Prazosin as an Adjuvant to Increase Effectiveness of Duloxetine in a Rat Model of Oxaliplatin-Induced Peripheral Neuropathy

Abstract

Objectives: Duloxetine, the only American Society of Clinical Oncology (ASCO) treatment recommended for chemotherapy-induced peripheral neuropathy (CIPN) in cancer survivors, is not effective for 40% of survivors. This study examined the ability of a duloxetine-prazosin combination to prevent the development of allodynia and hyperalgesia in a rat model of oxaliplatin-induced peripheral neuropathy (OPIN).

Methods: Female (n = 24) and male (n = 41) rats were started on duloxetine (15 mg), prazosin (2 mg), or a duloxetine-prazosin combination one week prior to administration of the chemotherapy drug, oxaliplatin, and continued the duloxetine-prazosin combination for 32 days. Behavioral testing for mechanical allodynia and mechanical hyperalgesia was done with selected von Frey filaments over the course of the study.

Results: Overall percent paw withdrawal for rats that received the duloxetine-prazosin combination was significantly lower in female (p < .001 for both conditions) and male (p = .029 for allodynia; p < .001 for hyperalgesia) than those that received water. No significant posttreatment differences were found for allodynia or hyperalgesia between rats treated with duloxetine and rats that received the duloxetine-prazosin combination in either sex.

Conclusions: These finding provide preliminary evidence that a duloxetine-prazosin combination can prevent the posttreatment development of allodynia and hyperalgesia in both male and female rats; however, the results suggest that the duloxetine-prazosin combination is no more efficacious than duloxetine alone in preventing chronic OIPN.

Implications for nursing practice: The profession of nursing is built on clinical practice supported by scientific research. The current study addressed the clinical practice problem of prevention and management of painful OIPN, which is a priority area in oncology nursing.

Keywords: Allodynia; Cancer; Hyperalgesia; Neuropathy; Oxaliplatin; ⍺-adrenoceptors.

FIG 1.

The effect of prazosin on oxaliplatin induce allodynia (A, B) and hyperalgesia (C, D). Following baseline withdrawal measurements, prazosin (◆) or water (▲) was administered via oral gavage following the prescribed treatment schedule. Female (n = 6) and male (n = 10) rats treated with prazosin were significantly different from female (n = 7) and male (n= 13) rats that received water. Mean percent paw withdrawal ± SEM is plotted on the ordinate as a function of time.

FIG 2.

The effect of duloxetine on oxaliplatin induce allodynia (A, B) and hyperalgesia (C, D). Following baseline withdrawal measurements, duloxetine (◆) or water (▲) was administered via oral gavage following the prescribed treatment schedule. Females pretreated with duloxetine (n = 5) were significantly different from females who received water (n = 7), but males pretreated with duloxetine (n = 8) were not significant from those who received water (n = 13) in conditions of allodynia. Both females and males pretreated with duloxetine were significantly different from females and males who received water in conditions of hyperalgesia. Mean percent paw withdrawal ± SEM is plotted on the ordinate as a function of time.

FIG 3.

The effect of a duloxetine-prazosin combination on oxaliplatin induce allodynia (A, B) and hyperalgesia (C, D). Following baseline withdrawal measurements, a duloxetine-prazosin combination (◼) or water (▲) was administered via oral gavage following the prescribed treatment schedule. Female (n = 6) and male (n = 10) rats treated with duloxetine-prazosin combination were significantly different from female (n = 7) and male (n = 13) rats that received water. Mean percent paw withdrawal ± SEM is plotted on the ordinate as a function of time.

FIG 4.

The effect of a duloxetine-prazosin combination compared to duloxetine alone on oxaliplatin induce allodynia (A, B) and hyperalgesia (C, D). Following baseline withdrawal measurements, a duloxetine-prazosin combination (◆) or duloxetine alone (◼) was administered via oral gavage following the prescribed treatment schedule. Female (n = 6) and male (n = 10) rats treated with duloxetine-prazosin combination were significantly different from female (n = 5) and male (n = 8) rats that received duloxetine alone. Mean percent paw withdrawal ± SEM is plotted on the ordinate as a function of time.