Controlled-release oxycodone and naloxone in the treatment of chronic low back pain: a placebo-controlled, randomized study.

BACKGROUND: For Canadian regulatory purposes, an analgesic study was required to complement previously completed, pivotal studies on bowel effects and analgesia associated with controlled-release (CR) oxycodone/CR naloxone. OBJECTIVES: To compare the analgesic efficacy and safety of CR oxycodone/CR naloxone versus placebo in patients with chronic low back pain. METHODS: Patients requiring opioid therapy underwent a two- to seven-day opioid washout before being randomly assigned to receive either 10 mg/5 mg CR oxycodone/CR naloxone or placebo every 12 h, titrated weekly according to efficacy and tolerability to 20 mg/10 mg, 30 mg/15 mg or 40 mg/20 mg every 12 h. After four weeks, patients crossed over to the alternative treatment for an additional four weeks. Acetaminophen/codeine (300 mg/30 mg every 4 h to 6 h as needed) was provided as rescue medication. RESULTS: Of the 83 randomized patients, 54 (65%) comprised the per-protocol population. According to per-protocol analysis, CR oxycodone/CR naloxone resulted in significantly lower mean (± SD)pain scores measured on a visual analogue scale (48.6 ± 23.1 mm versus 55.9 ± 25.4 mm; P=0.0296) and five-point ordinal pain intensity scores (2.1 ± 0.8 versus 2.4 ± 0.9; P=0.0415) compared with placebo. After the double-blinded phase, patients and investigators both preferred CR oxycodone/CR naloxone over placebo. These outcomes continued in the 79% of patients who chose to continue receiving CR oxycodone/CR naloxone in a six-month, open-label evaluation. CONCLUSIONS: In patients complying with treatment as per protocol, CR oxycodone/CR naloxone was effective for the management of chronic low back pain of moderate or severe intensity.

A randomized, double-blind, crossover comparison of the efficacy and safety of oral controlled-release tramadol and placebo in patients with painful osteoarthritis.

OBJECTIVE: To compare the efficacy and safety of controlled-release (CR) tramadol (Zytram XL, Purdue Pharma, Canada) and placebo in patients with painful osteoarthritis. METHODS: Patients underwent analgesic washout for two to seven days before random assignment to 150 mg daily of CR tramadol or placebo, and were titrated weekly to 200 mg, 300 mg or a maximum of 400 mg once daily. After four weeks, patients crossed over to the alternate treatment for another four weeks. Plain acetaminophen was provided as a rescue analgesic. All patients who completed the crossover study were eligible to receive open label CR tramadol for six months. RESULTS: Seventy-seven of 100 randomly assigned patients were evaluable for efficacy. CR tramadol resulted in significantly lower visual analogue scale pain intensity scores (37.4+/-23.9 versus 45.1+/-24.3, P=0.0009). Western Ontario and McMaster Universities osteoarthritis index subscale scores for pain (189.0+/-105.0 versus 230.0+/-115.4; P=0.0001) and physical function (632.4+/-361.3 versus 727.4+/-383.4; P=0.0205) were significantly better with CR tramadol. Total pain and disability (22.8+/-14.5 versus 27.2+/-14.8; P=0.0004), and overall pain and sleep (104.7+/-98.0 versus 141.0+/-108.2; P=0.0005) scores in the Pain and Sleep Questionnaire were significantly lower for CR tramadol. Short-form 36 Health Survey scores were significantly better during CR tramadol treatment for the pain index (38.8+/-10.8 versus 35.6+/-9.0; P=0.0100), general health perception (46.5+/-11.2 versus 44.4+/-11.6; P=0.0262), vitality (43.1+/-13.2 versus 40.2+/-13.7; P=0.0255) and overall physical components (40.8+/-8.9 versus 37.8+/-7.7; P=0.0002). CR tramadol treatment was preferred by 55.8% of patients (P=0.0005) versus 20.8% and 23.4% of patients who chose placebo or had no preference, respectively. These improvements were sustained for up to six months, and 86.5% of patients reported at least moderate benefit from CR tramadol during long-term treatment. CONCLUSION: CR tramadol is effective for the management of painful osteoarthritis.

Suppression of acute experimental allergic encephalomyelitis with a small molecule inhibitor of alpha4 integrin.

PURPOSE: To determine the efficacy of a small molecule inhibitor of alpha4 integrin (CT301) at reversing the clinical, pathological and MR-detectable deficits associated with the acute phase of experimental allergic encephalomyelitis (EAE). MATERIALS AND METHODS: EAE was induced in 36 female Hartley guinea pigs, and the treatment period was from day 11 to day 17 post-immunization. Animals received either saline (n = 12), anti-alpha4 integrin antibody (AN100226m; n = 12) or CT301 (n = 12). T2-weighted fast spin echo and T1-weighted pre- and post-contrast scans were performed at the beginning (day 11) and end (day 18) of the treatment period, and scored for cerebral inflammation and gadolinium enhancement. T1-weighted images were further analyzed to quantify this enhancement as a measure of blood-brain barrier integrity. Dissected CNS was evaluated for inflammation and demyelination. RESULTS: CT301 successfully reversed two clinical indicators of disease over the course of the treatment period. These animals showed decreased T2-weighted abnormalities, as well as a reduction in gadolinium leakage on T1-weighted images. Meningeal and perivascular inflammation was decreased by anti-alpha4 integrin treatments. CONCLUSION: CT301 effectively reverses the clinical, pathological and MR-detectable deficits of acute EAE, and may therefore be a promising therapeutic agent in multiple sclerosis (MS).

Spontaneous remyelination following prolonged inhibition of alpha4 integrin in chronic EAE.

Inhibition of alpha(4)beta(1) integrin blocks immune cell influx into the CNS providing benefit to patients with multiple sclerosis and in animal model systems. We have used this mechanism to examine whether the presence of inflammatory cells suppresses spontaneous myelin repair in experimental autoimmune encephalomyelitis. We observed (1) 87% of plaques showed remyelination after 40 days of treatment; (2) myelin repair occurred in half of the total lesion area; (3) half of the animals regained motor function. There was no significant repair or gain of motor function in vehicle-treated animals. Therefore, prolonged inhibition of CNS inflammation, in the absence of targeted myelin repair, facilitates mechanisms of spontaneous remyelination.

Prolonged reversal of chronic experimental allergic encephalomyelitis using a small molecule inhibitor of alpha4 integrin.

CNS leukocytic invasion in experimental allergic encephalomyelitis (EAE) depends on alpha4beta1 integrin/vascular cell adhesion molecule-1 (VCAM-1) interactions. A small molecule inhibitor of alpha4beta1 integrin (CT301) was administered to guinea pigs in the chronic phase (>d40) of EAE for 10, 20, 30 or 40 days. CT301 elicited a rapid, significant improvement in the clinical and pathological scores that was maintained throughout the treatment period. A progressive loss of cells in the spinal cord of treated animals confirmed the resolution of inflammation associated with clinical recovery. Therefore, prolonged inhibition of alpha4beta1 integrin caused a sustained reversal of disease pathology in chronic EAE and may be similarly useful in MS.

Biopsy findings in five hundred thirty-one patients with atypical glandular cells of uncertain significance as defined by the Bethesda system.

OBJECTIVES: Histologic findings in biopsy specimens obtained from patients with atypical glandular cells of uncertain significance were studied to define the utility and limitations of this category. STUDY DESIGN: Computerized records over a 3-year period were retrospectively analyzed. The most significant histologic diagnosis from all biopsy specimens submitted was compared with the subcategory of the first Papanicolaou smear obtained showing atypical glandular cells of uncertain significance. RESULTS: Biopsy results were available for 531 of 1117 patients with atypical glandular cells of uncertain significance (48%). Biopsy-proved preinvasive (83%) or invasive (17%) lesions were present in 191 patients (36%). Eighty-nine percent of the preinvasive lesions were squamous, whereas 97% of the invasive lesions were glandular. Glandular lesions were more likely to be invasive, whereas squamous lesions were more likely to be preinvasive (p < 0.001). Twenty-eight patients had endometrial carcinoma, which represents 88% of all invasive carcinomas detected. CONCLUSIONS: Almost three fourths of patients with atypical glandular cells of uncertain significance and with lesions have squamous lesions, not glandular as suggested by the name of the category. Unlike patients with atypical squamous cells of uncertain significance, patients with atypical glandular cells of uncertain significance have a significant risk of malignant lesions, which are nearly all glandular and predominantly arise from the endometrium.

Papanicolaou smears by the Bethesda system in endometrial malignancy: utility and prognostic importance.

OBJECTIVE: To evaluate the prognostic significance of the Bethesda system's cytologic categories in patients with endometrial malignancy. METHODS: Patients with biopsy or hysterectomy-proven endometrial malignancy and a Papanicolaou smear result reported using the Bethesda system within 1 year of diagnosis were identified through retrospective review of our computerized database. RESULTS: After introduction of the Bethesda system in our laboratory on November 1, 1992, until January 1, 1997, 112 eligible patients were identified (108 with carcinomas and four with carcinosarcomas). Patients with cytologic diagnoses of malignancy (n = 17) were significantly more likely to have International Federation of Gynecology and Obstetrics (FIGO) grade 3 tumors and high-risk histology (serous, clear cell, and adenosquamous carcinoma and carcinosarcoma) than those with atypical glandular cells of uncertain significance (n = 33) or those with cytology not suspicious for malignancy (n = 63). Patients with malignant smears were also significantly more likely to have cervical extension, malignant peritoneal cytology, and FIGO stage II, III, or IV than those with atypical glandular cells of uncertain significance or those with cytology not suspicious for malignancy. CONCLUSION: Papanicolaou smears obtained within 1 year of histologic diagnosis of endometrial malignancy and interpreted using the Bethesda system were suspicious for (atypical glandular cells of uncertain significance) or diagnostic of malignancy in nearly half of all cases (29 and 15%, respectively). Patients having malignant glandular cells were more likely to have poor prognostic pathologic findings.

Incidence of atypical glandular cells of uncertain significance in cervical cytology following introduction of the Bethesda System.

OBJECTIVE: To establish the frequency of the atypical glandular cells of uncertain significance (AGCUS) category, and its subcategories, as defined by the Bethesda System (TBS). METHODS: Our computerized records of cervical/vaginal cytology specimens submitted from January 1, 1993, through December 31, 1995, were retrospectively reviewed for specimens diagnosed as AGCUS. When appropriate, our subcategory of "AGCUS favor premalignant/malignant lesion" was further qualified as "favor endocervical adenocarcinoma in situ" or "suspicious for endometrial carcinoma." The number of specimens and patients diagnosed for each subcategory were grouped by calendar year. Differences in frequency between time periods were tested for statistical significance using chi 2 analysis. RESULTS: AGCUS was diagnosed in 1181 of 177,715 submitted specimens (0.66%). The frequency of subcategories was as follows: "favor reactive" (65%), "unable to further classify" (30%), "favor premalignant/malignant" (2.9%), "suspicious for endometrial carcinoma" (1.9%), and "favor endocervical adenocarcinoma in situ" (0.4%). From 1993 to 1995 there was an increase in the rate of diagnosis of AGCUS (0.55 to 0.73%; P < 0.001) and a decrease in the percentage of specimens with AGCUS subclassified as "favor premalignant/malignant" (6.2 to 0.5%; P < 0.001). Other subcategories showed no significant change in frequency over this time period. The rate of biopsy-proven preinvasive or invasive lesions in AGCUS patients also showed no significant change from year to year over this time period. CONCLUSION: The AGCUS diagnosis can be anticipated at a low but consistent rate from a cytology laboratory using TBS. Any comparison of laboratories should take into consideration the change in reporting frequencies that occurs as part of the "learning curve" following introduction of TBS reporting. Uniform diagnostic criteria and additional reports with large numbers of cytologic specimens will be needed to establish the expected frequency of AGCUS and its subcategories.