- Email: [email protected]
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SELECTED SUMMARIES LIN CHANG Oppenheimer Family Center for Neurobiology of Stress Department of Medicine David Geffen School of Medicine at UCLA Los Angeles, California
Reply. We appreciate the excellent summary and insightful commentary by Kim and Chang, regarding our recent paper entitled “Mindfulness training reduces the severity of irritable bowel syndrome in women: results of a randomized controlled trial” (Am J Gastroenterol 2011;106: 1678 –1688). We are in agreement with most of the authors’ points, and are grateful for the opportunity to respond. In terms of study design, we would like to clarify that the study was single-blind and that there was a longer follow-up period than was reported; data from the 6-month follow-up is currently being analyzed and will be reported separately. We agree that, although there was a trend toward improvement in quality of life at the 2-week follow-up, significant improvement did not occur until the 3-month follow-up; this time-period was chosen a priori as our primary outcome point, and our findings are, as Kim and Chang discussed, consistent with observations that beneficial effects of psychological therapies are typically demonstrated over longer follow-up periods. We also agree that including only women in our study limits our ability to generalize the usefulness of mindfulness to men with irritable bowel syndrome (IBS). However, for this feasibility study, we felt that exclusion of men was justified, given that IBS is relatively less prevalent in men, thereby leading to potentially greater difficulties in recruiting men to our study, as well as given our uncertainty regarding women’s comfort in discussing their IBS symptoms in a mixed-gender setting. Future studies should consider these factors in determining study design. We also agree that persistence and motivation are likely to be important factors in determining the success of mindfulness training, as with other interventions requiring behavioral change. Kim and Chang’s discussion of possible mechanisms of action of mindfulness in relieving IBS symptoms is of great interest and relevance to our research. In fact, in a follow-up paper published by our group, based on the same study data (J Behav Med 2011 Dec 8 [Epub ahead of print]), Garland et al explored the therapeutic mechanisms of action of mindfulness on IBS symptoms. We hypothesized that mindfulness training might target affective pain processing and catastrophic appraisals of gastrointestinal sensations. We used a theoretically grounded, multivariate path model to test therapeutic mediators of the effect of mindfulness training on IBS severity and quality of life. Study results suggest that mindfulness exerts therapeutic effects by training participants to observe their gut-related thoughts and feelings without catastrophizing or emotionally reacting to them, and to reappraise abdominal sensations in a less threatening way (eg, pressure instead of pain). Our future research agenda calls for further systematic investigation of the psychophysiologic mechanisms underlying the positive impact of mindfulness training on IBS symptoms.
GASTROENTEROLOGY Vol. 142, No. 5 SUSAN A. GAYLORD Program on Integrative Medicine Department of Physical Medicine and Rehabilitation School of Medicine The University of North Carolina at Chapel Hill Chapel Hill, North Carolina OLAFUR S. PALSSON Department of Medicine Center for Functional Gastrointestinal and Motility Disorders and Division of Gastroenterology and Hepatology School of Medicine The University of North Carolina at Chapel Hill Chapel Hill, North Carolina ERIC L. GARLAND College of Social Work Florida State University Tallahassee, Florida KETURAH R. FAUROT Program on Integrative Medicine Department of Physical Medicine and Rehabilitation School of Medicine The University of North Carolina at Chapel Hill Chapel Hill, North Carolina J. DOUGLAS MANN Department of Neurology School of Medicine The University of North Carolina at Chapel Hill Chapel Hill, North Carolina WILLIAM E. WHITEHEAD Department of Medicine Center for Functional Gastrointestinal and Motility Disorders and Division of Gastroenterology and Hepatology School of Medicine The University of North Carolina at Chapel Hill Chapel Hill, North Carolina
GASTROENTEROLOGISTS AND THE US OPIOID EPIDEMIC Dorn SD, Meek PD, Shah ND. Increasing frequency of opioid prescriptions for chronic abdominal pain in U.S. outpatient clinics. Clin Gastroenterol Hepatol 2011;9: 1078 –1085. Abdominal pain is present in approximately 10%–50% of adults based on large, epidemiologic studies (Scand J Gastroenterol Suppl 1999;231:3– 8) and is among one of the leading causes for consultation to a gastroenterologist (Am J Gastroenterol 2006;101:2128 –2138). The evaluation and management of abdominal pain has been associated with significant health care costs (Gastroenterology 2002;122:1500 –1511). Therapeutic options for abdominal pain depend on the underlying disorder and may range from proton pump inhibitor therapy for acid-peptic disorders and antispasmodics for irritable bowel syndrome to immunomodulator therapy for inflammatory bowel
May 2012
disease. Medications prescribed specifically to alleviate symptoms of abdominal pain can include nonopioid analgesic agents, including aspirin, nonsteroidal anti-inflammatory agents or cyclo-oxygenase-2 inhibitors (with the potential of causing gastrointestinal hemorrhage or aggravating peptic ulcer disease, esophagitis, and/or inflammatory bowel disease), tramadol (a central opioid agonist), tricyclic antidepressants (TCAs) and/or selective serotinin reuptake inhibitors, antiepileptic GABA analogues, topical analgesics, antispasmodics, and/or opioids. The purpose of this retrospective study was to determine national trends regarding the number of ambulatory visits for chronic abdominal pain in the United States, in addition to prescribing patterns for opioid analgesics. Chronic abdominal pain-related visits by adults in US outpatient clinics from 1997 to 2008 were identified using reason-for-visit codes from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey. Both surveys are sponsored by the National Center for Health Statistics, and collect annual data on ambulatory health care visits in the United States. Information was collected during the time period under study for up to 3 diagnoses (including 1 primary and 2 secondary) and prescribed medications. Because data were collected in 3-year time periods, the authors combined data from 4 periods that included 1997–1999, 2000 –2002, 2003–2005, and 2006 –2008. The data analysis focused on patients diagnosed with a chronic abdominal problem and ⱖ1 reason for visit code for abdominal pain, including upper and lower abdominal pain, cramping, spasms, and pain located in the liver, gallbladder, and/or biliary tract. Patients with pain related to an injury or neoplasm were excluded. In addition to demographic information, the authors collected information regarding co-occurring psychiatric disorders, visits related to substance abuse, and treatments for these disorders. To determine whether the decision to prescribe opioids was influenced by the usage of alternative management options for abdominal pain, the authors collected information specifically regarding usage of anticholinergic drugs, antispasmotic agents, and/or usage of any type of antidepressant therapy. An opioid-related visit was defined as ⱖ1 visit during which opioids were prescribed or refilled, and included the usage of tramadol. The primary outcome was the proportion of visits for abdominal pain during which time an opioid was prescribed. Between 1997 and 2008, there were ⬎55 million visits identified for chronic abdominal pain. The number of outpatient visits for chronic abdominal pain decreased over time from 14.8 million visits (95% confidence interval [CI], 12–18 million, or 2464 visits per 100,00 population) in 1997–1999 to 12.2 million visits (95% CI, 9 –16 million, or 1863 per 100,000 population) in 2006 –2008, which was highly significant (P for trend ⫽ .04). There was no change in patient demographics during the time period, including patient age, gender, or ethnicity. How-
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ever, significantly more patients were covered under private insurance from 2003 to 2005 and 2006 to 2008 compared with the earlier time periods, while the number of patients on Medicare and the uninsured population decreased (P ⬍ .01). Overall, 10% (95% CI, 8%–12%) of the total visits for chronic abdominal pain were associated with administration of an opioid analgesic. Approximately 20% of the prescriptions were administered for abdominal pain and another 20% for upper gastrointestinal disorders. The adjusted probability of visits for which an opioid was prescribed increased over time from 6% (95% CI, 3.5%– 8%) in 1997–1999 to 12% (95% CI, 7.5%–17%) in 2006 –2008 (P ⫽ .03) Opioid prescriptions were more common in 2006 –2008 (odds ratio [OR], 2.2; 95% CI, 1– 4) and among patients aged 25– 40 years (OR, 4.6; 95% CI, 1–18) and less common in the uninsured (OR, 0.1; 95% CI, 0.04 – 4) and African Americans (OR, 0.3; 95% CI, 0.1– 0.9). When the authors performed a subanalysis and removed tramadol from the list of opioid prescriptions, the percentage of opioid prescriptions increased over time, but the change was no longer significant (P ⫽ .06 comparing the first and last time periods). Comment. The use of narcotics for treatment of pain associated with neoplastic disorders has been described in the literature since the 1960s (Clin Pharmacol Ther 1966; 7:740 –751; Cancer 1971;27:842– 847). In the 1980s, the World Health Organization (WHO) published and validated guidelines for usage of analgesics to treat cancer pain, subsequently known as the “WHO analgesic ladder” (Cancer 1987;59:850 – 856). The WHO analgesic ladder recommend nonopioids with or without adjuvant therapy (including benzodiazepines, antispasmodics, and topical therapy) for mild pain followed by a trial of opioids with or without nonopioids with or without adjuvant therapy for mild to moderate pain. The findings from this article that the prevalence of opioid prescriptions more than doubled between 1997 and 2008 raise the question of whether primary care and other prescribers are using opioids earlier in the disease course than recommended by the WHO ladder, or whether the presence of other comorbid conditions, such as obesity, have increased the prevalence and severity of chronic pain. As discussed in the current article, opioid prescriptions have increased for other common chronic conditions in the United States, including musculoskeletal pain, arthritis, and headaches (Pain 2004;109:514 –519; Pain 2008;138:440 – 449). The percentage of patients using narcotics as chronic users has also been on the rise in the United States. In a large, population-based study, use of opioids among patients enrolled in 2 large health plans was assessed from 1997 to 2005. Long-term episodes were defined as usage of opioids for ⬎90 days with supply of ⱖ120 days or ⬎10 prescriptions per year. Over the study period, incident long-term use increased from 8.5 to 12.1 per 1000 at Group Health in Seattle, and changed from 6.3 to 8.6 per 1000 at Kaiser Permanente of Northern California. Prev-
1252
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alent long-term use doubled from 23.9 to 46.8 per 1000 at Group Health, and from 21.5 to 39.2 per 1000 at Kaiser Permanente during the study period. There was no change in average daily dose over the study period. The most common reason for usage was back and/or extremity pain in both populations, but chronic abdominal pain was listed as the indication for 4%– 6% of both cohorts. What does this increase in opioid prescriptions mean for the practicing gastroenterologist? Although the major side effects of these drugs include somnolence, respiratory depression, and dependence, utilization of opioids can also cause regional or generalized delays in gastrointestinal transit. The major gastrointestinal side effects associated with opioid usage include xerostomia (prevalence ⬎75%), constipation (9%– 40%), nausea (7%–28%), and vomiting, the latter associated with chronic usage. Management of opioid-induced constipation can be challenging, and has been demonstrated to have a negative impact on health-related quality of life and work productivity in this patient cohort (J Opioid Manag 2009;5:137–144). For patients not responding to treatment of constipation with dietary interventions and standard pharmacologic interventions, treatment with opioid antagonists can be attempted. A randomized, controlled trial of subcutaneous methylnaltrexone versus placebo demonstrated beneficial effects over a 2-week trial period (N Engl J Med 2008;358: 2332–2343). Low-dose naloxone has also been shown to be effective in reversing opioid-associated constipation, but can precipitate withdrawal symptoms (Pain 2000;84: 105–108). Administration of opioids has been associated with dysfunction of the entire gastrointestinal tract, from the esophagus to the rectum. The published side effects have included inhibition of relaxation of the lower esophageal sphincter, sphincter of Oddi spasm, inhibition of gastric emptying, stimulation of nonpropulsive motility in the small bowel and colon, and increase in pyloric and internal anal sphincter tone (Neurogastroenterol Motil 2004; 16:383–394). Although the use of morphine has not been shown to alter the amplitude of esophageal contractions, it has been associated with decrease in the duration and extent of lower esophageal sphincter relaxations associated with wet swallows (Gut 1985;26:802– 806). Administration of opioids paradoxically increase small bowel motility by generating bursts of contractions that resemble phase III of the migrating motor complex, an activity that can induce abdominal pain and cramping (Dig Dis Sci 1999;44:2178 –2186). Chronic usage of large doses of narcotics can induce narcotic bowel syndrome, or opioidinduced hyperalgesia. In this situation, patients on narcotics may develop tolerance and present with worsening abdominal pain, nausea, vomiting, and/or refractory constipation that can lead to further increases in the narcotic dosage. Although the increase in narcotics temporarily alleviates the pain, the pain subsequently worsens, resulting in a cycle that can only be reversed by narcotic withdrawal (Ann Intern Med 1984;101:331–334).
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Pain management has not been included in the curriculum of most gastroenterology training programs. Many gastroenterologists facing the patient with chronic pain place a referral to a pain clinic or local pain management physician, but the outcome may be more narcotic prescriptions rather than alternative therapy. However, given the increasing phenomenon of narcotic prescribing as shown by this article, we should become educated about alternative analgesics for our patients including tramadol, antidepressants, and anticonvulsants. Although tramadol binds to mu opioid receptors and is a central rather than peripheral opioid agonist, its use has not been demonstrated to significantly affect gastrointestinal function. Prior studies comparing tramadol to morphine demonstrated equivalent efficacy in pain reduction without effect on gastrointestinal transit times (Dig Dis Sci 1999; 44:1107–1116; Anesthesiology 1999;91:639 – 647). Use of antidepressants can include TCAs and/or selective serotinin reuptake inhibitors. Although the TCAs do not have a formal indication for pain management, they are assumed to have an analgesic effect by means of their action on serotonin and norepinephrine reuptake inhibitors, and may potentiate endogenous opioid release (Arch Int Med 1996;156:1047–1052). Because the major side effects associated with TCA therapy can include dry mouth, constipation, delayed gastric emptying, and sedation, it is recommended that the gastroenterologist use TCAs with the lowest side effect profiles (such as nortriptyline or desipramine), starting at the lowest available dose with gradual titration. Selective serotonin reuptake inhibitor therapy has also been shown to be useful for patients with diabetic neuropathy and fibromyalgia. The efficacy of selective serotonin reuptake inhibitor therapy for treatment of pain associated with irritable bowel syndrome has been mixed, however, with some studies suggesting benefit (Am J Gastroenterol 2004;99:914 –920; Aliment Pharmacol Ther 2005;22:381–385) compared with no effect in others, particularly among patients without clinical depression (Clin Gastroenterol Hepatol 2010;8:42– 48). Antiepileptic medications have been used for pain management successfully for patients with neuropathic pain conditions and include gabapentin and pregabalin. In a small study of patients with diarrhea-predominant irritable bowel syndrome, the threshold pressures for bloating, discomfort and pain significantly increased after gabapentin, but not after placebo (Aliment Pharmacol Ther 2005;22:981–988). With all of these alternative therapies, patients should be advised that it may take days to weeks for the analgesic effect, and they should be encouraged to follow up with their gastroenterologist or primary care physician for dose titration. Other agents to use include antispasmodics and topical agents for localized pain, including 5% lidocaine patch (Drugs 2004;64:937–947). In my Gastroenterology clinic at Stanford, I have often, but not always, been successful in the management of patients with chronic abdominal pain and the use of alternative medical therapies. It is often useful for the patient to receive a full explanation of why narcotics
May 2012
might worsen or cause their underlying symptoms. For patients refusing to stop these agents, management of their underlying motility disorders can be challenging, and a referral to a pain clinic should be considered for alternative therapies other than narcotics. It is important that a team approach be utilized so that all of a patient’s health care providers can be involved, particularly when patients visit other health care facilities with narcoticseeking behavior. We as gastroenterologists can provide a valuable service for our patients by educating them about the detriments to the gastrointestinal system associated with chronic narcotic abuse. LAUREN B. GERSON Department of Medicine and Division of Gastroenterology Stanford University School of Medicine Stanford, California
INTERFERON-FREE ORAL THERAPY FOR HEPATITIS C: “FARAWAY, SO CLOSE!” Chayama K, Takahashi S, Toyota J, et al. Dual therapy with the NS5A inhibitor BMS-790052 and the NS3 protease inhibitor BMS-650032 in HCV genotype 1b-infected null responders. Hepatology 2011;55:742–748. Recent advances in the understanding of the hepatitis C virus (HCV) life cycle coupled with the development of HCV culture systems have dramatically changed the landscape of treatment of chronic hepatitis C (J Hepatol 2009; 51:939 –948; Hepatology 2006;43[Suppl 1]:S207–220), as the first 2 directly acting antiviral (DAA) agents, telaprevir and boceprevir, were approved by the FDA in 2011 for the treatment of HCV genotype 1 in combination with pegylated interferon (PegIFN) and ribavirin (Rbv; Hepatology 201;54:1433–1444). Both are linear, peptidomimetic inhibitors of the NS3 protease, a key protein in the HCV life cycle, but they are not appropriate for monotherapy owing to rapid selection of resistant variants (Gastroenterology 2006;131:997–1002; Hepatology 2009;50:1709 –1718). Therefore, the backbone antiviral effect of the former standard of care therapy, PegIFN plus Rbv, remains key to achieving sustained virologic response (SVR). Although this new triple therapy regimen increases SVR rates to about 67%–73% in HCV-1 patients naïve to therapy (N Engl J Med 2011;364:2405–2416; N Engl J Med 2011; 364:1195–1206), telaprevir is associated with development of skin rash, boceprevir with ageusia, and both DAAs with more pronounced anemia in addition to the adverse events commonly associated with PegIFN plus Rbv. Therefore, the development of an IFN-free, possibly all oral, regimen with an improved adverse event profile is the next major goal of HCV therapy. This ambitious aim is possible owing to the plethora of DAAs targeting HCV cell-cycle enzymes other than the NS3 protease, such as the NS5A complex, the NS5B polymerase or cyclophillin, which are currently in phase II–III development (Hepatology 2011;53:1742–1751). Although several small studies
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analyzing the combination of these drugs and an NS3 protease inhibitor have shown promising results in terms of HCV RNA decline and safety (Lancet 2010;376:1467– 1475; Gastroenterology 2011;141:2047–2055; Hepatology 2011;55:742–748), most have just evaluated 2– 4 weeks of the IFN-free regimen without providing evidence of SVR. The first article to report SVR rates in HCV-1 patients receiving an all-oral, IFN-free regimen is the study by Chayama et al, from the University of Hiroshima in Japan (Hepatology 2011;55:742–748). In this phase IIa, open-label study, 10 HCV-1b patients with a previous null response (⬍2 log10 reduction of HCV RNA after 12 weeks) to PegIFN and Rbv, received 24 weeks of dual treatment with the NS5A replication complex inhibitor BMS-790052 (60 mg once daily) and the NS3 protease inhibitor BMS-650032 (600 mg twice daily). Excluded were patients with cirrhosis, co-infection with other viruses, and those taking medications known to be inducers or inhibitors of the cytochrome P450/3A4. During the study, BMS-650032 dosing had to be reduced to 200 mg twice a day after reports of hepatic enzyme elevations in a clinical study of BMS-650032 and PegIFN/Rbv. Nine patients (90%) were able to complete the scheduled 24 weeks of therapy; in 1 case, treatment had to be discontinued after 2 weeks for occurrence of grade 4 total bilirubin elevation. The mean decrease in serum HCV RNA at weeks 2 and 4 was 5.3 and 5.8 log10 IU/mL, respectively, with week 4 serum HCV RNA being under the limit of quantification of the assay (15 IU/mL) in 9 patients (90%) and undetectable in 4 (40%). Nine patients (90%) achieved the primary end point, which was HCV RNA undetectability 12 weeks after treatment completion (SVR12), and remained negative at week 24 of follow-up (SVR24). Although the patient who discontinued treatment at week 2 was counted as a treatment failure, she also achieved SVR12 and SVR24, ultimately meaning a 100% SVR12 and SVR24 was observed in the study. In terms of safety, most adverse events were mild, with diarrhea (70%) and headache (40%) being the most commonly reported. Two serious adverse events (SAEs) were reported: 1 patient was hospitalized with grade 3 pyrexia and diarrhea and another patient, a 60-year-old woman with ulcerative colitis, was hospitalized with grade 4 bilirubin elevation and gastroenteritis and was treated with meropenem, serum albumin infusions, and diuretics. Based on these results, the authors conclude that the 24 weeks of combination therapy with 2 DAAs (BMS-790052 and BMS-650032) in HCV-1b null responders achieves high SVR24 rates, reinforcing the concept that HCV infection can be “cured” without PegIFN/Rbv. Comment. The development of an oral IFN-free regimen for chronic hepatitis C has been hailed by some as the “holy grail” of anti-HCV therapy, providing HCV patients with a more tolerable and “user-friendly” antiviral regimen. It would also allow treatment of patients contraindicated or intolerant to IFN. Clearly, the benefits of an IFN-free regimen are many, but the challenges to get there are substantial.
SELECTED SUMMARIES LIN CHANG Oppenheimer Family Center for Neurobiology of Stress Department of Medicine David Geffen School of Medicine at UCLA Los Angeles, California
Reply. We appreciate the excellent summary and insightful commentary by Kim and Chang, regarding our recent paper entitled “Mindfulness training reduces the severity of irritable bowel syndrome in women: results of a randomized controlled trial” (Am J Gastroenterol 2011;106: 1678 –1688). We are in agreement with most of the authors’ points, and are grateful for the opportunity to respond. In terms of study design, we would like to clarify that the study was single-blind and that there was a longer follow-up period than was reported; data from the 6-month follow-up is currently being analyzed and will be reported separately. We agree that, although there was a trend toward improvement in quality of life at the 2-week follow-up, significant improvement did not occur until the 3-month follow-up; this time-period was chosen a priori as our primary outcome point, and our findings are, as Kim and Chang discussed, consistent with observations that beneficial effects of psychological therapies are typically demonstrated over longer follow-up periods. We also agree that including only women in our study limits our ability to generalize the usefulness of mindfulness to men with irritable bowel syndrome (IBS). However, for this feasibility study, we felt that exclusion of men was justified, given that IBS is relatively less prevalent in men, thereby leading to potentially greater difficulties in recruiting men to our study, as well as given our uncertainty regarding women’s comfort in discussing their IBS symptoms in a mixed-gender setting. Future studies should consider these factors in determining study design. We also agree that persistence and motivation are likely to be important factors in determining the success of mindfulness training, as with other interventions requiring behavioral change. Kim and Chang’s discussion of possible mechanisms of action of mindfulness in relieving IBS symptoms is of great interest and relevance to our research. In fact, in a follow-up paper published by our group, based on the same study data (J Behav Med 2011 Dec 8 [Epub ahead of print]), Garland et al explored the therapeutic mechanisms of action of mindfulness on IBS symptoms. We hypothesized that mindfulness training might target affective pain processing and catastrophic appraisals of gastrointestinal sensations. We used a theoretically grounded, multivariate path model to test therapeutic mediators of the effect of mindfulness training on IBS severity and quality of life. Study results suggest that mindfulness exerts therapeutic effects by training participants to observe their gut-related thoughts and feelings without catastrophizing or emotionally reacting to them, and to reappraise abdominal sensations in a less threatening way (eg, pressure instead of pain). Our future research agenda calls for further systematic investigation of the psychophysiologic mechanisms underlying the positive impact of mindfulness training on IBS symptoms.
GASTROENTEROLOGY Vol. 142, No. 5 SUSAN A. GAYLORD Program on Integrative Medicine Department of Physical Medicine and Rehabilitation School of Medicine The University of North Carolina at Chapel Hill Chapel Hill, North Carolina OLAFUR S. PALSSON Department of Medicine Center for Functional Gastrointestinal and Motility Disorders and Division of Gastroenterology and Hepatology School of Medicine The University of North Carolina at Chapel Hill Chapel Hill, North Carolina ERIC L. GARLAND College of Social Work Florida State University Tallahassee, Florida KETURAH R. FAUROT Program on Integrative Medicine Department of Physical Medicine and Rehabilitation School of Medicine The University of North Carolina at Chapel Hill Chapel Hill, North Carolina J. DOUGLAS MANN Department of Neurology School of Medicine The University of North Carolina at Chapel Hill Chapel Hill, North Carolina WILLIAM E. WHITEHEAD Department of Medicine Center for Functional Gastrointestinal and Motility Disorders and Division of Gastroenterology and Hepatology School of Medicine The University of North Carolina at Chapel Hill Chapel Hill, North Carolina
GASTROENTEROLOGISTS AND THE US OPIOID EPIDEMIC Dorn SD, Meek PD, Shah ND. Increasing frequency of opioid prescriptions for chronic abdominal pain in U.S. outpatient clinics. Clin Gastroenterol Hepatol 2011;9: 1078 –1085. Abdominal pain is present in approximately 10%–50% of adults based on large, epidemiologic studies (Scand J Gastroenterol Suppl 1999;231:3– 8) and is among one of the leading causes for consultation to a gastroenterologist (Am J Gastroenterol 2006;101:2128 –2138). The evaluation and management of abdominal pain has been associated with significant health care costs (Gastroenterology 2002;122:1500 –1511). Therapeutic options for abdominal pain depend on the underlying disorder and may range from proton pump inhibitor therapy for acid-peptic disorders and antispasmodics for irritable bowel syndrome to immunomodulator therapy for inflammatory bowel
May 2012
disease. Medications prescribed specifically to alleviate symptoms of abdominal pain can include nonopioid analgesic agents, including aspirin, nonsteroidal anti-inflammatory agents or cyclo-oxygenase-2 inhibitors (with the potential of causing gastrointestinal hemorrhage or aggravating peptic ulcer disease, esophagitis, and/or inflammatory bowel disease), tramadol (a central opioid agonist), tricyclic antidepressants (TCAs) and/or selective serotinin reuptake inhibitors, antiepileptic GABA analogues, topical analgesics, antispasmodics, and/or opioids. The purpose of this retrospective study was to determine national trends regarding the number of ambulatory visits for chronic abdominal pain in the United States, in addition to prescribing patterns for opioid analgesics. Chronic abdominal pain-related visits by adults in US outpatient clinics from 1997 to 2008 were identified using reason-for-visit codes from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey. Both surveys are sponsored by the National Center for Health Statistics, and collect annual data on ambulatory health care visits in the United States. Information was collected during the time period under study for up to 3 diagnoses (including 1 primary and 2 secondary) and prescribed medications. Because data were collected in 3-year time periods, the authors combined data from 4 periods that included 1997–1999, 2000 –2002, 2003–2005, and 2006 –2008. The data analysis focused on patients diagnosed with a chronic abdominal problem and ⱖ1 reason for visit code for abdominal pain, including upper and lower abdominal pain, cramping, spasms, and pain located in the liver, gallbladder, and/or biliary tract. Patients with pain related to an injury or neoplasm were excluded. In addition to demographic information, the authors collected information regarding co-occurring psychiatric disorders, visits related to substance abuse, and treatments for these disorders. To determine whether the decision to prescribe opioids was influenced by the usage of alternative management options for abdominal pain, the authors collected information specifically regarding usage of anticholinergic drugs, antispasmotic agents, and/or usage of any type of antidepressant therapy. An opioid-related visit was defined as ⱖ1 visit during which opioids were prescribed or refilled, and included the usage of tramadol. The primary outcome was the proportion of visits for abdominal pain during which time an opioid was prescribed. Between 1997 and 2008, there were ⬎55 million visits identified for chronic abdominal pain. The number of outpatient visits for chronic abdominal pain decreased over time from 14.8 million visits (95% confidence interval [CI], 12–18 million, or 2464 visits per 100,00 population) in 1997–1999 to 12.2 million visits (95% CI, 9 –16 million, or 1863 per 100,000 population) in 2006 –2008, which was highly significant (P for trend ⫽ .04). There was no change in patient demographics during the time period, including patient age, gender, or ethnicity. How-
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ever, significantly more patients were covered under private insurance from 2003 to 2005 and 2006 to 2008 compared with the earlier time periods, while the number of patients on Medicare and the uninsured population decreased (P ⬍ .01). Overall, 10% (95% CI, 8%–12%) of the total visits for chronic abdominal pain were associated with administration of an opioid analgesic. Approximately 20% of the prescriptions were administered for abdominal pain and another 20% for upper gastrointestinal disorders. The adjusted probability of visits for which an opioid was prescribed increased over time from 6% (95% CI, 3.5%– 8%) in 1997–1999 to 12% (95% CI, 7.5%–17%) in 2006 –2008 (P ⫽ .03) Opioid prescriptions were more common in 2006 –2008 (odds ratio [OR], 2.2; 95% CI, 1– 4) and among patients aged 25– 40 years (OR, 4.6; 95% CI, 1–18) and less common in the uninsured (OR, 0.1; 95% CI, 0.04 – 4) and African Americans (OR, 0.3; 95% CI, 0.1– 0.9). When the authors performed a subanalysis and removed tramadol from the list of opioid prescriptions, the percentage of opioid prescriptions increased over time, but the change was no longer significant (P ⫽ .06 comparing the first and last time periods). Comment. The use of narcotics for treatment of pain associated with neoplastic disorders has been described in the literature since the 1960s (Clin Pharmacol Ther 1966; 7:740 –751; Cancer 1971;27:842– 847). In the 1980s, the World Health Organization (WHO) published and validated guidelines for usage of analgesics to treat cancer pain, subsequently known as the “WHO analgesic ladder” (Cancer 1987;59:850 – 856). The WHO analgesic ladder recommend nonopioids with or without adjuvant therapy (including benzodiazepines, antispasmodics, and topical therapy) for mild pain followed by a trial of opioids with or without nonopioids with or without adjuvant therapy for mild to moderate pain. The findings from this article that the prevalence of opioid prescriptions more than doubled between 1997 and 2008 raise the question of whether primary care and other prescribers are using opioids earlier in the disease course than recommended by the WHO ladder, or whether the presence of other comorbid conditions, such as obesity, have increased the prevalence and severity of chronic pain. As discussed in the current article, opioid prescriptions have increased for other common chronic conditions in the United States, including musculoskeletal pain, arthritis, and headaches (Pain 2004;109:514 –519; Pain 2008;138:440 – 449). The percentage of patients using narcotics as chronic users has also been on the rise in the United States. In a large, population-based study, use of opioids among patients enrolled in 2 large health plans was assessed from 1997 to 2005. Long-term episodes were defined as usage of opioids for ⬎90 days with supply of ⱖ120 days or ⬎10 prescriptions per year. Over the study period, incident long-term use increased from 8.5 to 12.1 per 1000 at Group Health in Seattle, and changed from 6.3 to 8.6 per 1000 at Kaiser Permanente of Northern California. Prev-
1252
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alent long-term use doubled from 23.9 to 46.8 per 1000 at Group Health, and from 21.5 to 39.2 per 1000 at Kaiser Permanente during the study period. There was no change in average daily dose over the study period. The most common reason for usage was back and/or extremity pain in both populations, but chronic abdominal pain was listed as the indication for 4%– 6% of both cohorts. What does this increase in opioid prescriptions mean for the practicing gastroenterologist? Although the major side effects of these drugs include somnolence, respiratory depression, and dependence, utilization of opioids can also cause regional or generalized delays in gastrointestinal transit. The major gastrointestinal side effects associated with opioid usage include xerostomia (prevalence ⬎75%), constipation (9%– 40%), nausea (7%–28%), and vomiting, the latter associated with chronic usage. Management of opioid-induced constipation can be challenging, and has been demonstrated to have a negative impact on health-related quality of life and work productivity in this patient cohort (J Opioid Manag 2009;5:137–144). For patients not responding to treatment of constipation with dietary interventions and standard pharmacologic interventions, treatment with opioid antagonists can be attempted. A randomized, controlled trial of subcutaneous methylnaltrexone versus placebo demonstrated beneficial effects over a 2-week trial period (N Engl J Med 2008;358: 2332–2343). Low-dose naloxone has also been shown to be effective in reversing opioid-associated constipation, but can precipitate withdrawal symptoms (Pain 2000;84: 105–108). Administration of opioids has been associated with dysfunction of the entire gastrointestinal tract, from the esophagus to the rectum. The published side effects have included inhibition of relaxation of the lower esophageal sphincter, sphincter of Oddi spasm, inhibition of gastric emptying, stimulation of nonpropulsive motility in the small bowel and colon, and increase in pyloric and internal anal sphincter tone (Neurogastroenterol Motil 2004; 16:383–394). Although the use of morphine has not been shown to alter the amplitude of esophageal contractions, it has been associated with decrease in the duration and extent of lower esophageal sphincter relaxations associated with wet swallows (Gut 1985;26:802– 806). Administration of opioids paradoxically increase small bowel motility by generating bursts of contractions that resemble phase III of the migrating motor complex, an activity that can induce abdominal pain and cramping (Dig Dis Sci 1999;44:2178 –2186). Chronic usage of large doses of narcotics can induce narcotic bowel syndrome, or opioidinduced hyperalgesia. In this situation, patients on narcotics may develop tolerance and present with worsening abdominal pain, nausea, vomiting, and/or refractory constipation that can lead to further increases in the narcotic dosage. Although the increase in narcotics temporarily alleviates the pain, the pain subsequently worsens, resulting in a cycle that can only be reversed by narcotic withdrawal (Ann Intern Med 1984;101:331–334).
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Pain management has not been included in the curriculum of most gastroenterology training programs. Many gastroenterologists facing the patient with chronic pain place a referral to a pain clinic or local pain management physician, but the outcome may be more narcotic prescriptions rather than alternative therapy. However, given the increasing phenomenon of narcotic prescribing as shown by this article, we should become educated about alternative analgesics for our patients including tramadol, antidepressants, and anticonvulsants. Although tramadol binds to mu opioid receptors and is a central rather than peripheral opioid agonist, its use has not been demonstrated to significantly affect gastrointestinal function. Prior studies comparing tramadol to morphine demonstrated equivalent efficacy in pain reduction without effect on gastrointestinal transit times (Dig Dis Sci 1999; 44:1107–1116; Anesthesiology 1999;91:639 – 647). Use of antidepressants can include TCAs and/or selective serotinin reuptake inhibitors. Although the TCAs do not have a formal indication for pain management, they are assumed to have an analgesic effect by means of their action on serotonin and norepinephrine reuptake inhibitors, and may potentiate endogenous opioid release (Arch Int Med 1996;156:1047–1052). Because the major side effects associated with TCA therapy can include dry mouth, constipation, delayed gastric emptying, and sedation, it is recommended that the gastroenterologist use TCAs with the lowest side effect profiles (such as nortriptyline or desipramine), starting at the lowest available dose with gradual titration. Selective serotonin reuptake inhibitor therapy has also been shown to be useful for patients with diabetic neuropathy and fibromyalgia. The efficacy of selective serotonin reuptake inhibitor therapy for treatment of pain associated with irritable bowel syndrome has been mixed, however, with some studies suggesting benefit (Am J Gastroenterol 2004;99:914 –920; Aliment Pharmacol Ther 2005;22:381–385) compared with no effect in others, particularly among patients without clinical depression (Clin Gastroenterol Hepatol 2010;8:42– 48). Antiepileptic medications have been used for pain management successfully for patients with neuropathic pain conditions and include gabapentin and pregabalin. In a small study of patients with diarrhea-predominant irritable bowel syndrome, the threshold pressures for bloating, discomfort and pain significantly increased after gabapentin, but not after placebo (Aliment Pharmacol Ther 2005;22:981–988). With all of these alternative therapies, patients should be advised that it may take days to weeks for the analgesic effect, and they should be encouraged to follow up with their gastroenterologist or primary care physician for dose titration. Other agents to use include antispasmodics and topical agents for localized pain, including 5% lidocaine patch (Drugs 2004;64:937–947). In my Gastroenterology clinic at Stanford, I have often, but not always, been successful in the management of patients with chronic abdominal pain and the use of alternative medical therapies. It is often useful for the patient to receive a full explanation of why narcotics
May 2012
might worsen or cause their underlying symptoms. For patients refusing to stop these agents, management of their underlying motility disorders can be challenging, and a referral to a pain clinic should be considered for alternative therapies other than narcotics. It is important that a team approach be utilized so that all of a patient’s health care providers can be involved, particularly when patients visit other health care facilities with narcoticseeking behavior. We as gastroenterologists can provide a valuable service for our patients by educating them about the detriments to the gastrointestinal system associated with chronic narcotic abuse. LAUREN B. GERSON Department of Medicine and Division of Gastroenterology Stanford University School of Medicine Stanford, California
INTERFERON-FREE ORAL THERAPY FOR HEPATITIS C: “FARAWAY, SO CLOSE!” Chayama K, Takahashi S, Toyota J, et al. Dual therapy with the NS5A inhibitor BMS-790052 and the NS3 protease inhibitor BMS-650032 in HCV genotype 1b-infected null responders. Hepatology 2011;55:742–748. Recent advances in the understanding of the hepatitis C virus (HCV) life cycle coupled with the development of HCV culture systems have dramatically changed the landscape of treatment of chronic hepatitis C (J Hepatol 2009; 51:939 –948; Hepatology 2006;43[Suppl 1]:S207–220), as the first 2 directly acting antiviral (DAA) agents, telaprevir and boceprevir, were approved by the FDA in 2011 for the treatment of HCV genotype 1 in combination with pegylated interferon (PegIFN) and ribavirin (Rbv; Hepatology 201;54:1433–1444). Both are linear, peptidomimetic inhibitors of the NS3 protease, a key protein in the HCV life cycle, but they are not appropriate for monotherapy owing to rapid selection of resistant variants (Gastroenterology 2006;131:997–1002; Hepatology 2009;50:1709 –1718). Therefore, the backbone antiviral effect of the former standard of care therapy, PegIFN plus Rbv, remains key to achieving sustained virologic response (SVR). Although this new triple therapy regimen increases SVR rates to about 67%–73% in HCV-1 patients naïve to therapy (N Engl J Med 2011;364:2405–2416; N Engl J Med 2011; 364:1195–1206), telaprevir is associated with development of skin rash, boceprevir with ageusia, and both DAAs with more pronounced anemia in addition to the adverse events commonly associated with PegIFN plus Rbv. Therefore, the development of an IFN-free, possibly all oral, regimen with an improved adverse event profile is the next major goal of HCV therapy. This ambitious aim is possible owing to the plethora of DAAs targeting HCV cell-cycle enzymes other than the NS3 protease, such as the NS5A complex, the NS5B polymerase or cyclophillin, which are currently in phase II–III development (Hepatology 2011;53:1742–1751). Although several small studies
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analyzing the combination of these drugs and an NS3 protease inhibitor have shown promising results in terms of HCV RNA decline and safety (Lancet 2010;376:1467– 1475; Gastroenterology 2011;141:2047–2055; Hepatology 2011;55:742–748), most have just evaluated 2– 4 weeks of the IFN-free regimen without providing evidence of SVR. The first article to report SVR rates in HCV-1 patients receiving an all-oral, IFN-free regimen is the study by Chayama et al, from the University of Hiroshima in Japan (Hepatology 2011;55:742–748). In this phase IIa, open-label study, 10 HCV-1b patients with a previous null response (⬍2 log10 reduction of HCV RNA after 12 weeks) to PegIFN and Rbv, received 24 weeks of dual treatment with the NS5A replication complex inhibitor BMS-790052 (60 mg once daily) and the NS3 protease inhibitor BMS-650032 (600 mg twice daily). Excluded were patients with cirrhosis, co-infection with other viruses, and those taking medications known to be inducers or inhibitors of the cytochrome P450/3A4. During the study, BMS-650032 dosing had to be reduced to 200 mg twice a day after reports of hepatic enzyme elevations in a clinical study of BMS-650032 and PegIFN/Rbv. Nine patients (90%) were able to complete the scheduled 24 weeks of therapy; in 1 case, treatment had to be discontinued after 2 weeks for occurrence of grade 4 total bilirubin elevation. The mean decrease in serum HCV RNA at weeks 2 and 4 was 5.3 and 5.8 log10 IU/mL, respectively, with week 4 serum HCV RNA being under the limit of quantification of the assay (15 IU/mL) in 9 patients (90%) and undetectable in 4 (40%). Nine patients (90%) achieved the primary end point, which was HCV RNA undetectability 12 weeks after treatment completion (SVR12), and remained negative at week 24 of follow-up (SVR24). Although the patient who discontinued treatment at week 2 was counted as a treatment failure, she also achieved SVR12 and SVR24, ultimately meaning a 100% SVR12 and SVR24 was observed in the study. In terms of safety, most adverse events were mild, with diarrhea (70%) and headache (40%) being the most commonly reported. Two serious adverse events (SAEs) were reported: 1 patient was hospitalized with grade 3 pyrexia and diarrhea and another patient, a 60-year-old woman with ulcerative colitis, was hospitalized with grade 4 bilirubin elevation and gastroenteritis and was treated with meropenem, serum albumin infusions, and diuretics. Based on these results, the authors conclude that the 24 weeks of combination therapy with 2 DAAs (BMS-790052 and BMS-650032) in HCV-1b null responders achieves high SVR24 rates, reinforcing the concept that HCV infection can be “cured” without PegIFN/Rbv. Comment. The development of an oral IFN-free regimen for chronic hepatitis C has been hailed by some as the “holy grail” of anti-HCV therapy, providing HCV patients with a more tolerable and “user-friendly” antiviral regimen. It would also allow treatment of patients contraindicated or intolerant to IFN. Clearly, the benefits of an IFN-free regimen are many, but the challenges to get there are substantial.