Академический Документы
Профессиональный Документы
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Christophe Vanormelingen
, Jan Tack
Comments
Antidopaminergic
Domperidone 10 mg TID May lead to QT prolongation. Doses above 30 mg daily
increase risk of side effects. Doses up to 2025 mg QID are
used anecdotally
Metoclopramide 10 mg TID Avoid for long-term use (domperidone preferred) because of
neurologic adverse events
Levosulpiride 25 mg TID Not available in the UK
Itopride 50 mg TID Not available in the UK
Motilin agonists
Erythromycin 250 mg QID Tachyphyllaxis may worsen symptoms. May lead to QT
prolongation
Azithromycin 250 mg thrice
weekly
Less risk of drug interactions than erythromycin
Serotonergic
Cisapride 10 mg QID High risk of drug interactions. No longer available in the UK
Tegaserod 6 mg BID Risk of drug interactions. Not available in the UK
Prucalopride 2 mg daily Not studied in DGP
None of these medications have a formal indication for treatment of DGP and thus are used off label.
Dosages listed are typically used in DGP and may not be appropriate for every patient. Use of
combination prokinetic therapy should be done with caution due to the risk of drug interactions.
C. Vanormelingen et al.
224 British Medical Bulletin 2013;105
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Motilin agonists
Motilin is a gut-derived hormone that induces gastric emptying and peri-
stalsis through the motilin receptor. Motilin agonists include the macro-
lide antibiotics, with erythromycin being the classic agent used.
Erythromycin is generally not used as a first-line prokinetic due to issues
with tachyphylaxis and antibiotic resistance. Furthermore, its QT-
interval prolongation effects have led to suggestions that it should not be
used in conjunction with metoclopramide or domperidone due to the
risk of arrhythmia. Novel motilin receptor agonists without antimicro-
bial activity, such as GSK962040, are in late-phase trials for DGP.
Ghrelin agonists
Ghrelin is a stomach-derived peptide that stimulates interdigestive and
postprandial motor activit, and improves appetite. TZP-101, TZP-102
and RM-131 are novel ghrelin agonists that are under development for
the treatment of gastroparesis and postoperative ileus, with intraven-
ous, oral and subcutaneous routes of administration, respectively. Early
stage trials in DGP have shown a significantly enhanced gastric empty-
ing rate and reduced postprandial symptom ratings, in addition to
being well tolerated. Although there are no currently approved drugs
with this mechanism of action, this pathway appears promising and is
being applied directly to DGP patients.
Antinauseants
An exhaustive review of antinausea therapy is beyond the scope of this
paper, but is reviewed in detail elsewhere.
40
The general classes of anti-
nausea medications include 5HT3 antagonists, antimuscarinic anitcho-
linergics, D
2
antagonists, H
1
antagonists and NK
1
antagonists. Because
many of these agents ultimately lead to anticholinergic action (with the
exception of D
2
antagonists), they can counteract concurrent prokinetic
effects. However, they do form a mainstay of the management of DGP,
if nausea is a prominent symptom; however, given the lack of guide-
lines and the multitude of agents, their use is empiric. Patients may
require more than one agent and may require cycling through a
number of agents to find optimal response.
Pain modulators
Abdominal pain has increasingly been recognized as a significant com-
ponent in DGP in recent years. This makes sense, if DGP is understood
conceptually as an enteric neuropathy. In parallel, our understanding of
Diabetic gastroparesis
British Medical Bulletin 2013;105 225
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neuropathic pain and visceral hypersensitivity has improved substantially
over the last decade.
41
Thus, medications used for these indications may
be helpful in DGP, especially in the advanced stage, where multimodal
medical therapy may be required. For example, low-dose tricyclic antide-
pressants (TCA) work through a variety of mechanisms to improve
symptoms of functional gut disorders. These include antagonism at cho-
linergic, histamine, dopamine and serotonin receptors. A case series of
TCA in diabetics with vomiting showed promising results
42
, and a large
prospective trial of nortriptyline is currently in progress for management
of idiopathic gastroparesis,
43
and results will likely be translatable to
DGP. Only anecdotal evidence is available for other antidepressants in
DGP. Because serotonin norepinephrine reuptake inhibitors do not
appear to be helpful in functional dyspepsia,
44
by extrapolation it could
be speculated that they may not be helpful in DGP either. Mirtazapine,
a 5HT
2
antagonist approved for depression, has antinausea effects and
theoretically could hold promise in DGP, but has not been studied.
Other medications that can be used for treatment of pain in diabetic
neuropathy, such as gabapentin, pregabalin or duloxetine, have not
been studied directly in DGP; however, if patients have coexisting per-
ipheral neuropathy and DGP, their DGP symptoms may improve with
this treatment.
Opiates should generally be avoided for DGP due to their well-known
inhibitory effects on gut motility. However, this is not always possible in
patients with severe symptoms. In those cases, use of weaker opioids
such as tramadol is ideal. If stronger pain control is required, transder-
mal administration (e.g. Fentanyl patch) is typically a preferred approach
due to the unpredictability of absorption of oral medications in DGP.
Alternative treatments
A single-blinded, sham-controlled trial of electroacupuncture in DGP
patients significantly reduced symptoms and accelerated gastric empty-
ing, and symptoms remained improved 2 weeks after the treatment.
45
Although this approach appears promising, further study is required to
draw definitive conclusions.
Endoscopic and surgical approaches to DGP, including
electrical stimulation
Pylorospasm was described in a portion of DGP patients in early
reports of gastroduodenal manometry. Based on this concept, injection
of botulinum toxin into the pylorus was reported as helpful in initial
case series. However, randomized blinded studies of this therapy failed
C. Vanormelingen et al.
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to show any improvement in either symptoms or emptying and theyare,
thus, not recommended.
46
Gastric neurostimulation (Enterraw Therapy) provides regular inter-
mittent application of electrical stimulation to the antral muscularis to
improve DGP symptoms refractory for medical therapy. The current is
provided by an implanted pulse generator inserted at laparoscopy or
laparotomy. Although often called a pacemaker, the therapy does not
in fact entrain gastric electrical activity nor improve gastric emptying,
but works through a mechanism that is not well understood. Initial
studies have suggested that it may induce increased descending noxious
inhibitory control by the brain via vagal afferent nerves from the
stomach.
47
Neurostimulation for DGP has been shown to improve
nausea and vomiting and decrease hospitalization and need for enteral
feeding in uncontrolled case series. However, randomized blinded con-
trolled studies have shown equivocal benefit.
48
Enteral feeding through a jejunal feeding tube ( placed surgically or
endoscopically) allows secure administration of nutrition and medica-
tion beyond the stomach and has been shown to reduce hospitalization
for gastroparesis symptoms.
30
Similarly, venting gastrostomy improved
gastroparesis symptoms in a small case series.
30
Surgical resection of the stomach ( partial, subtotal or total) for
severe refractory gastroparesis has been described in a small number of
uncontrolled case series in the literature, mostly for postvagotomy
( postsurgical) gastroparesis. Completion gastrectomy seems to provide
symptom relief in postsurgical gastroparesis, but benefits of gastric
surgery for other forms of gastroparesis are not adequately studied.
49
Given this lack of evidence, along with the invasiveness and morbidity
of this procedure in a patient with end-stage diabetes, gastrectomy for
DGP, is not recommended.
Conclusion
DGP is a serious complication of diabetes with major effects on quality of
life, morbidity and mortality. Its incidence is unfortunately also projected
to rise with increasing diabetes rates. Thankfully, it has been recognized
as a significant issue, and recent research has furthered our understanding
of its pathophysiology. Furthermore, with DGP-specific therapeutics in
late stage trials, the future is hopeful for patients with this disease.
Conflict of interest
C.V. has no conflicts to disclose. Jan Tack has acted as a scientific
advisor to Almirall, AstraZeneca, Danone, Ironwood, Menarini,
Diabetic gastroparesis
British Medical Bulletin 2013;105 227
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Novartis, Sanofi-aventis, Shire, SK Life Sciences, Takeda, Theravance,
Tranzyme Pharma and Zeria and has undertaken speaking engage-
ments for Abbott, Alfa Wasserman, Almirall, AstraZeneca, Janssen,
Menarini, Novartis, Nycomed, Takeda and Shire. C.N.A. has received
research support from GSK and has acted as a consultant and speaker
for Janssen Inc.
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