Morphine induces hyperalgesia without involvement of µ-opioid receptor or morphine-3-glucuronide.

Opioid-induced hyperalgesia (OIH) is a paradoxical increase in pain perception that may manifest during opioid treatment. For morphine, the metabolite morphine-3-glucuronide (M3G) is commonly believed to underlie this phenomenon. Here, in three separate studies, we empirically assess the role of M3G in morphine-induced hyperalgesia. In the first study, CD-1 mice injected with morphine (15 mg/kg subcutaneously) after pretreatment with the opioid receptor antagonist naltrexone (NTX) (15 mg/kg) showed tail withdrawal latency reductions indicative of hyperalgesia (2.5 ± 0.1 s at t = 30 min, P < 0.001 versus baseline). In these mice, the morphine/M3G concentration ratios versus effect showed a negative correlation (r(p) = -0.65, P < 0.001), indicating that higher morphine relative to M3G concentrations are associated with increased OIH. In the second study, similar hyperalgesic responses were observed in mice lacking the multidrug resistance protein 3 (MRP3) transporter protein (Mrp3(-/-) mice) in the liver and their wild-type controls (FVB mice; latency reductions: 3.1 ± 0.2 s at t = 30 min, P < 0.001 versus within-strain baseline). In the final study, the pharmacokinetics of morphine and M3G were measured in Mrp3(-/-) and FVB mice. Mrp3(-/-) mice displayed a significantly reduced capacity to export M3G into the systemic circulation, with plasma M3G concentrations just 7% of those observed in FVB controls. The data confirm previous literature that morphine causes hyperalgesia in the absence of opioid receptor activation but also indicate that this hyperalgesia may occur without a significant contribution of hepatic M3G. The relevance of these data to humans has yet to be demonstrated.

Pulse dye densitometry and indocyanine green plasma disappearance in ASA physical status I-II patients.

BACKGROUND: Indocyanine green plasma disappearance rate (ICG-PDR) is used to evaluate hepatic function. Although hepatic failure is generally said to occur with an ICG-PDR <18%/min, ICG disappearance rate is poorly defined in the healthy population, and a clear cutoff value of ICG-PDR that discriminates between normal hepatic function and hepatic failure has not yet been described. We therefore defined the ICG disappearance rate in an otherwise healthy patient population. In addition, we evaluated the noninvasive measurement of ICG-PDR (transcutaneously by pulse dye densitometry [PDD] at the finger and the nose) and compared these with the simultaneously performed invasive measurements of ICG-PDR (in arterial blood). METHODS: In patients without signs of liver disease, scheduled for elective nonhepatic surgery, 10 mg ICG was administered IV and ICG-PDR measured by PDD (DDG-2001, Nihon Kohden, Tokyo, Japan). In a subset of patients, arterial blood samples were gathered to compare PDD with invasive ICG measurements. Methods were compared using Bland-Altman analysis. The results of our study and reported studies on discriminative use of ICG-PDR in assessing liver failure were used to construct receiver operating characteristic curves. RESULTS: Forty-one patients were studied: 33 using the finger probe and 8 using the nose probe. The mean +/- SD noninvasive ICG-PDR in this patient population is 23.1% +/- 7.9%/min (n = 41) with a range of 9.7% to 43.2%/min. Bias (+/-2 sd, limits of agreement) for ICG-PDR measured by PDD compared with those measured in arterial blood were 1.6%/min (-5.2% to 8.3%/min) for the finger probe and -6.0%/min (-15.5% to 3.4%/min) for the nose probe. CONCLUSION: ICG-PDR values in a population without liver failure ranged well below 18%/min, cited as the cutoff value for hepatic failure. This cutoff value needs reconsideration. In addition, we conclude that the ICG concentration is adequately determined noninvasively by PDD.

Cardiovascular monitoring by pulse dye densitometry or arterial indocyanine green dilution.

BACKGROUND: Noninvasive cardiac output (CO) monitoring is possible by indocyanine green (ICG) dilution measured by pulse dye densitometry (PDD). To validate the precision of this method, we compared hemodynamic variables derived from PDD (DDG-2001, Nihon Kohden, Japan) with those derived from simultaneously taken arterial blood ICG concentrations. METHODS: In 20 patients (6 M/14 F), ASA I or II, 36 sessions were performed (n = 24 with the PDD-finger probe, n = 10 with the PDD-nose probe). After IV administration of 10 mg ICG, 34 arterial blood samples were taken during each session, with 20 samples taken during the first 2 min. CO, central blood volume (CBV), and total blood volume (TBV) were calculated independently from ICG and PDD and the results compared between methods using Bland-Altman analysis. The results are reported as mean difference (bias) and limits of agreement (LOA = +/- 2 sd). RESULTS: PDD using the finger probe underestimated CO (LOA) by 5% (-56% and 47%); overestimated CBV by 21% (-54% and 96%) and underestimated TBV by -15% (-38% and 8%). PDD using the nose probe overestimated CO (LOA) by 30% (-67% and 127%); CBV by 48% (-98% and 193%) and underestimated TBV by -10% (-47% and 27%). CONCLUSION: Despite the permissible bias, the wide LOA of the PDD-derived hemodynamic variables CO and CBV, compared with those simultaneously obtained by invasive arterial ICG measurements, suggest that PDD is unsuitable for evaluation of cardiovascular variables in the individual patient. Hence, the reliability and clinical use of this method seem limited.