- Email: [email protected]
New approaches, including targeting the ganglia
New approaches, including targeting the ganglia Michael J. Levy, MD Rochester, Minnesota, USA
BACKGROUND Pancreatic cancer and chronic pancreatitis are commonly associated with intense and often refractory pain.1,2 Nonnarcotic medical therapies are often inadequate, and opioids commonly induce nausea, constipation, and other adverse effects.3,4 Nonpharmacologic therapies are often administered with the aim of improving pain control and quality of life while reducing the risk of drug-induced adverse effects. Such therapies include celiac plexus neurolysis (CPN) with injection of alcohol in patients with pancreatic cancer or celiac plexus block (CPB) with steroids in patients with chronic pancreatitis. Unfortunately, although CPN and CPB are considered safe, they provide limited benefit in terms of the degree and duration of pain relief, and little advance has been made since Kappis first described the technique in 1914 (Fig. 1).5 Since then, modifications have been created in an attempt to improve the accuracy of needle placement and pain relief, while reducing procedure-related complications. These techniques differ with respect to the route of needle insertion (Fig. 2), use of radiologic guidance versus a blind procedure, and chemical composition of the injectate. A meta-analysis by Eisenberg et al6 reviewed the percutaneous (PQ) approaches. They concluded that, despite few reports favoring one technique over another, efficacy of pain relief was not influenced by the technical approach or the use of radiologic guidance. Existing EUS data are limited and do not allow us to clarify whether minor technical variations, eg, unilateral versus bilateral injection, offers an advantage in terms of efficacy and safety.7,8 In addition, the lack of prospective comparative trials prohibits us from accurately evaluating EUS versus PQ approaches. The failure of radiologically guided CPN and CPB to enhance the efficacy of pain relief versus ‘‘blind’’ techniques was unexpected but was demonstrated in a meta-analysis. Further consideration of this issue suggests that this finding may have been anticipated for 2 reasons. First, given the failure of all imaging modalities to identify celiac ganglia, the use of radiologic guidance would not be expected to target this site with any more precision than anatomically guided blind techniques. The likelihood of placing
DISCLOSURE: M. J. Levy disclosed no financial relationships relevant to this publication. Copyright ª 2009 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2008.12.021
S166 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 2 : 2009
the needle within ganglia by random chance, given the inability to visualize the ganglia, is remote. In addition, the likelihood of inadvertent intraganglia injection within multiple ganglia is even more remote. Second, animal and human studies9 demonstrated that the injectate rapidly spreads from the site of injection in the celiac plexus region and over a wide dispersal pattern. Therefore, even if the injectate was placed in close proximity to the ganglia, it is unlikely that the agents would remain in contact with the ganglia for a sufficient duration to allow meaningful neurolysis or block. The recent recognition that celiac ganglia can be visualized and accessed by EUS (Fig. 3) allowed for direct injection into individual celiac ganglia to perform celiac ganglia neurolysis (CGN) and celiac ganglia block (CGB) (Fig. 4).10 We hypothesized that this more precise delivery of therapy offered the potential for enhanced efficacy and safety, and we recently published our pilot data and initial experience in patients undergoing direct CGN or CGB.11
METHODS All aspects of the procedure, including patient candidacy, sedation, antibiotic use, and follow-up, were identical to that of standard CPN and CPB, except for certain technical aspects detailed below. The linear echoendoscope (GF-UC140P-AL5 or GF-UC160P-AT8; Olympus America Inc, Center Valley, Pa) was positioned along the posterior lesser curve of the gastric fundus to locate the aorta and the celiac trunk in the longitudinal plane. Celiac ganglia were identified, numbered, and measured in the same manner as we previously reported.12,13 A 22-gauge needle (Cook Endoscopy, Winston-Salem, NC) was initially primed with the injectate. For the initial 9 patients, the drugs were injected sequentially, beginning with bupivacaine (0.25) followed by alcohol (99%) and/or Depo-Medrol suspension (80 mg per 2 mL). In the subsequent 27 patients, the medications were mixed and injected as a compound. Because direct ganglia injection is a new technique, we purposely did not control for the precise volume of injection and number of ganglia injected. However, in general, the needle was inserted under EUS guidance directly into as many ganglia as possible, which resulted in a mean of 2.7 ganglia (range 1-6) and 2.3 ganglia (range 1-4) for patients with pancreatic cancer and chronic pancreatitis, respectively. During injection, it was our general practice to position the needle tip within the central point of ganglion that was smaller than 1.0 cm within the axis of the needle plane. For ganglia 1.0 cm or www.giejournal.org
Levy
New approaches, including targeting the ganglia
Figure 1. Classic approach, also referred to as the posterolateral, retrocrural, or deep splanchnic approach as first described by Kappis in 1914.
larger in the needle plane axis, we typically advanced the needle tip to the deepest point within the ganglia and injected as the needle was slowly withdrawn. Direct injection was found to commonly result in enlargement of the ganglia (Fig. 5). Intraganglia injection was manifest by the immediate onset of pain, which developed in 30 of the 32 patients as an abrupt increase in patient movement, attempted verbalization, altered pulse, and respiration, including the patients undergoing anesthesia-assisted sedation. These manifestations abruptly resolved within a few seconds after ganglia injection. As per routine clinical practice, patients were evaluated 24 to 72 hours after biopsy to discuss results and assess for complications. All medical records were examined to assess the safety and efficacy of pain relief and changes in analgesic consumption. To assure quality of care for this new technique, patients were contacted by telephone 2 to 4 weeks after EUS, which was possible in 29 patients. Evaluation of the other 6 patients was based on later contact, at 5 to 10 weeks, in 4 patients, or by chart review alone in 2 patients. Patients rated their therapeutic response as either (1) complete, (2) partial, or (3) no response. Although efficacy and adverse reactions were assessed during the initial follow-up, data given regarding therapeutic response were based on the 2-week to 4-week follow-up. Specific details sought included efficacy categorized by the terms complete, partial, or no change. We also sought to determine whether analgesic consumption increased, remained stable, decreased, or was discontinued. The analgesic-equivalent dose was not calculated. Patients were also questioned as to the occurrence, severity, and means of therapy for initial pain exacerbation after the procedure. www.giejournal.org
Given the limited enrollment of this pilot study, the data provided were not sufficiently powered to discern the impact of many variables. We did not attempt to correlate outcomes with features such as patient demographics, pain features, use of chemoradiation, prior or subsequent interventions, tumor or chronic pancreatitis related variables, anatomical features of the ganglia, method of injection, or characteristics of the injectate.
RESULTS Thirty-three patients underwent 36 procedures for unresectable pancreatic cancer (CGN, n Z 17; CGB, n Z 1) or chronic pancreatitis (CGN, n Z 5; CGB, n Z 13) with bupivacaine (0.25%) and alcohol (99%) for CGN, or bupivacaine (0.25%) and Depo-Medrol (80 mg per 2 mL) for CGB. Clinical, technical, safety, and efficacy data are presented below. In 2 patients, the ganglia could not be identified (n Z 1) or were diminutive (n Z 1), and standard techniques were used. Ganglia could be seen and accessed in 33 of 35 patients (95%) (Table 1).
PANCREATIC CANCER Patients with cancer reported pain relief in 16 of 17 (94%) when alcohol was injected and in 0 of 1 (00%) (P Z .004) with steroid injection. For those who reported pain relief, 16 patients had partial relief and none experienced complete pain relief. Narcotic use increased in 2 patients, remained equivalent in 13 patients, and decreased in 3 patients. Volume 69, No. 2 : 2009 GASTROINTESTINAL ENDOSCOPY S167
New approaches, including targeting the ganglia
Levy
Figure 2. PQ modifications to the classic approach include the transcrural, transintervertebral, transaortic, and anterior approaches.
CHRONIC PANCREATITIS
Patients were described as having ‘‘immediate’’ pain when discomfort was observed while the needle was within the ganglion, which was distinguished from ‘‘initial’’ pain exacerbation, which began in the recovery room or soon thereafter. Thirteen patients (36%) (CGN, n Z 7; CGB, n Z 6) experienced an ‘‘initial’’ pain exacerbation that lasted a mean of 2.2 days for CGN and 1.1 days for CGB. Hospitalization was required in 3 patients (CGN, n Z 1, 1 day; CGB, n Z 2, 1 day and 2 days), and another patient who underwent CGB was evaluated in the emer-
gency department and was treated with opioid analgesics without hospitalization. Initial pain exacerbation predicted enhanced pain relief at follow-up. For pancreatic cancer, 7 of 7 patients (100%) who had an initial pain exacerbation reported eventual efficacy of CGN versus 9 of 11 (81%) (P Z .23). For patients with chronic pancreatitis, 5 of 6 (83%) versus 4 of 12 (33%) (P Z .05) had subsequent pain relief, which depended on whether they did or did not experience an initial exacerbation of their pain. For the group as a whole, eventual pain relief was more often reported in patients who developed initial pain compared with those who did not: 12 of 13 (92%) versus 13 of 23 (57%) (P ! .03), respectively. Transient hypotension, defined by a decrease in blood pressure of more than 20 mm Hg systolic or 10 mm Hg diastolic that occurs within 3 minutes of upright tilt, developed in 12 patients (33%), two of whom required additional fluid administration. For CGB, diarrhea was reported in 2 patients (11%) and lasted 1 and 2 weeks. Four patients with pancreatic cancer (22%) subjectively noted marked (n Z 2) and mild (n Z 2) improvement of their narcotic-induced constipation. No other complications were reported.
S168 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 2 : 2009
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In patients with chronic pancreatitis, 4 of 5 (80%) who received alcohol reported pain relief versus 5 of 13 who received steroids (38%) (P Z .11). When pain relief occurred, the benefit was rated as complete in 4 patients and partial in 5 patients. Use of narcotics increased, remained equivalent, and decreased in 0, 15, and 3 patients, respectively.
INITIAL PAIN EXACERBATION
Levy
New approaches, including targeting the ganglia
Figure 3. Celiac ganglion aspirate, showing nerve cell bodies. Top (Diff Quick, orig. mag. 20 [left], 40 [right]). Bottom (Papanicolaou’s, orig. mag. 20 [left], 40 [right]).
DISCUSSION A number of techniques are available to guide CPN and CPB, with EUS approaches most recently introduced. As part of an evidence-based review of the literature, we concluded the following14: 1. The weight of evidence suggests the safety and efficacy of PQ CPN for treating pain in a subgroup of patients with unresectable pancreatic cancer. Although the reported complication and efficacy rates of EUS-guided CPN were similar to those reported for PQ methods, the lack of comparative studies does not allow the assumed equivalence to be verified. CPN reduces but rarely eliminates cancer pain, and nearly all patients require continued opioid use, albeit often at a lower dose. 2. The efficacy data for CPB in treating chronic pancreatitis–induced pain, regardless of technique, are less www.giejournal.org
well established. We consider CPB to be investigational and only advocate the use as part of a clinical trial. Patients should be made aware of the uncertain benefit and potential risks. The suboptimal efficacy has diminished the enthusiasm for CPN and CPB in many centers, with a minority of potential candidates receiving therapy.15 However, the recent recognition that celiac ganglia can be visualized and targeted by EUS now allows us to perform direct CGN and CGB. The more precise delivery of therapy into the ganglia instead of in the vicinity of the ganglia offers the potential for enhanced efficacy and safety. Our data suggest that, in patients with moderate-to-severe pain secondary to pancreatic cancer, direct CGN with alcohol injection is safe and effective in initial pain management. However, in patients with chronic pancreatitis and moderate-to-severe pain, direct CGB with steroid injection infrequently Volume 69, No. 2 : 2009 GASTROINTESTINAL ENDOSCOPY S169
New approaches, including targeting the ganglia
Levy
Figure 4. Target site for celiac plexus (left) versus celiac ganglia (right) directed interventions.
Figure 5. Initial preinjection appearance (left) of a celiac ganglion compared with after injection (right).
provides initial pain relief. The results in this later group were more favorable for those receiving alcohol injections. Therefore, our data support the notion that alcohol provides greater neurolysis and pain relief compared with steroids. As a result, alcohol has long been favored for the treatment of patients with cancer, but some investigators question the use in benign disease. This use of alcohol injection should be further evaluated in patients with chronic pancreatitis. It is unclear why patients who develop an initial pain exacerbation appear to ultimately experience greater pain relief. We presume that this feature did not relate to differences in the accuracy of needle placement within the ganglia, given that nearly all patients experienced immediate pain during the injection, which suggests that the needle was accurately placed in the target structure. Furthermore, there was no clear difference between these
2 groups as to the volume or type of injectate. It is plausible, although unproven, that patients who experience initial pain experience greater neural destruction, thereby initially inducing pain but a greater likelihood of eventual pain relief. In addition, we anecdotally noted that, in a few patients in whom we inject a small volume initially outside of the ganglia, they did not appear to experience pain upon injection. However, with further advancement of the needle into the ganglia, they expressed mild discomfort that increased in intensity upon delivery of the injectate. Our small, retrospective, noncontrolled study provided inadequate power to permit firm conclusions and raised as many questions as it answered. Methodologic limitations included the varied and noncontrolled technique for injection, composition of the injectate, use of general descriptors of pain response instead of a visual analog scale, lack of a precise measurement of the impact on
S170 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 2 : 2009
www.giejournal.org
Levy
New approaches, including targeting the ganglia
TABLE 1. Patient results
Mean age (range), y
Mean no. ganglia identified (range)
Mean no. ganglia injected (range)
Mean bupivacaine volume (range), mL
Mean alcohol volume (range), mL
Mean Depo-Medrol dose (range), mg
Pain relief (complete/partial [no. of patients])
Pancreatic cancer (n Z 18)
66 (39-80)
3.0 (1-6)
2.7 (1-6)
8.3 (1-7) (n Z 18)
12.7 (2-20) (n Z 17)
80.0 (80, n Z 1)
Alcohol 16/17 (94%), steroid 0/1 (0%), P Z .004
Chronic pancreatitis (n Z 18)
29 (17-54)
2.7 (1-4)
2.3 (1-4)
12.0 (4-20) (n Z 18)
5.8 (4-8) (n Z 5)
76.4 (80, n Z 1) (40, n Z 1)
Alcohol 4/5 (80%), Steroid 5/13 (38%), P Z .11
Disease
opioid analgesic consumption, brief duration of follow-up, and lack of correlation with quality of life and with survival. In recognizing these limitations, our goal was simply to provide pilot data regarding the safety and initial efficacy of direct CGN and CGB. Because of the varied study limitations, the data do not allow us to firmly establish the efficacy or safety of this modified approach to pain management.
CONCLUSIONS New techniques are needed to improve the efficacy of pain relief over that provided by standard methods of celiac-guided therapy. Initial data suggest that, in patients with moderate-to-severe pain secondary to pancreatic cancer or chronic pancreatitis, direct CGN with alcohol injection is safe and effective in initial pain management. On the contrary, direct CGB with steroid injection less effectively alleviates pain in patients with chronic pancreatitis. Prospective, controlled, and comparative trials are needed to confirm the safety and to assess the long-term efficacy of this new approach to pain management relative to conventional techniques. Until then, this approach cannot be recommended in routine practice. Abbreviations: CGB, celiac ganglia block; CGN, celiac ganglia neurolysis; CPB, celiac plexus block; CPN, celiac plexus neurolysis; PQ, percutaneous.
REFERENCES 1. Ventafridda GV, Caraceni AT, Sbanotto AM, et al. Pain treatment in cancer of the pancreas. Eur J Surg Oncol 1990;16:1-6. 2. Lankisch PG. Natural course of chronic pancreatitis. Pancreatology 2001;1:3-14. 3. Ventafridda V, Tamburini M, Caraceni A, et al. A validation study of the WHO method for cancer pain relief. Cancer 1987;59:850-6.
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4. Yeager MP, Colacchio TA, Yu CT, et al. Morphine inhibits spontaneous and cytokine-enhanced natural killer cell cytotoxicity in volunteers. Anesthesiology 1995;83:500-8. 5. Kappis M. Erfahrungen mit local anasthesie bie bauchoperationen [German with English abstract]. Verh Dtsch Gesellsch Chir 1914;43: 87-9. 6. Eisenberg E, Carr DB, Chalmers TC. Neurolytic celiac plexus block for treatment of cancer pain: a meta-analysis. Anesth Analg 1995;80: 290-5, erratum 1995;81:213. 7. Leblanc J, DeWitt J, Calley C, et al. A prospective randomized trial of 1 versus 2 injections during a single EUS-guided celiac plexus block (CPB) procedure for chronic pancreatitis pain: final results [abstract]. Gastrointest Endosc 2008;67:AB224. 8. Usatii M, Paquin SC, Dagenais M, et al. Preliminary results of a randomized, double blind, controlled trial of early EUS-guided celiac plexus neurolysis (EUS-CPN) versus conventional management for pain in patients with inoperable pancreatic cancer [abstract]. Gastrointest Endosc 2008;67:AB211. 9. Wiersema MJ, Wong GY, Croghan GA. Endoscopic technique with ultrasound imaging for neurolytic celiac plexus block. Reg Anesth Pain Med 2001;26:159-63. 10. Gleeson FC, Levy MJ, Papachristou GI, et al. Frequency of visualization of presumed celiac ganglia by endoscopic ultrasound. Endoscopy 2007;39:620-4. 11. Levy MJ, Topazian MD, Wiersema MJ, et al. Initial evaluation of the efficacy and safety of endoscopic ultrasound-guided direct Ganglia neurolysis and block. Am J Gastroenterol 2008;103:98-103. 12. Levy MJ, Topazian M, Keeney G, et al. Preoperative diagnosis of extrapancreatic neural invasion in pancreatic cancer. Clin Gastroenterol Hepatol 2006;4:1479-82. 13. Levy MJ, Rajan E, Keeney G, et al. Neural ganglia visualized by endoscopic ultrasound. Am J Gastroenterol 2006;101:1787-91. 14. Levy MJ, Wiersema MJ. EUS-guided celiac plexus neurolysis and celiac plexus block. Gastrointest Endosc 2003;57:923-30. 15. Brown DL, Caswell RE, Wong GY, et al. Referral of patients with pain from pancreatic cancer for neurolytic celiac plexus block. Mayo Clinic Proc 1997;72:831-4.
Mayo Clinic, Rochester, Minnesota, USA. This article is from a meeting and has not undergone the GIE peer review process.
Volume 69, No. 2 : 2009 GASTROINTESTINAL ENDOSCOPY S171
BACKGROUND Pancreatic cancer and chronic pancreatitis are commonly associated with intense and often refractory pain.1,2 Nonnarcotic medical therapies are often inadequate, and opioids commonly induce nausea, constipation, and other adverse effects.3,4 Nonpharmacologic therapies are often administered with the aim of improving pain control and quality of life while reducing the risk of drug-induced adverse effects. Such therapies include celiac plexus neurolysis (CPN) with injection of alcohol in patients with pancreatic cancer or celiac plexus block (CPB) with steroids in patients with chronic pancreatitis. Unfortunately, although CPN and CPB are considered safe, they provide limited benefit in terms of the degree and duration of pain relief, and little advance has been made since Kappis first described the technique in 1914 (Fig. 1).5 Since then, modifications have been created in an attempt to improve the accuracy of needle placement and pain relief, while reducing procedure-related complications. These techniques differ with respect to the route of needle insertion (Fig. 2), use of radiologic guidance versus a blind procedure, and chemical composition of the injectate. A meta-analysis by Eisenberg et al6 reviewed the percutaneous (PQ) approaches. They concluded that, despite few reports favoring one technique over another, efficacy of pain relief was not influenced by the technical approach or the use of radiologic guidance. Existing EUS data are limited and do not allow us to clarify whether minor technical variations, eg, unilateral versus bilateral injection, offers an advantage in terms of efficacy and safety.7,8 In addition, the lack of prospective comparative trials prohibits us from accurately evaluating EUS versus PQ approaches. The failure of radiologically guided CPN and CPB to enhance the efficacy of pain relief versus ‘‘blind’’ techniques was unexpected but was demonstrated in a meta-analysis. Further consideration of this issue suggests that this finding may have been anticipated for 2 reasons. First, given the failure of all imaging modalities to identify celiac ganglia, the use of radiologic guidance would not be expected to target this site with any more precision than anatomically guided blind techniques. The likelihood of placing
DISCLOSURE: M. J. Levy disclosed no financial relationships relevant to this publication. Copyright ª 2009 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2008.12.021
S166 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 2 : 2009
the needle within ganglia by random chance, given the inability to visualize the ganglia, is remote. In addition, the likelihood of inadvertent intraganglia injection within multiple ganglia is even more remote. Second, animal and human studies9 demonstrated that the injectate rapidly spreads from the site of injection in the celiac plexus region and over a wide dispersal pattern. Therefore, even if the injectate was placed in close proximity to the ganglia, it is unlikely that the agents would remain in contact with the ganglia for a sufficient duration to allow meaningful neurolysis or block. The recent recognition that celiac ganglia can be visualized and accessed by EUS (Fig. 3) allowed for direct injection into individual celiac ganglia to perform celiac ganglia neurolysis (CGN) and celiac ganglia block (CGB) (Fig. 4).10 We hypothesized that this more precise delivery of therapy offered the potential for enhanced efficacy and safety, and we recently published our pilot data and initial experience in patients undergoing direct CGN or CGB.11
METHODS All aspects of the procedure, including patient candidacy, sedation, antibiotic use, and follow-up, were identical to that of standard CPN and CPB, except for certain technical aspects detailed below. The linear echoendoscope (GF-UC140P-AL5 or GF-UC160P-AT8; Olympus America Inc, Center Valley, Pa) was positioned along the posterior lesser curve of the gastric fundus to locate the aorta and the celiac trunk in the longitudinal plane. Celiac ganglia were identified, numbered, and measured in the same manner as we previously reported.12,13 A 22-gauge needle (Cook Endoscopy, Winston-Salem, NC) was initially primed with the injectate. For the initial 9 patients, the drugs were injected sequentially, beginning with bupivacaine (0.25) followed by alcohol (99%) and/or Depo-Medrol suspension (80 mg per 2 mL). In the subsequent 27 patients, the medications were mixed and injected as a compound. Because direct ganglia injection is a new technique, we purposely did not control for the precise volume of injection and number of ganglia injected. However, in general, the needle was inserted under EUS guidance directly into as many ganglia as possible, which resulted in a mean of 2.7 ganglia (range 1-6) and 2.3 ganglia (range 1-4) for patients with pancreatic cancer and chronic pancreatitis, respectively. During injection, it was our general practice to position the needle tip within the central point of ganglion that was smaller than 1.0 cm within the axis of the needle plane. For ganglia 1.0 cm or www.giejournal.org
Levy
New approaches, including targeting the ganglia
Figure 1. Classic approach, also referred to as the posterolateral, retrocrural, or deep splanchnic approach as first described by Kappis in 1914.
larger in the needle plane axis, we typically advanced the needle tip to the deepest point within the ganglia and injected as the needle was slowly withdrawn. Direct injection was found to commonly result in enlargement of the ganglia (Fig. 5). Intraganglia injection was manifest by the immediate onset of pain, which developed in 30 of the 32 patients as an abrupt increase in patient movement, attempted verbalization, altered pulse, and respiration, including the patients undergoing anesthesia-assisted sedation. These manifestations abruptly resolved within a few seconds after ganglia injection. As per routine clinical practice, patients were evaluated 24 to 72 hours after biopsy to discuss results and assess for complications. All medical records were examined to assess the safety and efficacy of pain relief and changes in analgesic consumption. To assure quality of care for this new technique, patients were contacted by telephone 2 to 4 weeks after EUS, which was possible in 29 patients. Evaluation of the other 6 patients was based on later contact, at 5 to 10 weeks, in 4 patients, or by chart review alone in 2 patients. Patients rated their therapeutic response as either (1) complete, (2) partial, or (3) no response. Although efficacy and adverse reactions were assessed during the initial follow-up, data given regarding therapeutic response were based on the 2-week to 4-week follow-up. Specific details sought included efficacy categorized by the terms complete, partial, or no change. We also sought to determine whether analgesic consumption increased, remained stable, decreased, or was discontinued. The analgesic-equivalent dose was not calculated. Patients were also questioned as to the occurrence, severity, and means of therapy for initial pain exacerbation after the procedure. www.giejournal.org
Given the limited enrollment of this pilot study, the data provided were not sufficiently powered to discern the impact of many variables. We did not attempt to correlate outcomes with features such as patient demographics, pain features, use of chemoradiation, prior or subsequent interventions, tumor or chronic pancreatitis related variables, anatomical features of the ganglia, method of injection, or characteristics of the injectate.
RESULTS Thirty-three patients underwent 36 procedures for unresectable pancreatic cancer (CGN, n Z 17; CGB, n Z 1) or chronic pancreatitis (CGN, n Z 5; CGB, n Z 13) with bupivacaine (0.25%) and alcohol (99%) for CGN, or bupivacaine (0.25%) and Depo-Medrol (80 mg per 2 mL) for CGB. Clinical, technical, safety, and efficacy data are presented below. In 2 patients, the ganglia could not be identified (n Z 1) or were diminutive (n Z 1), and standard techniques were used. Ganglia could be seen and accessed in 33 of 35 patients (95%) (Table 1).
PANCREATIC CANCER Patients with cancer reported pain relief in 16 of 17 (94%) when alcohol was injected and in 0 of 1 (00%) (P Z .004) with steroid injection. For those who reported pain relief, 16 patients had partial relief and none experienced complete pain relief. Narcotic use increased in 2 patients, remained equivalent in 13 patients, and decreased in 3 patients. Volume 69, No. 2 : 2009 GASTROINTESTINAL ENDOSCOPY S167
New approaches, including targeting the ganglia
Levy
Figure 2. PQ modifications to the classic approach include the transcrural, transintervertebral, transaortic, and anterior approaches.
CHRONIC PANCREATITIS
Patients were described as having ‘‘immediate’’ pain when discomfort was observed while the needle was within the ganglion, which was distinguished from ‘‘initial’’ pain exacerbation, which began in the recovery room or soon thereafter. Thirteen patients (36%) (CGN, n Z 7; CGB, n Z 6) experienced an ‘‘initial’’ pain exacerbation that lasted a mean of 2.2 days for CGN and 1.1 days for CGB. Hospitalization was required in 3 patients (CGN, n Z 1, 1 day; CGB, n Z 2, 1 day and 2 days), and another patient who underwent CGB was evaluated in the emer-
gency department and was treated with opioid analgesics without hospitalization. Initial pain exacerbation predicted enhanced pain relief at follow-up. For pancreatic cancer, 7 of 7 patients (100%) who had an initial pain exacerbation reported eventual efficacy of CGN versus 9 of 11 (81%) (P Z .23). For patients with chronic pancreatitis, 5 of 6 (83%) versus 4 of 12 (33%) (P Z .05) had subsequent pain relief, which depended on whether they did or did not experience an initial exacerbation of their pain. For the group as a whole, eventual pain relief was more often reported in patients who developed initial pain compared with those who did not: 12 of 13 (92%) versus 13 of 23 (57%) (P ! .03), respectively. Transient hypotension, defined by a decrease in blood pressure of more than 20 mm Hg systolic or 10 mm Hg diastolic that occurs within 3 minutes of upright tilt, developed in 12 patients (33%), two of whom required additional fluid administration. For CGB, diarrhea was reported in 2 patients (11%) and lasted 1 and 2 weeks. Four patients with pancreatic cancer (22%) subjectively noted marked (n Z 2) and mild (n Z 2) improvement of their narcotic-induced constipation. No other complications were reported.
S168 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 2 : 2009
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In patients with chronic pancreatitis, 4 of 5 (80%) who received alcohol reported pain relief versus 5 of 13 who received steroids (38%) (P Z .11). When pain relief occurred, the benefit was rated as complete in 4 patients and partial in 5 patients. Use of narcotics increased, remained equivalent, and decreased in 0, 15, and 3 patients, respectively.
INITIAL PAIN EXACERBATION
Levy
New approaches, including targeting the ganglia
Figure 3. Celiac ganglion aspirate, showing nerve cell bodies. Top (Diff Quick, orig. mag. 20 [left], 40 [right]). Bottom (Papanicolaou’s, orig. mag. 20 [left], 40 [right]).
DISCUSSION A number of techniques are available to guide CPN and CPB, with EUS approaches most recently introduced. As part of an evidence-based review of the literature, we concluded the following14: 1. The weight of evidence suggests the safety and efficacy of PQ CPN for treating pain in a subgroup of patients with unresectable pancreatic cancer. Although the reported complication and efficacy rates of EUS-guided CPN were similar to those reported for PQ methods, the lack of comparative studies does not allow the assumed equivalence to be verified. CPN reduces but rarely eliminates cancer pain, and nearly all patients require continued opioid use, albeit often at a lower dose. 2. The efficacy data for CPB in treating chronic pancreatitis–induced pain, regardless of technique, are less www.giejournal.org
well established. We consider CPB to be investigational and only advocate the use as part of a clinical trial. Patients should be made aware of the uncertain benefit and potential risks. The suboptimal efficacy has diminished the enthusiasm for CPN and CPB in many centers, with a minority of potential candidates receiving therapy.15 However, the recent recognition that celiac ganglia can be visualized and targeted by EUS now allows us to perform direct CGN and CGB. The more precise delivery of therapy into the ganglia instead of in the vicinity of the ganglia offers the potential for enhanced efficacy and safety. Our data suggest that, in patients with moderate-to-severe pain secondary to pancreatic cancer, direct CGN with alcohol injection is safe and effective in initial pain management. However, in patients with chronic pancreatitis and moderate-to-severe pain, direct CGB with steroid injection infrequently Volume 69, No. 2 : 2009 GASTROINTESTINAL ENDOSCOPY S169
New approaches, including targeting the ganglia
Levy
Figure 4. Target site for celiac plexus (left) versus celiac ganglia (right) directed interventions.
Figure 5. Initial preinjection appearance (left) of a celiac ganglion compared with after injection (right).
provides initial pain relief. The results in this later group were more favorable for those receiving alcohol injections. Therefore, our data support the notion that alcohol provides greater neurolysis and pain relief compared with steroids. As a result, alcohol has long been favored for the treatment of patients with cancer, but some investigators question the use in benign disease. This use of alcohol injection should be further evaluated in patients with chronic pancreatitis. It is unclear why patients who develop an initial pain exacerbation appear to ultimately experience greater pain relief. We presume that this feature did not relate to differences in the accuracy of needle placement within the ganglia, given that nearly all patients experienced immediate pain during the injection, which suggests that the needle was accurately placed in the target structure. Furthermore, there was no clear difference between these
2 groups as to the volume or type of injectate. It is plausible, although unproven, that patients who experience initial pain experience greater neural destruction, thereby initially inducing pain but a greater likelihood of eventual pain relief. In addition, we anecdotally noted that, in a few patients in whom we inject a small volume initially outside of the ganglia, they did not appear to experience pain upon injection. However, with further advancement of the needle into the ganglia, they expressed mild discomfort that increased in intensity upon delivery of the injectate. Our small, retrospective, noncontrolled study provided inadequate power to permit firm conclusions and raised as many questions as it answered. Methodologic limitations included the varied and noncontrolled technique for injection, composition of the injectate, use of general descriptors of pain response instead of a visual analog scale, lack of a precise measurement of the impact on
S170 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 2 : 2009
www.giejournal.org
Levy
New approaches, including targeting the ganglia
TABLE 1. Patient results
Mean age (range), y
Mean no. ganglia identified (range)
Mean no. ganglia injected (range)
Mean bupivacaine volume (range), mL
Mean alcohol volume (range), mL
Mean Depo-Medrol dose (range), mg
Pain relief (complete/partial [no. of patients])
Pancreatic cancer (n Z 18)
66 (39-80)
3.0 (1-6)
2.7 (1-6)
8.3 (1-7) (n Z 18)
12.7 (2-20) (n Z 17)
80.0 (80, n Z 1)
Alcohol 16/17 (94%), steroid 0/1 (0%), P Z .004
Chronic pancreatitis (n Z 18)
29 (17-54)
2.7 (1-4)
2.3 (1-4)
12.0 (4-20) (n Z 18)
5.8 (4-8) (n Z 5)
76.4 (80, n Z 1) (40, n Z 1)
Alcohol 4/5 (80%), Steroid 5/13 (38%), P Z .11
Disease
opioid analgesic consumption, brief duration of follow-up, and lack of correlation with quality of life and with survival. In recognizing these limitations, our goal was simply to provide pilot data regarding the safety and initial efficacy of direct CGN and CGB. Because of the varied study limitations, the data do not allow us to firmly establish the efficacy or safety of this modified approach to pain management.
CONCLUSIONS New techniques are needed to improve the efficacy of pain relief over that provided by standard methods of celiac-guided therapy. Initial data suggest that, in patients with moderate-to-severe pain secondary to pancreatic cancer or chronic pancreatitis, direct CGN with alcohol injection is safe and effective in initial pain management. On the contrary, direct CGB with steroid injection less effectively alleviates pain in patients with chronic pancreatitis. Prospective, controlled, and comparative trials are needed to confirm the safety and to assess the long-term efficacy of this new approach to pain management relative to conventional techniques. Until then, this approach cannot be recommended in routine practice. Abbreviations: CGB, celiac ganglia block; CGN, celiac ganglia neurolysis; CPB, celiac plexus block; CPN, celiac plexus neurolysis; PQ, percutaneous.
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Mayo Clinic, Rochester, Minnesota, USA. This article is from a meeting and has not undergone the GIE peer review process.
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