Should Surgery Replace Pneumatic Dilation in Achalasia?

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hibiting the release of acetylcholine and other neurotransmitters. Opioids have also been found to stimulate fluid and electrolyte absorption in the gut (Neurogastroenterol Motil 2004;16[Suppl 2]:17–28). More specifically targeted therapies for OIC have included both systemic and peripherally acting opioid antagonists. Oral naloxone, a systemic opioid antagonist with low bioavailability owing to first-pass hepatic metabolism, has been studied for its theoretical accumulation in the bowel without systemic levels in the blood. Unfortunately, when this hypothesis was subjected to clinical testing, a significant number of patients reported symptoms of unpredictable systemic opioid withdrawal and increased pain (J Pain Symptom Manage 2002;23: 48 –53). The desire to maintain analgesia without constipation has led to the investigation of peripherally acting opioid antagonists, such as methylnaltrexone and alvimopan. These agents selectively antagonize the peripheral ␮-opioid receptor receptor, without diminishing opioid effects on the central nervous system. Methylnaltrexone is a ␮-opioid receptor–selective antagonist that is being studied for its role in OIC. Methylnaltrexone can be supplied in various formulations (oral, subcutaneous, and IV) and has been shown to reverse morphine-induced oral– cecal transit delay (Clin Pharmacol Ther 200;67:398 – 404). In 1 study of oral methylnaltrexone, 12 chronic methadone users received placebo on the first day and methylnaltrexone on the second day in 1 of 3 doses (0.3, 1, or 3 mg/kg). No patient had a bowel movement after receiving placebo, and 11 of 12 patients experienced defecation after receiving methylnaltrexone. Higher methylnaltrexone doses were associated with a more rapid time to defecation, and there were no reports of systemic opioid withdrawal (JAMA 2000;284:1383–1384). In a double-blind, randomized, placebo-controlled study of 22 chronic methadone users receiving placebo or escalating doses of IV methylnaltrexone, 10 of 11 patients receiving IV methylnaltrexone experienced immediate laxation after 1 session, and 11 of 11 patients had immediate laxation after a second session without evidence of systemic opioid withdrawal (JAMA 2000;283:367–372). Given such encouraging results from smaller studies, it is intriguing to note that in the study by Thomas et al roughly half of patients achieved a bowel movement after receiving methylnaltrexone. This was clearly an improvement over placebo but by no means a silver bullet for OIC in this selected group of patients. These findings suggest that constipation in patients with advanced illness, unlike constipation in younger chronic methadone users, is multifactorial in etiology with contributions not only from the narcotic but also from diet, level of activity, other constipating medications, electrolyte abnormalities, and pelvic floor dysfunction. Furthermore, exogenous opioids may suppress intestinal transit through

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effects on opioid receptors in the central nervous system. This phenomenon has been previously described in animals, where sympathectomy and ␣-noradrenergic blockade have been shown to reverse the effects of morphine (Auton Neurosci 2002;100:27–31). Whether peripherally acting opioid receptor antagonists have a role in the treatment of other disorders such as OIC in nonmalignant conditions, postoperative ileus, gastroparesis, chronic constipation, and constipation-predominant irritable bowel syndrome (IBS-C) remains to be seen. Several studies have demonstrated the efficacy of alvimopan in postoperative ileus including a Phase III trial by Delaney et al, in which patients with postoperative ileus receiving alvimopan experienced a reduction in time to GI recovery and hospital discharge (Dis Colon Rectum 2005;48:1114 –1125). These data have led the US Food and Drug Administration (FDA) recently to approve alvimopan for use in postoperative ileus. The effects of peripheral opioid receptor antagonists on opioid-induced gastroparesis have been mixed. Unlike alvimopan, methylnaltrexone may reverse opioidinduced gastroparesis (Anesthesiology 1997;87:765–770). Peripherally acting opioid receptor antagonists may have a role in the treatment of functional GI disorders such as IBS-C or chronic constipation, particularly given evidence that endogenous opioids suppress intestinal motility when motor function is compromised (Neurogastroenterol Motil 2004;16[Suppl 2]:38 – 45). Whether this scientific observation will translate into clinical benefits for IBS-C or chronic constipation remains to be tested in appropriately designed clinical trials. Based on the available data, methylnaltrexone seems to provide a promising new treatment for OIC. As is nearly always the case with new drugs, FDA approval should be viewed as the beginning and not the end of the process of understanding where methylnaltrexone fits into clinical practice. In the preceding paragraphs, we have discussed a number of areas in which this drug might prove useful. It is also exciting to consider the mechanistic studies that can now be conducted to better understand the role of peripheral endogenous opiates in the pathogenesis of selected disorders of GI motility and neurogastroenterology. Hopefully, peripheral opiate antagonists, by eliminating bothersome side effects without affecting analgesia, will improve the quality of life of patients with intractable pain rather than promote the irresponsible use of opiate analgesics. AMOL S. RANGNEKAR, MD WILLIAM D. CHEY, MD, AGAF, FACG

SHOULD SURGERY REPLACE PNEUMATIC DILATION IN ACHALASIA? Ferulano GP, Dilillo S, D’Ambra M, et al. (Systemic Pathology, University of Naples Federico II, Naples, Italy). Short and long term results of the laparoscopic

November 2008

Heller–Dor myotomy. The influence of age and previous conservative therapies. Surg Endosc 2007;21:2017– 2023. Idiopathic achalasia is a primary esophageal motor disorder of unknown etiology characterized by esophageal aperistalsis and abnormal lower esophageal sphincter (LES) relaxation in response to deglutition. Although idiopathic achalasia is a rare disorder, specialized academic centers commonly encounter patients with this disorder presenting with dysphagia to solid and liquids, regurgitation, chest pain, and weight loss. The most effective treatment options for patients with achalasia include surgical myotomy and pneumatic dilation (PD). Other modes of therapy such as botulinum toxin injection and calcium channel blockers or nitrates are less effective and are usually reserved for patients who are not candidates for the more definitive endoscopic PD or surgical myotomy (Am J Gastroenterol 1999;94:3406 – 3412). The “expert” decision to perform PD or surgical myotomy in a given patient with achalasia is tainted by their training: surgeons opting for surgical myotomy and esophagologists choosing PD. In recent years the latter group has used esophageal scarring and change of normal anatomy owing to prior therapies to argue for why myotomy should be the treatment option in achalasia. Furthermore, some physicians have used the argument of patient age to discourage surgery. Ferulano et al studied the influence of age and prior conservative therapies on the short- and longterm outcomes of patients with achalasia treated by surgical myotomy. In this retrospective study, 35 patients with idiopathic achalasia who had undergone laparoscopic Heller– Dor myotomy were grouped based on age and prior therapies with PD or botulinum toxin therapy. Patient short- and long-term (5-year) outcomes were assessed by evaluation of a health-related quality-of-life instrument. The study population consisted of 20 patients ⬍70 and 15 patients ⬎70 years old who had mainly moderate to significant esophageal dilation (⬎60 mm) with near 50% having had prior therapies before undergoing surgical myotomy. The authors report 84% short-term and 77% long-term success with the procedure with a 13%–15% rate of gastroesophageal reflux disease (GERD) on pH monitoring and a 10%– 16% rate of dysphagia. Logistic regression analysis did not suggest any influence of patient outcome by age or prior therapies with prior PD or botulinum toxin. The authors concluded that treatment of idiopathic achalasia with a “laparoscopic Heller–Dor myotomy reaches [achieves] a functional recovery of the esophageal function in about 80% of patients regardless of age and previous treatments.” Comment. Achalasia therapy remains entirely palliative.

The objective of the current therapeutic options for achalasia is to reduce LES tone, relieve functional obstruction to the esophageal transit, and facilitate esophageal emptying by gravity. This goal is achieved best by either PD or

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surgical myotomy. The choice between these 2 definitive treatment options is a point of controversy. Surgeons argue that PD is “barbaric” by design; a large balloon is inflated in the LES region resulting in a “bloody balloon,” that it is indirect, uncontrolled, and less effective than surgical myotomy. They also suggest that, because of the scarring that may result from therapies such as botulinum toxin injection or PD, subsequent surgical myotomy may be less effective. However, the result of the study by Ferulnao et al argue against this contention, finding equal outcomes in their patients despite prior therapies. But why should we offer PD at all to our patients if surgery is so good? It is important to dissect each aspect of the 2 therapies and discuss the potential risks and benefits before we can answer this question. Are there differences in the effectiveness of the 2 therapies? The answer to this question cannot be answered directly because there are no large-scale, head-to-head randomized trials comparing the 2 therapies. The first randomized trial compared an old dilator (Mosher bag), which is no longer in use, to open myotomy, suggesting better outcomes in the latter group compared with dilation (Gastroenterology 1981;80:789 –795). The most recent trial compared the 12-month symptomatic outcome of patients undergoing Rigiflex dilation (n ⫽ 26) versus laparoscopic myotomy (n ⫽ 25), finding no difference between the groups by the intent-to-treat analysis (P ⫽ .09). The per protocol analysis suggested myotomy had significantly less treatment failure (P ⫽ .04). However, demographic differences between the PD and surgical myotomy groups may have confounded their results. Patients who had undergone PD were more likely to be male and have higher basal and nadir LES pressures. Because younger males have less robust response to PD (Clin Gastroenterol Hepatol 2004;2:389 –394) the findings by per protocol analysis may have been due to confounding by gender. Retrospective comparisons of the 2 modalities suggest equal efficacy in the short and long term (Dysphagia 2008;23:155–160; J Clin Gastroenterol 1998;27: 21–35). Thus, from the perspective of efficacy, data are equivocal but tend to favor myotomy if patients are younger males. How about complication differences between the 2 treatment options? The major complication associated with PD is a 2%–5% perforation risk, which could lead to surgery; surgical myotomy is complicated by development of clinically symptomatic GERD in up to 30% of patients. In the study by Ferulano et al, despite Heller– Dor fundoplication post myotomy, GERD was documented by 13%–15% of patients, who required long-term proton pump inhibitor therapy. Other potential complications of surgery may include pneumonia and wound or urinary tract infections. Given nearly equal efficacy and potential complications of the 2 modalities, one may ask which is most cost effective. In addition to previous cost-effectiveness data concluding superiority of PD over

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myotomy (Am J Gastroenterol 2005;95:2737–2745; Dig Dis Sci 2002;47:1516 –1525), the most recent study conducted by the same group that performed the only randomized trial comparing Rigiflex dilation to myotomy concluded that “the cost effectiveness of pneumatic dilation is superior” (Surg Endosc 2007;21:1184 –1189). In short, myotomy and PD have nearly equal shortand long-term outcomes; myotomy has the edge in overall complication rate, but is less cost effective. Given this scenario, the most important aspect of choosing 1 therapy over the other may be expertise of the institution at which the patient is seeking therapy. Myotomy performed by a surgeon who only does 1 or 2 cases per year is a recipe for adverse an outcome, as is PD offered by a gastroenterologist poorly trained. The suggestion that 1 therapy is superior to the other is often due to “expert” bias and not collective data in the field. Patients should have options in treating their achalasia and physicians should appropriately refer this group of patients to specialty centers with both expertise to improve patient outcome. So when it comes to treating achalasia, myopic views should be replaced by global collaborative approaches. MICHAEL F. VAEZI, MD, PHD, MS(EPI)

Reply. As surgeons dedicated to the repair of upper and lower gastrointestinal tract dysfunction, the main goal of our paper was to evaluate the influence of 2 different conditions on the surgical treatment of patients suffering from achalasia, referred to our outpatient endoscopy service. Historically, both patient age and previous nonsurgical treatments were regarded in the literature as relative contraindications to surgery. Our results did not support these contentions, provided that patients fulfilled the accepted criteria for a surgical procedure. As far as cost effectiveness is concerned (Surg Endosc 2007;21:1184 –1189), it seems that the comparison has been done between surgery and a single procedure (pneumatic dilation), but it is accepted that dilation often needs to be repeated 2–3 times to achieve a 90% shortterm success rate, which decreases to fewer than half the patients at 5 years follow-up (Am J Gastroenterol 2002; 97:1346). The literature suggests that these patients mandate a median of 2 (range, 1– 8) sessions of endoscopic dilations (Ann Surg 2002;236:750 –758), which could certainly impact the quality of life of these patients. The therapy of achalasia, whether surgical or endoscopic, should be regarded as palliative and consequently a long-term successful outcome after surgery in nearly 80% of our patients seems to be satisfying. Nevertheless, I suggest that it is best to avoid the potential to be caught in the trap of voicing the best option between the 2 very effective therapeutic options. I would like to stress that we perform surgery as well pneumatic dilation with Rigiflex balloons, but based on published literature and the analysis of our patients, I am more confident that dila-

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tion, if unsuccessful, will not alter the outcome of a subsequent myotomy. GIUSEPPE P. FERULANO, SAVERIO DILILLO, MICHELE D’AMBRA, RUGGERO LIONETTI, ROSSELLA BRUNACCINO, DOMENICO FICO, DOMENICO PELAGGI,

MD MD MD MD MD MD MD

ULCERATIVE COLITIS AND CROHN’S DISEASE GENETICS: MORE SIMILAR THAN WE THOUGHT? Fisher SA, Tremelling M, Anderson CA, et al. (Department of Medical and Molecular Genetics, King’s College London School of Medicine, London, UK; others). Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn’s disease. Nat Genet 2008;40:710 –712. Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic, inflammatory bowel diseases (IBD) with an increasing prevalence in developed countries, resulting in an enormous personal, social, and economic burden. Although the etiology of these disorders remains unknown, significant progress has been accomplished to help in our understanding of IBD pathophysiology in recent years. We now believe that IBD develops in genetically predisposed individuals owing to an abnormal recognition of microbiota antigens by certain elements and cells of the innate immunity, leading to a dysregulated immune reaction and, ultimately, resulting in bowel inflammation and injury (J Dig Dis 2007;8:171–178). The field of IBD genetics has experienced a dramatic growth since the recognition of NOD2/CARD15 as the first genetic factor conferring an increased susceptibility to develop CD (Nature 2001;411:599 – 603; Nature 2001;411: 603– 606; Lancet 2001;357:1925–1928). Although most progress in IBD had occurred in CD genetics to date, the present study reveals a number of new susceptibility genes for UC, representing a major advance for the field. In this collaborative study (Nat Genet 2008;40:710 – 712), Fisher et al focused their effort to define the main genetic factors conferring an increased susceptibility to develop UC. The authors analyzed ⬎10,000 nonsynonymous single nucleotide polymorphisms (SNPs) in a discovery cohort of 905 UC patients and 1,465 control subjects. In their initial study, they were able to identify 33 markers from 21 distinct loci associated with UC with a P-value of ⬍.001. These markers were subsequently genotyped in a second, replication cohort of 936 UC patients and 1,470 control subjects. The association with UC was replicated in 5 SNPs from 3 different loci. Finally, the authors also investigated 16 SNPs tagging 13 previ-