Cephalad Movement of Morphine and Fentanyl in Humans after Intrathecal Injection

Background: Despite decades of use, controversy remains regarding the extent and time course of cephalad spread of opioids in cerebrospinal fluid (CSF) after intrathecal injection. The purpose of this study was to examine differences between two often used opioids, morphine and fentanyl, in distribution in the CSF after intrathecal injection.

Methods: Eight healthy volunteers received intrathecal injection of morphine (50 [mu]g) plus fentanyl (50 [mu]g) at a lower lumbar interspace. CSF was sampled through a needle in an upper lumbar interspace for 60-120 min. At the end of this time, a sample was taken from the lower lumbar needle, and both needles were withdrawn. CSF volume was determined by magnetic resonance imaging. Pharmacokinetic modeling was performed with NONMEM.

Results: Morphine and fentanyl peaked in CSF at the cephalad needle at similar times (41 +/- 13 min for fentanyl, 57 +/- 12 min for morphine). The ratio of morphine to fentanyl in CSF at the cephalad needle increased with time, surpassing 2:1 by 36 min and 4:1 by 103 min. CSF concentrations did not correlate with weight, height, or lumbosacral CSF volume. The concentrations of morphine and fentanyl at both sampling sites were well described by a simple pharmacokinetic model. The individual model parameters did not correlate with the distance between the needles, CSF volume, patient height, or patient weight.     

Age-dependent Responses to Thermal Hyperalgesia and Mechanical Allodynia in a Rat Model of Acute Postoperative Pain

Background: Developmental differences in short- and long-term responses to pain, especially surgical pain, have received minimal attention. The purpose of the present study was to examine postoperative responses in rats of developmental ages paralleling the infant to young adult human.

Methods: The withdrawal threshold to von Frey filament testing and withdrawal latency to hind-paw radiant heating were determined before and for various times after hind-paw incision in rats 2, 4, and 16 weeks of age. Control rats of these ages were observed serially without surgery.

Results: In control animals, younger rats were more sensitive to mechanical stimulation and less sensitive to thermal stimulation. Paw incision resulted in similar changes to both types of stimulation in all age groups, peaking 4 h after surgery. However, the return to normal sensitivity to mechanical stimulation, as measured by return of threshold to 80% of normal, occurred more quickly in 2-week-old than in 4- and 16-week-old animals. In contrast, there was no age difference for time to return to normal sensitivity to thermal stimulation after surgery.     

Postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy.

PURPOSE: A postoperative nomogram for prostate cancer recurrence after radical prostatectomy (RP) has been independently validated as accurate and discriminating. We have updated the nomogram by extending the predictions to 10 years after RP and have enabled the nomogram predictions to be adjusted for the disease-free interval that a patient has maintained after RP. METHODS: Cox regression analysis was used to model the clinical information for 1,881 patients who underwent RP for clinically-localized prostate cancer by two high-volume surgeons. The model was externally validated separately on two independent cohorts of 1,782 patients and 1,357 patients, respectively. Disease progression was defined as a rising prostate-specific antigen (PSA) level, clinical progression, radiotherapy more than 12 months postoperatively, or initiation of systemic therapy. RESULTS: The 10-year progression-free probability for the modeling set was 79% (95% CI, 75% to 82%). Significant variables in the multivariable model included PSA (P = .002), primary (P < .0001) and secondary Gleason grade (P = .0006), extracapsular extension (P < .0001), positive surgical margins (P = .028), seminal vesicle invasion (P < .0001), lymph node involvement (P = .030), treatment year (P = .008), and adjuvant radiotherapy (P = .046). The concordance index of the nomogram when applied to the independent validation sets was 0.81 and 0.79. CONCLUSION: We have developed and validated as a robust predictive model an enhanced postoperative nomogram for prostate cancer recurrence after RP. Unique to predictive models, the nomogram predictions can be adjusted for the disease-free interval that a patient has achieved after RP.