Methylnaltrexone Treatment for Opioid-Induced Constipation in Patients with and without Cancer: Effect of Initial Dose.

Purpose: Opioid-induced constipation (OIC) is a common side effect of opioid therapy. Methylnaltrexone (MNTX) is a selective, peripherally acting µ-opioid receptor antagonist, with demonstrated efficacy in treating OIC. We pooled results from MNTX clinical trials to compare responses to an initial dose in patients with chronic cancer and noncancer pain. Patients and Methods: This post hoc analysis used pooled data from 3 randomized, placebo-controlled studies of MNTX in patients with advanced illness with OIC. Assessments included the proportions of patients achieving rescue-free laxation (RFL) within 4 and 24 hours of the first study drug dose, time to RFL, current and worst pain intensity, and adverse events, stratified by the presence/absence of cancer. Results: A total of 355 patients with cancer (MNTX n = 198, placebo n = 157) and 163 without active cancer (MNTX n = 83; placebo n = 80) were included. More patients treated with MNTX compared with those who received placebo achieved an RFL within 4 (cancer: MNTX, 61.1% vs placebo,15.3%, p<0.0001; noncancer: MNTX, 62.2% vs placebo, 17.5%, p<0.0001) and 24 hours (cancer: MNTX, 71.2% vs placebo, 41.4%, p<0.0001; noncancer: MNTX, 74.4% vs placebo, 37.5%, p<0.0001) of the initial dose. Cumulative RFL response rates within 4 hours of the first, second, or third dose of study drug were also higher in MNTX-treated patients. The estimated time to RFL was shorter among those who received MNTX and similar in cancer and noncancer patients. Mean pain scores declined similarly in all groups. The most common adverse events in both cancer and noncancer patients were abdominal pain, flatulence, and nausea. Conclusion: After the first dose, MNTX rapidly induced a laxation response in the majority of both cancer and noncancer patients with advanced illness. Opioid-induced analgesia was not compromised, and adverse events were primarily gastrointestinal in nature. Methylnaltrexone is a well-tolerated and effective treatment for OIC in both cancer and noncancer patients.

Subcutaneous Methylnaltrexone as Treatment for Opioid-Induced Constipation in Patients with Advanced Cancer and Noncancer Illnesses: A Post Hoc Analysis of Two Clinical Trials.

Purpose: To evaluate the efficacy and safety of subcutaneous (SC) methylnaltrexone for opioid-induced constipation (OIC) in patients with and without active cancer. Patients and Methods: We analyzed two randomized, double-blind, placebo-controlled, Phase 3/4 trials (NCT00402038, NCT00672477). Patients received SC methylnaltrexone (study 302, 0.15 mg/kg; study 4000, 8 mg or 12 mg based on body weight) or placebo every other day for 2 weeks. Patients were stratified by cancer status. Primary efficacy endpoints included proportion of patients achieving rescue-free laxation (RFL); secondary endpoints included time to RFL, pain intensity scores, and safety/tolerability. Trial results were evaluated separately. Results: The safety population (patients receiving ≥1 study drug dose) included 364 patients (study 302, n=134; study 4000, n=230). Study 302 had 78 patients with active cancer (methylnaltrexone, n=37; placebo, n=41) and 56 without cancer (methylnaltrexone, n=26; placebo, n=30); study 4000 had 152 patients with active cancer (methylnaltrexone, n=79; placebo, n=73) and 78 without cancer (methylnaltrexone, n=37; placebo, n=41). A significantly greater proportion of patients treated with methylnaltrexone achieved a laxation response within 4 hours after at least 2 of the first 4 doses versus placebo, dosed by body weight (cancer, 54.1% [methylnaltrexone] vs 7.3% [placebo], P<0.0001; noncancer, 48.0% vs 10.0%; P<0.005) or given as a weight-adjusted fixed dose (cancer, 59.5% vs 6.8%; noncancer, 70.3% vs 14.6%; P<0.0001 each). With fixed-dose methylnaltrexone, average time to RFL for patients with and without cancer was <1 hour of the first dose; with methylnaltrexone dosed by body weight, the first RFL occurred in <4 and <7 hours of treatment in patients with and without cancer, respectively. No significant differences were found in pain scores. SC methylnaltrexone was well tolerated at all doses in all patient cohorts. Conclusion: SC methylnaltrexone was efficacious in inducing rapid RFL and safe among patients with and without active cancer suffering from OIC.

Subcutaneous Methylnaltrexone for Treatment of Opioid-Induced Constipation in Cancer versus Noncancer Patients: An Analysis of Efficacy and Safety Variables from Two Studies.

PURPOSE: Methylnaltrexone inhibits opioid-induced constipation (OIC) by binding to peripheral µ-opioid receptors without impacting central opioid receptor mediated analgesia. This analysis compared methylnaltrexone efficacy and safety among advanced illness patients with and without active cancer and OIC. PATIENTS AND METHODS: This post hoc analysis included two multicenter, randomized, double-blind, placebo-controlled studies in adults with advanced illness and OIC who received subcutaneous methylnaltrexone. Efficacy endpoints included the proportion of patients achieving rescue-free laxation (RFL), time to RFL, weekly laxations within 24 hours after dosing, rescue laxative use, and pain scores. Adverse events were monitored for safety. RESULTS: After pooling, 178 patients received methylnaltrexone (n = 116 with cancer) and 185 received placebo (n = 114 with cancer). Median baseline daily opioid morphine equivalents (mg/d) were higher in cancer (methylnaltrexone: 180; placebo: 188) versus noncancer patients (methylnaltrexone: 120; placebo: 80). The proportions of patients achieving RFL within 4 hours after ≥2 of the first 4 doses were significantly greater with methylnaltrexone (cancer: 56.9%; noncancer: 58.1%) versus placebo (cancer: 5.3%; noncancer: 11.3%; P < 0.0001). The median time to laxation within 24 hours after the first methylnaltrexone dose was significantly shorter in cancer and noncancer patients versus placebo (cancer: 0.96 vs 22.53 hours, P < 0.0001; noncancer: 1.25 vs >24 hours, P = 0.0002). The mean number of weekly laxations within 24 hours after dosing by week 2 was significantly higher in methylnaltrexone- vs placebo-treated cancer and noncancer patients (cancer: 7.9 vs 4.9, P < 0.0001; noncancer: 8.4 vs 5.0, P < 0.0001). Methylnaltrexone reduced rescue laxative use without impacting pain scores. Consistent with previous data, methylnaltrexone was well tolerated in cancer and noncancer patients, and the AE profile did not suggest symptoms of opioid withdrawal. CONCLUSION: Methylnaltrexone reduced RFL time in advanced-illness patients with and without active cancer, while maintaining pain control with opioid treatment despite higher baseline opioid use among cancer patients.

Cancer breakthrough pain in the presence of cancer-related chronic pain: fact versus perceptions of health-care providers and patients.

Cancer breakthrough pain is a flare in pain that "breaks through" well-controlled persistent cancer pain. Although the condition is highly prevalent, the concept of cancer breakthrough pain is not well understood and is therefore underdiagnosed and undertreated. The purpose of this review is to examine the roles the health-care practitioner and patient/family caregiver play in the undertreatment of breakthrough pain. A lack of technical knowledge about pain management and pain assessment, attitudes about opioid addiction, and regulatory guidelines influence the manner in which opioids are prescribed. Patients harbor a variety of fears and misconceptions, such as opioid addiction, tolerance, side effects, and the meaning of pain, which can create a barrier to effective communication with their health-care provider regarding their cancer pain management and specifically their breakthrough pain. Identifying these issues gives health-care professionals and patients an opportunity to develop strategies that can improve the treatment of cancer breakthrough pain.

Subcutaneous methylnaltrexone for opioid-induced constipation in advanced-illness patients with or without active cancer.

Aim: To evaluate methylnaltrexone for opioid-induced constipation in patients with and without cancer. Methods: This post hoc analysis comprises two Phase III, multicenter, double-blind, randomized studies of advanced-illness patients who received methylnaltrexone subcutaneous injection or placebo. Results: Significantly more patients treated with methylnaltrexone than placebo experienced laxation within 4 (cancer = 55.5 vs 15.5%; noncancer = 55.6 vs 12.8%) and 24 (cancer = 64.7 vs 29.8%; noncancer = 64.4 vs 30.8%) h after the first dose (p < 0.01 vs placebo). Regardless of cancer status, methylnaltrexone reduced median time to laxation and improved constipation relief without impacting opioid analgesia or withdrawal symptoms. Conclusion: Methylnaltrexone provided significant improvements in opioid-induced constipation over placebo in advanced-illness patients with and without cancer. Clinical trial registration numbers: study 301: NCT00401362; study 302: NCT00402038.

From mechanisms to management: translating the neuropathic pain consensus recommendations into clinical practice.

Chronic neuropathic pain poses a treatment challenge, and is associated with significant psychologic distress, physical disability, and impaired functioning, which impact the activities of daily living. Efforts to provide relief are often inadequate and/or require polypharmacy. This has spurred interest among researchers and clinicians alike to develop early, intensive treatments that target the molecular and cellular mechanisms involved in pain transduction, transmission, and modulation, or ideally, that prevent neuropathic pain from occurring in the first place. Currently, researchers are attempting to capitalize on our understanding of neuropathic pain pathophysiology to develop drugs that interrupt distinct activities involved in its perpetuation. In this regard, several potential agents (eg, NMDA and AMPA/kainate antagonists) are in phase 2 and 3 clinical trials. In the interim, evolving data and evidence-based neuropathic treatment recommendations provide guidance for selecting first- and second-line medications that alone or in combination offer acceptable neuropathic pain control and allow clinicians to bridge the gap between current knowledge and its application in the clinical setting. Hopefully, as basic and clinical science progresses, further treatment advances and management tools will be found to improve the care of patients who live with neuropathic pain.

Treatment of opioid-induced delirium with acetylcholinesterase inhibitors: a case report.

A 55-year-old woman with advanced ovarian cancer and severe pain developed hypoactive delirium after an increase in her opioid dosage. Myoclonus and delirium improved dramatically with the intravenous injection of the acetylcholinesterase inhibitor physostigmine, and this improvement was maintained during the administration of donepezil, an oral medication with similar pharmacodynamic properties. Evidence for a disorder of cholinergic neurotransmission in opioid-induced delirium is discussed, as is the rationale for treatment with acetylcholinesterase inhibitors and other cholinomimetic agents.

Treatment of opiate-related sedation: utility of the cholinesterase inhibitors.

Daytime sedation is a common and potentially dose-limiting side effect of the opiate analgesics. The psychostimulants, such as methylphenidate, are frequently prescribed to treat this problem, but their use may be limited by side effects, such as weight loss, anxiety, or insomnia, or tolerance to their antisedative effects. Medications which enhance intracerebral cholinergic activity may offer an alternative treatment approach, since functional deficits of acetylcholine may, in part, account for the sedative and mind-dulling effects of opiates. Preliminary studies with donepezil, a centrally acting acetylcholinesterase (AChE) inhibitor approved for use in Alzheimer's disease, have suggested at least short-term benefit in treating opiate-related sedation. In a retrospective study, we reviewed the results of donepezil treatment in 40 patients, 37 of whom had cancer, which in most cases was in an advanced stage. All patients were receiving chronic opiate treatment, and the majority were on a stable opiate dose in the 2 weeks preceding the initiation of donepezil. The average opiate dose was 844 mg in oral morphine equivalents. Seventy-three percent of the patients experienced moderate or greater improvement on the Clinical Global Improvement Scale. Evaluations on the Epworth Sleepiness Scale (ESS; 0-24), visual analog sleepiness scale (VAS; 0-100), and average pain levels (0-100), before and after donepezil treatment, were obtained on 19 patients. Prior to donepezil, ESS, VAS, and pain scores were 18.5, 76.3, and 47.4. After an average of 21 days of donepezil treatment, scores were 9.5 (P < 0.001), 39.5 (P < 0.001), and 36.6 (P = 0.07), respectively. The mean total duration of treatment for patients was 54.4 days, with most patients stopping donepezil due to progression to a terminal state. Patients were generally started on 5 mg/ day, but 17 patients required higher doses to achieve or maintain efficacy, the average treatment dose being 9.13 mg/day. We concluded from this study that centrally acting AChE inhibitors are promising agents in the treatment of sedation,and perhaps of other neuropsychological side effects associated with the use of opiate analgesics.

Managing breakthrough pain: a clinical review with three case studies using oral transmucosal fentanyl citrate.

Pain management begins with the use of appropriate assessment tools and includes planning, implementing, and evaluating a comprehensive treatment plan that addresses persistent and breakthrough pain. Persistent pain is present to some degree throughout the day and primarily is controlled with around-the-clock medication. However, it often is accompanied by episodes of short, intermittent pain, also known as breakthrough pain. From a clinical perspective, breakthrough pain is characterized as a transitory exacerbation of pain that occurs on a background of otherwise stable pain in a patient receiving chronic opioid therapy. Breakthrough pain typically is moderate to severe in intensity and can be triggered by various activities (incident pain), be entirely unpredictable (idiopathic pain), or occur toward the end of around-the-clock medication (end-of-dose failure). Breakthrough pain occurs in as many as 86% of patients with cancer even when persistent pain is well controlled. Clinicians and patients should address persistent and breakthrough pain as distinct entities to accurately assess it and develop appropriate pain management plans. This article provides an overview of the clinical characteristics of persistent and breakthrough pain and, through the use of three case studies, illustrates practical strategies for managing breakthrough pain effectively.

Phenol saddle blocks for intractable pain at end of life: report of four cases and literature review.

Four cancer patients with prior bladder diversions had phenol neurolytic saddle blocks performed for intractable pelvi-sacral pain. All patients had advanced disease, the focus of their treatment being palliative. Treatment limiting side effects precluded further upward titration of systemic analgesic therapies. Pain control improved after intrathecal neurolysis and allowed a greater than 60 percent reduction in systemic opiate dosage. No significant block-related adverse effects were encountered. The value and technical aspects of intrathecal saddle blocks in end-of-life pain management is discussed.

The American Pain Foundation TARGET Chronic Pain Initiative: better patient/clinician communication to improve pain management.

The American Pain Foundation has developed a program to improve clinician-chronic pain patient communication. The program includes a card describing a six part evaluation process for clinicians and patient notebook in which important daily information is recorded. The program is described including information on how to obtain the resources.

Long-term tolerability and effectiveness of oxymorphone extended release in patients with cancer.

OBJECTIVE: To evaluate the long-term safety, tolerability, and effectiveness of oxymorphone extended release (ER) in patients with cancer-related pain. DESIGN: Post hoc analysis of two-1-year open-label extension studies. SETTING: Multiple US cancer treatment facilities. PATIENTS: Patients with cancer pain who had participated in two short-term crossover comparator trials of oxymorphone ER: one open-label and one double-blind randomized. INTERVENTIONS: Patients who had been taking oxymorphone ER continued the dose established in the previous study. Patients who had been taking a comparator opioid were switched to an equianalgesic dose of oxymorphone ER. All patients underwent individualized oxymorphone ER dose titration to optimize effectiveness and tolerability. ASSESSMENTS: Current, average, worst, and least pain scores were normalized to a 100-point scale. Patients rated treatment on a five-point global assessment of study medication (Poor = 1 to Excellent = 5). All adverse events (AEs) were recorded. RESULTS: Of the 80 patients who entered the extension trials, 26 completed 52 weeks, 7 discontinued owing to loss of effectiveness, and 20 discontinued owing to AEs, most of which were unrelated to study drug. No significant increase in mean (standard deviation [SDD average pain intensity was observed from baseline (30.5 [19.6], 100-point scale) to final visit (35.9 [21.1], p = 0.37). The most common AEs were concomitant disease progression (28.8 percent, n=23), nausea (22.5 percent, n=18), dyspnea (16.3 percent, n=13), fatigue (16.3 percent, n=13), and edema of the lower limb (15 percent, n=12). CONCLUSIONS: In these patients with pain related to cancer, oxymorphone ER was generally well tolerated and provided stable long-term pain control.

Topical ketamine in the treatment of mucositis pain.

Ketamine oral rinse provided effective palliation of intractable mucositis pain in a 32-year-old woman with squamous carcinoma of the tongue undergoing radiation therapy. Pain at rest and with eating decreased with ketamine, allowing for a tapering of her opiate dose. No side effects of ketamine were reported. Treatment benefits most likely arose from the inhibition by ketamine of peripheral N-methyl D-aspartate receptors, though other mechanisms of action may have been contributory. Further evaluation of topical ketamine in the treatment of mucositis-related pain, and, potentially, other causes of inflammatory oral pain, are warranted.