Professional Documents
Culture Documents
Nitrates
Nitrates are one of the earliest agents used to treat esophageal spasm.
These medications are potent relaxants of gastrointestinal smooth muscle
through the stimulation of cyclic guanosine monophosphate-dependent
pathway.44 In 1973, Orlando and Bozymski45 showed that nitrates
effectively reduced manometric findings and symptoms in a patient
suffering from DES. Since that original observation, several trials have
addressed the efficacy of nitrates in the treatment of DES. Table 3
summarizes the published data.
The published experience with these agents is limited to 51 patients. No
placebo-controlled trials have been completed (studies were all open
label). However, most authors describe symptomatic improvement after
primarily short-term studies, and, in some trials, long-term use. These
uncontrolled clinical observations suggest that nitrates induce chest pain
relief in selected patients with DES. However, side effects such as
headaches and hypotension may limit their use. It is also possible that
tachyphilaxis may develop. Administration every 6-12 hours may de-
crease the likelihood of this problem.44 There is no available information
regarding the effect of these compounds in patients with motility
disorders, other than DES.
The Role of NO
NO is an inhibitory neurotransmitter in the gastrointestinal tract.51 In
the smooth circular muscle of the human esophagus, it regulates the
latency gradient and the contraction amplitude of esophageal peristalsis.52
Elegant studies by Murray and coworkers53 and Konturek and cowork-
ers50,54 have shown that the experimental removal of NO in humans
induces a pattern of simultaneous contractions similar to DES. Therefore,
DM, September 2008 653
pharmacologic agents that result in the augmentation of NO may improve
the clinical and manometric patterns of patients with diffuse esophageal
spasm.
Glyceryl trinitrate (GTN) is a donor of NO.55 Acute (intravenous
administration in humans) of GTN produced a dose-dependent elon-
gation of peristalsis and duration of esophageal contractions accom-
panied by a significant improvement in symptoms in DES.50 L-
arginine is a basic, semi-essential amino acid that acts as a substrate
for the synthesis of NO. Bortolotti and coworkers56 found that
L-arginine IV did not affect esophageal peristalsis or LES parameters.
However, during a small, double-blind, crossover trial with each phase
(placebo or drug) lasting 6 weeks, oral administration (30 mL of a 10%
L-arginine solution tid versus placebo) induced chest pain improve-
ment in eight patients with spastic esophageal motility (DES, n ⫽ 3;
NE, n ⫽ 5). No side effects were reported. These observations suggest
that spastic disorders of the esophagus that may cause NCCP, such as
DES, may be due to either a dysfunctional L-arginine/NO system or a
deficient nitrergic system.
Phosphodiesterase Inhibitors
Phosphodiesterase-5 (PD-5) is an important modulator of smooth
muscle contraction. Both human and animal studies show that it regulates
esophageal contraction amplitude by increasing the availability of
NO.52-54 There are three commercially available PD-5 inhibitors: silde-
nafil, vardenafil, and tadalafil.
Several investigators have studied the effects of sildenafil in humans.
Overall, these studies indicate that sildenafil markedly inhibits the motor
activity of the esophageal musculature by decreasing LES pressure, wave
amplitude, and propagation velocity and increasing the onset latency of
pressure waves.57 It has also been shown to decrease esophageal bolus
transit and esophageal amplitude but have no effect on gastro-esophageal
reflux parameters.58,59 These studies suggest that this and related com-
pounds may have a beneficial effect in patients with spastic motility
disorders.
In a study of 11 patients with a variety of spastic motility disorders [NE,
n ⫽ 4; DES, n ⫽ 1; hypertensive LES (HLES), n ⫽ 3; achalasia, n ⫽ 3],
sildenafil improved the manometric pattern in 9 of 11 patients with
hypercontractile esophageal motility; however, only 4 of these patients
reported symptomatic improvement, and 2 of these 4 discontinued drug
therapy due to side effects.60 Agrawal and coworkers61 reported a case of
a patient with NCCP who at manometry showed simultaneous features of
654 DM, September 2008
NE and DES. The patient’s symptoms and motility pattern improved with
the use of all 3 available PD-5 inhibitors. Following acute administration
of sildenafil 50 mg versus placebo in a random, double-blinded trial,
sildenafil inhibited the LES tone and pressure wave amplitude of 7
patients with symptomatic HLES.62 No long-term or controlled trials are
available. These observations suggest that these agents deserve further
study in patients with NCCP.
Anticholinergic Agents
Cholinergic (muscarinic) innervation plays an important role in esoph-
ageal peristalsis and LES activity.63 Using cimetropium bromide (10 mg
IV)63 in a single-blind design, eight patients with NE and similar control
subjects had significant reduction of distal esophageal amplitude and LES
pressures. However, the effects of this agent on clinical symptoms have
not been studied. There are no other clinical trials supporting the use of
muscarinic blocking agents for the treatment of patients with painful
esophageal motility. Side effects, such as dry mouth and tachycardia, may
limit their use. The role of new muscarinic receptor antagonist with
specific selectivity remains to be evaluated.
Calcium Blockers
Calcium is a mediator of esophageal muscle contraction.64 In animal
studies, interference with calcium entry at the cellular level leads to
decreased LES pressure and esophageal contractions.65,66
Nifedipine
Nifedipine has been shown to decrease the frequency and amplitude of
nonperistaltic esophageal contraction in healthy subjects.67 Clinical
experience in the treatment of esophageal motility remains limited. Table 4
provides a summary of therapeutic trials in patients with DES.
In contrast to achalasia, where several investigators have examined the
effects of nifedipine, there is more limited information about the effects
of this drug in non-achalasia-related motility disorders other than DES.
Traube and coworkers74 studied the esophageal effects of nifedipine in
nine patients with high-amplitude peristaltic esophageal contractions (NE,
20 mg orally). Nifedipine decreased LES pressure by approximately 50%
and contraction amplitude in the body of the esophagus by approximately
25%. The effects of the drug on symptoms were not evaluated. Richter
and coworkers36 completed the only controlled trial of nifedipine in
patients with NE. Twenty patients received oral nifedipine (10-30 mg tid)
or placebo during a 14-week crossover study. Despite a statistically
DM, September 2008 655
TABLE 4. Nifedipine trials in diffuse esophageal spasm*
Author (Ref.) Year Study Design N Dose Outcome
Blackwell et al. (67) 1981 Open label 6 20 mg tid 3/6 improved
Davies et al. (68) 1982 Double-blind, 10 10-40 mg tid Short-term improvement
placebo
Nasrallah et al. (69) 1982 Open-label 1 10 mg tid Improved
Nasrallah et al. (70) 1985 Open-label 4 10 mg tid Improved
Thomas et al. (71) 1986 Open-label 6 10-20 mg tid Improvement of
dysphagia
Davies et al. (72) 1987 Placebo-controlled 8 10-30 mg tid No response (treatment
(a single and a (mean 64 for up to 3 months)
double-blinded mg)
phase)
Banciu et al. (73) 1990 Open-label 12† 10-20 mg Acute “improvement of
radiologic
appearance”
*Modified from Achem SR. Treatment of spastic esophageal motility disorders. Gastroenterol
Clin North Am 2004;33(1):107-24.37
†Patients defined radiologically.
Diltiazem
Richter and coworkers75 examined the effects of diltiazem (90, 120, or
150 mg orally) in healthy controls and found no effect on distal
esophageal contractions. The clinical effects of this calcium blocker have
been examined in two clinical studies in patients with NE and in a small
study of patients with DES (Table 5). These studies show that, despite
improvement in NE, studies involved very small number of patients. No
beneficial effects were observed in the few patients (n ⫽ 8) with DES
(Table 5).
Benzodiazepines
Benzodiazepines amplify gamma-aminobutyric acid throughout the
central nervous system and act more peripherally to reduce cat-
echolamines. Huffman and Stern suggest that these agents could be used
in the emergency room setting to treat NCCP, provided they are used on
a short-term basis in order to decrease the rate of dependency.114 Few
studies and of very small sample size have been done with these
agents.115 In a non-blind, 8-week trial of alprazolam in patients present-
ing with chest pain and panic disorder, 15 of 20 improved by 50% or
greater reduction in panic frequency. However, patients experienced only
a modest drop in episodes of chest pain or discomfort.116
A small, placebo-controlled, double-blind, flexible-dose (1-4 mg/day),
6-week trial of clonazepam was completed by Wuslim and coworkers.117
In 27 patients with NCCP and coexisting panic disorder, they found a
DM, September 2008 661
significant reduction in the 50% reduction in anxiety scores, in the
drug-treated group compared with placebo.117
Unfortunately, concerns with dependency make it unlikely that these
medications will be used in the daily treatment of patients with recurrent
chest pain.
The Role of Adenosine Receptors in NCCP
Mice lacking functional adenosine receptor activity show signs of
increased hyperalgesia and anxiety.118 In healthy volunteers, bolus
adenosine infusion induces angina-like pain shortly after infusion. The-
ophylline (a nonselective adenosine receptor antagonist) reduces this pain
significantly, suggesting that pain triggered by adenosine is, at least to
some degree, dependent on activation of theophylline-sensitive recep-
tors.119 Rao and coworkers120 reported data from consecutive patients
with recurrent NCCP who failed an 8-week therapeutic trial of double
dose PPI, and “various empirical trials” (not specified), or lacked
evidence of GER on 24-hour pH testing. They found that intravenous
infusion of theophylline (an adenosine receptor antagonist), but not
placebo, improves the biomechanical and sensory properties of the
esophageal wall. In a long-term study, 19 patients with esophageal
hypersensitivity, randomized to receive oral theophylline 200 mg bid for
4 weeks in a crossover design, experienced significant improvement in
pain parameters when compared with placebo. It is unlikely that theoph-
ylline will become in use for the treatment of NCCP due to its potential
toxicity. However, the findings of the above study suggest that research
involving newer selective adenosine receptor agents may offer new
opportunities for the treatment of NCCP.121
Summary
Treatment of NCCP remains a difficult problem due to the heteroge-
neous nature of the disorder. GER is the best studied condition contrib-
uting to NCCP. Pharmacological trials of acid inhibition show a robust
response rate for patients with NCCP-related GER. More rigorously
executed studies are needed to understand the role of endoscopic
therapies (if any) and surgery in patients with NCCP and coexisting GER.
For patients with spastic disorders without GER, most therapeutic trials
involve small, uncontrolled studies with variable outcome. Although a
number of therapeutic options have been used to treat spastic dysmotility
in these patients, no one agent has emerged as the drug of choice. Botox
is a promising agent for the treatment of selected patients due to its rapid
beneficial effect and relative simplicity (though invasive) of administra-
662 DM, September 2008
tion. However, placebo-controlled trials are lacking to validate its
efficacy. NO donors and phosphodiesterase inhibitors are attractive
compounds that warrant further testing since they seem to influence the
intimate mechanism involved in the pathogenesis of DES (simultaneous
contractions). Two TCA (imipramine and trazondone) remain valuable
drugs in NCCP since small, randomized, placebo-controlled trials support
their beneficial effect. The role of serotonin and the newly reported
adenosine receptor pathway opens another opportunity for further re-
search to better understand the neurotransmitters involved in the genesis
of visceral chest pain. Finally, the high prevalence of psychiatric
disorders in patients with NCCP is concerning. It begs for a combined
multidisciplinary approach to study the interaction between the esophagus
and the brain and better define the role, timing, and forms of psycholog-
ical intervention in these patients.
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