FEATURE ARTICLE

Cyproheptadine: A Potentially
Effective Treatment for Functional
Gastrointestinal Disorders in Children
Amornluck Krasaelap, MD; and Shailender Madani, MD

as well as in retrospective studies for

ABSTRACT treatment of FAP, FD, IBS, and AM.10-16
Functional gastrointestinal disorders (FGIDs) negatively affect children’s quality of life 5-HT is a polyfunctional signaling mol-
and health care costs. It has been proposed that alteration of gut serotonin leads to gas- ecule that serves as a paracrine factor,
trointestinal dysmotility, visceral hypersensitivity, altered gastrointestinal secretions, and endocrine hormone, neurotransmitter,
brain-gut dysfunction. Cyproheptadine, a serotonin antagonist, has been shown to be a and growth factor.17 Various 5-HT re-
potentially effective and safe treatment option in children who meet the clinical criteria ceptor subtypes regulate gut motility,
for FGIDs. Well-designed multicenter trials with long-term follow-up are needed to further secretion, and visceral sensitivity.18-20
investigate its efficacy. [Pediatr Ann. 2017;46(3):e120-e125.] Intraluminal pressure changes, me-
chanical stimulation, vagal stimulation,

I
t is challenging to provide symp- the initial gastroenterology consulta- ingestion of a meal, or the presence of
tomatic relief for children suffer- tion visit,5 and an average of $18,000 acid, amino acids, or hypo- or hyperos-
ing from functional gastrointestinal per hospital stay.6 Interactions of bio- motic solutions in the duodenum cause
disorders (FGIDs). Understanding the logical, psychological, and sociologi- release of 5-HT.21-25
pathophysiology of FGIDs will help cal factors contribute to its natural his-
the health care provider choose the ap- tory.7 Proposed mechanisms for FGIDs PATHOPHYSIOLOGY AND
propriate treatment. FGIDs are clini- include altered gut motility, visceral TREATMENT OF FGIDS
cal conditions that include functional hypersensitivity, altered gastrointesti- Visceral hypersensitivity, gastroin-
abdominal pain (FAP), functional dys- nal secretion, and brain-gut dysfunc- testinal dysmotility, altered secretion,
pepsia (FD), irritable bowel syndrome tion. Gut serotonin (5-HT) regulates gut and brain-gut dysfunction are putative
(IBS), abdominal migraine (AM), and motility, gastrointestinal secretion, and outcomes caused by alteration of gut
cyclic vomiting syndrome (CVS), and visceral sensitivity to normal sensations 5-HT. Hypersensitivity is generalized
they are diagnosed based on Rome III through specific gut receptors. in FAP,26 limited to the rectum in IBS,26
clinical criteria.1 FGIDs affect a large Cyproheptadine, a 5-HT receptor and limited to the stomach in FD.18 De-
number of children (up to 19%) in the antagonist, is used off-label for several creased gastric accommodation results
Western world,2 cause negative impact indications and is a potentially effective in early satiety and dyspeptic symp-
on childrens’ quality of life,3 and in- medication for FGIDs.8 Its efficacy in toms in FD.27,28 Dysmotility results in
crease the risk of depression.4 It costs children with FAP has been reported in a diarrhea, constipation, nausea, bloating,
approximately $6,100 per patient for double-blind, placebo-controlled trial,9 and abdominal distension in IBS.29-32
Altered selective serotonin transporter
Amornluck Krasaelap, MD, is a Pediatric Resident, Children’s Hospital of Michigan. Shailender expression33-35 results in altered 5-HT
Madani, MD, is an Assistant Professor and Pediatric Gastroenterologist, The Carman and Ann Adams levels in the intestinal mucosa, leading
Department of Pediatrics, Wayne State University School of Medicine; and a Pediatric Gastroenterolo- to IBS symptoms. The secretory ef-
gist, Children’s Hospital of Michigan. fects of 5-HT are mediated through the
Address correspondence to Shailender Madani, MD, Children’s Hospital of Michigan, 3901 Beaubien 5-HT4 subtype in human ileal mucosa,
Boulevard, Detroit, MI 48201; email: [email protected]. but through the 5-HT2A subtype in the
Disclosure: The authors have no relevant financial relationships to disclose. human sigmoid colon.19 The enteric ner-
doi: 10.3928/19382359-20170213-01 vous system and central nervous system

e120 Copyright © SLACK Incorporated

 FEATURE ARTICLE

are derived from the same embryologic not been formally studied in FD in hu- studied the role of cyproheptadine in ab-
tissues, have direct effects on each other, mans.18 To date, there are only two pub- dominal migraine prophylaxis in 12 pa-
and are proposed to contribute to the gas- lished retrospective studies (Madani et tients, and 10 of these patients had fair to
trointestinal and neurologic symptoms al.10 and Rodriguez et al.11) that showed excellent response. Madani et al.10 dem-
of AM.36 In a person with chronically efficacy of cyproheptadine in a majority onstrated complete resolution of symp-
low levels of 5-HT, a sudden release of children diagnosed with Rome III- toms in 13 of 18 patients with AM treat-
of 5-HT might trigger a migraine.37 An defined FD (77% and 55% resolution of ed with cyproheptadine (72% response
autonomic neuropathy with impairment symptoms, respectively). rate). Lewis55 noted that cyproheptadine
of the sympathetic nervous system but is a simple, effective, and safe treatment
normal parasympathetic nerve function Functional Abdominal Pain option for AM in children younger than
is a proposed cause of CVS.38 Exces- Studies in mice showed that 5-HT age 10 years who are not overweight.
sive corticotropin-releasing factor due to receptors, including 5-HT1, 5-HT2,
stress reportedly decreases gastric vagal 5-HT6, and especially 5-HT1B and Irritable Bowel Syndrome
efferents, leading to gastroparesis and 5-HT2A, are all involved in peripheral Similar to FD, patients with IBS have
vomiting.39 Based on the available data, nociceptive response induced by 5-HT.48 alterations in rectal sensitivity with low-
altered 5-HT appears to be involved in Cyproheptadine showed marked inhi- ered thresholds for pain and motility
FGID symptoms; thus cyproheptadine, bition of 5-HT nociceptive response, disturbances, as well as altered intesti-
which is a 5-HT antagonist, is a poten- possibly due to its nonselective binding nal secretion.30 Diarrhea-predominant
tial treatment option for the symptom- properties, allowing it to target more IBS is associated with elevated 5-HT,
atic management of FGIDs. than one receptor and leading to a wide- whereas constipation-predominant IBS
ranging effect. Cyproheptadine is also is associated with decreased levels of
CYPROHEPTADINE FOR known to inhibit calcium channel in the 5-HT in the colon mucosa.33 The etiol-
TREATMENT OF FGIDS intestinal muscle, providing relief of ogy of IBS is unclear, but likely due to
Studies on use of cyproheptadine for pain.49-53 alterations in 5-HT metabolism resulting
treatment of FGIDs are summarized in To date, there have been two stud- in impaired gastrointestinal motility and
Table 1. The following text provides a ies attesting to its efficacy in FAP. IBS.56,57 Multiple medications have been
brief discussion of its role in each of the A prospective double-blind study by reported to improve IBS symptoms in-
FGIDs. Sadeghian et al.9 in 2008 among 29 cluding alosetron, tegaserod, citalopram,
children with FAP demonstrated sta- amitriptyline, dicyclomine, and hyoscy-
Functional Dyspepsia tistically significant improvement of amine via effects on serotonin, on the
The symptoms of FD have been ex- pain frequency, intensity, and overall cholinergic pathway, and as antidepres-
plained by gastric hypersensitivity to improvement in the cyproheptadine sants. Cyproheptadine, a nonselective
distension and decreased gastric ac- group. Efficacy of cyproheptadine was serotonin antagonist with mild anticho-
commodation in response to a meal.40,41 also demonstrated in a retrospective linergic effect, might also be beneficial
Animal studies have shown that fundic study in 2016 among 55 patients who in the treatment of IBS. Cyproheptadine
contraction and relaxation of the stomach met Rome III criteria for FAP, with was found to block the 5-HT2 receptor,
are regulated by 5-HT via 5-HT2A and 66% experiencing complete resolution resulting in decreasing contraction of
5-HT2B receptors as reported in rats,42 of abdominal pain.10 longitudinal smooth muscles of small
guinea pigs,43 and chickens,44 as well as intestine in mice.58 Another animal study
in the antrum in dogs.11,45 Stimulation of Abdominal Migraine in rats demonstrated that cyproheptadine
the 5-HT2 receptor in dogs induced lower Although cyproheptadine has been also has a direct effect on the inhibition
esophageal sphincter contractions, which shown to be effective in prevention of of electrogenic ionic secretion in intes-
were later inhibited by cyproheptadine.46 migraine headache in children,54 there tinal epithelium.59 There have been no
A 5-HT3 receptor antagonist (ondan- are data suggesting its beneficial effects studies demonstrating a direct effect of
setron) is known to be effective in treat- in AM10,12,13 (Table 1). Pfau et al.13 re- cyproheptadine use in the treatment of
ment of postinfectious dyspeptic symp- ported complete abatement of symptoms IBS in humans; however, a recent study
toms.47 Cyproheptadine, a nonselective in 3 of 4 patients with AM treated with by Madani et al.10 reported, for the first
antagonist of 5-HT2A and 5-HT2B, has cyproheptadine. Worawattanakul et al.12 time, a complete resolution of symptoms

PEDIATRIC ANNALS • Vol. 46, No. 3, 2017 e121

 TABLE 1.

Efficacy of Cyproheptadine in Children with Functional Gastrointestinal Disorders

e122
Study Criteria
Author Participants Inclusion Exclusion Intervention Outcome Measures Results Side Effects
Sadeghian et al.9 Children age FAP (Rome III) Other dis- Dose 0.25-0.5 mg/kg/day (maxi- Self-reported Improved/resolved pain Increased appetite 3%
4.5-16 y eases, FAP with mum 12 mg/day children 2-6 y, scales: frequency (P = .002) Hypoactive airway 3%
(N = 29) atypical features, maximum 16 mg/day children Frequency and with RR 2.43 (95% CI, No serious side effects
abnormal ECG, 7-14 y) intensity of ab- 1.17-5.04),
Double-blinded, reported
abdominal Median duration: 2 wk dominal pain Decreased pain intensity
randomized,
migraine, chronic Children’s and par- (P = .001) with RR 3.03
placebo-
pain, RUQ/RLQ, ent’s impression (95% CI, 1.29-7.11)
controlled trial
pain relieved by Children’s/parents’
lactose-free diet impression in Cyp
group (87% vs 36%;
P = . 005)
Madani et al.10 Children age Rome III-defined FGIDs Cyp not used or Mean initial dose 0.14 mg/kg/day Graded responses Complete improvement 27% in CIG,
1-18 y 1-75 mo follow up used for other Mean final dose 0.14 mg/kg/day in FD 77% (26 of 34) 46% in NIG/PIG
(N = 34 for FD) causes, no follow- in CIG, 0.20 mg/kg/day in NIG/PIG in FAP 66% (36 of 55) Somnolence 12%
(N = 55 for FAP) up visit Median duration: 6 mo (range, in AM 72% (13 of 18) Weight gain 10%
(N = 18 for AM) 1-48 mo) in IBS 100% (10 of 10) Other 6%
(N = 10 for IBS) in CVS 75% (6 of 8) Combination 3%
(N = 8 for CVS) Increased appetite 1%
Retrospective
review
FEATURE ARTICLE

Rodriguez et al.11 Children age 9 Dyspepsia organic Cyp given solely Median dose 0.19 mg/kg/day Graded responses Significant response Side effects 30%
mo-20 y cause or FD (ROME III) as an appetite (range 0.04-0.62 mg/kg/day) 41%, resolved 14%, Somnolence 16%
(N = 44) refractory to conven- stimulant Median duration: 20 wk (range, failed 45% Behavioral change 6%
Retrospective tional treatment, given 2-222 wk) Weight gain 5%
review Cyp
Abdominal pain 2.5%
Worawattanakul Children age AM treated with medi- Follow-up data Dose 0.25-0.5 mg/kg /day Graded responses: 12 patients treated with Drowsiness 8%
et al.12 3-15 y cation could not be Median duration: 2-36 mo excellent, fair, poor Cyp: Weight gain 8%
(N = 12) obtained Excellent 33%
Retrospective Fair 50%,
review Poor 17%
13
Pfau et al. Children age Undiagnosed recur- Previously diag- 4 of 19 patients with AM received Graded re- Complete resolution No report
2-18 y rent vomiting nosed with other Cyp sponses: complete 75% (3 of 4 patients)
(N =106; n = 19 diseases Unknown dose and duration resolution, some
by Lundberg’s response, or no
criteria) response
Retrospective
review

Copyright © SLACK Incorporated

 TABLE 1. (continued)

Efficacy of Cyproheptadine in Children with Functional Gastrointestinal Disorders

Study Criteria
Author Participants Inclusion Exclusion Intervention Outcome Measures Results Side Effects
Li et al.14 Children CVS by Consensus Diagnosed with Unknown dose and duration of Percent reduction >50% reduction in Unknown
younger than Diagnostic Criteria61 other diseases treatment in numbers of em- vomiting in 46% in
age 18 y At least three discrete esis or episodes migraine-associated
(N = 214) episodes of vomiting CVS (N = 32), 0% in
nonmigraine-associated
Chart review
CVS (N = 5)
and structured

PEDIATRIC ANNALS • Vol. 46, No. 3, 2017

interviews
Boles et al.15 Patients (N = CVS by Fleischer62 Malrotation, Unknown dose and duration of Report per parent Beneficial in 8 of 14 Unknown
62 total, 58 and Li61 intracerebral treatment patients (57%)
children) Met 2 or more of tumor, fetal
Clinical inter- these criteria: global alcohol syndrome,
view using cognitive delay, seizure abnormal karyo-
questionnaire disorder, myopathy, type, metabolic
growth retardation, disorder
family history suspi-
cious for maternal
inheritance
Andersen et al.16 Children age CVS by Fleisher62 and Organic causes Dose 0.1-0.3 mg/kg/day Graded response 66% (4 of 6) complete Sedative effects
2-16 y Li61 response and weight gain
(N = 27) 17% (1 of 6) partial in some patients;
response no other signifi-
Retrospective
FEATURE ARTICLE

cant side effects

review

Abbreviations: AM, abdominal migraine; CI, confidence interval; CIG, complete-improvement group; Cyp, cyproheptadine; CVS, cyclic vomiting syndrome; ECG, electrocardiogram; FAP, functional abdominal pain; FD, functional dyspepsia; FGID, functional
gastrointestinal disorders; IBS, irritable bowel syndrome; mo, month; NIG, no-improvement group; PIG, partial-improvement group; RLQ, right lower quadrant; RR. relative risk; RUQ, right upper quadrant; wk, week; y, year.
acute attack of CVS.

CYPROHEPTADINE
ADVERSE EFFECTS OF
to cyproheptadine treatment.
Cyclic Vomiting Syndrome
IBS treated with cyproheptadine.

DOSAGE OF CYPROHEPTADINE

and its anticholinergic properties may

dine should be the first-line therapy

increased appetite and weight gain,

ness and disturbance of coordination,
No major adverse effects have
tion of therapy on the overall response
ies,9,11-13 have reported that there is no
0.5 mg/kg daily) in patients age 15
depends on the age of the patient. The
ing to the North American Society
proheptadine for CVS. Response rates

e123
its antiserotonergic effect may explain
cyproheptadine may cause drowsi-
The antihistaminergic properties of
ating its efficacy in treating FGIDs
times daily (maximum of 12 mg daily)

been reported in pediatric studies.

correlation between dose and the dura-
to 3 years.10,11 However, several stud-
(0.04-0.62 mg/kg daily) for 2 weeks
in children used wide dose ranges
clinical studies. All four studies evalu-
not been determined by randomized
tadine for treatment of FGIDs have
years and older. Dosages of cyprohep-
and 4 mg 3 times daily (maximum
The recommended dose for children
younger than age 5 years. However,

daily) in children age 7 to 14 years,

for prophylaxis of CVS in children
tology and Nutrition,60 cyprohepta-
for Pediatric Gastroenterology, Hepa-
ranged from 40% to 83%.14-16 Accord-
of children (n = 65) who received cy-
There have been three reports14-16

to 3 times daily (maximum of 16 mg

recommended dosages are 2 mg 2 to 3
there is no role of cyproheptadine in
in 10 of 10 children suffering from

in children age 2 to 6 years; 4 mg 2

 FEATURE ARTICLE

cause anticholinergic syndrome with terol Motil. 2015;27:684-692. staltic reflex induced by mucosal stimuli in
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