Download Idiopathic Pulmonary Arterial Hypertension? Is

Is Methamphetamine Use Associated With
Idiopathic Pulmonary Arterial Hypertension?
Kelly M. Chin, Richard N. Channick and Lewis J. Rubin
Chest 2006;130;1657-1663
DOI 10.1378/chest.130.6.1657
The online version of this article, along with updated information
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CHEST
Original Research
PULMONARY HYPERTENSION
Is Methamphetamine Use Associated
With Idiopathic Pulmonary Arterial
Hypertension?
Kelly M. Chin, MD; Richard N. Channick, MD, FCCP; and
Lewis J. Rubin, MD, FCCP
Background: Amphetamine, methamphetamine, and cocaine are suspected of being pulmonary
hypertension risk factors based on a small number of case reports along with pharmacologic
similarities to fenfluramine, a diet drug associated with pulmonary arterial hypertension (PAH).
We sought to determine whether rates of stimulant use are increased in patients believed to have
idiopathic PAH compared with patients with PAH and known risk factors and patients with
chronic thromboembolic pulmonary hypertension (CTEPH).
Methods: In this retrospective study, rates of stimulant use were determined for 340 patients with
idiopathic PAH, PAH and known risk factors, or CTEPH seen between November 2002 and April
2004. “Stimulant” use was defined as any reported use of amphetamine, methamphetamine, or
cocaine. Odds of stimulant use were calculated using a polychotomous logistic regression model.
Results: A history of stimulant use was found in 28.9% of patients with a diagnosis of idiopathic
PAH, compared with 3.8% of patients with PAH and a known risk factor, and 4.3% of patients with
CTEPH. After adjustment for differences in age, patients with idiopathic PAH were 10.14 times
(95% confidence interval, 3.39 to 30.3; p < 0.0001) more likely to have used stimulants than
patients with PAH and known risk factors, and 7.63 times (95% confidence interval, 2.99 to 19.5;
p < 0.0001) more likely to have used stimulants than patients with CTEPH.
Conclusions: Patients with idiopathic PAH are significantly more likely to have used stimulants
than patients with other forms of pulmonary hypertension.
(CHEST 2006; 130:1657–1663)
Key words: illicit drugs; methamphetamine; pulmonary hypertension; risk factors
Abbreviations: CTEPH ⫽ chronic thromboembolic pulmonary hypertension; PAH ⫽ pulmonary arterial hypertension
arterial hypertension (PAH) is a lifeP ulmonary
threatening and potentially fatal disorder. While
some risk factors for PAH have been identified,
many cases remain idiopathic. Amphetamines, cocaine, and other stimulants have been considered
*From the Department of Internal Medicine (Dr. Chin), Division
of Pulmonary and Critical Care Medicine, St. Paul University
Hospital, Dallas, TX; and Department of Internal Medicine (Drs.
Channick and Rubin), Division of Pulmonary and Critical Care
Medicine, University of California, San Diego, San Diego, CA.
The authors have no conflicts of interest to disclose.
Manuscript received March 28, 2006; revision accepted May 27,
2006.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Richard Channick, MD, 9330 Campus Point
Dr, MC 7381, La Jolla, CA 92037; e-mail: [email protected]
DOI: 10.1378/chest.130.6.1657
www.chestjournal.org
“possible” or “very likely” risk factors,1 but evidence
supporting this conclusion is limited. There are a
small number of case reports implicating cocaine2,3
and methamphetamine4 in the development of pulmonary hypertension, but stimulant use as a PAH
risk factor has not been investigated in detail.
Over the last decade, the use of stimulants for the
treatment of attention deficit disorder has increased
approximately threefold.5 Illicit stimulant use has
increased as well, with an estimated 5.2% of the
population reporting “ever” use of methamphetamine, and 0.6% reporting use in the last year.6
Frequency of methamphetamine and amphetamine
use varies by geographic location. Among persons
aged ⱖ 12 years, rates of use in the last year in
western states (including California) were highest,
ranging from 0.98 to 2.21%, while rates in the
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1657
northeast were lowest, with most states having rates
of use from 0.04 to 0.32%.7
In order to determine whether rates of stimulant
use were increased in idiopathic PAH compared
with other forms of pulmonary hypertension, we
For editorial comment see page 1633
performed a retrospective study evaluating amphetamine, methamphetamine, and cocaine use in patients with pulmonary hypertension seen at a large
pulmonary hypertension referral center. A portion of
these results were previously published in abstract
form.8
Materials and Methods
This was a retrospective study conducted at the University of
California at San Diego, Thornton Hospital, La Jolla, CA. The
study included all patients ⬎ 18 years old with PAH or chronic
thromboembolic pulmonary hypertension (CTEPH) seen over an
18-month period (November 2002 to April 2004) in the pulmonary hypertension clinics. Information on demographics, hemodynamics, pulmonary hypertension etiology, race, and prior
stimulant drug use was abstracted from medical records. Any use
of amphetamine, methamphetamine, or cocaine was considered a
positive history of “stimulant” use, as patients were routinely
asked about the use of these drugs during the initial history and
physical examination. Use of other amphetamine-like drugs was
not included, as reliable information was not available for many
patients.
Patients were categorized by their treating pulmonary hypertension specialist based on the 2003 revised clinical classification,1 and based on this diagnosis they were placed into one of
three groups: idiopathic PAH, PAH with known risk factors, and
CTEPH. Patients with other forms of pulmonary hypertension
such as pulmonary hypertension related to lung disease or
left-heart disease were excluded from the study (Table 1). All
patients were required to have undergone cardiac catheterization
Table 1—Patients Excluded From Analysis
Variables
Patients, No.
Excluded causes of pulmonary hypertension
Lung disease
Left-heart disease
HIV with PAH
HIV with CTEPH
Portal hypertension with PAH
Nonthromboembolic pulmonary artery
obstruction*
Acute/recent pulmonary embolism
No pulmonary hypertension found
Normal pressures by catheterization
PAH unlikely and catheterization not done
Incomplete workup
Age ⬍ 18 yr
Total
42
42
9
1
5
6
4
39
11
16
8
183
*Included fibrosing mediastinitis, intravascular leiomyomatosis, and
pulmonary artery sarcoma.
for the initial diagnosis, except those with either a ventricular
septal defect or patent ductus arteriosus. For these patients,
echocardiographic evidence of the congenital heart abnormality
plus pulmonary hypertension was accepted.
Patients with either familial PAH or PAH and one of the
“associated” conditions listed in the 2003 revised clinical classification1 of pulmonary hypertension were considered to have
PAH with known risk factors. This group included familial PAH,
PAH associated with collagen vascular disease, PAH associated
with congenital systemic-to-pulmonic shunts, and PAH associated with the use of fenfluramine or dexfenfluramine. HIV- and
portal hypertension-associated PAH patients were excluded because illicit drug use is a risk factor for HIV and liver disease.
Patients with PAH and none of the above risk factors were
categorized as having idiopathic PAH. Finally, patients with
angiographically proven thromboembolic disease were categorized as having CTEPH.
This study received approval by the University of California,
San Diego Institutional Review Board, including approval for a
waiver of informed consent. This waiver required that there be
no disclosure of protected health information and that patient
information be “de-identified” at the earliest possible date.
Statistical Analysis
Statistical analysis was performed using a logistic regression
model that included all three groups (polychotomous logistic
regression). Age, gender, and race were included in the model as
potential confounders due to associations between these variables
and type of pulmonary hypertension and the possibility that they
may also be associated with stimulant drug use.6 Interaction
between stimulant drug use and age, gender, and race was tested
using the log likelihood method. After testing for interaction,
these potential confounders were removed from the model
through backward elimination if the association (odds ratio)
between stimulant use and type of pulmonary hypertension
changed by ⬍ 10%. Statistical software (NCSS 2004; NCSS;
Kaysville, UT) was used for the analysis including tests for
collinearity; p ⬍ 0.05 was considered significant.
Results
Six hundred fourteen patients with a diagnosis of
possible or definite pulmonary hypertension were
seen over an 18-month period. One hundred eightythree patients were excluded from the analysis because inclusion criteria were not met, including 42
patients with left-heart disease, 42 patients with lung
disease, 25 patients with other forms of pulmonary
hypertension, 39 patients with normal hemodynamics at catheterization, and 35 patients excluded for
other reasons; additional details are given in Table 1.
Of the remaining 431 patients with PAH or CTEPH,
91 patients (21%) were excluded due to incomplete
or missing stimulant use histories. Rates of complete
stimulant use histories were significantly higher in
the idiopathic PAH group (87%) than in the group
with PAH and a known risk factors (79%), and in the
CTEPH group (74%). The final sample of 340
patients included 97 patients with idiopathic PAH,
106 patients with PAH and known risk factors, and
137 patients with CTEPH.
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Original Research
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More women than men were seen in all patient
groups, with women making up 56.2% of the
CTEPH group, 72.2% of the idiopathic PAH group,
and 88.7% of the group with PAH and known risk
factors (Table 2). Patients in the CTEPH group were
oldest, with a mean age of 53.0 years, compared with
49.1 years for those with PAH and known risk
factors, and 47.1 years for those with idiopathic
PAH.
Thirty-eight patients reported exposure to a stimulant-type drug, including 28 patients with a diagnosis of idiopathic PAH, 6 patients with CTEPH, and 4
patients with PAH and known risk factors (Table 3;
Fig 1). Methamphetamine use was reported most
frequently, with 23 patients reporting methamphetamine use alone and 8 patients reporting use of both
methamphetamine and cocaine. Three patients had
taken amphetamines illicitly, and two others reported amphetamine use as a diet pill (although one
patient had also used cocaine). Cocaine use alone
was uncommon, with only three patients describing
cocaine use without methamphetamine or amphetamine use. Route of exposure was described for 11
patients, including 2 patients who had used stimulants IV, and 9 patients who had used stimulants
through non-IV routes (inhaled, smoked, or oral).
Patients with reported stimulant use were significantly younger than patients without reported use
(mean age, 44.5 years vs 50.9 years; p ⫽ 0.006), but
no significant differences in rates of use by race or
gender were seen. Duration of use was not available
in all cases and was reported only as “long term” or
“frequent” in others, but 15 patients did report a
general duration of use ranging from 6 months to 25
years; Tables 4, 5 provide additional details. Two
patients had positive toxicology screen results at
diagnosis, and two other patients required hospitalizations for PAH exacerbations after resuming drug
use despite initial improvement with treatment.
Table 3—Specific Stimulants Taken by Pulmonary
Hypertension Group*
Variables
Methamphetamine alone
Amphetamine alone
Cocaine alone
Methamphetamine
plus cocaine
Amphetamine plus
cocaine
Total
Idiopathic
PAH
(n ⫽ 97)
PAH With Known
Risk Factors
(n ⫽ 106)
CTEPH
(n ⫽ 137)
16
3
1
7
4
0
0
0
2
0
2
1
1
0
1
28
4
6
*Data are presented as No. of patients.
Prior to adjustment for potential confounders,
patients with idiopathic PAH were significantly more
likely to have a history of stimulant use than patients
in either of the comparison groups, with an odds
ratio of 10.35 (95% confidence interval, 3.47 to 30.8;
p ⬍ 0.0001) for idiopathic PAH compared with PAH
and known risk factors, and 8.86 (95% confidence
interval, 3.5 to 22.4; p ⬍ 0.0001) for idiopathic PAH
compared with CTEPH (Table 6). The odds ratios
changed only modestly with the addition of age,
gender, and race into the model, and no significant
interaction between these possible confounders and
stimulant drug use was seen. After backwards elimination using the prespecified criteria, gender and
race were removed from the model, and age was
retained due to a modest decrease in the odds ratio
for CTEPH compared with idiopathic PAH patients.
The final age-adjusted odds ratios for a prior stimulant history were 10.14 (95% confidence interval,
Table 2—Demographics by Diagnosis Group
Variables
Patients, No.
Mean age, yr
Mean pulmonary artery
pressure, mm Hg
Female gender, %
Race, %
White
Black
Hispanic
Asian/Pacific Island
Other or unknown
www.chestjournal.org
Idiopathic
PAH
PAH With Known
Risk Factors
CTEPH
97
47.2
50.2
106
49.1
42.2
137
53.0
46.5
72.2
88.7
56.2
74.2
5.2
11.3
3.1
6.2
75.5
3.8
6.6
8.5
4.7
81.8
13.1
2.1
2.2
0.7
Figure 1. As shown, 28.9% of patients with idiopathic PAH
reported prior stimulant use, compared with 3.8% of patients
with PAH associated with other risk factors, and 4.4% of patients
with CTEPH (p ⬍ 0.0001 for comparison between idiopathic
PAH and PAH with known risk factors, and between idiopathic
PAH and CTEPH). Graph shows proportion and 95% confidence
interval.
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1659
Table 4 —Idiopathic PAH: Drug Use Histories
Age,
yr
Gender Uncertain
Duration of Use
Date of
Diagnosis
Most Recent Mean
Pulmonary Artery
Pressure, mm Hg
33
Male
2002
50
36
Female
2003
41
36
37
Female
Male
2004
2003
53
56
37
Female
2004
79
38
40
41
42
43
Female
Male
Male
Female
Male
1999
1999
2001
2003
2004
68
65
39
44
51
46
47
48
49
Female
Female
Female
Male
2003
2000
2002
1998
53
61
46
45
53
Female
1998
52
60
Female
2003
52
30
34
40
41
42
42
42
45
51
54
57
67
Female
Female
Male
Female
Female
Male
Female
Female
Female
Male
Male
Female
2003
2000
1999
2004
2001
2003
2002
1999
2004
1999
2004
2003
58
63
33
55
49
39
29
58
45
63
49
40
Probable Duration of Use ⱖ 6 mo
Long-term use of multiple drugs including heroin, cocaine (last use
1984), and methamphetamine (last use 1999).
Inhaled methamphetamine long term; none for “a few days” prior to
diagnosis; possible prior IV drug use.
Methamphetamine use from age 18 to 22 yr.
Methamphetamine use approximately 12 yr prior to diagnosis over a
period of at least 6 mo; none IV.
Crystal methamphetamine and cocaine use for 4 to 5 yr during the
1990s.
Inhaled methamphetamine use for 17 yr; last approximately 1994.
Amphetamines for 20 yr.
Methamphetamine use over approximately 7 yr.
Methamphetamine “during college years”, none IV.
Fifteen years of crystal methamphetamine and cocaine use continuing
until 5 d prior to hospital admission and diagnosis.
Cocaine and methamphetamine use for 13 yr; none for 5 yr.
Methamphetamine use for 15 yr; last use 1998.
Crystal methamphetamine “on and off for years”.
Cocaine, methamphetamine, and heroin IV for 25 yr; multiple
overdose episodes and several arrests; last use 1992.
Methamphetamine and cocaine use for 20 yr; in 2002, reported none
used “recently”; no history of IV drug abuse.
Amphetamine containing diet pills in the 1960s and cocaine use in the
1980s; none since approximately 1997.
Methamphetamine use continuing up until diagnosis, none IV.*
Methamphetamine use.*
Inhaled crystal methamphetamine use.*
Methamphetamine and cocaine use, last use 1 yr prior to diagnosis.*
Cocaine use.*
Methamphetamine use.*
Methamphetamine use.*
Amphetamine history, none in many years.*
Methamphetamine use (snorted) up until ⬍ 1 mo prior to diagnosis.*
Methamphetamine use; “none for 4 yr”.*
Crystal methamphetamine use.*
Amphetamine containing diet pills in her twenties.*
*Uncertain duration of use.
3.39 to 30.3; p ⬍ 0.0001) for idiopathic PAH compared with AH with known risk factors, and 7.63
(95% confidence interval, 2.99 to 19.5; p ⬍ 0.0001)
for idiopathic PAH compared with CTEPH. Odds
ratios for methamphetamine use were also significant. Amphetamine use and cocaine use alone were
too infrequent to evaluate separately.
Although HIV and portal hypertension patients
were excluded from the study, data on rates of
stimulant use were recorded for these groups.
Eighty-nine percent (eight of nine patients) with
HIV and PAH reported prior stimulant use, and 20%
(one of five patients) with portal hypertension had
taken stimulants. Due to small numbers as well as
the lack of an appropriate control group, formal
statistical analysis was not performed.
Discussion
The central finding of this study was that methamphetamine exposure appears to be strongly associated with idiopathic PAH. Patients with idiopathic
PAH were approximately 10 times more likely to
have a history of stimulant use than patients with
PAH and known risk factors, and almost 8 times
more likely to have a history of stimulant use than
patients with CTEPH, after adjustment for age.
These ratios are similar to those found in studies of
fenfluramine use. For example, the Surveillance of
North American Pulmonary Hypertension study9
found an odds ratio of 7.5 for ⬎ 6 months of
fenfluramine use comparing primary pulmonary hypertension patients to those with secondary pulmo-
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Table 5—PAH With Risk Factors and CTEPH: Drug Use Histories
Etiology
Most Recent Mean
Pulmonary Artery
Pressure, mm Hg
Date of
Diagnosis
Female
Atrial septal defect
63
2000
Female
Female
Male
Female
Female
Female
Male
Male
Atrial septal defect
Fenfluramine
CTEPH
CTEPH
CTEPH
Fenfluramine
CTEPH
CTEPH
97
63
45
41
53
62
76
41
2003
2003
1997
2003
2004
1997
2003
1999
Age,
yr
Gender
34
46
41
42
43
46
46
53
57
Probable Duration of Use ⱖ 6 mo
Inhaled methamphetamines throughout adolescence and up until a
hospital admission when the diagnosis of PAH was made; longest
prior drug-free period was 10 d.
Methamphetamines from age 18 to 40 yr; diagnosis at age 44 yr.
Methamphetamine use 20 yr prior to diagnosis.*
Cocaine and methamphetamine use.*
Cocaine and amphetamine use in her twenties.*
Crack cocaine “intermittently”.*
Methamphetamine use.*
Prior “rare” cocaine use.*
Methamphetamine use.*
*Uncertain duration of use.
nary hypertension, and the International Primary
Pulmonary Hypertension study10 found an odds ratio
of 6.3 for “any anorexigen use” in primary pulmonary
hypertension patients compared with control subjects. Rates of cocaine use alone were too infrequent
to make meaningful conclusions but were included
in the primary analysis, as stimulant use was defined
prior to data collection.
Because of methodologic limitations inherent in a
retrospective chart review study, these results must
be considered preliminary. Potential limitations include missing data and questions about the acceptability of the control groups. Pulmonary hypertension subtype is generally not known definitively at
the time of initial consultation, and we thus expected
to find similar rates of missing data. However, 21%
of patients with PAH and risk factors and 26% of
patients with CTEPH had missing or incomplete
stimulant use histories, compared with only 13% of
patients believed to have idiopathic PAH. Negative
stimulant-use histories may have been more likely to
be recorded as “noncontributory” or “unremarkable”
(considered incomplete), but this does not completely explain the different rates of missing data.
Another concern is that patients with CTEPH may
be referred from a wider geographic region, potentially affecting rates of stimulant use. The use of a
second control group made up of patients with PAH
associated with other risk factors should be reassuring, as the referral pattern in these patients is
generally similar to that of patients with idiopathic
PAH. Exclusion of individual subgroups within the
PAH with risk factors group (for example, excluding
those with fenfluramine use) also did not appreciably
change the calculated odds ratios.
A final concern is that other chronic illnesses in
the two comparison groups might somehow decrease
the rates of stimulant drug use below that of a
normal population. This is a potential factor, though
the rate of methamphetamine use in our two control
populations was only slightly lower than nationally
reported rates. Further, in most cases the symptoms
and disability from pulmonary hypertension are
more severe than the symptoms of any associated
condition.
Despite these methodologic limitations, the finding that 28 of 97 patients with idiopathic PAH have
a history of stimulant use is important and suggestive
Table 6 —Odds of Stimulant Use in Idiopathic PAH, PAH With Known Risk Factors, and CTEPH*
Variables
Idiopathic PAH vs PAH With
Known Risk Factors
Idiopathic PAH vs CTEPH
Any stimulant use
Unadjusted
Full model (includes age, gender, and race)
Final model
Methamphetamine, final model
10.35 (3.47–30.8); p ⬍0.0001
10.05 (3.32–30.4); p ⬍ 0.0001
10.14 (3.39–30.3); p ⬍ 0.0001†
7.73 (2.55–23.5); p ⫽ 0.0002‡
8.86 (3.5–22.4); p ⬍ 0.0001
8.14 (3.14–21.1); p ⬍ 0.0001
7.63 (2.99–19.5); p ⬍ 0.0001†
11.61 (3.34–40.3); p ⬍ 0.0001‡
*Data are presented as odds ratio (95% confidence interval).
†Final odds ratios for any stimulant use are adjusted for differences in age; gender and race were not significant confounders and were removed
from the model. Patients with idiopathic PAH were significantly more likely to have taken stimulants compared with other pulmonary
hypertension patients. Older patients were slightly less likely to have used stimulants; this results in a decrease in the odds ratios after adjustment
for age.
‡Age-adjusted odds of any methamphetamine use. Amphetamine and cocaine use were too infrequent to analyze separately.
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1661
of an association. The far-lower rates of stimulant use
found in the two comparison groups with pulmonary
hypertension add strength to this observation and
suggest that these findings are not just related to the
geographic location or some other aspect of our
patient population. While the results of retrospective
studies may be considered preliminary and less
robust than more formal case-control studies, they
can provide some evidence of an association along
with the rationale needed to conduct additional
studies. For example, the observation by Brenot et
al11 of frequent anorexigen use in a population with
primary pulmonary hypertension coupled with increasing use of these medications led to the performance of the International Primary Pulmonary Hypertension study,10 definitively linking anorexigen
use with the development of PAH.
The mechanisms through which methamphetamine use could lead to pulmonary hypertension are
unknown, and in vivo studies evaluating the effects
of stimulants on the pulmonary vasculature are
limited. One small study12 showed increased pulmonary arterial pressures after methamphetamine administration in humans, while another study13
showed that cocaine administration failed to increase
pulmonary arterial pressures.
Similarities in pharmacology between amphetamines and the diet drug fenfluramine, a known risk
factor for PAH, suggest that a common receptor or
pathway may exist. Like fenfluramine, amphetamines are “substrate-type” releasers,14 increasing
neurotransmitter release via substrate-mediated exchange and through disruption of intracytoplasmic
storage vesicles. Fenfluramine is specific for the
serotonin transporter protein, while methamphetamine and amphetamine act more potently on norepinephrine and dopamine transporters with modest
activity on the serotonin transporter15 (Fig 2).
Figure 2. Although all three molecules are structurally similar,
amphetamine and methamphetamine are more potent releasers
of dopamine and norepinephrine and relatively weak releasers of
serotonin, while fenfluramine acts mainly on serotonin release.15
Serotonin and norepinephrine have both been
proposed as potential contributors to the development of pulmonary hypertension. Both have vasoconstrictive and growth modulating effects on
smooth-muscle cells, and their transporters are
present in the pulmonary vasculature.16 –20 The serotonin transporter itself may also be important, as
levels of this transporter are increased in idiopathic
PAH, its overexpression in mice leads to modest
increases in right ventricular systolic pressures, and
serotonin transporter antagonists can block serotonin-mediated smooth-muscle cell growth in
vitro.21,22
If an association between stimulants and PAH
exists, it will be important to determine whether only
certain stimulants are associated or whether it is a
class effect. In this study, only 2 patients with
idiopathic PAH reported prescription amphetamine
use, compared with 1 patient reporting illicit amphetamine use, 24 patients reporting illicit methamphetamine use, and 1 patient reporting illicit cocaine
use. The majority of illicit methamphetamine users
in national surveys report either inhaling or smoking
the drug23,24; this direct exposure of drug to the
pulmonary vasculature may also be an important
determinant of overall risk.
The high rate of stimulant use among the nine
(excluded) HIV patients with PAH is also intriguing:
HIV infection is considered to be a “definite” PAH
risk factor,25 but how HIV leads to pulmonary
hypertension remains unclear, as neither CD4 count
or viral load have correlated well with the development of PAH.26 Higher-than-expected rates of IV
drug use have been reported in some series,27 but
rates of non-IV stimulant use have not been described.
Higher rates of use might have been expected
among patients with PAH associated with known risk
factors compared with patients with CTEPH, based
on pathophysiology in these forms of PAH that is
presumably more similar to idiopathic PAH than
CTEPH. It is unclear whether the lack of this finding
relates to a true lack of added risk vs limitations in
study design.
In summary, this study found a significant association between stimulant use and idiopathic PAH,
and suggests that stimulant use may be a risk factor
for PAH. Though preliminary, these results are
important because of the widespread and increasing
use of both prescription and illicit stimulants. Additional study of a wider spectrum of stimulant drugs is
warranted to more clearly define this risk, and
particular focus on the HIV-associated PAH subgroup is needed to clarify the role of stimulant use in
this patient population.
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Copyright © 2006 by American College of Chest Physicians
ACKNOWLEDGMENT: We thank Cindy Morgan, MS, and
Fernando Torres, MD, for assistance in statistical analysis and
manuscript preparation.
14
References
1 Simonneau G, Galie N, Rubin LJ, et al. Clinical classification
of pulmonary hypertension. J Am Coll Cardiol 2004; 43:5S–
12S
2 Collazos J, Martinez E, Fernandez A, et al. Acute, reversible
pulmonary hypertension associated with cocaine use. Respir
Med 1996; 90:171–174
3 Yakel DL Jr, Eisenberg MJ. Pulmonary hypertension in
chronic intravenous cocaine users. Am Heart J 1995; 130:
398 –399
4 Schaiberger PH, Kennedy TC, Miller FC, et al. Pulmonary
hypertension associated with long-term inhalation of “crank”
methamphetamine. Chest 1993; 104:614 – 616
5 Olfson M, Gameroff MJ, Marcus SC, et al. National trends in
the treatment of attention deficit hyperactivity disorder. Am J
Psychiatry 2003; 160:1071–1077
6 Lifetime use of specific stimulants and prescription diet pills.
2003 national household survey on drug abuse, Appendix G.
Available at: http://oas.samhsa.gov/NHSDA/2k3NSDUH/
appg.htm#tabg.2. Accessed November 17, 2006
7 National survey on drug use and health: the NSDUH report.
September 16, 2005. Available at: www.oas.samhsa.gov. Accessed November 17, 2006
8 Chin K, Channick R, Kim N, et al. Most patients with PAH
have identifiable risk factors and these risk factors vary by
gender [abstract]. Am J Respir Crit Care Med 2004; 171:A56
9 Rich S, Rubin L, Walker A, et al. Anorexigens and pulmonary
hypertension in the United States: results from the surveillance of North American pulmonary hypertension. Chest
2000; 117:870 – 874
10 Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant
drugs and the risk of primary pulmonary hypertension.
International Primary Pulmonary Hypertension Study Group.
N Engl J Med 1996; 335:609 – 616
11 Brenot F, Herve P, Petipretz P, et al. Primary pulmonary
hypertension and fenfluramine use. Br Heart J 1993; 70:537–
541
12 Kneehans S, Sziegoleit W, Krause M, et al. Clinical-pharmacological studies on the effect of mephantermine and methamphetamine on the hemodynamics of the lung circulation
[in German]. Z Gesamte Inn Med 1975; 30:227–230
13 Kleerup EC, Wong M, Marques-Magallanes JA, et al. Acute
www.chestjournal.org
15
16
17
18
19
20
21
22
23
24
25
26
27
effects of intravenous cocaine on pulmonary artery pressure
and cardiac index in habitual crack smokers. Chest 1997;
111:30 –35
Rothman RB, Ayestas MA, Dersch CM, et al. Aminorex,
fenfluramine and chlorphentermine are serotonin transporter
substrates: implications for primary pulmonary hypertension.
Circulation 1999; 100:869 – 875
Rothman RB, Baumann MH. Therapeutic and adverse actions of serotonin transporter substances. Pharm Ther 2002;
95:73–78
Tseng YT, Padbury JF. Expression of a pulmonary endothelial
norepinephrine transporter. J Neural Transm 1998; 105:
1187–1191
Marcos E, Fadel E, Sanchez O. Serotonin-induced smooth
muscle hyperplasia in various forms of human pulmonary
hypertension. Circ Res 2004; 94:1263–1270
Belohlavkova S, Simak J, Kokesova A, et al. Fenfluramineinduced pulmonary vasoconstriction: role of serotonin receptors and potassium channels. J Appl Physiol 2001; 91:755–761
Erami C, Zhang H, Ho JG, et al. ␣(1)Adrenoceptor stimulation directly induces growth of vascular wall in vivo. Am J
Physiol Heart Circ Physiol 2002; 283:H1577–H1587
Salvi SS. ␣1-Adrenergic hypothesis for pulmonary hypertension. Chest 1999; 115:1708 –1719
Marcos E, Fadel E, Sanchez O, et al. Serotonin-induced
smooth muscle hyperplasia in various forms of human pulmonary hypertension. Circ Res 2004; 94:1263–1270
MacLean MR, Deuchar GA, Hicks MN, et al. Overexpression
of the 5-hydroxytryptamine transporter gene: effect on pulmonary hemodynamics and hypoxia-induced pulmonary hypertension. Circulation 2004; 109:2150 –2155
The Dasis Report: Primary methamphetamine/amphetamine
treatment admissions: 1992–2002. Available at: http://oas.
samhsa.gov/2k4/methTX/methTX.htm. Accessed October 10,
2004
Wu LT, Pilowsky DJ, Wechsberg WM, et al. Injection drug
use among stimulant users in a national sample. Am J Drug
Alcohol Abuse 2004; 30:61– 83
Humbert M, Nunes H, Sitbon O, et al. Risk factors for
pulmonary arterial hypertension. Clin Chest Med 2001; 22:
459 – 475
Mehta NJ, Khan IA, Mehta RN, et al. HIV-related pulmonary
hypertension: analytic review of 131 cases. Chest 2000;
118:1133–1141
Nunes H, Humbert M, Sitbon O, et al. Prognostic factors for
survival in human immunodeficiency virus associated pulmonary arterial hypertension. Am J Respir Crit Care Med 2003;
167:1433–1439
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1663
Is Methamphetamine Use Associated With Idiopathic Pulmonary
Arterial Hypertension?
Kelly M. Chin, Richard N. Channick and Lewis J. Rubin
Chest 2006;130;1657-1663
DOI 10.1378/chest.130.6.1657
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