undergoing surgery with a nerve block alone, the duration of analgesia will exclusively be the consequence of the drugs that were used for the block. Strictly speaking, our results are applicable only to awake patients who receive a peripheral nerve or plexus block. In patients undergoing surgery with a combination of general anesthesia and interscalene plexus block with bupivacaine, the additional perineural injection of clonidine did not prolong postoperative analgesia.37Second, we were unable to demonstrate dose-responsiveness for either benefit or harm, which does not imply that there was none. One reason for that failure may have been that the majority of patients received the same dose, i.e. , 150 μg. Data from randomized dose-finding studies are largely inconclusive. In one, the authors claimed that 30, 90, and 300 μg of clonidine produced dose-dependent prolongation of analgesia when added to lidocaine for axillary plexus block.18However, ranges of duration of postoperative analgesia were very wide (with the largest dose, duration ranged from 190 to 1,440 min), need for rescue analgesia was not different between the three groups, and the lowest dose (30 μg) was more efficacious in producing sensory block than the medium dose (90 μg). In another dose-finding study, patients who had received 70 μg of clonidine added to lidocaine for ankle or metatarsal block reported less pain and needed less rescue analgesia postoperatively compared with controls who had received the lidocaine alone; however, those who had received 140 μg of clonidine were not different from controls.31Thus, data from these dose-finding studies do not help us further in deciding whether or not there is dose-responsiveness within the tested dose-range. A similar dilemma was described with clonidine added to LAs for intrathecal anesthesia.1Finally, data on postoperative pain intensity, at 12 and 24 h for instance, could not be analyzed because these data were only inconsistently reported in the original trials. Time to first analgesic request may be regarded as a surrogate for pain intensity; patients with moderate to severe pain are expected to request rescue analgesia earlier.

Our systematic review may be used as a rational basis for future research. There is an argument in favor of further investigations of very small doses of perineural clonidine. Very small doses are less likely to trigger systemic adverse effects. The benefit of other α²agonists should be elaborated. For instance, dexmedetomidine added to lidocaine for intravenous regional anesthesia improved the quality of anesthesia and decreased analgesic requirements.38,39Also, the observation that the additional, clonidine-related duration of analgesia or motor block does not depend on the nature of the LA begs the question as to whether and why the efficacy of perineural clonidine depended on the duration of effect of the LA itself. Finally, none of these studies was performed with ultrasound guidance, and this may have an effect on the results.40The performance of clonidine when used as an adjuvant to LAs in the setting of peripheral nerve or plexus blocks that are performed with ultrasound guidance remains unknown and should be included in the research agenda.

In conclusion, in patients undergoing surgery without general anesthesia, clonidine, when added to a LA for peripheral nerve or plexus block, prolongs the duration of postoperative analgesia by about 2 h. This beneficial, albeit limited, effect can be observed with both intermediate-acting and long-acting LAs. The relative benefit, however, will be more pronounced with intermediate-acting LAs. When clonidine is added to ropivacaine, prolongation of motor block will be shorter than when added to bupivacaine. Clonidine is associated with typical, systemic, adverse effects such as arterial hypotension and sedation that are most often minor. Orthostatic hypotension and fainting are more serious adverse effects; they may delay ambulation. The current literature does not allow establishing dose-responsiveness for either beneficial or harmful effects; thus, the optimal dose remains unknown.

Special thanks go to Marc Beaussier, M.D., Associate Professor, Department of Intensive Care, Hôpital St. Antoine, Université Pierre and Marie Curie, Paris, France; Sushma Bhatnagar, M.D., Professor, Department of Anaesthesiology, Institute Rotary Cancer Hospital, All India Institute of Medical Science, New Delhi, India; Johannes Buttner, M.D., Department Head, Department of Anaesthesiology and Intensive Care, Unfallklinik Murnau, Murnau, Germany; Darren J. Couture, M.D., Department of Anesthesiology, Naval Hospital Twentynine Palms, Twentynine Palms, California; Andreas Duma, M.D., Department of Anaesthesiology and Intensive Care, Medical University of Vienna, Vienna, Austria; Sandra Esteves, M.D., Servicio de Anestesia, Hospital Geral de Santo Antonio, Porto, Portugal; and Stephen Mannion, M.D., Department of Anaesthesia and Intensive Care, Cork University Hospital, Cork, Ireland, who responded to our inquiries. Ching-Hei Yeung, M.D., Ph.D., Institute of Reproductive Medicine, University Hospital of Münster, Münster, Germany, translated a Chinese paper into English.