MC

DecemberED

2017

Volume 3-The Informed Prescriber

N9

HECK

o

WHO downgrades Tamiflu
Suvorexant : A hypnotic causing cataplexy
Insomnia, Sleep Duration, Harm of hypnotics

PPI causes Pneumonia
CONTENTS （December 2017, Vol. 3, No. 9）

Editorial
WHO downgraded oseltamivir (Tamiflu)

28

New Products
Hypnotic (sleeping pill), suvorexant (brand name Belsomra)29

A substance that causes narcolepsy and cataplexy

Teriparatide

More harm than benefit:

34

Review
Insomnia, Optimal Sleep Duration and Harm of Sleeping pills

36

Pneumonia caused by proton pump inhibitors (PPI)(1) meta-analysis

40(2) Critical appraisal of a study

42

MED CHECK - TIP December 2017 / Vol.3 No.9 ・ Page 27

M
C

ED

-The Informed Prescriber

HECK

Editorial

WHO downgrades Tamiflu after reviewing evidence
Translated from the editorial in Med Check-TIP in Japanese Sept 2017 ; 17 (73): 99

WHO (World Health Organization) reviews their

behaviours and sudden death is not considered

model list of essential medicines every two years.

seriously in their decision. Second, they do not

In the revision launched in June 2017, oseltamivir

take into account that Tamiflu is more hazardous(Tamiflu) was downgraded in the World Healthfor severely complicated patients or for high-risk

Organization’s essential medicines list (EML) frominfluenza patients.

the “core” to the “complementary” list.
The Expert Committee made the decision for

However, it is epo ch-making that WHO
valued of the results of the systematicthe following reasons:review by Cochrane team than those by the1) Oseltamivir was included in the essential

pharmaceuticals-funded researches. The lattermedicine list (EML) in 2009 and remained inconcluded “Tamiflu has protective efficacy on

the EML for critically ill patients with influenza.

pneumonia, and it has no neuropsychiatric2) However, there now exists additional evidence

adverse effects". Moreover, WHO mentioned theindicating its reduced magnitude of effects.

possibility of “deletion" in the next revision.

3) Expert committee recommended the listing ofoseltamivir be amended and the medicine be

In Japan, it was decided recently that the

moved from the “core” to the “complementary” list,

amount of stockpile should be reduced slightly.

4) Unless new information supporting the use inThis was because no scientific evidence forseasonal and pandemic outbreaks is provided,

double dose and/or double duration of Tamiflu

the next Expert Committee might consider

use in seriously complicated patients with

oseltamivir for deletion.

influenza was found. However, neuraminidase"Additional evidence" means the results from

inhibitors are stockpiled for 48 million persons

systematic review and meta-analysis conducted

after that decision.

and published by the Cochrane neuraminidase

W e u s e 5 0 t i m e s t o 1200 t i m e s m o r e

inhibitor research team in April, 2014 and theneuraminidase inhibitors including oseltamivir

review results about mortality in the subsequentand laninamivir per capita in Japan than in

Health Technology Assessment report.

European countries.

Evidence from Cochrane team is summarised

Victims and the bereaved of harms of Tamiflu

as follows:

filed cases for the relief. In the suit, regulators,(1)Tamiflu did not reduce hospitalization andtheir witness and the court claim that Tamiflu ispneumonia in patients with influenza.

totally harmless. They do not accept abnormal(2) Tamiflu did not reduce influenza-like illness
when used for prophylaxis.
(3) Tamiflu did not reduce death either.

behaviours with fatal outcome, sudden death andsequelae as harm of Tamiflu. Consequently, their
damages remain unrelieved.

(4) Tamiflu caused psychiatric harm both in

We strongly recommend that in Japan wetreatment trials and in prophylaxis trials. It

should consider the Cochrane team’s results morecaused headache, diabetes and renal disease.

seriously and should downgrade the status of

The decision of WHO has some limitations.

oseltamivir and other neuraminidase inhibitors,

First, neuropsychiatric harm including abnormal

Page 28 ・ MED CHECK - TIP December 2017/ Vol.3 No.9

following the WHO’s decision.

New Products

Hypnotic (sleeping pill), suvorexant (brand name
Belsomra)

A substance that causes narcolepsy and cataplexy. Is it a “medicine”?
Translated from Med Check-TIP in Japanese Nov 2017 ; 17 (74):124-127
Wada M and Hama R

Summary● Suvorexant (brand name: Belsomra) is an orexin receptor antagonist which was approved for the treatment of“insomnia” in November, 2014. Clinical trials for this substance reported that participants in the treatment groupwere able to fall asleep 5.2 minutes quicker and slept 10.7 minutes longer than those in the placebo group.
● Orexin is secreted by the neuron in the brain and is responsible for arousal and various other functions for defense

response against stress. It also promotes growth of normal cells and inhibits growth of tumor cells. Hence its
antagonists may cause various harms.
●When suvorexant is taken daily, plasma level remains high even during daytime a few days after commencement.

In clinical trials, drowsiness, memory impairment, parasomnias ( nightmares, sleepwalking etc. ), narcolepsylike symptoms (including cataplexy, hypnagogic hallucination, sleep paralysis) and suicidal ideation increased dosedependently. In a case of death after drowning during swimming in the sea, cataplexy (emotion-induced paralysis) isstrongly suspected as the cause.
● Suvorexant might cause impaired functions of normal cells, inhibition of normal cell growth, immunosuppression,and tumor growth. These possibilities should be continuously monitored. Suvorexant is metabolized by CYP3A (note1). Slow metabolisers are susceptible to more harms, and it is risky to take the substance concomitantly with othermedicines which are also metabolized by CYP3A.
Conclusion: Unlike a lack of sleep, insomnia does not cause harm to health. Suvorexant (Belsomra) should
not be used because it may cause various harms including those leading to death.
Note 1：One of the subtypes of drug metabolizing enzymes called cytochrome P450. Because its level of activity greatly varies amongindividuals, blood concentration reaches extremely high and remains high in people with weaker enzymatic activity (slow metaboliser) as
compared with people with greater activity (rapid metaboliser). Moreover, when medicines which are metabolized by the same subtype of
enzyme are concomitantly used, blood concentrations of both medicines reach high, and their effects persist for a long time.

Keywords:
hypnotic, insomnia, lack of sleep, sleep debt, suvorexant, Belsomra, orexin, receptor antagonist, sleep latency, total sleep
duration, defense, memory impairment, fatigue, sleepwalking, narcolepsy, cataplexy, suicidal ideation, tumor growth, CYP3A

Introduction

is insufficient, and it is different from having short sleep

In evaluating hypnotics ( sleeping pills), it is essential toduration or a lack of sleep ( sleep debt ). Persons who

compare effects of insomnia and effects of hypnotics on

experience insomnia live longer than those who do not.

health. The reasons are summarized as follows ( for more

However, routine use of hypnotics for the treatment of

information in detail, refer to the Med-Check TIP in English No9 (thisinsomnia increases depression, infection, cancer, and evenissue p36) [1]).

death. A lack of sleep triggers intense stress and promotes

Insomnia is a subjective complaint that one feels sleep

aging, leading to various chronic diseases. However, when

MED CHECK - TIP December 2017 / Vol.3 No.9 ・ Page 29

New Products
optimal sleep duration is secured, stress is lessened andobserved on the next day, including various neuropsychiatrichealth condition is restored, although insomnia or difficulties

adverse reactions mentioned below.

in falling asleep is sometimes experienced.
Considering these points, this article examines suvorexant(brand name: Belsomra), an orexin receptor (note 2) antagonist.
Note 2：Because orexin is secreted by neurons in the hypothalamus, it
is also called “hypocretin”. It has two kinds of receptors, and suvorexant
inhibit both of them.

Note 4：The nadir (minimum blood level) after using the medication for
14 days was approximately a half of the maximum blood level on thefirst day (Figure 2, [2])Efficacy
Clinical trials in Review Report by the Japanese regulator
and Summary Bases of Approval ( SBA ) are reported by

Orexin and its receptor antagonists

merging a phase II Japanese study and phase III international

Orexin is a chemical substance in the brain which plays an

study (up to 12 months) [2]. They compared three groups,

important role in maintaining level of arousal [2-8]. In many

namely placebo groups ( group P ), suvorexant low-dose

narcolepsy patients (note 3), who feel strong drowsiness andgroup ( group L ) and suvorexant high-dose groups ( groupfall asleep even in the daytime, orexin level in cerebrospinalH). Participants in group L received 20mg/day ( non-elderly

fluid is decreased [9-11]. Suvorexant, an orexin receptor

persons aged below 65 years old) or 15 mg/day (elderly persons

antagonist, is believed to induce onset of sleep and maintainaged 65 years and older), while those in group H received 40

it by inhibiting the action of orexin [2]. Orexin-producing

mg/day (non-elderly) or 30mg/day (elderly).

neurons (orexin neurons) are found in the lateral hypothalamic

In the efficacy indicators for initiating sleep, such asarea and project to the entire central nervous system [3-7].

subjective sleep latency (time to falling asleep) and persistent

They are deeply associated with defense response, which issleep latency ( time to persistent sleep ), and in those fora response against stress [3,5-7]. When encountering danger,

maintaining sleep, such as durations of subjective sleep

we must quickly decide whether to “flight or fight” and takeand interrupted sleep, both suvorexant high-dose and low-an action, and this requires substantial amount of energy [6,7].

dose groups (group H and group L) demonstrated superiority

Therefore, catecholamine and orexin levels rise in the brain

over placebo [2]. However, when clinical dose (low-dose) was

to raise blood pressure, accelerate breathing, raise glucose

continued for three months, subjective sleep latency waslevel, and increase caloric intake. Moreover, while orexin

shortened only by 5.2 minutes and subjective sleep durationlets normal cells survive and grow, it suppresses growth ofwas prolonged only by 10.7 minutes.

tumour cells and eliminate them by promoting apoptosis(programmed natural death of cells) [8]. Suvorexant, an orexin
receptor antagonist, inhibited the growth of normal ovariancells in animals used for a chromosomal aberration test [2].

Adverse effects
Carrying-over effects: drowsiness, memory impairment,
body sway, fatigue

In a carcinogenicity study, adenoma in the thyroid gland

In a cross-over study (phase I) which compared placebo

and hepatocellular adenoma increased significantly, and in a(group P), suvorexant 20 mg (group L) and 40 mg (group H),

canine toxicity test, vomiting occurred even at the minimum

involving healthy volunteers, on the day after taking the test

dose, and reduced albumin and lymphocytes are observed atagent, increased body sway, lowered ability to recall words

the medium and high doses [2].

(memory impairment), and increased cancellation of driving

Suvorexant suppresses immunity and cause tumor growth.

test due to drowsiness were observed dose-dependently. Even
those who were able to undergo driving test performed more

Note 3： Narcolepsy is a disease characterized by excessive sleepinessin daytime, nap, sleep paralysis, cataplexy (emotion-induced paralysis),and hypnagogic hallucination [9].

poorly [2,11].
The figure 2 shows adverse events in the phase II and III
studies by groups P, L, and H. Dose-response relationshipPharmacokinetics of suvorexant
The time to maximum blood concentration (Tmax) of
suvorexant is 1.5 to 3 hours and its elimination half-life is 10

was found in somnolence ( p<0.0001 ), fatigue ( p=0.0027 ),and memory impairment among the elderly participants(p=0.0263).

to 11 hours, and thus high blood concentration remains in thedaytime (note 4, Figure 1). Because of these characteristics
and its mechanisms of action, carry-over effects were

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1)Parasomnias-related events
Dose-response relat ionship was also observed inFigure 1 ： Average plasma level of suvorexant in non-Japanese healthy women
Average plasma level of suvorexant in non-Japanese healthy
women (n=17-19) who took 40mg of suvorexant before bed time
every day and took a single dose of Orth Cyclen (low dose oral
contraceptive containing ethinyl estradiol and norgestimate) at
day 14.
Comments by MedCheckTIP: It is obvious that nadir on day
14 is equivalent to half of Cmax on day 1. By simulating theconcentration curve at 8 ~ 24 hrs after dosing on day 1
oron day 18, the level of suvorexamt at day time on day 14 isestimated 0.5 to 0.7μM which is equivalent to the level at night
on day 1. Hence, it cannot be avoidable for suvorexant users tohave insufficient awakening during daytime leading to attention
deficit, memory impairment, dizziness and depression.
Moreover, the level shown in the Figure 2 is the average of 17
to 19 persons. The level of suvorexant in the slow metaboliserswith extremely low CYP3A activity may increase far more during
daytime. Hence narcolepsy with or without cataplexy can occur.

parasomnias-related adverse events, such as abnormalgroups L and H. When the below-mentioned two cases,

dreams, nightmares, night walking etc. (p=0.0013) (Figure 2).

in which cataplexy is highly suspected, were added, dose-

Severe parasomnias occurred in a 65 year-old male of the

response relationship was significant (p=0.020).

high-dose group. About 2.5 hours after taking the medicine,

Next, each symptom which belongs to narcolepsy-

the patient suddenly got up from the bed, hit his head andlike symptoms is examined. One of the main narcoleptic

face against the wall. Two weeks after terminating thesymptoms is called “cataplexy” or emotion-induced paralysis.

medication, he exhibited moderate sleep walking, and theWhen strong emotional stimulation occurs, muscle tone isevents were classified as the test product related.

suddenly lost (the mechanism is explained in the column).
In one case, a 59-year-old male experienced muscle

2)Narcolepsy-like symptoms

weakness in lower limbs, and it seemed to worsen when heNarcolepsy-like symptoms include cataplexy ( emotion-

felt excess drowsiness in daytime, and when he laughed or

induced paralysis), hypnagogic/somnolent hallucination, andfelt other emotional impulses. This case can be considered

sleep paralysis. Narcolepsy-related events did not occur

as cataplexy, although the independent review bord ofin the group P, but they occurred more frequently in boththe clinical trials judged that it could not be categorized
as cataplexy because “no functional weakness was

Figure 2: Dose-related increase of major adverse events (extracted from [2])confirmed” [2].
The other case is a 40-year-old woman who drowned
during swimming in the sea and died from hypoxic
ischemic encephalopathy three days after drowning,
The manufacturer (MSD) explains that she died fromhypoxic ischemic encephalopathy three days after
drowning, and causal relationship with the test drug
has been denied. However, when she experienced
near drowning, she must have felt extremely strong
emotional impulse that led to cataplexy. It is very likelythat because of this, she was not able to swim nor
breathe and died. The causal relationship cannot bedenied, but strongly suspected.

* a: Elderly people * b: Narcolepcy-related events are the percent of patients with at least one
symptoms classified with *c or hypnagogic hallucination. P value is the results from Chi² for linear
trend.
Narcolepcy-related events and cataplexy are the percent of cases including those in which cataplexy isstrongly suspected, such as the case of drowning.

In a canine toxicity study on several orexin receptor
antagonists including suvorexant, when animals arepresented with special diet (biscuits wrapped in meat,

MED CHECK - TIP December 2017 / Vol.3 No.9 ・ Page 31

New Products
beef rolls etc.) after administration of the substances, they5)Summary of neuropsychiatric adverse reactions

exhibited characteristic behavioral changes (transient flexion of

Dose-response relationship was found in somnolence,

the limbs, gait ataxia and recumbency) that suggested cataplexy

fatigue, memory impairment, parasomnias, narcolepsy-[2].

like symptoms and suicidal ideation. Sleep paralysis also

Suvorexant may cause cataplexy. However, in its package

showed tendency for dose-dependent increase. Cataplexy

insert, “narcolepsy” and “cataplexy” are not listed as “sidewas strongly suspected in two cases in high-dose group.

effects”. “Suicidal ideation” and “depression-related symptoms”,

These neuropsychiatric symptoms are adverse reactions towhich will be discussed below, are also not included. This issuvorexant (Belsomra). It also causes depression.

because the manufacturer and the government did not accept
that the symptoms of the two trial participants and dogs

One literature explains about orexin nervous systemwere cataplexy (note 5). Hypnagogic hallucination, somnolent

as follows [7]. “Orexin nervous system, whose cell bodies

hallucination and sleep paralysis also occurred only inare located in the hypothalamus, is a nervous system thattreatment groups.

projects to almost all areas of the brain to maintain arousal.
It plays an essential role not only in arousal, but also in

Note 5： In Summary Bases of approval (SBA) (toxicity study), changes
were observed in behavior as well as electroencephalogram,
electromyography and electro-oculography. However, because they
were not accompanied by characteristics signs of cataplexy which had
been reported in literatures, and they were not induced in another foodinduced cataplexy tests with dogs, it was concluded that the symptomsof the animals were “not cataplexy, but caused by increased sleep
pressure related to pharmacology”. Although Review Report statedthat “careful examination is necessary…, considering serious risk ofnarcolepsy and suicide-related events”, they were not included in the
package insert.

activating biological functions that control autonomic nerves
such as breathing, circulation, body temperature etc. This
nervous system is crucial in initiating actions in response
to motives such as external stress and appetite. It acts likea master switch for changes in behaviors and autonomic
functions associated with sleep and arousal. When it isdisrupted, wakeful state cannot be appropriately maintained,
and breathing and control of body temperature are impaired.
(summary of citation from [7]).
In other words, orexin plays a key role as a master switch3)Suicide-related events and depression
As for suicidal ideation, clear dose-response relation was
found in the three groups ( p=0.0499 ); 0.1% ( P ), 0.2% ( L )for defense response, adjusting almost all organs to such a
response. Therefore, when it is inhibited, various peripheralorgans may be impaired.

and 0.7% (H) (Figure 1). Suicidal ideation is a crucial adverse
event related to depression. If suicidal ideation is included

Large individual differences and drug interaction

in “depression-related events” along with decreased interest,

Suvorexant is metabolized mainly by a drug metabolizing

depressed mood, and depression, clear dose-response relation

enzyme, CYP3A (note 1). In persons whose CYP3A activity

was observed in the three groups (p=0.0077); 0.5% (P), 0.4%

is low and metabolism is slow (slow metabolizers), the blood(L) and 1.5 % (H) .

level rises higher and they are more susceptible to harms.

In an animal experiment, when animals are administered

However, this is not mentioned in the package insert.

with orexin in the cerebral ventricle, increased nervous cells

As for drug interaction, when suvorexant was launched inwere observed in the dentate gyrus (a part of the hippocampus),

2014, the package insert contraindicated concomitant use

which is related to recognition, memory and affection, and itwith itraconazole and clarithromycin, which strongly inhibit

acts as an antidepressant. However, when an orexin receptor

CYP3A, and gave caution on concomitant use with diltiazem,

antagonist was given, this was inhibited [12].

verapamil and fluconazole[14]. However, only two years
later, in 2016, a low-dose formulation, suvorexant 10 mg, was4)Effects on respiratory function

released, and regarding the use of dilitiazem in combination,

Respiratory function-related events showed dose-dependent

the package insert mentioned to “consider reducing theincrease in the three groups marginally (p=0.096); 0.1% (1dosage to 10 mg once a day”. It explains that “this is because

exertional dyspnea in group P), 0.2% (1 dyspnea in group L) andincreased plasma concentration of the medicine may enhance

0.5% (5 dyspnea, 1 hypoxic-ischemic encephalopathy, total 6 cases

side effects such as somnolence, fatigue, hypnagogic sleepin group H).

paralysis, parasomnias and sleep walking”, admitting that the
medicine might cause narcolepsy-like symptoms. However, it

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gives no warning against cataplexy and suicide.
Concomitant use with itraconazole remains contraindicated.
However, suvorexant can be used in combination with other
CYP3A inhibitors according to the package insert. Acceptance

ColumnThe mechanisms of cataplexy caused by suvorexant:A hypothesis

HAMA, Rokuro

There is no literature that properly describes the mechanismsof such concomitant uses is dangerous not only in suvorexantof cataplexy in narcolepsy patients nor how suvorexant

but also in other drugs.

induces cataplexy. However, the following mechanism can be
hypothesized [1]. Intense stress promotes activity of glutamic
acid, catecholamine and orexin, and activates excitatory nerves.

In practice
Reviewing clinical trials revealed that significant dose-At the same time, in order to prevent overexcitement (exitotoxicity)

response relationship was found in narcolepsy-like symptoms

and ease anxiety or pain, GABA ( as endndogenous anxiolytics )including drowsiness, fatigue, memory impairment, cataplexy(emotion-induced paralysis), and depression-related symptoms
including suicidal ideation. The mechanism of action also
supports that these adverse reactions may occur. A case ofdeath from drowning during swimming due to suspected

and endogenous opioids such as endorphin are activated [2,3].
Stronger the emotional impulse is, stronger the inhibition by
GABA may be. However, in narcolepsy patients, whose orexin
level is already low, and patients on orexin receptor inhibitors,
orexin does not act, and excessive action of GABA induced bystrong emotional impulse may cause weakening of muscle tone

cataplexy has also been reported in the clinical trials forleading to cataplexy with dyspnea [1].

application of approval.

References for Column

Experiencing insomnia itself does not lead to poor health,but using hypnotics including suvorexant would be more
harmful to health. Do not prescribe, dispense, nor takesuvorexant.

1) Hama R, unpublished hypothesis
2) Inoue W, Baimoukhametova DV, Füzesi T, Wamsteeker Cusulin JI, Koblinger K,
Whelan PJ, Pittman QJ, Bains JS. Noradrenaline is a stress-associated metaplastic
signal at GABAsynapses. Nat Neurosci. 2013 May;16(5):605-12. https://www.ncbi.
nlm.nih.gov/pubmed/23563580
3) Bali A, Randhawa PK, Jaggi AS. Stress and opioids: role of opioids in modulatingstress-related behavior and effect of stress on morphine conditioned place
preference. Neurosci Biobehav Rev. 2015 Apr;51:138-50. https://www.ncbi.nlm.nih.
gov/pubmed/25636946

References
1) Hama R、 Insomnia, Optimal Sleep Duration and Harm of Sleeping pills

drug addiction, cancers and other physiological disorders. Cell Signal. 2013

MedCheckTIP in Japanese 2017;17 (73) :110-112. http://www.npojip.org/

Dec;25(12):2413-23. https://www.ncbi.nlm.nih.gov/pubmed/23917208

chk_tip.html#No73

9) Akamatsu et al Internal Medicine, Chapter 22 nerve diseases, Narcolepsy

MedCheckTIP in English 2017; 3 (9): 36-39

p1689-1690 Nishimura Co Ltd 2012 (in Japanese)

2) Belsomra (suvolexant) Information for approval: 1) examination results by

10) Dauvilliers Y, Arnulf I,Mignot E. Narcolepsy with cataplexy. Lancet

regulatory authorities, 2) Summary Basis of Approval, 3) package insert (in2007;369:499-511.

Japanese)https://www.ncbi.nlm.nih.gov/pubmed/17292770

http://www.pmda.go.jp/drugs/2014/P201400117/ 170050000_22600AM

11) Ritchie C, Okuro M, Kanbayashi T, Nishino S. Hypocretin Ligand Deficiency

X01302_A100_4.pdf (for 1)

in Narcolepsy: Recent Basic and Clinical Insights. Curr Neurol Neurosci

http://www.pmda.go.jp/PmdaSearch/iyakuSearch/ (for others)。

Rep.2010;10:180-189.

3) Ohno K, Sakurai T. Orexin neuronal circuitry : Role in the regulation of sleep

https://www.ncbi.nlm.nih.gov/pubmed/20425033

and wakefulness. Front Neuroendocrinol. 2008;29:70-87. https://www.ncbi.

12) Vermeeren A, Sun H, Vuurman EFPM, Jongen S,Leeuwen CJV, Oers ACMV,

nlm.nih.gov/pubmed/17910982

Li X,Laethem T, Heirman I, Bautmans A, Troyer MD, Wrishko R,4) Saper CB Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian

McCrea J. On-the-Road Driving Performance the Morning after Bedtime Userhythms. Nature 2005;437:1257-1263. https://www.ncbi.nlm.nih.gov/

of Suvorexant 20 and 40 mg: A Study in Non-Elderly Healthy Volunteers..

pubmed/16251950

SLEEP 2015;38:1803-1813.

5) Kayaba Y, Nakamura A, Kasuya Y, Ohuchi T, Yanagisawa M, Komuro I, Fukuda Y,

https://www.ncbi.nlm.nih.gov/pubmed/26039969

Kuwaki T. Attenuated defense response and low basal blood pressure in orexin13) Ito N, Yabe T, Gamo Y, Nagai T, Oikawa T, Yamada H, Hanawa T. I.c.v.

knockout mice. Am J Physiol Regul Integr Comp Physiol. 2003 Sep;285(3):administration of orexin-A induces an antidepressive-like effect throughR581-93. http://ajpregu.physiology.org/content/285/3/R581.long

hippocampal cell proliferation. Neuroscience. 2008 Dec 10;157(4):720-32.

6) Kuwaki T, Zhang W. Orexin neurons and emotional stress. Vitam Horm.

https://www.ncbi.nlm.nih.gov/pubmed/18952152

2012;89:135-58.

14) Interview form of Belsomra (2016) (in Japanese)

https://www.ncbi.nlm.nih.gov/pubmed/22640612

7) Kuwaki T. Orexin and sleep disturbance (in Japanese) The Lung-perspective

Palcza J,

http://www.info.pmda.go.jp/go/pack/1190023F1024_1_09/

2016: 24(1): 82-87.
http://med.m-review.co.jp/magazine/detail1/J0013_2401_0082-0087.html
8) Xu TR, Yang Y, Ward R, Gao L, Liu Y. Orexin receptors: multifunctional therapeutic targets for sleeping disorders, eating disorders,

MED CHECK - TIP December 2017 / Vol.3 No.9 ・ Page 33

New Products

Teriparatide (brand name: Forteo, Teribone)
More harm than benefit: Do not use these agents for osteoporosis:
Synopsis from Med Check-TIP in Japanese Nov 2017 ; 17 (74):127-130
Nakanishi T and Hama R
Therefore, hypercalcemia is caused by teriparatides as a

Synopsis● Teriparatides are products which act in the same way as

result of pharmacological action of PTH.

parathormone ( PTH). In Japan, two kinds of teriparatide● Also, PTH causes relaxation of the smooth muscle andformulations are approved and marketed now.

consequently dilatation of vessels, leading to hypotension,

One is Forteo, a preparation for daily subcutaneous

nausea, headache, dizziness and so on. It also affects

injection. The other is Teribone, a preparation for weekly

excitability of nerve cells, causing impotence, depression

subcutaneous injection.

and dyspnea. Osteosarccoma was reported in animal toxicity

It is reported that mild elevation in PTH can exert ananabolic effect on bone and increase bone tissues. Somestudies. Due to these findings, initial clinical trials weresuspended prematurely.

clinical trials show that frequency of vertebral fracture
decreased to approximately one-third by using these

The Figure shows dose-related increase of adverse events

preparations. Frequency of fractures other than vertebra also

in two pivotal international clinical trials of Forteo. Nausea,

decreased to approximately two-thirds in clinical trials.

asthenia, headache and withdrawal due to adverse events
showed statistically significant dose-response. Depression,● However, they cause hypercalcemia.

This harmful effectis derived from the fundamental pharmacological action

dyspnea and dizziness showed marginally significant doseresponse.

of teriparatides as PTH. PTH releases calcium from bones,
increases reabsorption of calcium from the kidney, and● In the clinical trials, odds of mortality increased non-increases absorption of calcium from the intestinal tract.

significantly by 1.7 times as compared with placebo (Figure).

Fig : Adverse events (AE) with dose-dependent increase(from the two pivotal international clinical trials of Forteo)

Page 34 ・ MED CHECK - TIP December 2017/ Vol.3 No.9

● Many spontaneous adverse reaction cases were reported

The costs exceed 1 million yen (about 8,000 Euros) for one

on conscious loss/ syncope and shock after marketing.

course of treatment (24 months). They are not worth 94 billion

E s p e c i a l l y, c i r c u l a t o r y f a i l u r e / s h o c k , h y p o t e n s i o n ,yen (about 710 million Euros) of annual drug price in 2015.

unconsciousness/syncope, fever and anaphylaxis were much
more frequently reported after using the weekly preparation,

CONCLUSIONS: in practice, it is not recommended to use.

Teribon (see Table).

Table: Comparison of number and frequency of spontaneous reports in Japan(Forteo vs Teribone)*a: The numbers of users were estimated to be 335,000 person-years for Forteo and 177,000 person-years for Teribone. These
were calculated by the drug prices and total shipment since launching. We calculated odds ratios for Teribone compared with
Forteo based on the estimated numbers of users (person-years).
*b: The lower limits of 95% confidence interval (CI) were shown only in the adverse reactions with significant difference.
*c: We included one case described as "coronary complete occlusion" in the report for Teribone.

Keywords:
Teriparatide, parathormone, PTH, Forteo, Teribone, osteoporosis, vertebral fracture, hypotension, hypercalcemia, highprice, spontaneous report, osteosarcoma

References
1) Hama, R. Denosumab for osteoporosis, Medcheck TIP 2,017:17 (72):76-802) Forteo, Examination report by PMDA, Summary basis of approval,
package insert and interview form.
3) Teribone, Examination report by PMDA, Summary basis of approval,
package insert and interview form.
4) Longo DL et al eds Harrison's Principles of internal medicine 18th ed
McGrawHill Medical New York 2012
5) Guise TA, Mundy GR. Physiological and pathological roles of parathyroid
hormone-related peptide. Curr Opin Nephrol Hypertens. 1996 Jul; 5(4):7) Usdin TB, Wang T, Hoare SR, Mezey E, Palkovits M. New members of theparathyroid hormone/parathyroid hormone receptor family: theparathyroid hormone 2 receptor and tuberoinfundibular peptide of 39
residues. Front Neuroendocrinol. 2000 Oct; 21(4): 349-83.
8) Goldman L et al edds Goldman's Cecil Medicine 24th ed Elsevier. 20129) PMDA, The information about the case report with suspected side effects
http://www.info.pmda.go.jp/fsearchnew/jsp/menu_fukusayou_base.jsp
10) Prescrire team. Teriparatid. Prescrire Int. 2005 14(75): 5-9.
11) University of Washington Parent Directory
https://courses.washington.edu/conj/bess/bone/bone2.html

307-15.
6) Martin TJ, Moseley JM, Williams ED. Parathyroid hormone-related
protein: hormone and cytokine. J Endocrinol. 1997 Sep; 154 Suppl:
S23-37.

MED CHECK - TIP December 2017 / Vol.3 No.9 ・ Page 35

Review
Insomnia, Optimal Sleep Duration and Harm ofSleeping pills
On Essential Points for Evaluating Hypnotics
Translated from Med Check-TIP in Japanese Sept 2017: 17(73):110-112

Summary:●For evaluation of hypnotics (sleeping pills), it is essential to compare effects of insomnia and hypnotics on health.
●Risk of death in persons who experienced insomnia was lower by 10%-19% than that in persons who did not.
In other words, the former lived longer. Similar to changes caused by aging, when the participants were forcibly
deprived of sleep, their glucose tolerance (sugar processing capacity) and thyroid function deteriorated, and their stresshormone increased. In contrast, when they were allowed to have optimal sleep duration, their conditions were
restored.
●Persons who do not experience insomnia usually have deficient sleep, and thus they can fall asleep immediately.
However, they maintain high level of stress. On the other hand, persons who usually sleep sufficiently sometimes
experience difficulty in falling asleep. Because of that, they tend to feel that they have “insomnia.” However,
because they usually have adequate sleep duration and have less stress, they remain healthy.
●Risk ratio for death in persons who routinely used hypnotics was higher by 25%-39% than that in persons who did
not.
●Incidence of depression was 2.4 times higher in persons on hypnotics as compared with those on placebo.
Infection and cancer also increased by 44% and 35%, respectively. The use of hypnotics and anxiolytics may cause
traffic accidents, falls, and addiction. When they are discontinued, they may cause withdrawal symptoms as well.
These may contribute to increased risk for death.
●Hypnotics and anxiolytics such as benzodiazepines reduce secretion of endogenous anxiolytic substance (GABA)
which is secreted as needed at stress. They also down-regulate their receptors, leading to insufficient suppressionof excitement when they encounter danger or difficulties. Consequently, they feel excess anxiety, leading to panic
disorders and depression. In addition, the medicines also suppress immunity, causing infection and cancer. For
assessment of new hypnotics, their effects on receptors and immunity must be examined.

Keywords:
insomnia, optimal sleep duration, sleep latency, sleep debt, hypnotics, risk of death, depression, infection, cancer morbidity, GABA,
down-regulation, immunosuppression

Introduction
This issue featured a hypnotic, suvorexant as a “New
Product”. When considering harm and benefit of hypnotics,

insomnia is - person’s perception of “not having satisfactory
sleep” [1]. It is only a subjective complaint [2]. It is different
from short sleep duration or deficient sleep.

it is essential to compare the effects ( harm and benefit) ofIn general, insomnia is believed to be harmful to health.

insomnia and effects (harm and benefit) of hypnotics on health.

When patients are not satisfied with their sleep, they want

There are various types of “insomnia”, including having

to secure enough sleep even by using hypnotics. Furthermore,difficulty in falling asleep, waking up at the middle of sleep,

physicians casually prescribe them. However, is it really true

and waking up too early in the morning. The main feature ofthat “insomnia is harmful” and “having adequate sleep by

Page 36 ・ MED CHECK - TIP December 2017/ Vol.3 No.9

using hypnotics is beneficial for our health”? This article willa lack of sleep.

examine these questions.

(2) Persons who sometimes experience insomnia usually havesufficient sleep for them, and thus tend to live longer.

Sleep duration and risk of death
The study conducted in the United States followed over

What happens when one is forcibly deprived of sleep?

1 million men and women aged 30 years or older for

Other studies support our views above. One is anapproximately 5 years [3]. The results adjusted by over 30

experiment involving 11 males in their twenties (note 1). In

kinds of risk factors such as smoking and major diseases

this study, the participants were restricted to sleep only 4( hypertension, diabetes etc. ) as well as age and sex werehours a day for 6 days, and then allowed to sleep 12 hours

reported. Below is the summary of the study [3].

a day for the next 6 days. Their glucose tolerance (note 2)(1) Most people had average of about 8 hours (7.5-8.4 hours)

worsened when they were deprived of sleep as compared withof sleep, followed by about 7 hours (6.5-7.4 hours).

when they had sufficient sleep (p<0.02). Secretion of thyroid-(2) People who slept for 7 hours lived the longest.

stimulating hormone decreased, and level of stress hormone,(3) About a half of the women and about 70% of the men

cortisol (corticosteroid), increased (p=0.0001). Hyperactivity ofreported that they never had insomnia.

sympathetic nervous system was observed (p<0.02).

The Japanese study [4] did not examine "insomnia", but it
showed similar results regarding (1) and (2).

The authors concluded “The effects are similar to thoseseen in normal ageing and, therefore, sleep debt may increase
the severity of age-related chronic disorders.” [6].

Does insomnia shorten life expectancy?

Another study [7] was conducted in Japan to experiment

In the U.S. study [3], hazard ratio for death was lower by

the opposite condition. This study involved 15 healthy men

19% and 13% in women and men who reported insomnia

in their twenties. They were allowed to sleep as much as they

once a month, respectively as compared with those who neverwished. Their usual sleep duration was 5.8-8.9 hours (average

did. Even in women and men who reported insomnia 10 times

7.4 hours).

or more a month, hazard ratio for death was lower by 13%

At day 1, they slept for average 10.6 hours. At day 2 and 3,

and 10%, respectively (Figure.1). This means that people with

their sleep duration gradually became shorter, and after days

insomnia live longer than those without. While the authors

4-9, it stayed at average 8.4 hours. This is considered to beof the study did not give clear explanation about this result

the average optimal sleep duration although it does not apply

which seemingly contradicted with the common view on

to all age groups.

insomnia, the Med Check No. 13 (Jan. 2014) [5] discussed as

After securing optimal sleep duration, their glucose

follows.

level and cortisol level decreased significantly, and thyroid(1) Persons who never experience insomnia may actually havehormone increased significantly as compared with the

Figure 1: Frequency of insomnia per month and risk of death

Risk of death is expressed as the adjusted hazard ratio compared with “person who
never experience insomnia” as the baseline (1.0) [3]

MED CHECK - TIP December 2017 / Vol.3 No.9 ・ Page 37

Review
Reviewbaseline. These changes are totally opposite of those after

Figure 2: Frequency of hypnotic use and risk ratio for death

having deficient sleep. In other words, the participants
became healthier and had less stress after the experiment.
Having adequate sleep may sometimes cause difficulty infalling asleep – “Insomnia”
Note 1：Lack of sleep = sleep debt. The term, sleep debt is sometimes
used in other literatures, but this article uses the term “a lack of sleep”
or “deficient sleep”.
Note 2：Test for measuring glucose processing capacity: After taking
a certain amount of glucose, changes in glucose level or insulin level
are measured. If insulin secretion is insufficient and glucose level rises,
poor glucose tolerance is detected.
Risk of death is expressed as the adjusted hazard ratio compared

Sleep latency (time from bedtime to falling asleep) of persons
who never experience insomnia tend to be as short as 5-10

with “person who never experience insomnia” as the baseline (1.0)[3]minutes. In contrast, people who usually have sufficient sleep
may takes 30-40 minutes to fall asleep [7]. When it takes

occurred 2.4 times more frequently (p=0.0092). NNTH was 58.

long time to fall asleep, one may feel that s/he has “insomnia”.

This means that 1 person out of 58 persons had depression

People who sometimes experience “insomnia” may havebecause of the use of hypnotics. One takes hypnotics, thinking

sufficient sleep duration, and thus they have better functions

that insomnia causes sickness. However, the consequence isof thyroid and pancreatic β -cells. They may be less prone tototally opposite.

chronic diseases, and may tend to be healthy. This may be thereason why they live longer.

Moreover, the other meta-analyses of RCTs suggested that
infection increased by 44% due to using hypnotics (p<0.0001）[12]. An epidemiological study using database also showed

Using sleeping pills is as risky as having a major disease
The U.S. study [3] proved that the use of hypnotics
increased risk ratio for death (Figure. 2).
Hazard ratio for death in women and men who took
hypnotics everyday increased by 24% and 25%, respectively,that cancer increased by 35% [9]. In Japan, the leading causeof death is cancer. The lifetime cancer morbidity among
Japanese is nearly two-thirds (63%) in men and almost a half(47%) in women [13]. If the cancer morbidity increases by
35% with the use of hypnotics, it is a serious harm.

as compared with those who never did [3]. Another study [8]According to the 2014 stat ist ics reported by thealso suggested 39% increase in risk ratio for death when men

International Narcotics Control Board (INCB) [14],and women are combined. Large-scale studies using databases

the consumption of sleeping and sedative drugs wasreported that risk ratio for death was 4-5-fold higher [9,10].

67S-DDD/1,000 persons/day in Japan. This is equivalent

People who complain insomnia would live longer if they doto that 67/1,000 persons use hypnotics every day. In

not use hypnotics. However, using hypnotics would shorten

other words, 1/15 persons use hypnotics ( e.g. equivalent

their life expectancy rather than improving their health.

to Ambien=zolpidem 10 mg x 1) every day. Considering thatIndeed, 25% increase in hazard ratio for death is equivalentmortality increases at least by 20% or more by using

to having one major disease. People are tempted to rely on

hypnotics, such wide use of hypnotics would considerably

hypnotics, believing that an inability to sleep is unhealthy.

contribute to increased cancer mortality.

However, quite contrarily, the use of hypnotics is morehazardous.

The reason why depression increases with hypnotic use
When an animal encounters danger or a difficulty,

Increased depression, infection and cancer

sympathetic nervous system ( adrenalin ) and pituitary-

A meta-analysis of randomized control trials (RCTs) which

adrenocortical system are activated. At the same time,compared hypnotics and placebo showed that depression

gamma-aminobutyric acid (GABA), an endogenous anxiolytic

occurred 2.1 times more frequently in hypnotic groups thansubstance, is secreted to inhibit overexcitement [15-16].

in placebo groups (p=0.0019) [11]. As for benzodiazepines, it

However, when hypnotics or anxiolytics are routinely

Page 38 ・ MED CHECK - TIP December 2017/ Vol.3 No.9

used, endogenous secretion of GABA is reduced, and GABA

References

receptors are continuously stimulated, leading to subsequent

1) Longo DL, Fauci AS, Kasper DL, Et al (eds): Harrison's Principles of Internal

reduction of receptors (down-regulation). As a result, evendaily stress and excitement cannot be coped with, as theycannot be suppressed by reduced endogenous GABA nor

Medicine 18th ed, McGraw-Hill Companies, New York, 2012
2) Medicine Net. Medical Definition of Insomnia
http://www.medicinenet.com/script/main/art.asp? articlekey=17762
3) Kripke DF, Garfinkel L, Wingard DL et al. Mortality associated with sleep

medications with reduced receptors. This leads to over-duration and insomnia. Arch Gen Psychiatry. 2002 Feb; 59(2): 131-6.

excitement. Then, neuronal cells in the brain are damaged4) Tamakoshi A, Ohno Y; JACC Study Group. Self-reported sleep duration as

by excitotoxicity, leading to sustained panic disorder anddepression.
In addition, a lack of attention by hypnotics or anxiolytics
leads to traffic accidents and other types of accidents. Falls atnight and bone fractures associated with falls may increasein the elderly people. Addiction and withdrawal symptoms
may also be caused [17]. These all contribute to increased
mortality.
Depending on hypnotics or anxiolytics may simply
postpone the problem that we have to face and to resolve.
However, those who depend on such medications cannot solve
the problem, and the cause of anxiety remains. Hypnotics
and anxiolytics even disable them from dealing with the issue
effectively and adjusting themselves to real situations. As aresult, they may have financial and health problems, and even
their life expectancy may be shortened.

a predictor of all-cause mortality: results from the JACC study, Japan. Sleep.
2004 Feb 1;27(1): 51-4.
5) Hama R, Do those with insomnia live long? MedCheck, 2004：4(13)：12-13.
6) Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic andendocrine function. Lancet. 1999 Oct 23;354(9188): 1435-9
7) Kitamura S, Katayose Y, Nakazaki K et al. Estimating individual optimal sleep
duration and potential sleep debt. Sci Rep. 2016 Oct 24; 6: 35812.
8) Hublin C, Partinen M, Koskenvuo M, Kaprio J. Sleep and mortality: apopulation-based 22-year follow-up study. Sleep. 2007 Oct; 30(10):1245-53.
9) Kripke DF, Langer RD, Kline LE. Hypnotics' association with mortality orcancer: a matched cohort study. BMJ Open. 2012 Feb 27;2(1): e000850
10) Kripke DF. Hypnotic drug risks of mortality, infection, depression, andcancer: but lack of benefit. F1000Res. 2016 May 19;5:918.
11) Kripke DF. Greater incidence of depression with hypnotic use than withplacebo. BMC Psychiatry. 2007 Aug 21;7:42.
12) Joya FL, Kripke DF, Loving RT, Dawson A, Kline LE. Meta-analyses of
hypnotics and infections: eszopiclone, ramelteon, zaleplon, and zolpidem. J
Clin Sleep Med. 2009 Aug 15;5(4): 377-83.
13) National Cancer Center Japan, National Cancer Information Center,

The reason why infection and cancer increase
Most of the substances that are essent ial during
vigorous activity, such as adrenalin and corticosteroids,
have immunosuppressive effects. GABA, which inhibits
overexcitement, is also one of them [18,19].
All immunosuppressive medicines increase infection andcancer. Immunosuppressive effects may also be related to thereason why hypnotics increase infection and cancer.

Probability having cancer, risk of cumulative incidence of cancer risk
(calculated based on the data 2012) http://ganjoho.jp/reg_stat/statistics/
stat/summary.html
14) International Narcotic Control Bord. Psychotropic Substances-Statistics for2014 https://www.incb.org/documents/Psychotropics/technicalpublications/2015/Tech_PSY_2015.pdf
15) Singewald N, Zhou GY, Schneider C. Release of excitatory and inhibitory
amino acids from the locus coeruleus of conscious rats by cardiovascular
stimuli and various forms of acute stress. Brain Res. 1995 Dec 15;704(1):42-50.

Furthermore, benzodiazepines are clastogenic and16) Inoue W, Baimoukhametova DV, Fuzesi T et al. Noradrenaline is a stress-

teratogenic, and carcinogenicity was also reported in animals

associated metaplastic signal at GABA synapses. Nat Neurosci. 2013 May;[10].

16(5): 605-12.
17) Menkes DB. Hypnosedatives and anxiolytics. In Dukes MNG et al Eds
Meyler's Side Effects of Drugs 14th Edition Elsevier Amsterdam, 2000.

Conclusion
Securing adequate sleep duration, which might sometimes
cause “insomnia”, is needed for healthy and long life. Do
not depend on hypnotics. They are hazardous to health as
they increase accidents, depression, infection and cancer18) Huemer HP, Lassnig C, Nowotny N et al Diazepam leads to enhanced
severity of orthopoxvirus infection and immune suppression. Vaccine. 2010
Aug 31;28(38): 6152-8
19) Sanders RD, Godlee A, Fujimori T et al. Benzodiazepine augmented
γ-amino-butyric acid signaling increases mortality from pneumonia in mice.
Crit Care Med. 2013 Jul; 41(7): 1627-36.

by paralyzing nerves and suppressing immunity. Whenevaluating new hypnotics, it is essential to consider theiradverse effects on health.

MED CHECK - TIP December 2017 / Vol.3 No.9 ・ Page 39

Review
Review

Pneumonia caused by proton pump inhibitors (PPI):(1)Meta-analysis

Synopsis from MedCheckTIP in Japanese Sept 2017 : 17(73):114-115

Keywords:
Proton pump inhibitor, PPI, pneumonia, gastric acid suppression, meta-analysis, peptic ulcer, V-type proton pump, infection

Introduction
Proton pump inhibitors (PPI) exert strong inhibition of

Systematic review and meta-analysis on PPI and pneumonia

gastric acid secretion. They have apparently few immediate

The systematic review [9] retrieved 33 studies, of which 26

adverse reactions, and they are often used for eradication ofstudies were included in the meta-analysis. These 26 studies

H. pylori, Gastroesophageal Reflux Disease (GERD), prevention

included 226,769 cases of community acquired pneumonia

of gastric ulcer in low-dose aspirin users and prevention of(CAP) among 6,351,656 participants. A pooled risk of CAP

stress ulcer in seriously ill patients. They are often used evenwith ambulatory PPI therapy was 1.49 (95% CI: 1.16, 1.92; I2

in elderly persons and the use of PPIs seems excessive in

99.2%).

total.

The risk increased during the first month of therapy (OR2.10; 95% CI: 1.39, 3.16), regardless of PPI dose or patient age.

Over use of PPIs
The number of PPI users who were prescribed withAmong 26 studies, statistically increased risk was reported in
15 studies.

equivalent to 8 weeks course of PPI for gastric ulcers was

Moreover, even in the studies in which no statisticallyestimated to be 23,600,000 person-courses in 2014. Thissignificant increase in overall risk was observed, statistically

was calculated from the total amount of shipment of only 5

significantly increased odds ratio ( e.g. 3.8 ) was reported

major brand names of PPIs reported [1]. These data support

if the analysis was restricted within one week from theexcessive use of PPIs.

commencement of treatment. Hence, it is true that pneumonia
risk is high in the short term.

Insufficient warning description on PPI labels
There are descriptions and warning of bone fractures andFigure Meta-analysis results of 26 studies

infection with clostridium (C. difficile) in the labels of PPIs as
adverse reactions [2]. However, the labels of PPIs in Japando not mention pneumonia at all [2]. It is not well known
that PPIs inhibit another type of proton pump, V-type proton
pump or V-ATPase [3-5].
Epidemiologic studies on PPI and pneumonia
After 2003, a large number of epidemiologic studies which
reported the link of PPI use and pneumonia risk have been
published. Some of Japanese review papers introduced thesestudies [6,7]. The Guidelines by the American College of
Gastroenterology (ACG) mentioned "pneumonia risk of PPI" [8].

The paper [9] can be accessed for free. Please see the figure on the original paper.

A systematic review and meta-analysis were reported in2015 [9]. However, in 2016 an epidemiologic paper with
opposite results was published [10], which is criticized in thisissue [11]. (p42-45)
Page 40 ・ MED CHECK - TIP December 2017/ Vol.3 No.9

Warnings in prescribing PPIs
The authors of the systematic review [9] concluded
that outpatient PPI use was associated with a 1.5-foldincreased risk of CAP with the highest risk within the firstnormal functions of these cells: acidification of urine, bone

30 days after initiation of therapy. They also discussed that

resorption, appropriate pH maintenance in the immune

providers should be aware of this risk when consideringsystem cell and sperm maturity.

PPI use, especially in cases where alternative regimens may

As for neoplastic cells it helps to invade to other tissus.

be available or the benefits of PPI use are uncertain [9].

Inhibition of V-type proton pump may induce decreased

These conclusions and discussions are very thoughtful andsurfactant production by type II alveolus cells, impairment

appropriate.

of intra-alveolar cleaning by alveolar macrophages, leading
to pneumonia. Impaired urinary acidification may also cause
urinary infection such as cystitis and/or pyelonephritis. Bone

Mechanism of infections caused by PPI
It is generally believed that secretion of gastric acid issuppressed by PPIs as the mechanisms of pneumonia caused

fracture may be induced as the consequence of impaired
function of bone metabolism.

by PPI use. However, more important mechanisms, V-type
proton pump (V-ATPase) should be discussed [3-5].

PPIs

In practice

inhibit not only the gastric proton pump but also V-type

The use of PPIs increases pneumonia especially within one

proton pump which are found in almost all cells in the body,month of treatment. Doctors should explain the harm to their

including alveolus type II cells [12], macrophages (including

patients, consider the balance of benefit and harm of PPI use

the alveolar macrophages ) [13], neutrophils, kidney cells,

and decide whether they should prescribe or not.

osteoclasts, testicular cells and plasma membrane of certain

When they prescribe, patients should be closely followed-

neoplastic cells. It plays a very important role in maintaining

up. The prescription of PPIs should be restricted to six weeks

Table: Summary of systematic review and subgroup analyses.by Lambert et al [9]*a Dose is categorized as Low for doses <1 defined daily dose, High for doses > 1 defined daily dose*b Duration refers to duration of time taking PPI prior to community-acquired pneumonia diagnosis
These data are also available in the original paper [9]References
1) A handbook of pharmaceutical affairs (2016) published by JIHO Ltd.

TA. Risk of community-acquired pneumonia with outpatient proton-pump2) Labels of some PPIs (omeprazole and lansoprazole etc)

inhibitor therapy: a systematic review and meta-analysis. PLoS One. 20153) MedCheck TIP editorial team, H. pylori eradication may shorten life
span. MedCheck TIP in English 2015: 1 (1): 7-9. (Translated from
MedCheckTIP in Japanese. 2015: 15 (58): 37-39.
4) Cipriano DJ, Wang Y, Bond S et al. Structure and regulation of thevacuolar ATPases. Biochim Biophys Acta. 2008;1777(7-8): 599-604
5) Jefferies KC, Cipriano DJ, Forgac M. Function, structure and regulationof the vacuolar (H+) -ATPases. Arch Biochem Biophys. 2008 Aug 1;476(1):33-42
6) Yoshiichi Kinoshita, Safety of PPIs 2013, latest findings. Therapeutic
Research.2014; 35 (4): 410-421.
7) Takeshi Kamiya, On the safety of PPI Mebio 2012, 29 (4): 12-17.
8) Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis andJun 4; 10(6): e0128004
10) Othman, F, Crooks, C.J, Card, T.R. Community acquired pneumonia
incidence before and after proton pump inhibitor prescription: Population
based study. BMJ (Online): 355,i5813
11) Hama R. Pneumonia caused by proton pump inhibitor (PPI):(2) Criticalappraisal of a study using prior event rate ratio adjustment method,
MedCheckTIP in English. 2017: 3 (9): 42-45 (translated from MedCheck
TIP in Japanese 2017: 17 (74): 131-132.
12) Chintagari NR, et al. Vacuolar ATPase regulates surfactant secretionin rat alveolar type II cells by modulating lamellar body calcium. PLoS One.
2010 Feb 16;5(2):e9228. PMID:20169059
13) Bidani A, et al. Bactericidal activity of alveolar macrophages ismanagement of gastroesophageal reflux disease. Am J Gastroenterol

suppressed by V-ATPase inhibition. Lung. 2000;178(2):91-104. PMID:

2013;108: 308-28.

10773135

9) Lambert AA, Lam JO, Paik JJ, Ugarte-Gil C, Drummond MB, Crowell

MED CHECK - TIP December 2017 / Vol.3 No.9 ・ Page 41

Review
Review

Pneumonia caused by proton pump inhibitor (PPI):(2) Critical appraisal of a study using prior event rate
ratio adjustment method

Translated from MedCheckTIP in Japanese Mov 2017 : 17(74):131-132

Summary:
Othman et al. denied the risk of community acquired pneumonia caused by proton pump inhibitors (PPI) based on
their study results from both PERR (prior event rate ratio adjustment) method and self-controlled case series study (SCCS)
adjusted by prior event rate ratio.
The results are very different from the results obtained by conventional cohort studies, case-control studies and asystematic review and meta-analysis of 26 epidemiologic studies. The reasons of discrepancy between these results
are discussed.
It is highly probable that the prior event influenced the prescription of the drug concerned and the importantbackground characteristics (major confounding risk factors) fluctuate very widely between prior to and after theprescription of the drug concerned. In other words, the prior rate ratio adjustment method is misused.
The hazard ratio of pneumonia by the narrow primary care definition was 3.9 (by cohort study) and 2.7 to 3.2 (bySCCS method). These results are consistent with the results from conventional epidemiologic studies and those fromthe meta-analysis.
It can be concluded that PPIs cause pneumonia.

Keywords:
Proton pump inhibitor (PPI), pneumonia, cohort study, self-control case series, prior event rate adjustment methods,
confounder, immunosuppressantIntroduction

three methods:

This issue reports about pneumonia caused by proton(1) Cohort study in which incidence rate ratio ( hazard

pump inhibitors (PPI) [1] referring to a systematic review andratio: HR) is calculated by adjusting various confounding risk

meta-analysis results [2] . On the other hand, Othman et al [3]factors.

reported contrary results.

(2) The prior event rate ratio adjustment method: crude HR

They conclude that the association between the use of PPIs

during post period adjusted by crude HR during prior period.

and risk of community acquired pneumonia was likely to be(3) HR by self-control case series method is also adjusted

due entirely to confounding factors [3]. In other words, theyby prior event rate ratio.

claimed that the main reason of this discrepancy was derived(1) The conventional method of cohort study

from entirely insufficient adjustment of the confounder by thepast studies.

In their conventional cohort study, "pneumonia" event ratein the PPI prescribed patients (160,000 PPI new users) was

This article discusses Othman’s prior event rate adjustmentcompared with that in the 160,000 PPI non-users who were

method and its pitfall, modifying the rapid response [4] toindividually matched the exposed patients one to one by age

Othman et al [3].

(within 5 years), sex, and year of prescription.
In the Othman’s report, event rate ratio (Hazard ratio: HR)

The outline of the Othman article
Othman et al [3] conducted their studies by the following
Page 42 ・ MED CHECK - TIP December 2017/ Vol.3 No.9

was calculated by adjusting various confounding risk factors
such as comorbidities, corticosteroid use, immunosuppressantFigure1: Outlines of cohort study methods by Othman et al

The fundamental method of cohort study is to calculate pneumonia incidence rate ratio (hazard ratio) for drug users compared with
non-users with adjustment by various confounding factors (HR-Dadj). Othman et al calculated ratio of post exposure crude hazard ratio(HR-Dcr) to prior exposure crude hazard ratio (HR-Pcr) as prior risk adjusted hazard ratio (HR-Dcr/HR-Pcr). Their patients analysed
were exposed to highly immunosuppressive agents that induce pneumonia prior to PPI use and the immunosuppressants might havebeen stopped after the complication of pneumonia and PPI might have been prescribed in order to prevent stress ulcer in severe septic
infections. Adjustment by prior hazard ratio is unnecessary.

use and so on as usually conducted in conventional cohort

time, so only exposed patients with events can be included.

studies.

The advantage of this design is that the influence of between

Pneumonia risk of PPI use was evident in the conventional
cohort methods they reported. HR of pneumonia by thebroad primary care definition (Pneumonia 1) was 1.65 (95%CI:

person confounding will be eliminated [3].
For pneumonia-1, 48,451 patients were analyzed and 4,461
patients were analyzed for pneumonia-2.

1.53-1.77), while HR of pneumonia by the narrow primary

By this method, HR for pneumonia-1 was 1.19 and 1.49

care definition (Pneumonia 2) was 3.87 (95%CI: 2.75-5.44).

during D1 and D2 period, respectively (see Figure 2 for D1 andThese results are consistent with the results from otherD2). HRs for pneumonia-2 during D1 and D2 period were 2.70

epidemiologic studies and from the meta-analysis of them [2].

(95%CI: 2.29-3.19) and 3.18 (95%CI:2.93-3.46), respectively.

(2) The prior event rate ratio adjustment method

However, HRs were changed to below 1.0 and the results

The second method of Othman et al. is “the prior event

were similar to those obtained by the second method (PERR)

rate ratio adjustment method: PERR method” [5-7] which has(problem of this method is discussed in the footnotes of Figure 2

recently been proposed as a means of reducing the bias thatbriefly and precisely in the following section).

results from residual confounding [3].
The principal benefit claimed is that if crude HR during post
period (right half of Figure 1) is adjusted by crude HR during

Major reasons for discrepancies lie in the Othman’s methods,
not in the past studies

prior period ( left half of Figure 1), all residual confounders

The results by Othman et al [3] are very different frommay be adjusted. Crude HR means that HR is not adjusted by

the results obtained by the past conventional cohort studies,confounding risk factors.

case-control studies and a systematic review and meta-

As a result, HR for pneumonia-1 was reported to be
0.91 (95% CI: 0.83-0.99). This is the results that crude HR

analysis of 26 epidemiologic studies [2]. The reasons of sucha discrepancy are discussed [4].

2.06 during post period was divided by the crude HR 2.26

Uddin et al [7] discussed that PERR provided more biased

during prior period of PPI prescription. For pneumonia-2,

estimates than the conventional method when the prior

the adjusted HR was 0.82 ( 95% CI: 0.53-1.20 ). This is theevent rate strongly influenced the probability of exposure.

result that Crude HR 2.82 during post period was divided byMoreover, they discussed that PERR method was sensitive

crude HR 3.41 during prior period (problem of this method is

to small violation of one of the key assumptions (i.e. constantdiscussed in the footnotes of Figure 1 briefly and later precisely).

effects of confounders in both prior periods and post-periods) [7].

(3) The self-control case series
The self-controlled case series analysis method is a type of

Let us take a look at the situation of pneumonia incidence
prior to PPI prescription in the cohort study and self-cohort study in which relative risk is based on within person

controlled case series study by Othman et al [3].

comparisons between exposed and unexposed observation

PPI-users had more complications than non-users and

MED CHECK - TIP December 2017 / Vol.3 No.9 ・ Page 43

Review
Review
Figure 2: Outline of self-controlled case series (SCCS) methods by Othman et al

Original Figure presented by Othman et al is modified in this article for easy understanding. In ordinary SCCS study,
pneumonia incidence rate ratio during of PPI exposure (D1, or D1+D2) to that during baseline period (B) is calculated (Hazard
ratio: HR-D). On the other hand, Othman reported adjusted HR (HR-D/HR-P) which is adjusted by hazard ratio at P (30 days
prior to PPI exposure). During the period P, immunosuppressants might induce pneumonia and the immunosuppressantsmight have been stopped after the complication of pneumonia, and PPI might have been prescribed in order to prevent
stress ulcer in severe septic infections. Adjustment by prior hazard ratio is unnecessary.

included more immunosuppressed patients (10.3 %) than non-

(95%CI: 2.69 to 5.16) by the conventional cohort methods,

Immunosuppressed patients were defined according toto 3.46) by the SCCS method as compared with the baseline

criteria to contraindicate vaccination [6]: in brief; patients

period. These results are consistent with the results from thewith immunosuppressive chemotherapy or radiotherapy,

past epidemiologic studies and from meta-analysis by theorgan transplant patients with immunosuppressive treatment

systematic review [1].

users (3.0%): odds ratio = 3.68 (95%CI: 3.56-3.80, p<0.0001).

and HRs were 2.70 (95%CI: 2.29-3.19) to 3.18 (95% CI: 2.93

or patients with high dose systemic corticosteroids (2 mg/kg/
day of oral prednisolone for at least one week or 1 mg/kg or more
for one month).

Conclusion
In the study of Othman et al., it is highly probable that theThese immunosuppressants induce pneumonia moreprior event influenced the prescription of the drug concernedfrequently than PPI. Hence, pneumonias as prior events may

and the important background characteristics ( major

include immunosuppressant-induced pneumonias which may

confounding risk factors) fluctuated very widely between prioroften be very serious and complicated with septic shock withto and after the prescription of the drug. In other words, theseptic-encephalopathy.

prior rate ratio adjustment method is misuesed. The hazard

After such serious conditions are observed,

ratio of pneumonia by the narrow primary care definition was

immunosuppressants are usually stopped or at least the doses

3.9 (by cohort study), and 2.7 to 3.2 (by SCCS method). These

are reduced. PPIs are frequently prescribed for prophylaxis

results are consistent with the results from conventionalof stress-induced peptic ulcer in these situations.

epidemiologic studies and those from the meta-analysis. It

Essential conditions for PERR methods which Uddin et al [5]mentioned are as follows:(1) Prior events (pneumonias) do not influence the probabilityof exposure (PPI) and(2) Confounders (immunosuppressant use) are constant in bothprior periods and post-periods.
Hence, both conditions are probably violated in the study byOthman et al [3].
The results from the conventional cohort method(hazard ratio adjusted by various confounding factors including
immunosuppressants) and hazard ratio compared with baseline

period by SCCS method are the appropriate estimates of PPI
risk of pneumonia in the study by Othman et al: adjusted HR
for pneumonia (the narrow primary care definition) was 3.73

Page 44 ・ MED CHECK - TIP December 2017/ Vol.3 No.9

can be concluded that PPIs increase (or cause) pneumonia.

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M
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HECK

The Informed Prescriber
2017

Vol.3

No.9

Editor-in-Chief: HAMA, Rokuro (MD)
Deputy Editor: KIMOTO, Yasusuke (MD); TANIDA, Noritoshi (MD)Managing Editor: SAKAGUCHI, Keiko
Editorial Staff: NAKANISHI,Takeaki(Pharmacist); OHTSU,
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Advisors:HONZAWA,Tatsuo (MD[GP]); KIM,Mieko(Pharmacist);
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