The facilitation of
opioid medication is eliciting a nemetic problem since increasing overdose deaths involve prescription of
opioid pain relievers. Chronic painful diseases require higher doses of
opioids, progressively with the development of tolerance to the antinociceptive effect. Novel strategies for the maintenance of low dosed
opioid effectiveness are necessary to relieve
pain and decrease abuse, overdose, and side effects.
N-Palmitoylethanolamine (PEA) is an endogenous compound able to preserve the homeostasis of the nervous system and to delay the development of
morphine tolerance. In the present study, a preemptive and continuative treatment with PEA (30 mg/kg, daily, per os) enhanced the acute antinociceptive efficacy of
morphine (10 mg/kg subcutaneously) in rats and prolonged the responsiveness to the natural
opioid. Moreover, PEA-treated animals had a more rapid recovery from tolerance. Four
opioid free days were enough to regain sensitivity to
morphine whereas control animals needed 31 days for full recovery of tolerance. Characteristically, PEA acquired per se antinociceptive properties in tolerant animals, suggesting the possibility of an integrated
morphine/PEA treatment protocol. To maintain a significant
analgesia,
morphine dose had to be increased from 5 up to 100 mg/kg over 17 days of daily treatment. The same pain threshold increase was achieved in animals using preemptive PEA (30 mg/kg, daily) joined to a combinatorial acute treatment with
morphine (5-20 mg/kg s.c.) and PEA (30-120 mg/kg, p.o.). Representatively, on day 17, the magnitude of
analgesia induced by 100 mg/kg
morphine was obtained by combining 13 mg/kg of
morphine with 120 mg/kg of PEA. PEA strengthens the efficacy and potency of
morphine analgesia, allowing prolonged and effective
pain relief with low doses. PEA is suggested in association with
morphine for
chronic pain therapies distinguished by low risk of side effects.