Pharmacological characterization of paracetamol: new therapeutic approach to postoperative pain.

Acetaminophen, commonly known as paracetamol, is an active ingredient possessing analgesic and antipyretic activity used widely in medical practice to alleviate acute and chronic pain and to reduce the body temperature when this exceeds physiological values. Paracetamol, conversely to the majority of commonly used analgesic drugs, is not an non-steroidal anti-inflammatory drug (NSAIDs), since it is almost devoid of antiaggregant and anti-inflammatory activity. The most typical paracetamol-based pharmaceutical formulations are those in solid tablet form, in granule form or in the form of suppositories. Moreover, formulations containing paracetamol in the form of a solution for intravenous infusion can also be found on the market. These are formulations indicated for the short-term treatment of pain of medium intensity, in particular of the type experienced following a surgical intervention. Intravenous administration is reserved for cases in which, from a clinical viewpoint, there is the need to treat the pain and/or hyperthermia with urgency or in cases in which it is impossible to implement the other administration methods. Administration of paracetamol by means of methods alternative to traditional ones is still to be explored, no specific applications have been found in the field of analgesic therapy. Acute postoperative pain is a normal response to surgical intervention and is a cause of delayed recovery and discharge after surgery as well as increased risk of wound infection and respiratory/cardiovascular complications. Untreated acute pain leads to reduced patient satisfaction and increased morbidity and mortality and also places a burden on the paient and health system finances. Acute pain that becomes intractable and persists is referred to as chronic postsurgical pain (CPSP). CPSP can have a significant impact on the patient’s quality of life and daily activities, including disturbances of sleep and affective mood In the clinical field, paracetamol is used fundamentally as an antipyretic in the treatment of febrile states and as an analgesic in the treatment of mild and medium pain as postoperative pain. Traditional pharmacological approaches to pain management in the postoperative period include oral or intravenous administration of opioids and oral administration of paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs); nevertheless these approaches are associated with a variety of adverse events. Recently, much attention was focused on spinal administration of paracetamol, in order to overcome the possible hepatotoxicity after oral administration. The administration of injectable solutions by spinal administration generally presents limitations. A first limitation is of the physical type, because the drug is perfused in a defined and confined space in which a limited quantity of solution can be infused. This limit can be overcome using a paracetamol hypersaturated solution. In this regard, our aim has been to verify effect of a new supersaturated aqueous solution of paracetamol (SINTETICO; SIN) at different doses (100-500 μg/it) after spinal administration in an animal model of postoperative pain. Mechanical hyperalgesia was evaluated by mechanical stimuli using the Randall-Selitto analgesimeter for rats. Hyperalgesia was assessed on incision paw 2, 4, 24, 48, 72 h after spinal administration. Data showed that spinal Sintetico administration produced a significant antihyperalgesic effect, in dose and time manner. In particular, the high doses of Sintetico (500 µg) produced a significant analgesic effect until 72 h after surgery. Moreover, knowing the marked analgesic effect of paracetamol following oral administered, and considering the use of this drug as a premedication before surgery, we investigated efficacy of combination of oral and spinal routes of paracetamol and SIN using inactive and active doses (PARA 200 and 500 mg/kg/os and SIN 100 and 500 µg/it/ respectively). Surprisingly, a synergic effect was obtained after oral and intrathecal combination of inactive doses; in fact PARA 200 mg/kg/os and SIN 100 µg/it produced a prolonged analgesic effect up to 24 h after administration. Despite its medical use is consolidated by many years, its mechanism of action is still poorly understood. There are several hypothesis concerning the possible mechanism of action; for this reason we investigated the involvement of cannabinergic (CB1 and CB2), opioidergic (μ and κ receptors) and serotoninergic (5HT3) systems. Our results indicated that in paracetamol-induced analgesdia all these system are involved, confirming data reported in literature. Finally, it is well known that orally high doses of paracetamol could cause perilobular hepatotoxicity, which is the main limit to use this drug, especially in fasting patients before chirurgical surgery. It very poor the knowledge about the possible toxicity of paracetamol after intrathecal administration. We examined if single or repeated spinal Sintetico administration by spinal catheter showed physiological and/or morphological modification of cauda equina or nerve bundles of the lumbosacral spinal cord sections. Both acute (500µg) or repeated (200-500 µg for 7 days) administration of SIN resulted in a mild degree of toxicity with little or no degeneration of nerve fibers and there was no difference between SIN-treated and vehicle-treated rats. Furthermore, we observed macroscopically, whether the administration of Sintetico for 7 days had produced liver toxicity. No significant alteration of margins and sizes was observed in SIN-treated rats respect vehicle group. In conclusion, during this my PhD, we evaluated the pharmacological effects and toxicological profile of a new supersaturated aqueous solution of paracetamol; results obtained confirm the efficacy of this drug in postoperative pain, offering a new therapeutic approach based on spinal route