New York State Psychiatric
Institute, Columbia University, USA
This review paper presents an amplification
of the suffocation false alarm theory (SFA) of
spontaneous panic. SFA postulates the existence
of an evolved physiologic suffocation alarm
system that monitors information about potential
suffocation. Panic attacks maladaptively occur
when the alarm is erroneously triggered.
That panic is distinct from Cannon's
emergency fear response and Selye's General
Alarm Syndrome is shown by the prominence of
intense air hunger during these attacks.
Further, panic sufferers have chronic sighing
abnormalities outside of the acute attack.
Another basic physiologic distinction
between fear and panic is the counter-intuitive
lack of hypothalamic-pituitary-adrenal (HPA)
activation in panic. Understanding panic as
provoked by indicators of potential suffocation,
such as fluctuations in pCO2 and brain lactate,
as well as environmental circumstances fits the
observed respiratory abnormalities.
However, that sudden loss, bereavement and
childhood separation anxiety are also
antecedents of "spontaneous" pahic requires an
integrative explanation. Because of the opioid
system's central regulatory role in both
disordered breathing and separation distress, we
detail the role of opioidergic dysfunction in
decreasing the suffocation alarm threshold.
Ptretr and Klein present results from their
laboratory where the naloxone-lactate challenge
in normals produces supportive evidence for the
endoephinergic defect hypothesis in the form of
a distress episode of specific tidal volume
hyperventilation paralleling challenge-produced
and clinical panic.
1. Introduction
The authors extend the suffocation false
alarm theory (SFA) of Panic Disorder (PD)
(Klein, 1993) by hypothesizing that an episodic
dysfunction in endogenous opioidergic regulation
- a phylogenetically old system that
co-regulates breathing as well as
social-affihiative behavior - explains this
adaptive failure. This makes it possible to
integrate separation anxiety disorder, CO2 and
lactate hypersensitivity, and a range of
respiratory phenomena and pathology with Panic
Disorder.
2. Experimental challenge studies: Lactate
infusion and CO2 inhalation in panic
Panic Disorder is unique among psychiatric
disorders in that its salient component, the
panic attack, can be reliably incited in
laboratory settings by specific chemical
challenges as well as having challenges
specifically blocked by anti-panic agents, e.g.
imipramine. We can experimentally turn panic on
and off, producing trenchant causally related
data rather than inferences from naturalistic
data. These challenge studies, using intravenous
lactate infusion and carbon dioxide inhalation
led to a number of unexpected laboratory
findings that have advanced our understanding of
clinical panic pathophysiology (see Klein, 1993
for details).
Patients who panic to CO2 are a subset of
lactate panickers (Klein, 1993). It was the
recognition that increasing brain CO2 and
lactate are both harbingers of potential
asphyxiation that prompted the suffocation false
alarm theory of Panic Disorder. This theory is
consonant with many recent observations detailed
and expanded below.
3. Air hunger (dyspnea) and Panic
Disorder
That panic is distinct from Cannon's
emergency fear response (Cannon, 1920) and
Se1y's General Alarm Syndrome (Se lye, 1956) is
shown by the prominence of intense air hinger
during these attacks. Acute air hunger rarely
occurs in acute, external-danger initiated fear
(Klein, 1993; Preter and Klein, 1998). Further,
PD patients have chronic sighing abnormalities
outside of the acute attack. Smoking and
pulmonary complaints are independent,
multiplicative risk factors for PD, but not for
other anxiety disorders (Pohi et al., 1992;
Amering et al., 1999). Panic is highly prevalent
in lung disease (asthma, chronic obstructive
pulmonary disease) and in torture victims who
specifically suffered suffocation torture rather
than other assaults (Bouwer and Stein,
1999).
Although increasing hypercapnia is the
salient indicator of potential suffocation,
hypoxia also serves this function. Beck et al.
(1999; 2000) showed that panic patients respond
with increased panic symptoms not only to CO2
inhalation, but also to normocapnic hypoxia, as
predicted by SFA. Patients with prominent
respiratory symptoms during attacks, showed
greater fluctuations in tidal volume during and
after the challenge, as well as overall lower
levels of end-tidal CO2 than those whose
clinical attack did not include respiratory
symptoms. Equivalent increases in anxiety and
panic symptoms were noted, although the sample
size (seven patients in each group) limits
conclusions from this particular null result
These findings support the centrality of the
suffocation alarm system as a detector of the
range of suffocation predictive data
8. Opiolds as physiologic regulators
Since separation anxiety and CO2 sensitivity
are both under opioidergic control (see below),
we hypothesized that PD may be due to an
episodic functional endogenous opioid deficit
(amplified SFA theory).
The endogenous opioid system was unknown
until the early 1970's. Naloxone prevents
exogenous opiate effects, but has little effect
on normal animals (Akil et al., 1998). This
hindered a search for endogenous opioids.
However, electrical stimulation of the
periaqueductal gray (Mayer et al., 1971)
produced naloxone-reversible analgesia, strongly
suggesting the existence of an endogenous opioid
system.
Opioid molecules are among the oldest
evolved signaling substances. Remarkably
conserved structurally, they are involved in
diverse functions, e.g., pain perception,
respiration, homeothermy, nutrient intake and
immune response (Stefano et al., 1996). Their
reward-signaling function may have evolved from
anti-nociceptive properties.
Currently three peptide groups, comprising
over a dozen molecules, are identified. All
arise from prohormones: Proenkephalin contains
Met- and Leu-enkephalin; prQdynorphin contains
dynorphin A, dynorphin B, and neo-endorphin.
Enkephalins and dynorphins may be the
predominant central transmitters. 3-Endorphin is
cleaved from the prohormone,
pro-opio-melanocortin (POMC) and co-released
with ACTH from the anterior pituitary. It is
considered the major, circulating endogenous
¶pioid agonist.
The opioids interact with three major
classes of receptors, the, ¶, k and µ
receptors (Reisine, 1995), each with several
subtypes (Connor and Christie, 1999). The
enkephalins and 3-endorphin have a high affinity
for the µ and ¶ receptors, whereas
dynorphin A may stimulate the ic receptor. The
receptors have different affinities for the
prototypical opioid antagonist, nabxone, with
the .t receptor exhibiting the highest affmity.
Novel opioid receptors and corresponding
agonists are still regularly discovered.
Morphine and codeine are synthesized by
vertebrate species, including humans (Glattard
et al., 2006; Stefano and Scharrer, 1994;
Stefano et al., 2000; Zhu et al., 2001). Our
knowledge of this system is still quite
incomplete.
µ Receptor activation has been seen
responsible for the analgesic, respiratory and
addictive effects of opioids and opiates, but
more recently, ¶ blockade leading to reversal of
.t agonist-induced respiratory depression
without loss of analgesia has been described (Su
et al., 1998; Verborgh and Meert, 1999).
Therefore, the effects of R active agents may
partly depend on ¶ receptor activation. The dose
of naloxone (2 mg/kg) that induced panic-like
reactions to lactate in normals (Preter et al.,
2007, in preparation; Sinha et al., 2007) is
well beyond the point of R receptor saturation
and is at the level required for ¶ blockade
(Sluka et al., 1999).
The cranial nerves and muscles for
expressing affect all evolved from the primitive
gill arches that extract oxygen from water
(Porges, 1997). The extent to which endogenous
opioids participate in respiratory control in
non-stressed human adults, i.e. under normoxic,
normocapnic conditions, remains controversial.
However, their role in fetal and neonatal
respiration, situations in which even small gas
exchange abnormalities may be devastating, is
clear (Santiago and Edelman, 1985). Endogenous
opioids are activated in hypoxic or hypercapnic
respiratory distress (Santiago and Edelman,
1985; OIson et al., 1997) and are inhibitory to
CRH release (De Souza and Nemeroff, 1989; Dunn
and Berridge, 1990). Opioids decrease
respiratory sensitivity (Eldridge and Millhorn,
1981; lasnetsov et al., 1984; Akiyama et al.,
1990) and increase survival under hypoxic and
hypercapnic conditions. Opioid modulation of CO2
sensitivity may be ofparticular importance
during sleep, when plasma CO2 concentration
becomes the primary breathing stimulus.
Dyspnea is modulated by central and
peripheral opioid levels in both rodents and
humans (Santiago and Edelman, 1985). Mice
exposed to severe, intermittent hypoxia
prolonged their survival during subsequent
lethal suffocation (Mayfield and D'Alecy, 1992).
Naloxone blocked this effect, suggesting that
endogenous opioids increase adaptability to
low-oxygen environments. Opioids lowered body
temperature in mice, thus slowing
counter-productive metabolic activity during
hypoxia (Mayfield and D'Alecy, 1992). Stark et
al. (1983), in a placebocontrolled trial in
normal human subjects, showed that codeine
allows high levels of carbon dioxide to be
tolerated during breath holding. Opioid
receptors, including 'non-conventional' ones,
are located throughout the respiratory tract.
Nebulized morphine is being investigated as a
chronic dyspnea treatment (Baydur, 2004; Bruera
et al., 2005; Zebraski et al., 2000).
Polyvagal Theory (Porges, 1995, 1997, 2003,
2007) may add an important structural element to
SFA. Porges argues that Cannon unduly'
emphasized that emergency adaptations were due
to sympatho-adrenal excitation. In mammals, the
vagus evolved into two separate branches, both
involved in the mammalian procreative process
(feeding, nursing, copulation etc.). The
phylogenetically older, unmyelinated dorsal
vagal complex (DVC) regulates digestion and
responds to novelty or threat, specifically to
hypoxia, by reducing metabolic output
Oxytocinergic hypothalamic projections activate
DVC output, whose sensory component monitors
circulating neuropeptide levels. Porges
hypothesizes that this vagal component has
evolved to support, in conjunction with
neuropeptide systems, mammalian bonding and
attachment.
The ventral vagal complex (WC), unique to
mammals, carries myelinated vagal axons and
portions of other branchiomeric cranial nerves
(V, VII, IX, XI). Together, these pathways
control facial expression, sucking, swallowing,
breathing, crying, and vocalization. Further,
the myelinated vagus (VVC) controls resting
heart rate by tonic inhibition of the sinoatrial
node.
Thus, VVC inhibition provides a rapid
response system without the need to immediately
activate the metabolically costly
sympatho-adrenal system (Porges et al., 1996).
The mechanism of acute tachycardia during
lactate-induced panic has been attributed to
vagal withdrawal (Yeragani et al., 1994) rather
than sympathetic discharge. For unknown reasons,
the vagal withdrawal response seems excessive in
Panic Disorder. For instance, patients with PD
show vagal withdrawal on standing in contrast to
normal and depressed subjects (Yeragani et al.,
1990, 1991).
10. Sighing,
yawning and
respiratory chaos
The neural structures necessary for yawning
are located near (or identical with) other
phylogenetically old, respiratory and vasomotor
centers. Anencephalic infants, born with only
the medulla oblongata, yawn. Hypothalamic
neurons originating in the paraventricular
nucleus facilitate yawning by releasing oxytocin
at distant sites, such as the hippocampus and
pontomedullaiy structures. Opioids inhibit the
yawning response at the level of the
paraventricular nucleus by decreasing central
oxytocinergic transmission. Conversely, naloxone
may increase yawning, a classic sign of opiate
withdrawal (Argiolas and Melis, 1998).
Both yawning and sighing are contagious.
Observed acute inspirations may be interpreted
as tests of increased ambient carbon dioxide or
efforts to overcome breathlessness. Thus,
observing another's yawn may incite one's own
yawning test, without any relevant cognition, by
activation of a phylogenetically fixed action
pattera.
Venerable features of "neurosis" are
frequent sighs and yawns. A feeling of
respiratory oppression precedes sighing. The
deep inspiration of a sigh doubles the normal
tidal volume, abruptly lowers pCO2, and relieves
respiratory distress. Although PD and
generalized anxiety disorder (GAD) patients were
equivalent on baseline anxiety levels, Hegel and
Ferguson (1997) demonstrated significantly lower
baseline end-tidal CO2 levels (EtCO2) in PD
compared to GAD and normal controls. Moreover,
eight of sixteen panic patients who reported a
high level of respiratory symptoms during
attacks had the lowest baseline end-tidal CO2
levels.
Comparing, at rest, Panic Disorder with
generalized anxiety disorder (GAD) and normal
controls, Wilhelm et al. (2001a) showed marked
differences between PD and normals: respiratory
rate was lower, tidal volume was higher,
end-tidal CO2 (EtCO2) was lower, and the number
of sighs was higher. In GAD some of these
respiratory abnormalities were present in
attenuated form.
Wilhelm et al. (2001b) found that panic
patients at rest for 30 min sighed more
frequently than normals. Episodic sighing,
rather than sustained increases in ventilation,
accounted for the decreased EtCO2 in PD. In
normals, the precipitous drop in EtCO2 after a
sigh was nullified by an immediate tidal volume
decrease, thus raising EtCO2 levels to baseline.
However, panic patients continued to ventilate
at an increased tidal volume for a number of
post-sigh breaths, maintaining EtCO2 at a lower
level before returning to baseline. This may
indicate a defense against a swift EtCO2
increment that could trigger the suffocation
alarm.
Abelson et al. (2001) studied
breath-by-breath tidal volume and respiratory
rate responses to a doxapram challenge in PD and
a normal control group. Half of each group
received a cognitive intervention designed to
reduce doxapram induced anxiety/distress
responses. Compared to normals, PD patients had
a characteristic sighing pattern of breathing,
thus producing significantly greater tidal
volume irregularity. Of note, the cognitive
intervention attenuated fearful response, but
did not significantly influence doxapram-induced
hyperventilation.
11. Opioids and the control of separation,
and social-affiliative behavior
The first neurochemical system found to
inhibit separation distress was the endogenous
opioid system. Originally formulated by
Panksepp, the brain opioid theory of social
attachment was based on phenomenological
similarities between social and narcotic
dependence, including the stages of euphoria,
tolerance and withdrawal. It predicted that
opioid release would result in feelings of
comfort and alleviation of emotional distress
arising from loss and social isolation (Panksepp
2003, 2005, Panksepp et al., 1978, 1980).
Opiates, mimicking endogenous opioids,
artificially create feelings of social
comfortbut decrease motivation to seek out
social contact. Opiate. antagonists increase
social motivation, but reduce the reward
afforded by endogenous opioid release. .
This evolutionary, neurobiologie attachment
theory has received much empirical support
(NelsOn and Panksepp, 1998):-It is now appears
that:
1. the endogenous opioid system is activated
by several positive social interactions, ranging
from mutual grooming in young animals (Keverne
et al., 1989; Knowles et al., 1989) to sexual
gratification;
2. opioids attenuate the reaction to social
separation;
3. a low (but not a high) basal level of
opioids increases motivation to seek social
contact.
Panksepp (1998) hypothesizes that certain
people become addicted to external opiates
because they artificially induce feelings of
gratification similar to - and probably above
and beyond - those achieved by the release of
endogenous opioids in social interactions.
13. Conclusion
Our current model provides a framework
connecting PD data to endogenous opioidergic
dysfunction, separation anxiety, and respiratory
vulnerabilities, thus amplifying the suffocation
false alarm theory (Klein, 1993). We propose
that panic, separation anxiety and opioid
dysfunction-related conditions, such as
premenstrual dysphoria, may be due to a
disturbance of endogenous opioid systems that
adaptively regulate respiration, separation
anxiety, consummatory pleasures, and
social-affihiative rewards, in addition to
pain.
The present review has focused on the
possible central role of the opioid receptor in
pathological panic as it occurs in PD. One of
the necessary limitations of this article is
that we have not critically discussed
alternative views considering the relevance of
other neural systems, e.g. cholinergic
(Battaglia, 2002), adrenergic (Charney et al.,
1990), amygdalocentric (LeDoux, 1998) etc.
Further SFA refinements are necessary to
address the gastrointestinal (Fleisher et al.,
2005, Lydiard, 2005) and headache symptomatology
of separation anxious children and some adult
panic patients. That migraine headaches are
highly comorbid with PD (Hatter et al., 2003),
and bi-directional risk factors for onset
(Breslau et al., 2001) may provide clues.
Prospective, longitudinal psychobiological
studies of genetic predisposition, separation,
divorce, grief, bereavement, abortion, birth and
adoption, in the context of challenge and
therapeutic approaches offer pointed
investigative opportunities. The neuroscience
and evolutionary psychobiology frameworks serve
as heuristic stimuli.
Our hypotheses are sufficiently concrete
that falsifications, amplifications and
modifications are possible (Klein, 1969).
However, developing stable funding mechanisms to
support such complex, longitudinal,
person-oriented and physiologically
sophisticated studies are a necessary
precondition.
