Psychological Medicine

Original Articles

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. Pretera1 c1, S. H. Leea2, E. Petkovaa3, M. Vannuccia4, S. Kima5 and D. F. Kleina6

a1 Department of Psychiatry, Columbia University, and New York State Psychiatric Institute, New York, NY, and Department of Neurology, State University of New York, Downstate Medical Center, Brooklyn, NY, USA

a2 The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA

a3 Department of Child and Adolescent Psychiatry, New York University School of Medicine, New York, USA

a4 Department of Statistics, Rice University, Houston, TX, USA

a5 Department of Biostatistics, University of Michigan, Ann Harbor, MI, USA

a6 Phyllis Green and Randolph Cowen Institute for Pediatric Neuroscience, Department of Child and Adolescent Psychiatry, New York University Langone Medical Center; The Nathan S. Kline Institute for Psychiatric Research; Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA


Background 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.

Method 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.

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

Conclusions 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.

(Received October 01 2008)

(Revised March 15 2010)

(Accepted March 19 2010)

(Online publication May 06 2010)


c1 Address for correspondence: M. Preter, M.D., 1160 Fifth Avenue, Suite 112, New York, NY 10029, USA. (Email: