Oxycodone recycling: A novel hypothesis of opioid tolerance development in humans Oscar A. Linares a,⇑ , Jeffrey Fudin b,c,d,e , William E. Schiesser f , Annemarie Daly Linares g,h , Raymond C. Boston i a Plymouth Pharmacokinetic Modeling Study Group, Plymouth, MI, USA b University of Connecticut, School of Pharmacy, Storrs, CT, USA c Western New England University, College of Pharmacy, Springfield, MA, USA d State University of New York at Buffalo College of Pharmacy, Buffalo, NY, USA e Pain and Palliative Care Pharmacy Residency, Stratton VA Medical Center, Albany, NY, USA f Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, PA, USA g Wayne State University Law School, 471 W Palmer Ave., Detroit, MI, USA h Grace Hospice of Ann Arbor, 2755 Carpenter Rd., Ann Arbor, MI, USA i Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, 3600 Market Street, Philadelphia, PA, USA article info Article history: Received 23 April 2014 Accepted 9 June 2014 abstract We hypothesize that oxycodone (OC) recycling promotes sustained synaptic OC content, which prolongs OC’s exposure to local l-opioid receptors (lORs). In that way, OC recycling gives rise to OC tolerance in humans. To pilot test our hypothesis, we developed a whole-body OC mass transport tolerance recovery model. The model derived quantifiable measure of tolerance is T X . T X estimates OC’s tolerance recovery in days; It is defined as the rate of recovery of OC’s pharmacologic response after OC is stopped. We studied a random sample of five opioid intolerant healthy male subjects with no history of opioid or illicit drug use, or comorbidities in silico. Subjects were age 24.5 ± 2.3 yr (all values mean ± SD), weight 93 ± 20 kg, and CYP2D6 EM phenotype. Each subject was studied under two experimental conditions: (1) administration of a single oral dose of OC 12 ± 7 mg; and, after complete washout of OC from the intravascular pool, (2) administration of repetitive oral OC doses every 4h for 5 half-lives (t 1/ 2 = 4.5 h)—after which time steady-state was assumed. Repetitive OC dose T X fell 61% compared to single OC dose T X (5.2 ± 1.1 vs. 3.5 ± 0.7 days, p= 0.001). The fall in T X was associated with a significant 3-fold increase in extravascular OC content, which was accompanied by 2-fold increase in OC spillover from the extravascular pool, into the intravascular pool. Thus, the model predicted that a single dose of orally administered OC could give rise to tolerance. This is consistent with the widely held view of acute opioid tolerance. In addition, the dynamic changes accompanying repetitive OC dosing suggested that local unbound OC gave rise to both higher extravas- cular OC content and increased OC spillover. This reflects that OC stimulated endocytosis of lORs was accompanied by a reduction in the availability OC responsive neuroeffector cell surface lOR binding sites. We conclude that our hypothesis extends current concepts of opioid tolerance development to include OC recycling. OC recycling is a novel hypothesis of OC tolerance development in humans. Ó 2014 Elsevier Ltd. All rights reserved. Background Oxycodone (OC) is commonly used to treat acute and chronic non-cancer and cancer pain, and pain related with general and orthopedic surgery [1]. However, achieving pain control with OC is sometimes hindered by tolerance [2]. Opioid tolerance requires increased opioid dosing over time to maintain the same level of analgesic efficacy. Tolerance may occur due to pharmacokinetic and/or pharmacodynamic changes over a ‘‘prolonged’’, nonspecific treatment span. Pharmacokinetic tolerance occurs when the OC clearance rate increases through its major elimination pathway by hepatic cytochrome 2D6 or 3A4 isoenzymes. This process can be accelerated or decelerated by concomitant use of foods or http://dx.doi.org/10.1016/j.mehy.2014.06.006 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Address: Plymouth Pharmacokinetic Modeling Study Group, 46425 Southview Lane, Plymouth, MI 48170, USA. Tel.: +1 734 735 4022; fax: +1 734 404 6869. E-mail address: OALinaresMD@gmail.com (O.A. Linares). Medical Hypotheses 83 (2014) 326–331 Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy