Safety of single large oral doses of guanethidine

The cardiovascular effects of single 100-mg doses of guanethidine were assessed in hypertensive patients by measurement of arterial pressure, heart rate, and systolic time intervals. In the 3-hr period following a dose there was no evidence of an inotropic effect. Therefore, large doses of guanethidine as required for the guanethidine loading regimen would seem to be safe even in patients in whom inotropic effects of released catecholamines would be contraindicated.     

Bioavailability of morphine after oral administration as retard tablets

The oral bioavailability of morphine following administration of a single dose of 30 mg morphine hydrochloride as Vendal retard film tablets (Lannacher Heilmittel) was investigated and compared with the bioavailability of morphine following administration of 30 mg morphine sulphate as Mundidol retard film tablets (Mundipharma). A randomized crossover study was conducted in 24 male, healthy volunteers. In 6 of them a pilot study with formulations containing 60 mg was conducted. Morphine and its metabolites were quantitated with an immunofluorimetric solid-phase assay (DELFIA). With regard to the following parameters the novel controlled-release formulation was statistically different from the reference formulation: area under the concentration-time curve, time to maximum and half value duration. After a single dose of the test formulation analgesic serum levels were maintained over a longer lasting period of time than after administration of the reference formulation. The maximal levels in serum and the elimination half life were not different. From the improved pharmacokinetic parameters of the novel controlled-release formulation an improved clinical efficacy can be expected.     

Long-term administration of controlled-release oxycodone tablets for the treatment of cancer pain

We conducted a study of the safety of controlled-release (CR) oxycodone tablets (OxyContin Tablets) administered chronically to patients with cancer-related pain in a usual clinical setting. These patients had participated in 1 of 2 double-blind, active-control studies. Our study was an open, 3-month treatment study that included 87 patients. Patients received CR oxycodone tablets every 12 hr in a manner that reflected typical clinical practice. Supplemental immediate-release (IR) oxycodone was available PRN for breakthrough pain. Patients recorded medication use, adverse events, and evaluations of pain intensity and acceptability of therapy in a daily diary. Forty-four patients (51%) completed all 12 weeks of study; 43 patients (49%) discontinued participation. At baseline and throughout the study period, the overall mean pain-intensity score was slight to moderate. A comparison of initial and final doses showed a significant but modest increase in total daily CR oxycodone dose. An increase or decrease in titration of the oxycodone dose occurred for 66 patients (84%) at least once during the 12-week study period, primarily for increased pain. Forty-four patients (56%) did not undergo dose titration when the latter was indicated. Half of the patients used IR oxycodone rescue almost daily; the mean number of rescue doses per day was 1.5. Despite stable pain control and an increasing total daily CR oxycodone dose, the percentage of patients reporting common opioid-related adverse events decreased over the course of the study. CR oxycodone tablets administered every 12 hr were successfully used to manage cancer pain over a 12-week period. Importantly, side effects diminished over time without a concomitant change in efficacy.     

Concentrations of morphine and morphine metabolites in CSF and plasma during continuous subcutaneous morphine administration in cancer pain patients

Plasma and cerebrospinal fluid (CSF) steady-state concentrations (Css) of morphine (M) and the main metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), were determined by high performance liquid chromatography (HPLC) in 21 cancer patients treated with chronic subcutaneous morphine infusion. There was a moderate, but statistically significant correlation between the daily dose of morphine and the concentrations of morphine, M3G and M6G in CSF. A poorer correlation to concentrations were seen in plasma. The mean +/- SEM CSF/plasma morphine concentration ratio was 0.36 +/- 0.07. In plasma and CSF, the mean steady state concentration of M3G but not M6G substantially exceeded that of morphine where the mean CSF M/M3G/M6G ratio was 1:15:0.5 (molar basis), and the mean plasma ratio was M/M3G/M6G 1:31:3 (molar basis). The mean M3G and M6G concentrations in CSF were approximately 8 and 10% of those found in plasma, but there was a wide interindividual variation. Plasma concentrations of both morphine glucuronides were positively correlated to serum creatinine. Neither pain intensity, evaluated by visual analogue scale (VAS), nor side effects showed any relationship to the CSF M3G concentrations, M3G/M or the M3G/M6G ratios. We conclude that during steady state subcutaneous administration of morphine, there is a large interindividual variation in plasma morphine with poor relationship to the daily administered dose. In CSF this correlation was more evident. Plasma and CSF concentrations of M3G and CSF concentrations of M6G correlated with administered morphine dose. There was an accumulation of both morphine glucuronides in patients with elevated serum creatinine. Measurements of morphine, M3G and M6G in CSF did not show any overt relationship to analgesia or side effects.     

Effects of continuous epidural administration of fentanyl and morphine on postcesarean pain

We studied the effects of continuous epidural administration of fentanyl and morphine with bupivacaine for management of postcesarean pain. Eighteen patients received either bolus epidural administration of fentanyl 100 micrograms or morphine 3 mg with 0.5% bupivacaine 4 ml, followed by continuous infusion of fentanyl 33 micrograms.ml-1 with 0.17% bupivacaine or morphine 0.21 mg.ml-1 with 0.17% bupivacaine for 48 hours, respectively. Pain score was assessed at 0 h, 12h, 24h and 48h after leaving the operating room. Pain score increased significantly and progressively in the fentanyl group. In all cases pruritus was noted. Severe pruritus was observed in the morphine group significantly more than in the fentanyl group. The current results indicate that morphine may be preferable to fentanyl for postcesarean pain control using the present opioid doses.     

Influence of timing of morphine administration on postoperative pain and analgesic consumption

Flow cytometry was used to demonstrate that cultured human melanoma BRO cells expressed membrane-bound tumour necrosis factor-alpha (TNF-alpha) and were able to release TNF-alpha upon treatment with glucosaminylmuramyl dipeptide (GMDP). The released TNF-alpha was shown to prime melanoma cells, previously unable to respond to GMDP by increasing expression of melanoma-associated antigens, making them sensitive to GMDP treatment.     

Sustained relief of chronic pain. Pharmacokinetics of sustained release morphine

There are a number of modified release formulations of morphine with recommended dosage intervals of either 12 or 24 hours, including tablets (MS Contin, Oramorph SR), capsules (Kapanol, Skenan), suspension and suppositories. Orally administered solid dosage forms are most popular but significant differences exist in the resultant pharmacokinetics and bioequivalence status of morphine after both single doses and at steady state. Following single doses, the plasma morphine concentrations showed pronounced differences in the 0- to 12-hour period with a 4- to 5-fold difference in the mean peak concentration (Cmax) for morphine and the time to Cmax (tmax) The area under the concentration-time curve (AUC) from 0 to 24 hours for the 4 formulations show greater similarity. None of the formulations were shown to be bioequivalent according to US Food and Drug Administration (FDA) criteria. At steady state, fluctuations in plasma morphine concentrations throughout a 12-hour dosage interval were greatest for MS Contin and least for Kapanol. In fact, the relatively small fluctuations in plasma morphine concentrations following Kapanol administration suggested the same formulation could successfully be used with a 24-hour dosage interval. The pharmacokinetic parameters of morphine following Kapanol once daily were similar to MS Contin (12 hours) with the obvious exception of the longer tmax. There is also another once daily oral morphine preparation (MXL) which has been shown to be bioequivalent to Kapanol under fasting conditions only in a single dose study in volunteers. Food has been shown to have an effect on the pharmacokinetics of morphine following doses of immediate release solution and the modified release preparations. However, bioequivalence is generally maintained between the fed and fasting states for most preparations. MS Contin tablets have been administered rectally, but morphine pharmacokinetic parameters show greater variability compared with oral administration and the 2 routes are not bioequivalent. The results suggest a slower rate but greater extent of morphine adsorption. Somewhat similar results were obtained when Kapanol granules are administered rectally. The morphine pharmacokinetics following administration of a specifically formulated controlled release suppository showed less variability (rectal bioavailability was 42%). The pronounced differences in morphine pharmacokinetics between the various formulations are not translated into measurable differences in the pharmacodynamic effects of pain relief and adverse effects. The lack of bioequivalence between some of the formulations suggests that care should be exercised if physicians change modified release formulations as dosage adjustments may be necessary in some patients.     

Long-term prognosis for women with chronic pelvic pain without laparoscopically demonstrable cause

With the object of assessing the long-term prognosis and the frequencies of recurrence and remission in women chronic low abdominal pain without laparoscopically visible cause, questionnaire were sent in 1985 and 1991 to 55 women who had been submitted to laparoscopy in 1982-1984 for this reason. These women had been told that there was no demonstrable explanation of the pain experienced and were then discharged. 65% and 55% respectively had experienced and unfavourable course with considerable and continued symptoms. Only 22% stated in both investigations that they had experienced a favourable course and that they were, by and large, free from pain. 36% changed from an unfavourable to a favourable course or the reverse. The assessment made by the women was confirmed by a series of subordinate questions and this demonstrated a marked difference between the favourable and unfavourable courses of the condition. It is concluded that laparoscopy with exclusion of significant pathology is not, in itself, satisfactory as treatment of this patient group and that no improvement occurs in the course of time. The condition varies greatly with many recurrences and remissions and, for this reason, uncontrolled reports of the therapeutic effects are of no significance. When compared with the literature, it is suggested that this patient group should be referred early in the course of the condition to a therapist with specialist psychological/sexological insight and/or to a physiotherapist with interest in this patient group.     

Influence of dose and timing of administration of morphine on postoperative pain and analgesic requirements

In a randomized, double-blind study, we have investigated the effect of dose and timing of administration of morphine on postoperative pain and analgesic requirements in 60 patients undergoing hysterectomy, with or without salpingo-oophorectomy. Patients were allocated randomly to one of three groups: during standardized general anaesthesia, group post received morphine 0.15 mg kg-1 i.v. at peritoneal closure after hysterectomy; group pre-low received morphine 0.15 mg kg-1 on induction of anaesthesia; and group pre-high received morphine 0.3 mg kg-1 on induction of anaesthesia. Median postoperative morphine consumption (first 24 h) from a PCA system was 68 mg (group post), 56 mg (group pre-low) and 43 mg (group pre-high), and total perioperative morphine consumption (induction of anaesthesia to end of 24 h after surgery) was 77 mg (group post), 65 mg (group pre-low) and 63 mg (group pre-high). Pain scores (at rest and on movement) were similar in the three groups. A large dose of morphine 0.3 mg kg-1 i.v. on induction of anaesthesia significantly reduced postoperative PCA morphine requirements compared with the smaller dose (0.15 mg kg-1) administered at induction or peritoneal closure, in patients undergoing hysterectomy, with or without salpingo-oophorectomy.     

Clinical pharmacology of moclobemide during chronic administration of high doses to healthy subjects

A study was conducted to determine the relation between the consumption of contaminated local fish and concentrations of total polychlorinated biphenyls (PCBs) and 68 PCB congeners in the milk of nursing Mohawk women residing near three hazardous waste sites. From 1986 to 1992, 97 Mohawk women were interviewed and donated at least 50 ml of breast milk. The comparison population consisted of 154 Caucasians. After adjustment for potential confounders, Mohawk mothers who gave birth in 1986-1989 had a geometric mean milk total PCB concentration of 0.602 ppm (fat basis) compared with 0.375 ppm for the control group (p = 0.009). These Mohawk women also had significantly higher geometric mean concentrations of nine congeners. Beginning in 1990, however, there were no significant differences between the Mohawk women and the comparison group. Estimated cumulative lifetime exposure from local fish consumption was significantly related to milk total PCB and to three congeners only among those Mohawks who gave birth from 1986 to 1989. The reduction in breast milk PCB concentrations parallels a corresponding decrease in local fish consumption and may be the result of the advisories that have been issued over the past decade recommending against the consumption of local fish by pregnant and nursing Mohawk women.     

Long-term survival of vascular accesses in a large chronic hemodialysis population

Complications associated with vascular accesses account for approximately 30% of hospital admissions for chronic hemodialysis patients. Long-term patency of access was evaluated in 76 patients, without diabetes mellitus, who had been on dialysis for at least 3 years and 41 patients, with diabetes mellitus, who had been on dialysis for over 2 years. Fistulas functioned longer than grafts (58 vs. 22 months, p < 0.01, in nondiabetics and 70 vs 22 months, p < 0.01, in patients with diabetes). Declotting or revision of restored graft function for short periods of time (< 6-10 months) and subsequent declotting was ineffective. Infections were uncommon in grafts (1 per 13.5 years of dialysis) and in fistulas (1 in 200 years of dialysis).     

A prospective study of long-term intrathecal morphine in the management of chronic nonmalignant pain

OBJECTIVE: To examine in a prospective manner the long-term safety and efficacy of chronic intrathecal morphine in patients with severe, nonmalignant pain refractory to less invasive modalities. METHODS: Forty patients with severe, chronic nonmalignant pain poorly managed by systemic medications were identified as candidates for intraspinal trial of morphine. Thirty participants reported successful pain relief during trial and were implanted with an intraspinal delivery system. Standardized measures of pain and functional status were assessed before treatment was begun and at defined intervals during the subsequent 24 months. Intrathecal opioid use and pharmacological and device-related complications were also monitored. RESULTS: The participants had a mean age of 58 +/- 13 years and a mean pain duration of 8 +/- 9 years. Fifty-three percent of the study participants were women. Pain type was characterized as mixed neuropathic-nociceptive (15 of 30 patients, 50%), peripheral neuropathic (10 of 30 patients, 33%), deafferentation (4 of 30 patients, 13%), or nociceptive (1 of 30 patients, 3%). Forty-seven percent of the patients were diagnosed with failed back surgery syndrome. Significant improvement over baseline levels of visual analog scale pain was measured at each follow-up examination after implant. Overall, 50% (11 of 22 patients) of the population reported at least a 25% reduction in visual analog scale pain after 24 months of treatment. In addition, the McGill Pain Questionnaire, visual analog scale measures of functional improvement and pain coping, and several subscales of the Chronic Illness Problem Inventory showed improvement throughout the follow-up period. Pharmacological side effects were managed medically by morphine dose reduction, addition of bupivacaine, or replacement of morphine with hydromorphone. Device-related complications requiring repeat operations were experienced by 20% of the patients. CONCLUSION: Continuous intrathecal morphine can be a safe, effective therapy for the management of severe, nonmalignant pain among a carefully selected patient population and can result in long-term improvement in several areas of daily function.     

Correlation of lethal doses of industrial chemicals between oral or intraperitoneal administration and inhalation exposure

To further explore barrier properties of the sclera, the diffusion of 3H-hydrocortisone and 14C-mannitol was measured across isolated rabbit scleral membrane. In vitro permeability studies were performed using side by side diffusion cells. Bicarbonated Ringer Solution with oxidized glutathione (GBR) at pH 7.4 was the perfusion medium, and the temperature was kept at 37 degrees C. Diffusion of hydrocortisone through the cornea was also measured to compare scleral and corneal permeation. Scleral permeability was found to be five times greater than corneal permeability. Drug analyses were performed by radionuclide counting (LSC), and permeability coefficients were obtained. In vitro metabolism of hydrocortisone was examined by incubation of tissue in hydrocortisone solution in GBR for 5 hours and 37 degrees C. Permeability coefficients of hydrocortisone diffusion through the sclera were also obtained at 25 degrees C, 15 degrees C, and 5 degrees C. Activation energy of scleral transport of hydrocortisone was calculated from an Arrhenius plot. The low activation energy suggests an aqueous pore pathway unlike permeation of the drug across the cornea which uses a transcellular pathway.     

Effect of large oral doses of ascorbic acid on uric acid excretion by normal subjects

The effects of large and oral doses of ascorbic acid on renal clearance and excretion of uric acid were studied in nongouty subjects because ascorbic acid has been reported to increase renal uric acid clearance. Our results indicate that 4 or 12 gm ascorbic acid taken in divided doses had no effect on serum uric acid concentration or uric acid excretion and clearance by the kidney. Reasons for these results, which differ from previous reports, are discussed. We quantitated the magnitude of the interference of ascorbic acid in the measurement of uric acid by the nonspecific methods frequently used, since falsely elevated urine uric acid could lead to misinterpretation of screening tests.     

Empirical scaling of single oral lethal doses across mammalian species based on a large database

The scaling of administered doses to achieve equal degrees of toxic effect in different species has been relatively poorly examined for noncancer toxicity, either empirically or theoretically. We investigate empirical patterns in the correspondence of single oral dose LD50 values across several mammalian species for a large number of chemicals based on data reported in the RTECS database maintained by the National Institute for Occupational Safety and Health. We find a good correspondence of LD50 values across species when the dose levels are expressed in terms of mg administered per kg of body mass. Our findings contrast with earlier analyses that support scaling doses by the 3/4-power of body mass to achieve equal subacute toxicity of antineoplastic agents. We suggest that, especially for severe toxicity, single- and repeated-dosing regimes may have different cross-species scaling properties, as they may depend on standing levels of defenses and rate of regeneration of defenses, respectively.     

Long-term effects of continuous intrathecal opioid treatment in chronic pain of nonmalignant etiology

In the present retrospective investigation, the long-term effects of continuous intrathecal opioid therapy via implantable infusion pump systems were examined in 120 patients with chronic, nonmalignant pain syndromes. The follow-up period was 6 months to 5.7 years (mean 3.4 years +/- 1.3 standard error of the mean). Deafferentation pain and neuropathic pain showed the best long-term results, with 68% and 62% pain reduction (visual analog scale), respectively. The mean morphine dosage initially administered was 2.7 mg/day (range 0.3-12 mg/day); after an average of 3.4 years, it was 4.7 mg/day (range 0.3-12 mg/day). In a long-term observation of 28 patients who received intrathecal morphine for longer than 4 years. 18 patients (64.3%) had a constant dosage history and 10 patients (35.7%) showed an increase in morphine dosage to more than 6 mg/day 1 year after dosage determination. In seven cases, a tolerance developed: in four patients the tolerance was controlled by means of "drug holidays"; but in three patients it was necessary to remove the pump systems. Explantation of the pump system occurred in 22 additional cases for other reasons. Throughout the follow-up period, 74.2% of the patients profited from the intrathecal opiate therapy: the average pain reduction after 6 months was 67.4% and, as of the last follow-up examination, it was 58.1%. Ninety-two percent of the patients were satisfied with the therapy and 81% reported an improvement in their quality of life. The authors' 6-year experience with administration of intrathecal opioid medications for nonmalignant pain should encourage the use of this method in carefully selected patients.     

Chronic morphine reduces pain-related disability in a rodent model of chronic, inflammatory pain.

Chronic pain is disabling, and the adverse effects of morphine are also disabling. The best way to assess the beneficial effects relative to the potential adverse effects of chronic morphine may be through the use of quantitative measures of functional disability in people and animals experiencing pain. If chronic morphine alleviates chronic pain and its beneficial analgesic effects outweigh whatever adverse effects it may produce, then it should reduce pain-related disability. Rats with adjuvant-induced arthritis were implanted with subcutaneous morphine pellets. Continuous morphine reduced pain-related disability in tasks motivated by food reward or shock avoidance throughout the 35 days of continuous administration—first, in tests that primarily assessed the function of the less severely affected forelimbs, and later, as the inflammation subsided, in tests more dependent on the function of the more severely affected hind limbs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)