mise à jour du
1 mars 2009
Prog NeuroPsychoPharmacol
Biol Psychiatry
Panic, suffocation false alarms, separation anxiety
and endogenous opioids
Maurice Preter & Donald F. Klein
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.
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