Chronic pain management requires increasing doses of
opioids, the milestone of painkillers, which may result in the onset of tolerance with exacerbated side effects. Maintaining stable
analgesia with low doses of
opioids is thus imperative.
N-palmitoylethanolamine (PEA) is an endogenous
lipid compound endowed with
pain-relieving as well as anti-inflammatory properties. The ultramicronized formulation of PEA was recently demonstrated to be able to modulate
morphine's effects, delaying tolerance and improving efficacy. To evaluate the possible application to other
opioids, in this study, we analysed the capacity of ultramicronized PEA to regulate
analgesia and tolerance induced by
oxycodone and
tramadol. Pre-emptive and continuative treatment with ultramicronized PEA (30 mg kg-1, daily, per os) delayed the onset of
opioid tolerance and enhanced
opioid analgesia when it was acutely administered in association with
tramadol (20 mg kg-1, daily, subcutaneously) or
oxycodone (0.5 mg kg-1, daily, subcutaneously). Moreover, PEA exerted antinociceptive effects on tolerant rats, suggesting the use of PEA together with
opioids for stable, long-lasting
analgesia. To that purpose, the
oxycodone dose needed to be increased from 0.3 mg kg-1 (day 1) up to 1 mg kg-1 (day 31) in the
oxycodone + vehicle group; the
tramadol dose was progressively enhanced from 15 mg kg-1 to 50 mg kg-1 in 31 days in the
tramadol + vehicle group. Acute oral co-treatment with PEA (120 mg kg-1) achieved the same
analgesia without increasing the dose of both
opioids. The behavioural effects of PEA on
opioid chronic treatment paralleled a decrease in astrocyte activation in the dorsal horn of the spinal cord (a marker of the development of
opioid tolerance) and with a modulation of
mRNA expression of
IL-6 and serpin-A3. In conclusion, pre- and co-administration of ultramicronized PEA delayed the development of
tramadol tolerance, potentiating either
oxycodone or
tramadol analgesia and allowing a long-lasting
analgesic effect with a low
opioid dose regimen. The use of PEA is suggested for clinical purposes to support the
opioid-based management of persistent
pain.