C 2005) Digestive Diseases and Sciences, Vol. 50, No. 11 (November 2005), pp. 2059–2062 ( DOI: 10.1007/s10620-005-3007-9
CASE REPORT
Successful Use of Phosphodiesterase Type 5 Inhibitors to Control Symptomatic Esophageal Hypercontractility: A Case Report AMIT AGRAWAL, MD, RADU TUTUIAN, MD, AMINE HILA, MD, and DONALD O. CASTELL, MD KEY WORDS: esophageal motility; chest pain; PD-5 inhibitors.
Patients with distal esophageal spasm (DES) or nutcracker esophagus (NE) traditionally receive treatment with calcium channel blockers, nitrates, or antimuscarinics. However, the results are at best variable. Sildenafil blocks the phosphodiesterase type 5 (PDE-5) enzyme that degrades cyclic guanine monophosphate (CGMP) and, thus, results in relaxation of smooth muscle (including esophagus). This drug has been shown to improve symptoms in some patients with a hypercontractile esophagus, by lowering both lower esophageal sphincter pressure and esophageal contraction amplitudes. Recently, two new PDE-5 inhibitors, vardenafil and tadalafil, have been approved for clinical use. We report a patient who presented with severe retrosternal chest pain episodes for 3 years diagnosed with highamplitude and simultaneous esophageal contractions consistent with NE and DES with complete bolus transit for liquid and viscous swallows by multichannel intraluminal impedance manometry. There was no symptom response to empiric therapy with proton pump inhibitors and H2 blockers, calcium channel blockers, nitrates, antimuscarinics, tricyclic antidepressants, and anxiolytics. The patient was then started on sildenafil and sequentially changed to vardenafil and tadalafil, with a marked decrease in chest pain episodes, distal esophageal contraction amplitude, and lower esophageal sphincter pressure (LESP) from each medication. The patient had longer and better control of the severity of his chest pain episodes with Manuscript received December 9, 2004; accepted February 1, 2005. From the Digestive Diseases Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA. Address for reprint requests: Amit Agrawal, MD, Medical University of South Carolina, Digestive Disease Center, 96 Jonathan Lucas Street, 210 Clinical Sciences Building, Charleston, South Carolina 29425;
[email protected].
tadalafil. To our knowledge, this is the first case reported comparing the effects of sildenafil, vardenafil, and tadalafil on esophageal dysmotility and symptoms. CASE REPORT A 37-year-old white man presented with daily severe retrosternal chest pain episodes (four or five episodes per day) for 3 years, often occurring at night, with a marked effect on sleep and activities of daily living. He stated that the severity of his chest pain was 10 of 10 (described below) and that these episodes were intermittent and lasted for hours, with no clear precipitating or alleviating factors. His medical history was significant only for a cholecystectomy and for chronic back pain secondary to a 15-foot fall from a ladder. He is a smoker (1.5 packs/day) but denies any alcohol or recreational drug use. He has been on pain medications (percocet and oxycontin) for chronic low back pain for about 6 months. On presentation, clinical examination revealed stable vital signs and no abnormal physical findings. Evaluation. Cardiac catheterization showed no coronary artery disease and chest x-ray showed no remarkable findings. Upper endoscopy and barium swallow revealed no abnormal findings in the esophagus. Multichannel intraluminal impedance–esophageal manometry (MII-EM) performed in our laboratory showed a mixed motility abnormality with highamplitude contractions that were intermittently simultaneous, consistent with NE and DES. There was complete bolus transit for liquid and viscous swallows. Mean distal esophageal amplitude (DEA) was 239 mm Hg with occasional contractions exceeding 500 mm Hg. An example of the baseline tracing is shown in Figure 1. Baseline LESP was 40 mm Hg, with incomplete LES relaxations (mean residual pressure, 13 mm Hg). Treatment and Course. The patient was reassured that his condition was not life-threatening. Prior to presentation, empiric antireflux therapy with proton pump inhibitors, H2 blockers, and antacids were tried, with no symptom response. Over the course of the next year, the patient was treated with nitrates, calcium channel blockers, antimuscarinics, antidepressants, and anxiolytics, with no significant improvement in the severity and
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Fig 1. Baseline multichannel intraluminal impedance–esophageal manometry tracing of two swallows showing high peristaltic contraction amplitudes (left) and simultaneous contractions (right) in the distal esophagus with normal bolus transit.
frequency of chest pain episodes. The patient was then started on sildenafil, 50 mg qhs, with a marked decrease, from four or five severe chest pain episodes down to one mild episode per day. He stated that the severity of his chest pain had decreased to 5 of 10. The symptom score was defined on a 0–10 scale, where 0 = no chest pain and 10 = the most severe pain. He was changed sequentially to vardenafil, 10 mg qd, and tadalafil, 10 mg qd, with a similar rapid and dramatic response to treatment (Table 1). There was at least 1 week off therapy between the switch from sildenafil to vardenafil and tadalfil. The patient did not complain of dysphagia, heartburn, or other side effects from any of the three medications. He was placed on each of these medications to compare the effects of the three available drugs in this class. Repeat MII-EM after 2–4 weeks of sildenafil, 50 mg qhs, vardenafil, 10 mg qhs, and tadalafil, 10 mg qd, showed the DEA decreasing from 239 mm Hg at baseline to 134, 54, and 51 mm Hg 1 hr after sildenafil, vardenafil, and tadalafil, respectively (Figure 2). The LESP decreased from 40 to 23, 8.6, and 18.9 mm Hg, after sildenafil, vardenafil, and tadalafil, respectively. Manometric improvement was reflected in the patient’s symptoms, with remission of the severity and frequency of his chest pain episodes. Bolus transit at baseline was normal; however, it became abnormal with sildenafil, vardenafil, and tadalafil (Figure 3). He stated that he had symptom relief for approximately 2 hr after 50 mg
of sildenafil, 4 hr after vardenafil, and 24 hr after tadalafil. He also reported that his symptoms had worsened during the periods when he was not taking PD-5 inhibitors.
DISCUSSION In this communication we report on the improvement in chest pain paralleled by manometric and bolus transit changes induced by currently available PD-5 inhibitors in a 37-year-old man with daily severe retrosternal chest pain episodes and manometric features of DES and NE. Given the clinical features of the chest pain and the negative cardiac workup, this patient’s complaints were considered to be associated with esophageal motility abnormalities. The lack of response to traditional therapies (nitrates, calcium channel blockers, and antimuscarinic agents) is not unusual for this condition. The positive clinical and manometric response to PD-5 inhibitors was impressive and was consistent among all currently available members of this class.
TABLE 1. COMPARISON OF MANOMETRIC FEATURES AND SYMPTOM SCORE AT PRETREATMENT AND WITH THE THREE PDE-5 INHIBITORS
LESP DEA Symptom score
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Baseline
Postsildenafil
Postvardenafil
Posttadalafil
40 239 10
23 134 5
8.6 54 5
18.9 51 3
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PD-5 INHIBITORS TO CONTROL ESOPHAGEAL HYPERCONTRACTILITY
Fig 2. Baseline DEA (average contraction amplitude in the distal esophagus of all swallows) decrease from 239 to 134, 54, and 51 mm Hg 1 hr after sildenafil, vardenafil, and tadalafil, respectively.
The use of combined MII-EM allowed simultaneous evaluation of esophageal pressures and bolus transit. The pharmacologic decrease in contraction amplitude and LESP did alter bolus transit. This was a concern since data from our laboratory suggested that higher contraction amplitudes may be required for effective bolus transit during manometric simultaneous swallows (1). Previous studies by Allen et al. (2) found that patients with higheramplitude simultaneous contractions are more likely to present with chest pain compared to patients with lower contraction amplitudes.
The rationale of using PD-5 inhibitors in the treatment of spastic/hypercontractile esophageal motility disorders is based on recent publications that have suggested that the abnormal motility of DES may be caused by defects in the nitric oxide (NO)-mediated neuromuscular signaling system. Studies in healthy volunteers by Murray et al. (11) found an increased frequency of simultaneous and high-amplitude esophageal contractions after the intravenous infusion of recombinant human hemoglobin (rHb1.1; a scavenger of nitric oxide). In five patients with DES, Konturek et al. (12) reported a significant dose-dependent elongation of the latency period for distal esophageal contractions and a decrease in the mean duration of contraction after intravenous infusion of graded doses of glyceryl trinitrate, a NO donor. While NO is a very potent extracellular smooth muscle relaxing agent, PD-5 inhibitors act at the level of intracellular signal transmission. The smooth muscle relaxation induced by these agents is a result of intracellular accumulation of cGMP, secondary to inhibiting the phosphodiesterase responsible for the degradation of this intracellular messenger. Ehrer et al. (13) were among the first investigators to report on the clinical application of PD-5 inhibitors in the treatment of hypercontractile motility abnormalities. In their study they found that sildenafil produced a decrease in both LESP and amplitude of esophageal contractions in DES patients, NE patients, and healthy volunteers. However, side effects were a major
Fig 3. Bolus transit measured by multichannel intraluminal impedance for 10 swallows at baseline and 1 hr after sildenafil, vardenafil, and tadalafil. Digestive Diseases and Sciences, Vol. 50, No. 11 (November 2005)
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limitation for many patients. Studies by Simren et al. (14) suggested that sildenafil transiently provoked a graded impairment in esophageal motility in healthy subjects. Recently, two new PD-5 inhibitors, vardenafil and tadalafil, have been FDA approved for the treatment of patients with erectile dysfunction. Although the three drugs have the same mechanism of action, the effects of tadalafil last for up to 36 hr, suggesting that this compound might provide the best coverage in patients with hypercontractile esophageal motility abnormalities. Indeed, our patient reported longer and better control of the severity of his chest pain episodes with tadalafil. Concerns about the long-term use of daily PD-5 inhibitors have prompted additional research, primarily in the urologic field. Nathan et al. performed a study showing that nightly administration of sildenafil for 9 months in 76 patients complaining of erectile dysfunction post-nerve sparing retropubic radical prostatectomy was well tolerated, without any serious adverse events (15). In this group of patients they found a low incidence of adverse events; the most commonly reported adverse events included dyspepsia (15%), headache (10%), flushing (7.5%), abnormal vision (5%), rhinitis (2.5%), and dizziness (1%). Most adverse events were transient and mild in nature. Additional reported side effects include headache (11%–15%), dyspepsia (4%–10%), back pain (3%–6%), myalgia (1%– 4%), nasal congestion (2%–3%), flushing (2%–3%), and limb pain (1%–3%). Montorsi et al. (16) performed a study showing that administration on demand of tadalafil, 20 mg, for 3 months in men complaining of erectile dysfunction post-nerve sparing retropubic radical prostatectomy was also well tolerated, without any serious adverse events. In summary, PD-5 inhibitors appear to lower LESP and esophageal contraction amplitudes and may reduce the frequency and severity of chest pain related to hypercontractile esophagus. Long-term daily PD-5 inhibitor appears to be well tolerated, without any serious adverse events. The currently available PD-5 inhibitors seem to have comparable manometric effects, with potentially longer and better symptom control with tadalafil. Further studies are warranted to evaluate the role of PD-5 inhibitors in the therapeutic armamenterium for hypercontractile esophageal motility abnormalities.
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