Phantom limb syndrome (PLS) is a postamputation syndrome that is characterized by pain in the stump, phantom limb pain, and phantom sensations.1–4 The incidence of this syndrome varies from 30% to 90%, with an onset in the early postoperative period in 75% of the cases1–3,5,6 and an average duration of 7 years after limb amputation.7 Risk factors include preamputation pain (especially in patients with vascular damage),8 loss of dominant upper limb, bilateral amputation, lower limb amputation, proximal amputation, the presence of stump pain, and depression.5,9–12
It has been suggested that changes in the peripheral nervous system after nerve transection are produced by ongoing noxious input into the spinal cord, leading to central sensitization with persistent postoperative pain and phantom sensations, which are resistant to frequently used analgesic and psychotropic drugs.3,13,14 Several different treatment approaches have been used to reduce phantom limb pain, including surgical, medical, physical, and behavioral therapy strategies, but the results have been disappointing. Therefore, the search for more effective therapies continues, but has proven to be challenging because of the varying types of amputations, and the differing reasons for performing the operation.
The purpose of this prospective study was to evaluate the effectiveness of a prolonged perineural infusion of a high concentration of a local anesthetic as an alternative to patient-controlled analgesia (PCA) with morphine for the prevention of chronic phantom limb pain in patients undergoing lower limb amputations.
This prospective study was approved by the ethical committee at the Istituto Ortopedico Rizzoli in Bologna, Italy. The IRB approval was given for a randomized, prospective, double-blind study comparing the efficacy of PCA morphine therapy with a continuous perineural infusion of local anesthetic. All the patients signed an IRB-approved informed consent form before they were entered into the study. However, the first 4 patients randomized to the PCA morphine group reported persistent severe-to-intolerable pain and requested to be crossed over to the local anesthetic infusion group. Therefore, a decision was made by the principal investigator (BB) to discontinue the PCA morphine arm of the study, and the study became an “observational study” involving only the use of the continuous perineural local anesthetic block technique.
Seventy-one consecutive patients undergoing lower limb amputation between 2004 and 2008 were subsequently assigned to treatment with a continuous infusion of 0.5% ropivacaine during and after surgery. All patients had to be capable of answering an “in-depth” questionnaire and quantifying their level of pain using a standard verbal rating scale (VRS), with a score of 0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain, and 4 = intolerable pain. According to the protocol, patients undergoing emergency amputation or contralateral amputation were excluded from the study. However, patients undergoing a stump revision or an ipsilateral reamputation were permitted to enroll in the study. No consenting patients underwent a further amputation during the follow-up period.
Sciatic nerve perineural catheters were placed before surgery in the subgluteal region with ultrasound guidance or nerve stimulator guidance (frequency stimulation 2 Hz, 0.1 millisecond, initial intensity of current 1 mA gradually decreased to <0.5 mA after the appropriate muscular twitch response was observed). The insertion site when using the nerve stimulator technique was identified by drawing a line from the patient's greater trochanter to the ischial tuberosity; then, from the midpoint of this line, a second line was drawn perpendicularly and extended caudally for 4 cm.15 Femoral catheters were placed with ultrasound guidance or nerve stimulator (2 Hz, initial current 1 mA, 0.1 millisecond) 1 to 1.5 cm lateral to the femoral artery, 4 cm below the inguinal ligament with the needle inserted with a 45-degree angle to the skin in the direction of the umbiliicus. In patients undergoing a stump revision, all catheters were placed using ultrasound guidance. In patients with hip amputation, a continuous posterior lumbar plexus block was placed before the operation with Chayen16 technique using nerve stimulator guidance. The site of insertion was identified by locating the fourth lumbar spine by a line passing through the iliac crests and then drawing from this point a 3-cm line in the caudal direction and a 5-cm line in lateral direction. Frequency stimulation (2 Hz, 0.1 millisecond, initial current 2 mA) gradually decreased to <0.5 mA after the quadriceps twitch response was observed. The sciatic catheter was placed intraoperatively by the surgeon inside the transected nerve in the caudal-cephalic direction (over a distance of 4 cm to minimize the risk of catheter dislocation), and then it was tunneled to the surface and fixed to the skin. A continuous infusion of 0.5% ropivacaine was started at 5 mL/h using an elastomeric pump (REF C9961K Multirate Infusor LV; Baxter Healthcare, Chicago, IL). The perineural catheters were fixed at the skin with a LockIt system (Smith Medical ASD, Weston, MA). All amputations were performed under general anesthesia. The catheter system remained in situ for varying periods of time after the patient was discharged from the hospital.
“Rescue” analgesic medications were administered as needed during the hospital stay and after discharge according to a standard laddered algorithm. Namely, if the VRS pain score was >1 during the period the patient was receiving the perineural infusion, a nonsteroidal antiinflammatory drug (NSAID) was administered. While in the hospital, the NSAID administered was ketoprofen (to a maximum dose of 300 mg/d), and postdischarge, ibuprofen was administered to a maximum dose of 1.2 g/d. Tramadol (to a maximum dose of 300 mg/d) was added if the VRS pain score remained >1 after starting the NSAID. If the VRS pain score persisted at a level >1 despite the administration of the NSAID-tramadol combination, oxycodone was added to a maximum dose of 20 mg/d. At the time of discharge from the hospital, patients were given a diary to complete at home. This diary contained specific questions about the sensations they might experience after an amputation procedure. Patients were carefully instructed how to distinguish stump pain (i.e., pain localized in the amputated extremity [also known as residual limb pain]) from phantom limb pain (e.g., any painful sensation around the absent limb, usually described as shooting, stabbing, and burning) and phantom limb sensations (e.g., sensations in the absent limb other than pain).4 They were asked to update the questionnaire daily to provide a more accurate postdischarge evaluation of their pain sensations. Phantom sensations were evaluated as present if the patient reported that these symptoms were present for >12 hours each day and they interfered with their daily activities. Patients were also asked to record in their diary the use of all rescue analgesic medications after discharge to home and to report every complication possibly related to the presence of the catheter (intolerance, inflammatory reaction) or to the infusion of the local anesthetic (motor blockade).
The elastomeric pump was refilled with 0.5% ropivacaine as necessary at the Analgesic Therapy Center nearest to the patient's home. The correct use of the catheter system at home was explained to the patient and family members before hospital discharge, and they were instructed to temporarily discontinue the local anesthetic infusion for 6 to 12 hours every 7 days to evaluate stump and phantom limb pain and other sensations. If stump pain (VRS score >1), phantom limb pain (VRS score >1), or phantom sensations returned during the time period in which the infusion was turned off, the infusion was restarted at a rate of 5 mL/h. However, if the stump and phantom pain symptoms remained absent or mild (VRS score = 1) without phantom sensations for a minimum period of 48 hours, the patient was instructed to discontinue the infusion and remove the catheter. Follow-up evaluations were performed using a standardized telephone questionnaire at 3, 6, 9, and 12 months after the amputation procedure to inquire about the presence of any residual phantom symptoms.
The period of active treatment was considered complete when the catheter could be removed without significant stump or phantom pain (i.e., VRS score of 0 or 1), and phantom sensations were no longer present. All patients were contacted by telephone at weekly-to-monthly intervals for up to 1 year after surgery to inquire about the severity of their stump pain and phantom limb symptoms, as well as to document the status of the perineural catheter system.
All continuous data are expressed in terms of median and 95% confidence intervals. All values were rounded off to the nearest significant decimal point. The Mann-Whitney U test was used to assess differences for nonparametric variables. Nominal nonparametric data were analyzed using the Fisher exact test, with P values <0.05 considered statistically significant. Data were analyzed using SPSS version 16.0 statistical software (SPSS, Inc., Chicago, IL).
Of the 71 patients receiving the perineural local anesthetic infusions, 9 died of their primary disease (bone cancer) before completing the 12-month study. Although relatives returned their questionnaires, these incomplete data were not included in the final statistical analysis. For the 62 patients who completed the study and returned their questionnaires, the reasons for amputation were oncologic (n = 42), traumatic (n = 14), ischemic (n = 2), or stump revision (n = 4). The median age of the patients was 50.5 years (35–50 years) (minimum-maximum range: 18–94 years). Only 5 patients reported no pain before amputation (3 oncologic and 2 trauma patients). All the patients in the stump revision subgroup (n = 4) manifested symptoms of the phantom limb pain (VRS score >1) before their reamputation. Half of the patients (n = 31) underwent below-knee amputation with sciatic (n = 25) or combined sciatic-femoral (n = 6) blocks, with 21 performed for cancer, 7 for trauma, and 3 for revision of a previous amputation. Twenty-five patients (41%) underwent above-knee amputation with combined sciatic-femoral blocks for cancer (n = 17), trauma (n = 6), stump revision (n = 1), or ischemia (n = 1). Two patients underwent foot amputation, 1 for trauma and 1 for ischemia, with a sciatic nerve block. Finally, 4 patients underwent complete hip amputations for bone cancer in the femur with posterior lumbar plexus and sciatic nerve blocks.
The median duration of the infusion for the 62 patients who completed the study was 30 days (25–30 days) (with a minimum to maximum range from 4 to 83 days [Fig. 1]). In 40 of the patients (65%), the perineural local anesthetic infusion was continued for 1 month or longer. Not surprisingly, for the 24 patients who prematurely removed the catheter system (i.e., before complete resolution of their phantom sensations), the duration of the local anesthetic infusion was significantly shorter compared with those patients who fully complied with the protocol instructions (20 days [12–26 days] vs 30 days [30–35 days], P < 0.01). Of these 24 patients, 20 removed the catheter when stump and phantom limb pain was minimal or nonexistent (VRS score = 0 or 1) but with phantom sensations still present. The remaining 4 patients removed the catheter despite significant phantom pain (VRS score >1) and the presence of phantom sensations. All of these patients reported phantom sensations at the 3-, 6-, 9-, and 12-month follow-up evaluations. In contrast, none of the 38 patients who followed the instruction given at the time of discharge from the hospital regarding the discontinuation of the local anesthetic infusion and removal of the catheter system experienced residual pain or sensations at the end of the 12-month evaluation period (P < 0.01). When the catheter was removed with phantom sensations still present, the severity of the symptoms reported remained unchanged at the subsequent follow-up assessment periods. Only the 4 patients who also reported significant phantom pain (VRS score >1) after the premature removal of the catheter system required opioid-containing oral analgesic medication for pain control in the postinfusion period.
The oral rescue analgesic medication in the hospital and the postdischarge period consisted of NSAIDs (n = 7), tramadol (n = 16), and oxycodone (n = 5). No differences were observed among oncologic, ischemic, trauma, or revision stump patients. One of the catheters was accidentally removed after 1 week of continuous infusion and that patient reported persistently high pain scores (VRS score >2), necessitating the use of oral oxycodone. There was only 1 other patient who experienced severe phantom limb pain (VRS score = 3) at the end of the follow-up period, and it was suspected that the perineural catheter migrated from the correct perineural position. In the 2 patients with moderate pain (VRS score = 2) at the end of the follow-up period, the catheter was removed after 1 week (because of an adverse local reaction to the catheter during the hospital stay) and 5 weeks (by decision of the patient reporting an unspecified intolerance to the catheter), respectively. None of the patients who complied with the protocol instructions for discontinuation of the local anesthetic infusion had a recurrence of their phantom pain symptoms after removal of the perineural catheter. During the continuous infusion of the local anesthetic, none of the patients reported a clinically significant muscular weakness or motor blockade.
The distribution of stump pain VRS scores during the 12-month assessment follow-up period is summarized in Table 1. On the first postoperative day, >90% of the patients reported a stump pain VRS score of 3 or 4. After 5 weeks, >90% of the patients reported no stump pain. The distribution of phantom pain VRS scores is summarized in Table 2. After the first week of treatment, a majority of the patients reported phantom pain VRS scores of 2, 3, or 4. However, by the fifth week of treatment, fewer than 10% reported more than mild pain and none of the patients reported severe or intolerable pain. All of the 4 patients with preexisting phantom limb pain (VRS score = 2 and 3) before our intervention at the end of the follow-up period showed a decrease of phantom limb pain VRS score (VRS score = 1). There was no difference in pain trend between the catheters inserted preoperatively and those inserted by the surgeon during the operation.
Finally, phantom sensations were reported by 92% of the patients at the end of the first week of treatment. However, at the 3-month follow-up assessment period, fewer than 40% reported any phantom sensations. None of the patients who experienced phantom sensations (without associated phantom pain) lasting longer than 3 months required chronic opioid analgesic medication after the end of the study period.
The favorable results reported in this observational study on the use of a continuous infusion of a 0.5% ropivacaine for the treatment of phantom limb symptoms may be related to the effect of the local anesthetic in preventing the central sensitization resulting from the increased activity of the transected nerves. It has been suggested that central sensitization can lead to permanent changes in the synaptic structure of the dorsal horn of the spinal cord with increased excitability and a reduction in the inhibitory processes,3,4,17 peripheral hypersensitivity of the cut nerve endings to mechanical, chemical, and thermal stimulation,3,4 and activation of abnormal supraspinal impulses from the missing limb.4,17
There is increasing evidence that the reduction of afferent nerve impulses can lead to cortical reorganization and result in phantom limb pain. Magnetic resonance imaging techniques have shown that this reorganization is present in patients with a painful missing limb, but not in amputees without phantom pain.17 It has been suggested that patients receiving peripheral local anesthetic nerve blocks experience reversal of cortical reorganization; however, there was no reversal of cortical reorganization in patients whose peripheral nerve block was unsuccessful in relieving their phantom limb pain.18
The extent of cortical reorganization seems to be directly proportional to the degree of phantom limb pain.19 Previous studies19,20 focused on the reduction of the preamputation pain because it is considered to be an important risk factor for the development of phantom limb pain. In several studies, investigators administered epidural analgesia before the amputation procedure and then continued the therapy for up to 3 days postoperatively.14,21–23 Although this so-called preemptive analgesic therapy was initially alleged to prevent phantom limb pain,21–25 subsequent studies failed to support these findings.14,26,27 For example, Bach et al.21 reported the absence of phantom limb pain 1 year after the limb loss in 11 patients after preemptive epidural analgesia started 3 days before the amputation. Jahangiri et al.22 compared preemptive epidural analgesia (24–48 hours before the operation) with postoperative systemic opioid analgesia and reported a lower incidence of phantom pain and phantom sensations at 6 months after surgery in the preemptive epidural group. Katsuly-Liapis et al.23 compared preoperative epidural analgesia with bupivacaine and morphine for 3 days before amputation and continued for 3 days after surgery to postoperative epidural analgesia for 3 days after surgery. The preemptive group reported a significantly lower incidence of phantom pain at the 6-month follow-up evaluation. Unfortunately, the methodology was possibly flawed in these studies because there was a lack of information regarding the randomization process, the blinding procedures, and the pain assessment methodology.
In the studies by Nikolajsen et al.,26,27 the epidural infusion was started an average of 18 hours and 16.5 hours, respectively, before amputation and these investigators reported no benefit in preventing phantom syndrome. In a study by Lambert et al.,14 the epidural infusion was started 24 hours before amputation and showed no difference compared with intraoperative perineural blocks in the prevention of PLS. Although these data suggest that a short-lasting preoperative epidural infusion (24 hours before surgery) does not prevent PLS, there is a clear need for additional randomized, controlled, blinded trials to evaluate whether a longer preoperative epidural infusion might be useful. Preemptive (perioperative) analgesia seems to be of limited, if any, additional value28 compared with postoperative analgesia alone in reducing postoperative pain.
The effects of local anesthetic perineural blocks with and without opioid analgesics in preventing PLS have been studied in patients undergoing limb amputations.18,29–33 However, the reported beneficial effects of perineural blocks are also inconsistent. In the published studies, the local anesthetic infusion was administered for a maximum of 3 postoperative days and the perineural catheter was removed after a maximum of 9 days. The highest concentrations of local anesthetics were 0.25% bupivacaine at 10 mL/h or 0.325% ropivacaine at 5 mL/h. A direct comparison of continuous perineural and epidural blocks did not show any significant difference between the 2 local anesthetic techniques with respect to postoperative pain control or long-term patient outcome measures.14 In addition to the use of regional analgesic techniques, oral non-opioid analgesic drug regimens (e.g., gabapentin, memantine, ketamine) have also been evaluated for the prevention of PLS with varying degrees of success.34–38
The use of a prolonged perineural infusion of a high concentration of a local anesthetic solution was initially described in a patient with PLS who was not responsive to oral, parenteral, or intrathecal opioid analgesics in combination with oral gabapentin and an antidepressant drug.39 Approximately 6 hours after starting a 0.5% ropivacaine infusion, the patient's visual analog scale pain score on a 100-mm scale decreased from >90 mm to <10 mm and was associated with the disappearance of the phantom sensations. The patient discontinued the infusion for 6 to 12 hours every 7 days to evaluate their phantom limb pain and phantom sensations. After 28 days, the catheter was removed because the patient reported being without any phantom symptoms for >48 hours after stopping the perineural infusion. This patient subsequently remained free of PLS at 3-year follow-up.
Although the precise mechanism for the development of phantom pain and other phantom symptoms is still unclear, it is possible that the first event occurs in the periphery3 with a subsequent cascade of events that ultimately seem to involve both the spinal cord and cerebral cortical structures. Based on the presumed mechanisms of phantom limb pain1,3,33 and the beneficial effect of the prolonged blockade of the mechanoreceptive Aβ fibers by the local anesthetic infusion, we would speculate that the abnormal nerve sprouting of these fibers at laminae I and II in the dorsal horn3 is responsible for the pathological activation of nociceptive neurons in the spinal cord. It is possible that by interrupting the feedback mechanism at the posterior horn of the spinal cord, the local anesthetic infusion blocks the centralization of phantom pain and related symptoms. Moreover, we hypothesize that, by preventing the transmission of nociceptive input from C and Aδ fibers over a prolonged period of time, it is possible to prevent the increased spontaneous firing of the sensory nerve endings that can lead to the development of central sensitization, and permanent structural changes in the synaptic region of the dorsal horn of the spinal cord.
Based on the data from these 62 amputees, use of a prolonged perineural infusion of 0.5% ropivacaine seems to be a valid therapeutic option for the treatment of PLS (e.g., stump pain, phantom limb pain, and phantom limb sensations). Previous work1–5 regarding the natural history of PLS found a progressive disappearance of stump pain in the early postoperative recovery period. However, a high prevalence of phantom pain can remain for a long period of time after amputation (70%–80% incidence of phantom pain in the first week and a 60%–70% prevalence at 1 year postamputation). The clinical trials of epidural analgesia in the preoperative and postoperative periods for the prevention of phantom limb pain showed a prevalence of the phantom limb pain at 6/12 months after the amputation changing from a minimum of 0% to 7%21,22 to a maximum of 75% to 78%26,27 of the enrolled patients. In the clinical trials examining the preventive role of short-lasting perineural analgesia, the prevalence of phantom limb pain at 12 months after the amputation increases from 0%29 to 67%18 of examined patients. Although almost all of the patients in this study reported high VRS pain scores on postoperative day 1, a marked reduction in these symptoms (including phantom limb pain) occurred during the 12- month follow-up period, with 84% of patients reporting no stump or phantom limb pain at the 1-year follow-up. The primary differences in our study compared with other local anesthetic techniques for PLS described in the literature were in the duration of the infusion after surgery (lasting approximately 4–5 weeks) and in the use of a high concentration of the local anesthetic.40–42
The prolonged duration of the perineural infusion required for the phantom limb symptoms to disappear (or become minimal in intensity) in the majority of the patients was 4 to 5 weeks and clearly affected the ability of some patients to complete the protocol. Most of the patients (n = 20) who discontinued the local anesthetic infusion without completing the full intent of the treatment protocol were simply tired of having to deal with the catheter system and considered the presence of only phantom sensations to be an acceptable outcome. In the 4 patients who reported significant residual phantom pain and phantom sensations at the time that the treatment was discontinued, 2 removed the catheter because of local intolerance and in the other 2 cases it was accidentally removed during a dressing change (n = 2). The latter 2 patients chose not to have the catheter reinserted.
Of the patients who prematurely discontinued the protocol while experiencing phantom sensations only (i.e., no phantom limb pain), none reported recurrence of phantom pain in the follow-up period or required use of oral opioid analgesic medication after discontinuing the local anesthetic infusion. Therefore, this was considered to be an acceptable outcome. The results of this preliminary study suggest that the decision to prematurely interrupt the infusion increases the risk for persistence of PLS. The full completion of our protocol until the disappearance of both phantom pain and sensations required a perioperative team approach,43 with the collaboration of surgeons, anesthesiologists, ward nurses, as well as patients and their family members (who must understand the operation of the local anesthetic pump delivery system and be able to manage the perineural catheter system after discharge from the hospital).
The rate and concentration of the local anesthetic infusion (5 mL/h of 0.5% ropivacaine) was chosen based on information from the published literature on this topic and a desire to maintain a prolonged infusion without local anesthetic side effects. In previous publications describing the use of short-term perineural infusions of local anesthetics, the infusion rates varied from 1 to 10 mL/h.29,32,33 For example, Pinzur et al.33 used bupivacaine 0.5% 1 mL/h (with morphine). In other trials,18,29–32 bupivacaine 0.25% at 10 mL/h, ropivacaine 0.325% at 5 mL/h, and bupivacaine 0.1% at 10 mL/h (with clonidine) have been reported. Our aim was to safely administer a high concentration of a local anesthetic infusion over a sufficient period of time to prevent the long-term sequelae related to postamputation PLS. All patients were instructed to discontinue the infusion every 7 days to assess residual extremity pain and phantom sensations in the absence of the local analgesic effects. They were also instructed to assess the correct functioning of the catheter system when they restarted the infusion because of persistent pain or phantom symptoms. Moreover, at the chosen infusion rate of 5 mL/h, the elastomeric pumps were refilled approximately every 3 days by an anesthesiologist working in one of the local analgesic therapy centers in Italy.
Muscular weakness in the stump was our principal concern related to the use of a high concentration of the local anesthetic in patients undergoing below-the-knee amputations. However, none of our patients reported clinically significant differences in the muscular response in the stump before or after restarting the local anesthetic infusion at the postoperative evaluation periods. The absence of the expected motor weakness due to the use of 0.5% ropivacaine in this surgical population may have been attributable to the effects of the operation itself. The inability of some patients to tolerate the catheter delivery system was the primary reason for the premature interruption of the perineural infusion therapy despite the persistence of phantom limb sensations.
The 4 patients who underwent a secondary amputation (and complained of moderate-to-severe phantom limb pain before the reamputation) experienced a decrease in the intensity of their phantom limb pain (VRS score <2) after the prolonged high-concentration local anesthetic infusion. These anecdotal results suggest that long-lasting perineural continuous blocks may also be useful in patients who have already developed severe PLS. It may be possible to reverse preexisting cortical reorganization using perineural continuous blocks as previously reported with magnetic resonance imaging techniques.18 Unfortunately, because of the small number of reamputation patients in this study, we were unable to evaluate the effectiveness of the prolonged perineural continuous blocks in the subpopulation with preexisting PLS.
The termination of the morphine control group after only 4 patients were enrolled in the original protocol is one of the main limitations of this study. All 4 of these patients asked to discontinue their participation in the study and switch to the perineural local anesthetic group because of their inability to achieve adequate pain control with PCA morphine in the early postoperative period. The failure of the first 4 patients in the morphine group also created an adversarial atmosphere on the postsurgical ward toward the PCA morphine therapy, especially when the nursing staff observed the patients who had the same operation with the continuous perineural block technique during the postoperative period. A second criticism of the study relates to our failure to evaluate outcomes when patients having lower extremity amputations were administered the high-concentration local anesthetic infusions for specific (fixed) predetermined weekly intervals after the amputation procedure. Clearly, additional controlled studies are needed to evaluate the effect of the duration of the perineural local anesthetic infusion on patient outcomes after lower extremity amputations (e.g., 1-, 2-, or 4-week infusions after amputations).
We conclude that perineural infusion of 0.5% ropivacaine is a useful therapeutic option for the treatment and prevention of PLS. The persistence of phantom limb sensations in 30% to 40% of the patients at the end of the follow-up period seemed to have been related, in part, to the premature discontinuation of the perineural local anesthetic infusion.
From the *Department of Surgery and Anesthesiology Sciences, University of Bologna; †Research Unit of Anesthesia and Intensive Care, Rizzoli Orthopedic Institute, Bologna; ‡Department of Anesthesia & Critical Care, Policlinic Abano Medical Center, Abano Terme, Italy; §Department of Anesthesia, Cedars Sinai Medical Center, Los Angeles, California; #Pain Therapy and Palliative Care Unit, Hospital of Rimini, Rimini; and ¶Fourth Ward of Oncologic Orthopedic–Trauma Surgery, Rizzoli Orthopedic Institute, Bologna, Italy.
Paul F. White is section Editor of Book, Multimedia and Meeting Reviews for the Journal. The manuscript was handled by Spencer S. Liu, section Editor of Pain Medicine, and Dr. White was not involved in any way with the editorial process or decision.
The authors thank Elettra Pignotti for assistance with the statistical analysis, and Keith Smith for assistance with the translation of the manuscript.
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