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Controlled cross-over study in normal subjects of naloxone-preceding-lactate infusions; respiratory and subjective responses: relationship to endogenous opioid system, suffocation false alarm theory and childhood parental loss

  • M. Preter (a1), S. H. Lee (a2), E. Petkova (a3), M. Vannucci (a4), S. Kim (a5) and D. F. Klein (a6)...

The expanded suffocation false alarm theory (SFA) hypothesizes that dysfunction in endogenous opioidergic regulation increases sensitivity to CO2, separation distress and panic attacks. In panic disorder (PD) patients, both spontaneous clinical panics and lactate-induced panics markedly increase tidal volume (TV), whereas normals have a lesser effect, possibly due to their intact endogenous opioid system. We hypothesized that impairing the opioidergic system by naloxone could make normal controls parallel PD patients' response when lactate challenged. Whether actual separations and losses during childhood (childhood parental loss, CPL) affected naloxone-induced respiratory contrasts was explored. Subjective panic-like symptoms were analyzed although pilot work indicated that the subjective aspect of anxious panic was not well modeled by this specific protocol.


Randomized cross-over sequences of intravenous naloxone (2 mg/kg) followed by lactate (10 mg/kg), or saline followed by lactate, were given to 25 volunteers. Respiratory physiology was objectively recorded by the LifeShirt. Subjective symptomatology was also recorded.


Impairment of the endogenous opioid system by naloxone accentuates TV and symptomatic response to lactate. This interaction is substantially lessened by CPL.


Opioidergic dysregulation may underlie respiratory pathophysiology and suffocation sensitivity in PD. Comparing specific anti-panic medications with ineffective anti-panic agents (e.g. propranolol) can test the specificity of the naloxone+lactate model. A screen for putative anti-panic agents and a new pharmacotherapeutic approach are suggested. Heuristically, the experimental unveiling of the endogenous opioid system impairing effects of CPL and separation in normal adults opens a new experimental, investigatory area.

Corresponding author
*Address for correspondence: M. Preter, M.D., 1160 Fifth Avenue, Suite 112, New York, NY10029, USA. (Email:
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O Agid , B Shapira , J Zislin , M Ritsner , B Hanin , H Murad , T Troudart , M Bloch , U Heresco-Levy , B Lerer (1999). Environment and vulnerability to major psychiatric illness: a case control study of early parental loss in major depression, bipolar disorder and schizophrenia. Molecular Psychiatry 4, 163172.

B Bandelow , C Spath , GA Tichauer , A Broocks , G Hajak , E Ruther (2002). Early traumatic life events, parental attitudes, family history, and birth risk factors in patients with panic disorder. Comprehensive Psychiatry 43, 269278.

M Battaglia , P Pesenti-Gritti , SE Medland , A Ogliari , K Tambs , CA Spatola (2009). A genetically informed study of the association between childhood separation anxiety, sensitivity to CO(2), panic disorder, and the effect of childhood parental loss. Archives of General Psychiatry 66, 6471.

J Biederman , CR Petty , SV Faraone , DR Hirshfeld-Becker , A Henin , L Brauer , B Kaufman , JF Rosenbaum (2006). Antecedents to panic disorder in nonreferred adults. Journal of Clinical Psychiatry 67, 11791186.

GA Borg (1982). Psychophysical bases of perceived exertion. Medicine and Science in Sports and Exercise 14, 377381.

S Brannan , M Liotti , G Egan , R Shade , L Madden , R Robillard , B Abplanalp , K Stofer , D Denton , PT Fox (2001). Neuroimaging of cerebral activations and deactivations associated with hypercapnia and hunger for air. Proceedings of the National Academy of Sciences USA 98, 20292034.

DW Brown , RF Anda , H Tiemeier , VJ Felitti , VJ Edwards , JB Croft , WH Giles (2009). Adverse childhood experiences and the risk of premature mortality. American Journal of Preventive Medicine 37, 389396.

DR Corfield , GR Fink , SC Ramsay , K Murphy , HR Harty , JD Watson , L Adams , RS Frackowiak , A Guz (1995). Evidence for limbic system activation during CO2-stimulated breathing in man. Journal of Physiology 488, 7784.

DJ Dillon , JM Gorman , MR Liebowitz , AJ Fyer , DF Klein (1987). Measurement of lactate-induced panic and anxiety. Psychiatry Research 20, 97–105.

P Fearon , M Hotopf (2001). Relation between headache in childhood and physical and psychiatric symptoms in adulthood: national birth cohort study. British Medical Journal 322, 1145.

G Gerra , C Leonardi , A D'Amore , G Strepparola , R Fagetti , C Assi , A Zaimovic , A Lucchini (2006). Buprenorphine treatment outcome in dually diagnosed heroin dependent patients: a retrospective study. Progress in Neuropsychopharmacology and Biological Psychiatry 30, 265272.

R Gittelman , DF Klein (1984). Relationship between separation anxiety and panic and agoraphobic disorders. Psychopathology 17 (Suppl. 1), 5665.

RR Goetz , DF Klein , D Gully , J Kahn , M Liebowitz , A Fyer , JM Gorman (1993). Panic attacks during placebo procedures in the laboratory: physiology and symptomatology. Archives of General Psychiatry 50, 280285.

MC Harter , KP Conway , KR Merikangas (2003). Associations between anxiety disorders and physical illness. European Archives of Psychiatry and Clinical Neurosciences 253, 313320.

GT Jones , C Power , GJ Macfarlane (2009). Adverse events in childhood and chronic widespread pain in adult life: results from the 1958 British Birth Cohort Study. Pain 143, 9296.

KD Juang , SJ Wang , JL Fuh , SR Lu , YS Chen (2004). Association between adolescent chronic daily headache and childhood adversity: a community-based study. Cephalalgia 24, 5459.

NH Kalin , SE Shelton , CM Barksdale (1988). Opiate modulation of separation-induced distress in non-human primates. Brain Research 440, 285292.

DA Katerndahl (2008). Chest pain and its importance in patients with panic disorder: an updated literature review. Primary Care Companion to the Journal of Clinical Psychiatry 10, 376383.

ME Keck , A Strohle (2005). Challenge studies in anxiety disorders. Handbook of Experimental Pharmacology 449468.

KS Kendler , MC Neale , RC Kessler , AC Heath , LJ Eaves (1992). Childhood parental loss and adult psychopathology in women. A twin study perspective. Archives of General Psychiatry 49, 109116.

DF Klein (1964). Delineation of two drug-responsive anxiety syndromes. Psychopharmacologia 5, 397408.

DF Klein (1993). False suffocation alarms, spontaneous panics, and related conditions. An integrative hypothesis. Archives of General Psychiatry 50, 306317.

JA Kopec , EC Sayre (2005). Stressful experiences in childhood and chronic back pain in the general population. Clinical Journal of Pain 21, 478483.

MG Kushner , BD Beitman (1990). Panic attacks without fear: an overview. Behaviour Research and Therapy 28, 469479.

SH Lee , J Lim , M Vannucci , E Petkova , M Preter , DF Klein (2008). Order-preserving dimension reduction procedure for the dominance of two mean curves with application to tidal volume curves. Biometrics 64, 931939.

MR Liebowitz , AJ Fyer , JM Gorman , D Dillon , IL Appleby , G Levy , S Anderson , M Levitt , M Palij , SO Davies , DF Klein (1984 a). Lactate provocation of panic attacks. I. Clinical and behavioral findings. Archives of General Psychiatry 41, 764770.

MR Liebowitz , JM Gorman , AJ Fyer , M Levitt , D Dillon , G Levy , IL Appleby , S Anderson , M Palij , SO Davies , DF Klein (1985). Lactate provocation of panic attacks. II. Biochemical and physiological findings. Archives of General Psychiatry 42, 709719.

M Liotti , S Brannan , G Egan , R Shade , L Madden , B Abplanalp , R Robillard , J Lancaster , FE Zamarripa , PT Fox , D Denton (2001). Brain responses associated with consciousness of breathlessness (air hunger). Proceedings of the National Academy of Sciences USA 98, 20352040.

Z Liu , X Li , X Ge (2009). Left too early: the effects of age at separation from parents on Chinese rural children's symptoms of anxiety and depression. American Journal of Public Health 99, 20492054.

M Olsson , HP Ho , K Annerbrink , J Thylefors , E Eriksson (2002). Respiratory responses to intravenous infusion of sodium lactate in male and female Wistar rats. Neuropsychopharmacology 27, 8591.

J Panksepp (2003). Feeling the pain of social loss. Science 302, 237239.

LM Parsons , G Egan , M Liotti , S Brannan , D Denton , R Shade , R Robillard , L Madden , B Abplanalp , PT Fox (2001). Neuroimaging evidence implicating cerebellum in the experience of hypercapnia and hunger for air. Proceedings of the National Academy of Sciences USA 98, 20412046.

M Preter , DF Klein (2008). Panic, suffocation false alarms, separation anxiety and endogenous opioids. Progress in Neuro-Psychopharmacology and Biological Psychiatry 32, 603612.

JP Shonkoff , WT Boyce , BS McEwen (2009). Neuroscience, molecular biology, and the childhood roots of health disparities: building a new framework for health promotion and disease prevention. Journal of the American Medical Association 301, 22522259.

SS Sinha , RR Goetz , DF Klein (2007). Physiological and behavioral effects of naloxone and lactate in normal volunteers with relevance to the pathophysiology of panic disorder. Psychiatry Research 149, 309314.

RL Spitzer , JB Williams , M Gibbon , MB First (1992). The Structured Clinical Interview for DSM-III-R (SCID). I: History, rationale, and description. Archives of General Psychiatry 49, 624629.

MC Wallen , WJ Lorman , JL Gosciniak (2006). Combined buprenorphine and chlonidine for short-term opiate detoxification: patient perspectives. Journal of Addictive Diseases 25, 2331.

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Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
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