One of the most important research emphases of Dr. Cicero’s is the role of endogenous opioid peptides (EOP) in the control of hypothalamic-pituitary function – especially in the release of hypothalamic releasing factors. These interactions are crucial, and endocrine changes associated with drugs of abuse, particularly the opioids, are now recognized as a pivotal aspect of their acute and chronic effects. Dr. Cicero was the first to show that morphine suppresses testosterone production in the male rat, which he later confirmed in humans in a 1976 New England Journal of Medicine article. It should be stressed that in this pivotal study, he conclusively established for the first time that males maintained on chronic opioid treatment were hypogonadal. The latter condition is now, 32 years later, recognized not only as a common side effect of chronic opioid treatment in humans, but also as a major factor in break-through pain, the development of tolerance and physical dependence and the neurobiological correlates of pain.
He was also one of the first to demonstrate that paternal ingestion of drugs - alcohol and morphine - influenced the development and maturation of their offspring. The only explanation for this phenomenon was that the function of sperm had in some way been affected. The most obvious possibility was that the expression of genes was affected, and this was postulated by his group in 1988. However, this flew in the face of conventional wisdom which posited that such “Lamarckian” charges in DNA expression did not occur. Interestingly, 15 years later, it has been shown in several landmark studies that environmental toxins and drugs influence the methylation of DNA, a process which influences gene expression. This launched the new field of “epigenetics” and Dr. Cicero’s research in the late 1980s is uniformly cited as the original observations documenting epigenetic processes. He is presently re-engaging in this research and exploring the molecular genetics of this phenomenon.
Dr. Cicero is currently engaged in several post-marketing surveillance programs to assess the abuse of newly marketed opioid drug preparations. Although these surveillance programs are an essential aspect of the approval of all drugs with abuse potential and are therefore extremely important in their own right, Dr. Cicero has extended their significance by his most recent research in two recent articles, both of which prompted recognition as the lead articles in their respective journals (Pharmacoepidemiology & Drug Safety and Pain), he examined first, the relationship between therapeutic exposure to opioids and their abuse; and, second, co-morbid factors in those abusing their opioid analgesics.
Dr. Cicero has also been on the front lines of research on two major issues in the epidemic of prescription opioid abuse. He was the first to publish data analyzing the impacts of an abuse deterrent formulation of OxyContin®, in which the delivery device was chemically altered to be much harder to crush and snort, or solubilize and inject. While the ADF was shown to be effective in reducing rates of abuse for OxyContin®, one of the most commonly abused prescription drugs, an unintended consequence was that abusers shifted to other, more potent opiates, in particular heroin. Dr. Cicero further investigated changes in heroin abuse, the results of which were published in JAMA Psychiatry, in which the demographics of heroin abusers have shifted dramatically in the past fifty years from an urban issue among young males, to one prevalent in both older males and females living in non-urban areas who started their drug abuse with prescription opioids. He is currently focused on further researching the relationship between prescription drugs and heroin.