Opioids administered during surgery may be beneficial by preempting postoperative pain or detrimental by causing acute tolerance. We used a stable model of hyperalgesia in volunteers to test whether acute opioid exposure also results in such pain sensitization over a period of hours in humans. Ten healthy volunteers were studied. Areas of mechanical hyperalgesia and allodynia were induced by topical capsaicin application plus intermittent heating. Computer-controlled IV remifentanil infusion was titrated to a targeted plasma concentration that reduced pain report to noxious heat by 70% and was maintained at this level for 60-100 min. Areas of hyperalgesia and allodynia were measured during and after remifentanil infusion. Remifentanil (targeted concentration of 3.1 +/- 1.2 ng/mL) reduced areas of hyperalgesia and allodynia by 33% +/- 31% and 65% +/- 28%, respectively, during infusion (P < 0.05). Areas of hyperalgesia and allodynia continuously enlarged 4 h after remifentanil was stopped, to 180% +/- 47% and 180% +/- 86%, respectively. This study demonstrates that acute opioid exposure enhances hypersensitivity for hours after exposure. If applicable to the surgical setting, this could increase the dose of opioid required for postoperative analgesia and enhance, rather than inhibit, postoperative pain.

These data suggest that gabapentin activates the descending noradrenergic system and induces spinal norepinephrine release, which produces analgesia via spinal alpha2-adrenoceptor stimulation, followed by activation of G protein-coupled inwardly rectifying potassium channels. The authors' clinical data suggest that gabapentin activates the descending noradrenergic system after preoperative oral administration at the time of surgery. These data support a central mechanism of oral gabapentin to reduce postoperative pain and suggest that this effect could be magnified by treatments that augment the effect of norepinephrine release.

Intrathecal adenosine reduces allodynia from intradermal capsaicin in human volunteers, and reduces hypersensitivity to mechanical stimuli in animals with nerve injury. Although both intrathecal and intravenous adenosine have been reported to relieve pain in patients with neuropathic pain, there are no controlled trials of this therapy. In order to determine the effect of adenosine, seven patients with chronic neuropathic pain and stable areas of mechanical hyperalgesia and allodynia were recruited. Using a double-blind, cross-over design, patients were studied on two occasions - once with intrathecal adenosine, 2 mg and once with intravenous adenosine, 2 mg, using saline by the alternate route. Areas of hyperalgesia and allodynia and pain from von Frey stimulation in the area of allodynia were determined up to 24 h after drug injection. Intrathecal, but not intravenous adenosine reduced area of allodynia by approximately 25% (P<0.05) from 2 to 24 h after injection. Intrathecal adenosine reduced pain from von Frey filament stimulation in the area of allodynia by approximately 20% (P<0.05). Ongoing pain was unaffected by adenosine by either route. Intrathecal, but not intravenous adenosine, caused backache in five of seven patients, lasting 6 h. These results indicate that intrathecal adenosine reduces allodynia and pain from stimulation in the area of allodynia, whereas the same dose of adenosine intravenously was ineffective. Given the modest effect and common side effects, the role for intrathecal adenosine as a sole agent for the treatment of neuropathic pain may be limited.

Preclinical studies suggest that visceral afferents constitutively express kappa-opioid receptors (KORs) and that noxious visceral stimuli can be inhibited at a peripheral site by KOR activation. To test the relevance of these observations to humans, we infused, in a randomized, double blind manner, a peripherally selective KOR agonist (ADL 10-0101) or placebo into six patients with chronic pancreatitis and ongoing abdominal pain despite mu-opioid agonist therapy. Pain was assessed using a pain magnitude estimate, an open ended scale of each patient's choosing and compared to their rating of pain from a 1.6 cm(2) thermode applied to the skin and heated to 49 degrees C for 5s. Normalizing pain scores to this rating as 100, pain prior to study drug treatment was 4070, and was unaffected by placebo infusion in the two individuals receiving this therapy. In contrast, ADL 10-0101 infusion reduced pain score from 63+/-7.6 (mean+/-SE) prior to infusion to 23+/-15 4h after infusion (P<0.05 vs. baseline). One patient receiving placebo and one receiving ADL 10-0101 experienced a mild headache during the study. One patient receiving ADL 10-0101 experienced restlessness and another had assymptomatic transient dysrhythmia upon standing after the 4h study. Neither of the treatments affected blood pressure, heart rate, respiratory rate, or oxyhemoglobin saturation, and no patient experienced nausea during the study. These limited data support the hypothesis that human visceral afferents express KOR and that peripherally restricted KOR agonists produce analgesia in patients with chronic visceral pain.