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Ultralow doses of naloxone (0.001-0.1 microg/kg) produce analgesia in animal models. However, no clinical study has evaluated the combination of ultralow dose naloxone and morphine using patient-controlled analgesia (PCA). This randomized, double blind controlled study sought to determine if the combination of ultralow dose naloxone and morphine in PCA solutions affects opioid requirements, analgesia, and side effects. Two-hundred and sixty-five patients (18-65 years old) undergoing operations were randomized to receive PCA morphine 1 mg/ml (n=129) or PCA morphine 1 mg/ml plus naloxone 0.6 microg/ml (n=136). We evaluated the numbers of supplemental rescue doses, the cumulative dose of each PCA solution, pain intensity, pain relief, and opioid side effects during the first 24 h after surgery. We found that opioid requirements did not differ significantly between groups. The morphine+naloxone group on average required 0.07 mg more morphine (95% CI -1.1 to 1.3) during the 24 h than the morphine group. Pain intensity levels were also similar in both groups. The morphine+naloxone group had 0.06 units lower (95% CI -0.5 to 0.4) pain intensity levels than the morphine group. The morphine+naloxone group had a lower incidence of nausea and pruritus than the morphine group (P=0.01 for both symptoms). However, the incidence of vomiting, time to tolerate fluids, sedation, and urinary retention were similar between groups (all P values >0.1). The combination of ultralow dose naloxone and morphine in PCA does not affect analgesia or opioid requirements, but it decreases the incidence of nausea and pruritus.

Despite widespread use of the 0-10 numeric rating scale (NRS) of pain intensity, relatively little is known about the meaning of decreases in pain intensity assessed by means of this scale to patients. We aimed to establish the meaning to patients of declines in pain intensity and percent pain reduction. Upon arrival to the postanesthesia care unit, postsurgical patients rated their baseline pain intensity on both a 0-10 NRS and on a 4-point verbal scale. Patients whose NRS was higher than 4/10 received intravenous opioids until their pain intensity declined to 4/10 or lower. During opioid titration, patients were asked every 10 min to rate pain intensity on a NRS and to indicate the degree of pain improvement on a 5-point Likert scale from 'no improvement' to 'complete pain relief'. Seven hundred adult patients were enrolled. For patients with moderate pain, a decrease of 1.3 units (20% reduction) corresponded to 'minimal' improvement, a decrease of 2.4 (35% reduction) to 'much' improvement, a decrease of 3.5 units (45% reduction) corresponded to 'very much' improvement. For patients with severe pain, the decrease in NRS pain score and the percentage of pain relief had to be larger to obtain similar degrees of pain relief. The change in pain intensity that is meaningful to patients increases as the severity of their baseline pain increases. The present findings are applicable in the clinical setting and research arena to assess treatment efficacy.

The continuous infusion of low doses of naloxone has been reported to decrease postoperative opioid requirements and opioid side effects. However, there is no study that evaluates the effectiveness of the combination of a low dose of naloxone and morphine using patient-controlled analgesia (PCA). This prospective, randomized double-blind controlled study sought to determine if the combination of a low dose of naloxone and morphine in a PCA solution decreases postoperative opioid requirements and pain intensity. One hundred sixty-six patients (18-65 years old) undergoing operations of less than 3 h duration with an American Society of Anesthesiologist physical status I or II were randomized to receive PCA morphine 1 mg/cc plus normal saline or PCA morphine 1 mg/cc plus naloxone 6 microg/cc. Initial PCA settings were 0.5 cc per demand with a lockout time of 10 min. The numbers of 2.5 cc supplemental rescue doses and the cumulative dose of each solution were recorded in the first 24 h after the surgical procedure. Pain intensity and opioid side effects were evaluated every 10 min in the post-anesthesia care unit and every 4 h afterwards. Patient satisfaction was assessed at the end of the 24 h of observation. The morphine+naloxone group had more treatment failures (P=0.0001), higher opioid requirements (P=0.0097), greater pain intensity (P=0.04), less pain relief (P=0.004), and less satisfaction (P=0.01) than the morphine group. The incidence of side effects was similar in both groups (P=0.3). Contrary to previous reports, adding low doses of naloxone to a morphine PCA solution increases opioid requirements and pain.

Recent animal models of experimental nerve injury have proven useful in evaluating potential sympathetic involvement in neuropathic pain syndromes. We have employed a widely adopted unilateral L 5 /L 6 spinal nerve ligation model to compare the development of mechanical allodynia with neurochemical changes both at the site of peripheral nerve injury and in the dorsal root ganglia (DRG). We have focused on the expression of neuropeptide Y (NPY), a well-studied regulatory peptide and phenotypic marker of sympathetic neurons, and functionally related Y-receptor binding sites following nerve injury. In sympathetic neurons, NPY is colocalized and coreleased with norepinephrine (NE) at peripheral sites of action. Furthermore, NPY gene expression is induced within the population of medium- and large-diameter DRG neurons of the A β -fiber class after experimental nerve injury. We therefore hypothesized that concurrent alterations in NPY and NE expression by sympathetic and sensory neurons may be a contributing factor to sympathetically-maintained neuropathic conditions. Animals with unilateral L 5 /L 6 spinal nerve ligation developed mechanical allodynia of the hind paw ipsilateral to the site of injury that persisted until sacrifice at postoperative day 10. A significant induction of preproneuropeptide Y-encoding (PPNPY) mRNA, as detected by in situ hybridization histochemistry (ISHH), occurred in populations of medium- and large-diameter DRG neurons ipsilateral to the site of injury. Immunohistochemical analysis indicated a marked decline in the number of labeled sympathetic axons positive for tyrosine hydroxylase-like and NPY-like immunoreactivities (TH-Ll and NPY-LI, respectively) proximal to the site of nerve injury and almost complete elimination of immunopositive fibers distal to the site of ligation. Whereas, the extent of colocalization of NPY-LI to TH-LI-positive sympathetic axons in unaffected L 4 or L 5 nerve segments exceeded 80%, this figure declined to approximately 50% in regenerating axons of ligated spinal nerve L 5 . The portion of NPY-LI that was not colocalized to sympathetic TH-LI-positive fibers was most likely contributed by regenerating sensory axons, consistent with marked de novo synthesis of NPY by DRG neurons. In end bulb axon terminals, i.e. morphological profiles characteristic of neuromas, NPY-LI-positive elements that were not colocalized to TH-LI-positive sympathetic elements appeared to be spatially segregated from those of sympathetic origin with colocalized TH-LI and NPY-LI. Receptor autoradiography indicated that small- and medium-diameter DRG somata of the C-fiber class normally express both Y 1 and Y 2 receptor subtypes. The pattern of the distribution of Y-receptor binding sites appeared to be relatively unaffected by spinal nerve ligation. In contrast, there was a marked increase in the density of Y 2 receptor binding sites in the proximal segment of ligated spinal nerve L 5 , consistent with previously published data indicating differential transport of the Y 2 autoregulatory receptor subtype to nerve terminals. Induction of NPY gene expression in injured DRG neurons is consistent with appearance of NPY-LI-positive end bulbs derived from regenerating sensory axons that are found in developing neuromas containing a relatively high density of transported prejunctional Y 2 receptors. Newly established functional interactions of spatially segregated sensory- and sympathetically-derived end bulbs in developing neuromas may enhance neuronal hyperexcitability engendered by aberrant electrical activity at the site of injury. Injury-related alterations in the regulatory activities of NPY released within the DRG at somally-distributed Y-receptors may also contribute to the development and/or persistence of symptoms characteristic of sympathetically-maintained pain. Finally, at later times NPY-mediated modulation of NE release from invading sympathetic axon terminals within the DRG may affect the extent of α 2 receptor-mediated neuronal hyperexcitability associated with neuropathic pain.