Recent studies suggest that opioids can have an adverse impact on the immune system. Because surgical stress also induces immune dysfunction, the search for analgesic drugs devoid of immunosuppressive effects is of import. This study compared the effects on immune responses of morphine and of the atypical opioid analgesic, tramadol, given for postoperative pain to gynecological cancer patients. Tramadol and morphine showed comparable analgesic activity; however, tramadol, in contrast to morphine, induced an improvement of postoperative immunosuppression and, therefore, may be preferred to morphine for the treatment of postoperative pain.

Recent studies indicate that the proinflammatory enzyme cyclooxygenase (COX)-2, an enzyme involved in inflammatory cascades but also normal neuronal activities, is elevated in the brain and spinal cord of amyotrophic lateral sclerosis (ALS) patients and ALS mouse model systems. On the basis of this evidence, we explored the impact of COX-2 inhibition on the onset and progression of ALS-like disease in the G93A human superoxide dismutase (SOD)1 mouse model of ALS. We found that prophylactic administration of nimesulide, a preferential COX-2 inhibitor, in the feed resulted in a significant delay in the onset of ALS type motor impairment. This delay of ALS symptomatology temporally overlapped with the inhibition of prostaglandin E2 elevation in the spinal cord of SOD1-G93A transgenic mice relative to untreated SOD1-G93A controls. This study strongly supports a role for COX-2 in the pathophysiology of ALS and provides the first experimental evidence that prophylactic treatment with COX-2 inhibitors can significantly delay the onset of motor dysfunction in the SOD1-G93A transgenic mouse model of ALS.

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The antinociceptive properties of cannabinoids in persistent pain are not fully elucidated. We investigated the effect of repeated treatment with the synthetic cannabinoid receptor agonist WIN 55,212-2 on the neuropathic pain induced in rats by chronic constriction of the sciatic nerve. WIN 55,212-2 administered daily throughout the development of neuropathy reversed the hyperalgesia, at a dose (0.1 mg kg À1 , s.c.) that had no effect on the nociceptive responses of either paw contralateral to the sciatic ligation or of animals subjected to sham surgery. At 14 days after injury, the levels of mediators known to be involved in neuropathic pain, such as prostaglandin E2, NO and the neuronal NOS, were increased. Repeated treatment with WIN 55,212-2 abolished these increases. In the light of the current clinical need for neuropathic pain treatments, these findings indicate that cannabinoid agonists, at doses devoid of psychoactive effects, could constitute important compounds for the development of new analgesics.

Breakthrough pain is normally severe in intensity and has a rapid onset. The availability of supplemental doses of opioids (rescue medication) in addition to the continuous analgesic medication is the main treatment suggested to manage these pain flares. The intravenous (i.v.) route may provide analgesia fast enough, but has never been assessed in clinical studies. The aim of this open-label study was to verify the safety and effectiveness of an i.v. dose equal to one-fifth the calculated equianalgesic total daily dose in advanced cancer patients with episodic pain. A consecutive sample of 48 cancer patients treated with oral morphine, who reported an acceptable basal analgesia and reported episodic pains, were selected for the study. The intravenous dose of morphine was one-fifth of the oral daily dose, converted into an i.v. dose using an equianalgesic ratio of 1/3 (i.v./oral). Written orders were given and intravenous morphine (i.v.-M) was administered by nurses. For each episode, pain intensity and opioid-related symptoms were recorded at the start (T0), after achieving maximum pain relief (T1), and one hour after (T2). In five patients, blood samples were taken at the time intervals described for measuring plasma concentrations of morphine and related glucuronated metabolites. One hundred seventy-one breakthrough pains were recorded during admission. In 162 episodes, a reduction of pain intensity of more than 33% was obtained within a mean of 17.7 minutes, from a mean intensity of 7.9 (on a 0-10 numeric scale) to 3. One hundred thirty-six episodes had more than a 50% pain intensity decrease after the i.v.-M within a mean of 16.6 minutes, from a pain intensity of 7.9 to 2.6. No differences in age, sex, pain mechanism, and time of events were found. There was a trend but no statistically significant differences between the groups receiving different basal doses and time to reach the maximum effect. Twenty episodes in ten patients required an additional dose within 2 hours. Adverse effects were uncommon and were significantly related to the basal dose, and as a consequence, with the i.v.-M dose. Morphine concentration significantly increased at the time of pain intensity reduction, and then decreased. These observations suggest that i.v.-M at a dose equivalent to 20% of the basal oral dosage is safe and effective in the majority of patients experiencing pain exacerbation. This treatment is inexpensive and can be used at little risk to patients.

Plasma ADMA levels were significantly higher in the ERA patients. A statistically significant negative effect of ADMA levels on CFR value was observed. The effect of ADMA levels on IMT is not significant.

Tramadol is a centrally acting analgesic drug with a dual mechanism of action: binding to mu-opioid receptors and potentiation of the monoaminergic systems. In this study, we evaluated the effects of the acute and chronic administration of tramadol on nociceptive thresholds (by the hot-plate test) and on immune responses (by measuring Concanavalin A-induced splenocyte proliferation, IL-2 production and natural killer activity) in the mouse. After acute subcutaneous administration, tramadol induced antinociception starting from a dose of 20 mg/kg, whereas it significantly enhanced natural killer activity and IL-2 production at doses as low as 1 mg/kg and splenocyte proliferation starting from a dose of 10 mg/kg. After the chronic administration, the antinociceptive effect of the drug was still present, whereas the immune modifications disappeared. Thus, the pharmacological profile of tramadol is totally different from that of other drugs which bind mu-opioid receptors. Our results suggest that tramadol could be a good choice for the treatment of pain in patients where immunosuppression may be particularly contraindicated.