Oxycodone Produces Antinociception, but Worsens Functional Behaviors, in Humanized Sickle Cell Disease Mice

Introduction: Sickle Cell Disease (SCD) is a major cause of morbidity and mortality worldwide, and affects more than 100,000 people in the US. Acute, vaso-occlusive pain crises are the hallmark of the disease and the primary cause of hospitalization. Recurrent, acute pain episodes compound and result in chronic pain for many patients, though the mechanisms of this transition are poorly understood. Opioids remain the standard of care for chronic SCD pain, despite their adverse side effects (e.g., constipation, respiratory depression, abuse liability, dependence) and the fact that prolonged opioid treatment results in tolerance. Thus, a pressing need exists to identify effective non-opioid analgesics to reduce SCD chronic pain. Humanized mouse models of SCD, such as the Berkeley (BERK) model, provide a useful tool to investigate disease pathophysiology and evaluate novel therapeutic strategies. Though oxycodone is one of the most commonly prescribed analgesics for SCD chronic pain, it has yet to be evaluated in this SCD mouse model. Therefore, we assess whether oxycodone would ameliorate phenotypic hypernociception and behavioral deficits in the BERK mouse model of chronic pain.

Methods: Male and female HbSS-BERK (sickle) and HbAA-BERK (control) mice were used as subjects. Stimulus-evoked nociceptive behaviors were assessed using the Von Frey and Hot Plate; and functional non-evoked behaviors were assessed using Grip Strength, Inverted Screen, and Nesting tests. Oxycodone (0, 1.25, 2.5, 5, and 10 mg/kg, s.c.) was administered one hour prior to testing. Data were analyzed as Student's t-test, one- and two-way ANOVAs followed by Tukey or Sidak post-hoc analysis when appropriate (p < 0.05 considered significant).

Results: Oxycodone (2.5, 5, and 10 mg/kg) fully attenuated mechanical allodynia in HbSS-BERK mice; and produced significant antinociception in HbAA-BERK mice at the highest dose (10 mg/kg). Oxycodone (1.25 and 2.5 mg/kg) partially and fully attenuated thermal hyperalgesia in HbSS-BERK mice, respectively. 5 and 10 mg/kg of oxycodone in HbSS-BERK and 2.5, 5, and 10 mg/kg in HbAA-BERK mice produced significant antinociception. In the grip strength assay, oxycodone had no significant effect in HbSS-BERK mice, but worsened performance in HbAA-BERK mice. Conversely, oxycodone worsened inverted screen deficits in HbSS-BERK mice, with no significant effect in HbAA-BERK mice. Finally, oxycodone (2.5 and 5 mg/kg) worsened nest-building behavior regardless of genotype.

Conclusion: Oxycodone, a gold standard analgesic for pain management, acutely reverses the hyperalgesic phenotype in BERK mice. However, oxycodone not only produces complete antinociception in those same assays, but also worsens functional deficits in the HbSS-BERK mice along with their controls. These findings demonstrate that oxycodone is suboptimal for restoring normal pain sensation as well as daily functioning.

Goldsborough:Forma Therapeutics: Current Employment, Other: Internship. Gupta:Novartis: Honoraria, Research Funding; CSL Behring: Honoraria; Cyclerion: Research Funding; 1910 Genetics: Research Funding; Grifols: Research Funding; Zilker LLC: Research Funding; UCI Foundation: Research Funding; SCIRE Foundation: Research Funding; Tautona Group: Honoraria. Smith:Emmaus: Consultancy; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Novo Nordisk: Other: DSMB; Novartis: Consultancy, Honoraria; Imara: Research Funding; Pfizer: Consultancy, Research Funding.