Frade, Luiz-Cleber P. MD; Lauretti, Gabriela R. MD, MSc, PhD; Lima, Izabel C.P.R. MD, MSc, PhD; Pereira, Newton L. B Pharm, MSc, PhD
The pathophysiology of complex regional pain syndromes (CRPS) includes both central and peripheral aspects, which includes IV regional block (1). Either case reports (2–6), retrospective studies (7–10), or controversial double-blind prospective trials (11–13) have suggested its role as part of a multimodal treatment. IV guanethidine resulted in only 35% of CRPS patients experiencing significant pain relief (11), and it was more effective than stellate ganglion block (12). However, a subsequent study did not demonstrate outcome improvement after IV regional guanethidine in CRPS type I, which was accompanied by delayed resolution of vasomotor instability (13). A meta-analysis of randomized trials of IV regional guanethidine block also failed to prove its effectiveness in CRPS.
A prospective non-blinded report of seven patients with a diagnosis of CRPS of the knee suggested a role for IV regional clonidine. In this study, five of seven patients experienced complete pain relief with 4–6 treatments with IV regional 1 μg/kg of clonidine combined with 0.5% lidocaine (14). In agreement with others (3,14), we have been routinely using IV regional clonidine/lidocaine as a valuable component for the management of the CRPS type I (15) for the past 8 yr. Further laboratory research, in agreement with clinical data (7,16), has suggested up-regulation of cyclooxygenase-2 (COX-2) as a common event after peripheral nerve injury (17).
The purpose of the current study was to determine whether the inclusion of either peripheral or systemic parecoxib, a specific COX-2 inhibitor, would improve analgesia when combined with serial IV regional clonidine/lidocaine in CRPS type I.
Our ethics committee approved the study protocol. After written informed consent, 30 adult outpatients suffering from CRPS type I in the upper limb were computer-randomized to one of three groups and prospectively studied using a placebo-controlled, double-blind design to examine analgesia and adverse effects (n = 10). Because imaging diagnostic tools and laboratory findings are of little predicting value (16), the diagnosis of CRPS type I was based upon a carefully taken case history and a clinical examination by an experienced practitioner. The diagnosis was made when patients had at least four of the following symptoms: allodynia, hyperesthesia, edema, vasomotor changes, pain with a burning quality, sudomotor changes, joint stiffness, or temperature differences between the extremities (16). The inclusion criterion was an unsatisfactory response after 5 weekly sequential stellate ganglion blocks with 70 mg of lidocaine plus 30 μg of clonidine. All patients were taking 25 mg of oral amitriptyline at bedtime and continuous physiotherapy as part of the treatment program.
The dose of IV loco-regional parecoxib was evaluated in a preliminary trial in which loco-regional IV 40-, 20-, and 5-mg doses were administered to CRPS patients. The doses of 40 and 20 mg resulted in transient superficial thrombophlebitis of the upper arm after the first application and were no longer used. Subsequently, we tried 10 and 5 mg of loco-regional IV parecoxib, and the analgesic effect described by patients (pain visual analog scale (VAS) and number of rescue analgesics after 1 wk) was similar among groups. The dose of IV systemic parecoxib was empirically defined as 20 mg, because approved dosage recommendations for chronic pain states vary from 10 mg once a day up to 20 mg twice daily (18).
The study was conducted in the operating room, as part of our routine. A venous access was obtained in both hands. IV regional analgesia was performed using an upper arm tourniquet applied to the affected extremity, which was not exsanguinated. The IV regional block was established using bolus IV 1 mg/kg of lidocaine/30 μg of clonidine combined with either IV 5 mg of parecoxib or saline diluted to a final volume of 10 mL (clonidine and parecoxib were diluted in saline). Simultaneously, a 10-mL volume of either saline or 20 mg of parecoxib was injected by the second blinded investigator into the contralateral upper limb.
The serial interventions were performed three times at weekly intervals. The tourniquet was kept inflated for 5 min and then deflated over a period of 1 min. Arterial blood pressure was monitored noninvasively before the procedure and every 5 min after tourniquet deflation. Heart rate and oxyhemoglobin saturation (Spo2) were continuously monitored throughout the procedure. Patients were discharged home after 60 min of close observation. The control group (CG) received both IV saline in the contralateral arm and IV regional administration of lidocaine and clonidine in the affected limb. The systemic parecoxib group (SPG) received a regional block, similar to that for the CG, but systemic IV 20 mg of parecoxib in the contralateral limb, whereas the IV regional anesthesia with parecoxib group (IVRAPG) received an additional IV 5 mg of parecoxib combined with lidocaine/clonidine and IV saline in the contralateral limb (Table 1).
The analgesic efficacy was evaluated by: (a) the mean daily rescue analgesic consumption of 100 mg of ketoprofen tablets in the following week, with patients being free to take up to 3 tablets per day (or a total of 300 mg) and (b) the weekly pain visual VAS, which consisted of a 10-cm line with 0 equal to “no pain at all” and 10 equal to “the worst possible pain” representing the overall impression of the past week. The concept of pain VAS was previously explained to the patients. The VAS data were collected before and after each weekly section for four consecutive times (including the fourth week when no block was applied but the analgesic data were collected).
Adverse effects assessed included hypotension (mean arterial blood pressure ≤ 15% baseline), hypoxemia (Spo2 ≤ 90%), bradycardia (heart rate ≤ 60 bpm), excessive sedation (score ≥ 4 of 10 by the VAS 0–10 cm), and clinical signs of IV lidocaine toxicity. Hypotension was treated with increasing doses of ephedrine 5 mg IV and bradycardia with increasing doses of atropine 0.25 mg IV up to 20 μg/kg.
The number of subjects was based on preliminary experimental data. We expected that the association of a COX-2 inhibitor would improve analgesia efficacy by 50% or 3 cm on the initial VAS19. It was hypothesized that systemic IV parecoxib would increase analgesia efficacy by 20% compared with the CG and that the administration of IV loco-regional parecoxib would increase analgesic efficacy by 100% compared with the CG. If we estimated a 40% standard deviation for this prospective power analysis and α = 0.05, these assumptions would require at least five patients in each group for a 100% increase in analgesic efficacy.
The normality of the distributions was assessed by the Shapiro-Wilk test. Groups were compared for demographic data (age, weight, and height) by the Kruskal-Wallis test. Arterial blood pressure, VAS, heart rate, and Spo2 were compared among groups by two-way analysis of variance for repeated measures. The number of rescue analgesics was compared among groups by the Kruskal-Wallis test followed by the Newman-Keuls test, whereas data within the same group were compared by Friedman test followed by the Wilcoxon's ranked sum test. P < 0.05 was considered significant. The incidence of adverse events and sex were compared among groups by the χ2 test corrected for multiple comparisons, and P was considered significant if <0.0166 (0.05 divided by the number of groups). Data are expressed as mean ± sd, unless otherwise stated.
All patients had been suffering from unilateral CRPS type 1 in the dominant upper limb for the past 7–18 months (P > 0.05). The demographic data are described in Table 2. Patients were similar regarding sex, height, age, and weight (P > 0.05). Seven patients in the CG and SPG and six in the IVRAPG had a history of surgical release of carpal tunnel syndrome. The others had a history of limb torsion or small injuries of the hand (P > 0.05).
The weekly VAS scores before and 60 min after each intervention are described in Table 3. There was a subsequent weekly decrease in VAS score within the IVRAPG (P < 0.05). A comparison within CG and SPG showed a VAS score decrease from the first to the second week (P < 0.05), whereas the second and third weeks were similar within these groups. The comparison among groups revealed that groups were similar during the first and second weeks of observation. The IVRAPG showed smaller VAS scores in the third week compared with both CG and SPG (P < 0.05). The mean daily oral ketoprofen consumption at the end of each week intervention is described in Table 4. The comparison among groups revealed that CG and SPG were similar. The IVRAPG showed less daily ketoprofen consumption in the second and third weeks compared with the others (P < 0.05). The IVRAPG also showed less ketoprofen consumption when the first with second weeks were compared to the third week (P < 0.05).
No adverse effect was noted while performing the interventions or during the 60-min observation. There were no differences regarding the incidence of gastric irritation during the weekly treatment among groups (P > 0.05).
Pathophysiologically, in CRPS there is evidence of functional changes within the central nervous system (20,21) and of involvement of peripheral inflammatory processes (17,22). In the present study, the specific COX-2 inhibitor parecoxib was evaluated after peripheral and systemic administration, combined with serial IV loco-regional block. We loco-regionally administered IV 5 mg of parecoxib combined with 30 μg of clonidine and 70 mg of lidocaine, which resulted in a better analgesic profile after the second week evaluation, as shown by a reduced consumption of ketoprofen tablets in the second week and, subsequently, both less daily ketoprofen consumption and lower VAS pain scores. These results may suggest that the dose of 5 mg may be effective through a local mechanism of action because the loco-regional IV prodrug parecoxib might undergo local metabolism by the CYP3A4-NADPH-cytochrome P450 reductase system located in peripheral vessels (23,24) and become the active COX-2 valdecoxib within the vessel in these study conditions. Nevertheless, without measuring serum levels of parecoxib, one cannot determine whether parecoxib is merely being released slowly over a period of time and becoming effective after undergoing hepatic metabolism by CYP3A4 (25).
Independent of either a local or systemic mechanism of action, the regulation of local COX-2 in injured nerves is a common event during the first several months after nerve injury, and abundant COX-2 immunoreactive cell profiles appeared in injured nerves of rats after spinal nerve ligation, chronic constriction injury, and complete sciatic nerve transection (17), a fact that would justify the better loco-regional response to the COX-2 inhibitor. Apart from locally induced COX-2, substance P has also been reported to contribute to spontaneous extravasation, edema, warmth, mechanical hyperagesia (22), and skin hypoxia (26) in CRPS, as well as inducing the expression of the local proinflammatory mediator nerve growth factor (27), which could exacerbate CRPS pathophysiology. Nevertheless, no correlation between peripheral COX-2 and substance P has been reported, although formation and facilitation of induced substance P release were primarily mediated by COX-1 without detectable involvement of COX-2 (28).
As part of our technique, IV regional analgesia was performed using an upper arm tourniquet applied to the affected limb for only five minutes, and the limb was not exsanguinated. We found this method to be simple, easy to perform, and safe, because the patient stay was 60 minutes, and there were no adverse effects (mainly because of the small doses of clonidine and lidocaine used). The fact that the limb was not exsanguinated permitted us to inject a small volume (10 mL), because the blood remaining within the vessels acted as a volume reservoir for better drug distribution, whereas the technique involving an exsanguinated limb would require a larger volume, resulting in the need for a longer time for tourniquet inflation and medical care.
CRPS also involves central nervous system changes. The occurrence of bilateral disinhibition of the motor cortex (20), and cortical representation of the CRPS-affected hand was significantly less than that of the contralateral healthy hand (21). As part of the study design, IV parecoxib (20 mg) was injected into the contralateral limb to obtain a systemic action, which would represent the final summation of its peripheral and central effect. After IV injection, parecoxib undergoes hepatic metabolism before becoming the active COX-2 inhibitor valdecoxib (25). Physiologically, constitutively expressed spinal COX-2 plays a role in the initial hyperalgesia that normally occurs after peripheral tissue injury because its inhibition reduced injury-induced activation of primary afferent neurons and activation of spinal neurons, reducing central sensitization29. In contrast to the effective action of loco-regional IV 5 mg of parecoxib, the administration of IV systemic 20 mg of parecoxib combined with loco-regional clonidine/lidocaine had an effect similar to that observed in the CG, implying no benefit after three weekly applications of IV 20 mg of parecoxib over the loco-regional block itself. An important point was that IV loco-regional clonidine/lidocaine block may have acted as an active placebo. However, because of ethical reasons, the study design did not allow the inclusion of a fourth group with placebo loco-regional block. Although the VAS score was decreased, the daily consumption of ketoprofen tablets was similar throughout the study, indicating that 20 mg of parecoxib, the dose recommended for chronic pain states (18), was not so effective as its locoregional administration. However, whether larger systemic doses would have been of further benefit cannot be concluded from the present study.
Oral ketoprofen tablets were used as rescue analgesic as part of the protocol. Apart from classical COX-1/COX-2 inhibition, the antinociceptive response to S-(+)-ketoprofen involves serotoninergic mechanisms via both supraspinal 5-hydroxytryptamine (1) (5-HT)/5-HT(2)/5-HT(7) receptors and 5-HT(3) receptors located at the spinal level (30), and it also displays a protective effect against neurotoxicity and microgliosis, based on its inhibitory activity on the inflammatory response or on microglia activation but not on its COX-inhibiting property (31), Whether ketoprofen had any effect on the final result, it indeed affected all patients and probably did not interfere with the final statistical analysis.
We conclude that, in contrast to IV systemic 20 mg of parecoxib, IV 5 mg of parecoxib was an effective co-adjuvant combined with weekly clonidine/lidocaine loco-regional block for CRPS type 1. Whether its analgesic benefit was the result of its metabolism in liver blood vessels or in the liver after slow release caused by the tourniquet cannot be determined from these data.
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