Najib Babul

Comparative clinical efficacy and safety of a novel controlled-release oxycodone formulation and controlled-release hydromorphone in the treatment of cancer pain

The use of oxycodone to treat chronic cancer pain has been hampered by its short elimination half‐life, which necessitates administration every 4 hours. This study compared the clinical efficacy and safety of a novel oxycodone formulation with that of hydromorphone in the treatment of cancer pain.

A Double-Blind, Crossover Study of Controlled-Release Metoclopramide and Placebo for the Chronic Nausea and Dyspepsia of Advanced Cancer

To compare a novel controlled-release formulation of metoclopramide with placebo in patients with cancer-associated dyspepsia syndrome, 26 adult patients with a >/=1 month history of cancer-associated dyspepsia syndrome were randomized to receive either controlled-release metoclopramide 40 mg every 12 hours or matching placebo for a period of 4 days. On day 5, patients crossed over to the alternate treatment for a further period of 4 days. Dose adjustments and rescue antiemetics were permitted during both phases. Nausea, anorexia, bloating, vomiting/retching, and drowsiness were assessed on a 100-mm VAS scale in a daily diary. On the last day of treatment of each phase, nausea was significantly lower in the controlled-release metoclopramide group compared to placebo (17 +/- 12 mm versus 12 +/- 10 mm). Nausea scores tended to increase across days during the placebo phase and to decrease during the controlled-release metoclopramide phase. There was a trend for improvement in the intensity of all symptoms on controlled-release metoclopramide with the exception of appetite, but this trend only reached statistical significance for nausea. The frequency and severity of elicited adverse events did not differ significantly between treatments, although drowsiness, dizziness, and poor sleep were somewhat higher in the placebo group. In no case was it necessary to discontinue controlled-release metoclopramide because of toxicity. These results indicate that controlled-release metoclopramide reduces gastrointestinal symptoms in this population of advanced cancer patients.

Comparative clinical efficacy and safety of immediate release and controlled release hydromorphone for chronic severe cancer pain

Background. The short elimination half‐life of hydromorphone necessitates 4‐hourly dosing to maintain optimal levels of analgesia in patients with chronic cancer pain. The purpose of this study was to compare the clinical efficacy and safety of controlled release hydromorphone administered every 12 hours and immediate release hydromorphone administered every 4 hours in patients with chronic severe cancer pain.

Chronic nausea in advanced cancer patients: A retrospective assessment of a metoclopramide-based antiemetic regimen

The purpose of this retrospective study is to assess the frequency and intensity of chronic nausea in patients admitted to the Palliative Care Unit and the results of a metoclopramide-based treatment regimen. We reviewed the medical records of 100 consecutive patients admitted to the Palliative Care Unit at the Edmonton General Hospital until death during 1992-1993. All patients had terminal cancer and normal cognitive function. All patients completed the Functional Analogue Scale for appetite, nausea, pain, activity, shortness of breath, and sensation of well-being at 1000 and 1600 hours every day. Patients who complained of nausea initially received metoclopramide 10 mg every 4 hr orally or subcutaneously (Step 1). If nausea persisted, dexamethasone 10 mg twice daily was added (Step 2). Step 3 consisted of a continuous subcutaneous infusion of metoclopramide of 60-120 mg/day plus dexamethasone. If no response was observed, other antiemetics were administered (Step 4). Upon admission to the unit, 32 patients (32%) presented with nausea. During the average admission of 25 +/- 13 days, 98 patients (98%) developed nausea. Twenty-five patients (25%) required other antiemetics because of bowel obstruction (18), extrapyramidal side effects (3), or other reasons (4). Most patients without bowel obstruction achieved excellent control of nausea using the metoclopramide-based regimen. During the first 5 days and last 5 days of admission, nausea had significantly lower intensity than the rest of the symptoms that were monitored. Our results suggest that, although nausea is very frequent, it can be well controlled in the majority of patients using safe and simple antiemetic regimens.

Comparison of the efficacy, safety, and pharmacokinetics of controlled release and immediate release metoclopramide for the management of chronic nausea in patients with advanced cancer

Background. The short elimination half‐life of met‐oclopramide necessitates frequent administration for optimal relief of nausea. This study compares a newly developed controlled release preparation of metoclopram‐ide (CRM) and immediate release metoclopramide (IRM) with respect to efficacy, safety, and pharmacokinetics in patients with chronic nausea associated with advanced cancer.

Steady‐State Pharmacokinetics of Hydromorphone and Hydromorphone‐3‐Glucuronide in Cancer Patients After Immediate and Controlled‐Release Hydromorphone

Although the pharmacokinetics of oral hydromorphone has been evaluated in healthy volunteers after small single oral doses, data are not available regarding the disposition of hydromorphone and its principal metabolite, hydromorphone‐3‐glucuronide (H3G), at steady‐state and after large oral doses. The authors studied the pharmacokinetics of hydromorphone and H3G after oral administration of an immediate‐release (IR) and controlled‐release (CR) formulation of hydromorphone at a daily dose of 48 ± 11 mg (range 6–216 mg) in a randomized, double‐blind, steady‐state, two‐way crossover evaluation in 18 patients with chronic cancer pain. Controlled‐release hydromorphone demonstrated equivalent bioavailability and acceptable CR characteristics, when compared with IR hydromorphone (CR vs. IR: AUC0–12 123.10 ± 20.38 vs. 118.98 ± 20.92 ng · hr · mL−1, P = NS, Cmax 17.76 ± 3.07 vs. 19.70 ± 4.04 ng · mL−1, P = N.S., Cmin 6.04 ± 1.01 vs. 5.28 ± 1.00 ng · mL−1, P = NS, and Tmax 4.78 ± 0.78 vs. 1.47 ± 0.22 hr, P = 0.0008). A significant linear relationship existed between hydromorphone dose and hydromorphone AUC (r = 0.8315, P = 0.0001) and between hydromorphone AUC and H3G AUC (r = 0.8048, P = 0.0001) over a wide dose range. The steady‐state molar ratio of H3G to hydromorphone was 27:1. The authors conclude that CR hydromorphone provides a pharmacokinetic profile consistent with 12 hourly dosing and that at steady state, oral hydromorphone is extensively metabolized to H3G, although the pharmacologic activity of this metabolite remains unknown.

Disposition of morphine and its glucuronide metabolites after oral and rectal administration : evidence of route specificity

Morphine‐6‐glucuronide is a metabolite of morphine that shows significant analgesic effects in animals and humans. To evaluate route‐specific differences in the potential contribution of morphine‐6‐glucuronide to morphine analgesia, we studied the pharmacokinetics of morphine, morphine‐6‐glucuronide, and morphine‐3‐glucuronide after oral and rectal administration of morphine sulfate in a six‐subject randomized, single‐dose, two‐way crossover evaluation. The mean area under the plasma concentration‐time curve (AUC) molar ratios of morphine‐6‐glucuronide (M6G) and morphine‐3‐glucuronide (M3G) to morphine (M) were greater after oral morphine administration compared with rectal morphine administration (M6G/M ratio, 2.7:1 versus 1.3:1, p= 0.025; M3G/M ratio, 18.3:1 versus 9.3:1, p= 0.002). Systemic bioavailability and peak plasma concentrations of morphine‐6‐glucuronide and morphine‐3‐glucuronide were significantly greater after oral morphine administration compared with the rectal route (AUC: M6G, 377.1 ± 124.2 versus 236.2 ± 133.7 nmol · hr/L, p= 0.05; M3G, 2610.1 ± 446.4 versus 1650.2 ± 309.0 nmol · hr/L, p= 0.004; maximum concentration: M6G, 110.9 ± 37.5 versus 64.6 ± 28.8 nmol/L, p= 0.002; M3G, 576.9 ± 155.8 versus 266.8 ± 110.5 nmol/L, p= 0.007). Conversely, the systemic availability of morphine was lower after oral administration, although this difference failed to achieve statistical significance (142.3 ± 17.1 versus 176.6 ± 69.4 nmol · hr/L, p= 0.14). These data suggest that rectal administration of morphine is associated with significant avoidance of hepatic biotransformation, and they provide a convincing argument for the evaluation of morphine‐6‐glucuronide concentrations in pharmacokinetic and pharmacodynamic comparisons involving different routes of morphine administration.

Comparative Efficacy and Safety of Controlled‐Release Morphine Suppositories and Tablets in Cancer Pain

Although the oral route is the preferred method of opioid therapy in patients with cancer pain, many patients will require an alternate route of analgesic administration at some point during the trajectory of their illness. This study compared the efficacy and safety of a novel, controlled‐release suppository of morphine (MSC‐R) and controlled‐release morphine tablets (MSC‐T) in patients with cancer pain. In a double‐blind crossover study, 27 patients with cancer pain were randomized to receive MSC‐R or MSC‐T every 12 hours for 7 days each, using a 1:1 analgesic equivalence ratio. Pain intensity was assessed using a visual analog scale (VAS) and the Present Pain Intensity Index of the McGill Pain Questionnaire. Nausea and sedation were also assessed with a VAS. Pharmacodynamic assessments were made by the patient at 8:00 am, 12:00 pm, 4:00 pm, and 8:00 pm and rescue morphine use recorded in a daily diary. There were no significant differences between MSC‐R and MSC‐T in overall scores for pain intensity VAS, ordinal pain intensity, and sedation. There was a small but significant difference in overall nausea VAS score in favor of MSC‐R. Mean daily rescue analgesic use did not differ significantly during between treatment with MSC‐R and MSC‐T. MSC‐R provides pain control comparable to that provided by MSC‐T when given every 12 hours at a 1:1 dose ratio, and represents a reliable alternative method of pain control for patients unable to take oral opioid agents.

Extended-release opioids for the management of chronic non-malignant pain

Recent clinical trials have documented the use of extended-release (ER) opioids in the management of chronic non-malignant pain. This manuscript reviews the clinical pharmacology of investigational and current marketed ER opioids. Recent randomised clinical trials of ER opioids that document the efficacy and safety of opioid therapy for chronic pain are reviewed. Finally, the abuse liability of ER opioids is discussed. Current technologies aimed at defeating the abuse of ER opioids will also be presented.

Efficacy of oxymorphone extended release in postsurgical pain: a randomized clinical trial in knee arthroplasty.

Patients with moderate or severe pain following knee arthroplasty and washout from standard patient‐controlled analgesia (PCA) were randomized to receive 20 mg of an extended‐release (ER) oxymorphone formulation (n = 65) or placebo (n = 61) q12h for 1 day. Oxymorphone PCA was used as rescue analgesic. Oxymorphone ER provided significant improvements over placebo for most standard single‐dose analgesic parameters, including mean total pain relief (TOTPAR) over 0 to 12 hours (19.30 vs. 13.72; p = 0.0056), as well as for all multiple‐dose (24‐h) efficacy assessments. Oxymorphone‐treated patients used significantly less rescue PCA than those who received placebo (p < 0.02). Adverse events such as nausea and constipation were typical of opioids, and laboratory and physical findings were similar between groups. Oxymorphone ER was effective and generally well tolerated. A single dose was active from 2 hours until ≥ 12 hours after administration. Comparisons with other oral opioids are warranted, especially in the setting of outpatient and day surgery