A retrospective review of the use of oxymorphone immediate release for long term pain control in cancer patients with gastrostomy tubes.

BACKGROUND: Cancer patients often require feeding or venting gastrostomy-tubes (G-tubes) for enteral nutrition or symptom palliation. The administration of most extended-release (ER) opioids via the G-tube or orally followed by clamping of the venting G-tube is contraindicated. Oxymorphone immediate release (IR) may be useful because of its longer half-life compared to other IR opioids. We examined the use of oxymorphone IR administered every 8 hours in patients with G-tubes. METHODS: This was a retrospective chart review of 40 consecutive cancer patients with G-tubes who underwent opioid rotation (OR) to oxymorphone. Demographics, symptoms, morphine equivalent daily dose (MEDD), and oxymorphone dose were collected. Successful OR was defined as a 2-point or 30% reduction in pain score and continued use of oxymorphone at follow-up in outpatient setting, or discharge in inpatient setting. Opioid rotation ration (ORR) between MEDD and oxymorphone in patients with successful OR was calculated as MEDD before the OR divided by total oxymorphone dose/day at follow-up or discharge. RESULTS: The median age was 56 years, 57.5% were white, 68% male, 47.5% (n=19) had head and neck cancer, 90% had advanced disease, 67.5% (n=27) were inpatient, and 15% (n=6) had venting G-tubes. 25/40 (62.5%) patients had successful OR to oxymorphone. The median ORR from MEDD to oxymorphone was 3.5 (IQR, 3.1-4). There were no independent predictors for successful OR, and ORR did not significantly differ among various groups. CONCLUSIONS: Oxymorphone IR can be used successfully in cancer patients with G-tubes using an ORR of 3.5 to calculate dose from MEDD.

Online Conversation Monitoring to Understand the Opioid Epidemic: Epidemiological Surveillance Study.

BACKGROUND: Between 2016 and 2017, the national mortality rate involving opioids continued its escalation; opioid deaths rose from 42,249 to 47,600, bringing the public health crisis to a new height. Considering that 69% of adults in the United States use online social media sites, a resource that builds a more complete understanding of prescription drug misuse and abuse could supplement traditional surveillance instruments. The Food and Drug Administration has identified 5 key risks and consequences of opioid drugs-misuse, abuse, addiction, overdose, and death. Identifying posts that discuss these key risks could lead to novel information that is not typically captured by traditional surveillance systems. OBJECTIVE: The goal of this study was to describe the trends of online posts (frequency over time) involving abuse, misuse, addiction, overdose, and death in the United States and to describe the types of websites that host these discussions. Internet posts that mentioned fentanyl, hydrocodone, oxycodone, or oxymorphone were examined. METHODS: Posts that did not refer to personal experiences were removed, after which 3.1 million posts remained. A stratified sample of 61,000 was selected. Unstructured data were classified into 5 key risks by manually coding for key outcomes of misuse, abuse, addiction, overdose, and death. Sampling probabilities of the coded posts were used to estimate the total post volume for each key risk. RESULTS: Addiction and misuse were the two most commonly discussed key risks for hydrocodone, oxycodone, and oxymorphone. For fentanyl, overdose and death were the most discussed key risks. Fentanyl had the highest estimated number of misuse-, overdose-, and death-related mentions (41,808, 42,659, and 94,169, respectively). Oxycodone had the highest estimated number of abuse- and addiction-related mentions (3548 and 12,679, respectively). The estimated volume of online posts for fentanyl increased by more than 10-fold in late 2017 and 2018. The odds of discussing fentanyl overdose (odds ratios [OR] 4.32, 95% CI 2.43-7.66) and death (OR 5.05, 95% CI 3.10-8.21) were higher for social media, while the odds of discussing fentanyl abuse (OR 0.10, 95% CI 0.04-0.22) and addiction (OR 0.24, 95% CI 0.15-0.38) were higher for blogs and forums. CONCLUSIONS: Of the 5 FDA-defined key risks, fentanyl overdose and death has dominated discussion in recent years, while discussion of oxycodone, hydrocodone, and oxymorphone has decreased. As drug-related deaths continue to increase, an understanding of the motivations, circumstances, and consequences of drug abuse would assist in developing policy responses. Furthermore, content was notably different based on media origin, and studies that exclusively use either social media sites (such as Twitter) or blogs and forums could miss important content. This study sets out sustainable, ongoing methodology for surveilling internet postings regarding these drugs.

Model-based Meta-analysis to Compare Primary Efficacy-endpoint, Efficacy-time Course, Safety, and Tolerability of Opioids Used in the Management of Osteoarthritic Pain in Humans.

BACKGROUND: Despite recent therapeutic advances, osteoarthritis continues to be a challenging health problem, especially in the elderly population. Opioids, which are potent analgesics, have shown an extraordinary ability to reduce intense pain in many osteoarthritic clinical trials; however, there is an increased need for a study to integrate the reported outcomes and utilize them to achieve a better understanding. Herein, efficacy and safety aspects of opioids used to manage osteoarthritic pain were assessed and compared using a model-based meta-analysis (MBMA). METHODS: To perform the analysis, a comprehensive database consisting of pain relief compounds with information on summary-level of efficacy over time, adverse events and dropout rates was compiled from multiple sources. MBMA was conducted using a nonlinear mixed-effects modeling approach. RESULTS: The results of primary efficacy endpoint analysis indicated that the doses of oxycodone, oxymorphone, and tramadol required to produce 50% of the maximum effect were 47, 84, and 247 mg per day, respectively. Efficacytime course analysis showed that opioids had rapid time to efficacy onset, suggesting potentially powerful painrelieving effects. It was also found that gastrointestinal adverse events were the most opioid-associated and dosedependent adverse effects. In addition, the analysis revealed that opioids were well-tolerated at low to moderate doses. CONCLUSION: This MBMA provides clinically meaningful insights into the efficacy and safety profiles of oxycodone, oxymorphone, and tramadol. Resultantly, the presented framework analysis can have an impact in the clinic on drug development where it can guide: the optimization of doses of opioids required to manage osteoarthritic pain; the making of precise key decisions for the positioning of new drugs, and; the design of more efficient trials.

Concomitant Filled Prescriptions of Oxymorphone or Oxycodone with CYP3A Inhibitors and Inducers.

BACKGROUND: Oxymorphone's metabolism does not involve the hepatic cytochrome P450 (CYP) system. The effect of this pharmacokinetic feature of oxymorphone on opioid prescribing is unknown. OBJECTIVE: To assess the relative frequency with which oxymorphone and oxycodone (a CYP3A-metabolized opioid analgesic) were each prescribed to patients concomitantly receiving CYP3A-modifying drugs (i.e., inducers and inhibitors) to characterize opioid-prescribing patterns in patients at risk for CYP3A-related drug interactions. METHODS: We analyzed the Sentinel Distributed Database from January 1, 2013, to December 31, 2016, to identify the proportion of patients with concomitant dispensing of selected CYP3A modifiers among initiators of oxymorphone. We then repeated the analysis using oxycodone instead of oxymorphone. We conducted sensitivity analyses that varied the washout periods for each opioid to account for potential opioid switching. RESULTS: In the primary analysis, the proportion of patients with concomitant incident dispensings of oxymorphone and selected CYP3A modifiers was 3.26% (95% CI = 3.09%-3.43%), and the proportion of patients with incident dispensings of oxycodone and selected CYP3A modifiers was 2.82% (95% CI = 2.79%-2.85%). The difference between proportions was 0.43% (95% CI = 0.26%-0.60%). Sensitivity analyses that varied the washout periods for each opioid with respect to the other opioid to account for switching yielded similar results. CONCLUSIONS: We observed similar proportions of patients using selected CYP3A modifiers concomitantly with both oxymorphone and oxycodone. While the CIs of the point estimates did not overlap, the absolute differences between the proportions were small. DISCLOSURES: This project was supported by Task Order HHSF22301001T under Master Agreement HHSF223201400030I from the U.S. Food and Drug Administration (FDA). The FDA approved the study protocol, including the statistical analysis plan, and reviewed and approved the manuscript. Coauthors from the FDA participated in the results interpretation and in the preparation and decision to submit the manuscript for publication. Coyle, Money, Staffa, Meyer, and Woods are employed by the FDA. The other authors have no financial conflicts of interest to report. The views expressed are those of the authors and not necessarily those of the U.S. Department of Health and Human Services, U.S. Food and Drug Administration.

Synthesis, Biological, and Structural Explorations of New Zwitterionic Derivatives of 14- O-Methyloxymorphone, as Potent µ/δ Opioid Agonists and Peripherally Selective Antinociceptives.

Herein, the synthesis and pharmacological characterization of an extended library of differently substituted N-methyl-14- O-methylmorphinans with natural and unnatural amino acids and three dipeptides at position 6 that emerged as potent µ/δ opioid receptor (MOR/DOR) agonists with peripheral antinociceptive efficacy is reported. The current study adds significant value to our initial structure-activity relationships on a series of zwitterionic analogues of 1 (14- O-methyloxymorphone) by targeting additional amino acid residues. The new derivatives showed high binding and potent agonism at MOR and DOR in vitro. In vivo, the new 6-amino acid- and 6-dipeptide-substituted derivatives of 1 were highly effective in inducing antinociception in the writhing test in mice after subcutaneous administration, which was antagonized by naloxone methiodide demonstrating activation of peripheral opioid receptors. Such peripheral opioid analgesics may represent alternatives to presently available drugs for a safer pain therapy.

Ketorolac, Oxymorphone, Tapentadol, and Tramadol: A Comprehensive Review.

Pain remains a tremendous burden on patients and for the health care system, with uncontrolled pain being the leading cause of disability in this country. There are a variety of medications that can be used in the treatment of pain, including ketorolac, oxymorphone, tapentadol, and tramadol. Depending on the clinical situation, these drugs can be used as monotherapy or in conjunction with other types of medications in a multimodal approach. A strong appreciation of pharmacologic properties of these agents and potential side effects is warranted for clinicians.

Benzylideneoxymorphone: A new lead for development of bifunctional mu/delta opioid receptor ligands.

Opioid analgesic tolerance remains a considerable drawback to chronic pain management. The finding that concomitant administration of delta opioid receptor (DOR) antagonists attenuates the development of tolerance to mu opioid receptor (MOR) agonists has led to interest in producing bifunctional MOR agonist/DOR antagonist ligands. Herein, we present 7-benzylideneoxymorphone (6, UMB 246) displaying MOR partial agonist/DOR antagonist activity, representing a new lead for designing bifunctional MOR/DOR ligands.

A tale of 2 ADFs: differences in the effectiveness of abuse-deterrent formulations of oxymorphone and oxycodone extended-release drugs.

The introduction of extended-release opioid analgesics helped initiate an epidemic of prescription opioid abuse in the United States. To make access to the drug by crushing or dissolution more difficult, abuse-deterrent formulations (ADFs) of OxyContin (Purdue Pharma, Stamford, CT) and Opana ER (Endo Pharmaceuticals Inc., Malvern, PA), which use the same foundation technology (Intac, Grunenthal, Aachen, Germany), were introduced in 2010 and 2012, respectively. To examine their relative effectiveness, we used a structured survey of 12,124 individuals entering treatment for opioid use disorder followed by a more focused online survey with a subset of these patients (N = 129) using both structured and open-ended questions. Data showed that the OxyContin ADF was highly effective in reducing nonoral abuse (91.4% before the ADF, 47.9% afterwards), particularly with insufflation (78%-28.8%) and intravenous injection of the active drug (42.7%-21.4%). However, although the Opana ER ADF was effective in reducing insufflation (80%-37.1%), injection (60.0%-51.4%), and overall nonoral abuse (94.3%-77.1%), it showed no significant decrease over time. Bearing in mind that the Opana ER sample was smaller in size than that for OxyContin, our results nonetheless suggest disparate outcomes resulting from the introduction of the ADFs, which could indicate that an ADF's effectiveness may be drug-specific. Given the public health impact of prescription opioids and the considerable effort being expended to develop ADFs as a partial solution to the problem, our preliminary studies suggest that each ADF must be evaluated on its own merits even if the same proprietary technology is used.

Abuse-Deterrent Opioid Formulations: Pharmacokinetic and Pharmacodynamic Considerations.

Abuse-deterrent formulations (ADFs) are technologically sophisticated pharmaceutical formulations that impede manipulation and extraction of opioids and/or provoke unpleasant effects when they are taken in excessive quantity. This is implemented by creating physical barriers, inseparably combining the opioid with an opioid antagonist or adding aversive agents to the formulation. These pharmaceutical changes may potentially alter the pharmacokinetics and consequently the pharmacodynamics of the opioid. In this review, comparative evidence on pharmacokinetic differences between abuse-deterrent and classical formulations of the same opioids is summarized; furthermore, pharmacodynamic differences, with a focus on analgesia and abuse-related symptoms, are addressed. Most of the 12 studies comparing opioid pharmacokinetics have judged the physically intact ADF as being bioequivalent to the corresponding classical formulation. Pharmacokinetic differences have, however, been reported with physically manipulated ADFs and have ranged from moderate deviations from bioequivalence to complete changes in the pharmacokinetic profile (e.g. from a sustained-release formulation to a fast-release formulation). Pharmacodynamic effects were assessed in 14 comparative studies, which reported that intact ADFs usually provided clinically equivalent analgesia and clear advantages with respect to their addiction potential. However, withdrawal symptoms could be induced by the ADFs, although rarely and, in particular, when the ADFs had been physically altered. This evidence suggests that opioid ADFs are a working concept resulting in mostly minor pharmacokinetic and pharmacodynamic differences in comparison with classical formulations; however, they may deviate from this equivalence when physically altered.

Can Chronic Pain Patients Be Adequately Treated Using Generic Pain Medications to the Exclusion of Brand-Name Ones?

According to the Food and Drug Administration (FDA) reports, approximately 8 in 10 prescriptions filled in the United States are for generic medications, with an expectation that this number will increase over the next few years. The impetus for this emphasis on generics is the cost disparity between them and brand-name products. The use of FDA-approved generic drugs saved 158 billion dollars in 2010 alone. In the current health care climate, there is continually increasing pressure for prescribers to write for generic alternative medications, occasionally at the expense of best clinical practices. This creates a conflict wherein both physicians and patients may find brand-name medications clinically superior but nevertheless choose generic ones. The issue of generic versus brand medications is a key component of the discussion of health payers, physicians and their patients. This review evaluates some of the important medications in the armamentarium of pain physicians that are frequently used in the management of chronic pain, and that are currently at the forefront of this issue, including Opana (oxymorphone; Endo Pharmaceuticals, Inc., Malvern, PA), Gralise (gabapentin; Depomed, Newark, CA), and Horizant (gabapentin enacarbil; XenoPort, Santa Clara, CA) that are each available in generic forms as well. We also discuss the use of Lyrica (pregabalin; Pfizer, New York, NY), which is currently unavailable as generic medication, and Cymbalta (duloxetine; Eli Lilly, Indianapolis, IN), which has been recently FDA approved to be available in a generic form. It is clear that the use of generic medications results in large financial savings for the cost of prescriptions on a national scale. However, cost-analysis is only part of the equation when treating chronic pain patients and undervalues the relationships of enhanced compliance due to single-daily dosing and stable and reliable pharmacokinetics associated with extended-duration preparations using either retentive technologies or delayed absorption strategies. Medications given to chronic pain patients should be individualized to best serve analgesic needs and assure patient safety primarily, based on high levels of scientific and economic evidence. Decisions regarding utilization should not be made based solely on limited or faulty assessments of cost-benefit analyses.

A Randomized, Double-blind, Placebo-Controlled Crossover Trial of Oxymorphone Hydrochloride and Propoxyphene/Acetaminophen Combination for the Treatment of Neurogenic Claudication Associated With Lumbar Spinal Stenosis.

STUDY DESIGN: Randomized, double-blind, placebo-controlled, single-dose crossover study. OBJECTIVE: To test the analgesic efficacy of oxymorphone hydrochloride (OH) and propoxyphene/acetaminophen (PA) for patients with neurogenic claudication associated with lumbar spinal stenosis. SUMMARY OF BACKGROUND DATA: Although opioids are often prescribed for neurogenic claudication, no randomized controlled studies support their efficacy for this condition. Patients with neurogenic claudication are generally excluded from clinical trials or included with patients who have nonspecific chronic low back pain, yielding a heterogeneous study population with very different pathophysiologies and clinical presentations. METHODS: Participants received a single dose of each of the 3 treatments in random order. Treatments were separated by at least 3-day washout periods. The primary outcome variable was the time to first treadmill walking-induced moderate pain (≥4 out of 10 on a Numeric Rating Scale) (Tfirst) assessed 90 minutes after treatment administration. Secondary outcome measures included patient global assessment of low back pain, Roland-Morris Disability Questionnaire, Modified Brief Pain Inventory-Short Form, Oswestry Disability Index, and Swiss Spinal Stenosis Questionnaire. RESULTS: The study was prematurely terminated because of the removal of PA from the US market. Twenty-four patients were randomized; 21 completed all 3 treatment periods. There were no significant differences among the treatment groups with respect to the median Tfirst (OH-placebo: median [98.3% confidence limits]=-0.25 min [-6.54, 5.00]; PA-placebo: 0.02 min [-7.65, 4.90]; OH-PA: -0.27 min [-5.56, 6.66]). CONCLUSION: This trial failed to demonstrate a benefit of OH or PA in patients experiencing neurogenic claudication. Considering the potential negative side effects of chronic opioid use, additional research is necessary to evaluate the efficacy of sustained opioid treatment specifically for neurogenic claudication. LEVEL OF EVIDENCE: 2.

[Long-term opioid therapy in chronic noncancer pain. A systematic review and meta-analysis of efficacy, tolerability and safety in open-label extension trials with study duration of at least 26 weeks]. / Langzeittherapie mit Opioiden bei chronischem nicht-tumorbedingtem Schmerz. Systematische Übersicht und Metaanalyse der Wirksamkeit, Verträglichkeit und Sicherheit in offenen Anschlussstudien über mindestens 26 Wochen.

BACKGROUND: The efficacy and safety of long-term (≥ 6 months) opioid therapy (LtOT) in chronic noncancer pain (CNCP) is under debate. A systematic review with meta-analysis of the efficacy and harms of opioids in open-label extension studies of randomized controlled trials (RCTs) has not been conducted until now. METHODS: We screened MEDLINE and clinicaltrials.gov (through to December 2013), as well as reference sections of systematic reviews of long-term RCTs of opioids in CNCP. We included open-label extension trials with a study duration ≥ 26 weeks of RCTs of ≥ 2 weeks duration. Using a random effects model, pooled estimates of event rates for categorical data and standardized mean differences (SMD) for continuous variables were calculated. RESULTS: We included 11 open-label extension studies with 2445 participants with nociceptive (low back, osteoarthritis) and neuropathic (radicular, polyneuropathy) pain. Median study duration was 26 (range 26-108) weeks. Four studies tested oxycodone, two studies tramadol and buprenorphine; hydromorphone, morphine, oxymorphone and tapentadol were each tested in one study. Of the patients randomized at baseline, 28.5 % (95 % confidence interval, CI, 17.9-39.2 %) finished the open-label period; 53.5 % (95 % CI 38.1-68.2 %) of patients entering the open-label period finished the open-label period. In sum, the total loss was 71.5 % (95 % CI 60.9-83.1 %) of all patients primarily included into the RCT. A total of 4.9 % (95 % CI 2.9-8.2 %) of patients dropped out due lack of efficacy; 16.8 % (95 % CI 11.0-24.8 %) dropped out to due adverse events (AE) in the open-label period and 0.08 % (95 % CI 0.001-0.05 %) of patients died during the open-label period. Only one study systematically assessed aberrant drug behavior of the patients: 5.7 % (95 % CI 3.4-9.6 %) showed aberrant drug behavior in the opinion of the investigators and 2.6 % (95 % CI 1.2-5.8 %) were judged to show aberrant drug behavior by independent expert assessment. There was no significant change (p = 0.50) in pain intensity between the end of the randomized period and the end of open-label phase (SMD 0.19 [- 0.03, 0.41]; six studies with 1360 participants). CONCLUSION: Only a minority of patients selected for opioid therapy at randomization finished the long-term open-label study. However, sustained effects of pain reduction could be demonstrated in these patients. LtOT can be considered in carefully selected and monitored CNCP patients who experience clinically meaningful pain reduction with at least tolerable AE in short-term opioid therapy. The English full-text version of this article is freely available at SpringerLink (under "Supplementary Material").

Use of prescription opioids with abuse-deterrent technology to address opioid abuse.

OBJECTIVE: The development of new formulations of extended-release (ER) opioids with abuse-deterrent technology attempts to deter prescription opioid abuse while maintaining appropriate access to care for pain patients. This study examined the degree to which some patients may avoid switching to reformulated ER opioids with abuse-deterrent technology and the extent to which those patients are more likely to be abusers. RESEARCH DESIGN AND METHODS: We analyzed Truven MarketScan pharmacy and medical claims data following the introduction of two reformulated ER opioids with abuse-deterrent technology. Adults aged 18-64 who were continuous users of extended-release oxycodone HCl (ER oxycodone) or extended-release oxymorphone HCl (ER oxymorphone) in a 6 month period prior to the introduction of the respective reformulations of those products were identified and categorized based on whether they switched to the reformulation, switched to other ER/long-acting (LA) opioids (without abuse-deterrent technology), or discontinued ER/LA opioid treatment in a 6 month post-reformulation period. Abusers were identified using ICD-9-CM diagnosis codes for opioid abuse/dependence. Pearson's chi-squared tests and Fisher's exact tests were then used to compare rates of abuse between patients who avoided switching to a reformulated ER opioid. Sensitivity analyses examined several definitions used in this analysis. MAIN OUTCOME MEASURES: ER/LA opioid utilization; rates of diagnosed opioid abuse. RESULTS: A total of 31%-50% of patients avoided switching to reformulated ER opioids. Rates of diagnosed opioid abuse were higher among these patients compared to patients who transitioned to the reformulated ER opioids. LIMITATIONS: Due to the observational research design, caution is warranted in causal interpretation of the findings. The study was conducted among commercially insured continuous ER oxycodone or ER oxymorphone users; future research should consider additional patient populations, such as non-continuous users and those without commercial insurance (i.e., Medicare, Medicaid, uninsured). CONCLUSIONS: Some patients switched to other ER/LA opioids without abuse-deterrent technology or discontinued ER/LA opioid treatment when their existing ER treatment was reformulated. Rates of opioid abuse were higher among patients who switched to other ER/LA opioids or discontinued ER/LA opioid treatment, suggesting that abusers may seek more easily abuseable alternatives such as prescription opioids without abuse-deterrent technology.

Changes in prevalence of prescription opioid abuse after introduction of an abuse-deterrent opioid formulation.

OBJECTIVE: The reformulation of oxycodone hydrochloride controlled-release (CR) tablets in August 2010 created a natural experiment at a national scale, providing an opportunity to evaluate patterns of abuse of prescription opioids and other drugs before and after introduction of this abuse-deterrent formulation (ADF). DESIGN: Observational, cross-sectional study SETTING: Sentinel sample of adults assessed for substance abuse treatment within the NAVIPPRO® surveillance system SUBJECTS: Two hundred thirty-two thousand and eight hundred seventy-four adults at 437 facilities during January 1, 2008 through December 31, 2011. METHODS: Time-series analysis using logistic regression to estimate quarterly prevalence of past 30-day abuse (adjusted for covariates and prescription volume) and changes in abuse pre-and post-ADF introduction. RESULTS: Increases in abuse prevalence occurred for all prescription opioids as a class and for extended-release (ER) opioids. Significantly greater abuse of ER oxymorphone and buprenorphine occurred in the post-ADF period (relative risk [RR] = 2.91, 95% confidence interval [CI] = 2.59-3.27 and RR = 1.85, 95% CI = 1.74-1.96). Increases in abuse for these two compounds were significant among groups who reported abuse via preferential routes of administration (oral only, snorting only, injection only) post-ADF introduction. CONCLUSIONS: Replacement of a widely prescribed opioid formulation known for its abuse potential alone may have had little impact on overall rates of prescription opioids as a class. However, changes in abuse levels of certain opioids coinciding with ADF introduction suggest possible switching of abuse among this study sample to specific long-acting opioid analgesics. Additional follow-up studies will be important to monitor changing abuse patterns and their public health impact as new opioid formulations are developed and introduced to market.

The safety and effectiveness of a long-acting transdermal fentanyl solution compared with oxymorphone for the control of postoperative pain in dogs: a randomized, multicentered clinical study.

A prospective, double-blinded, positive-controlled, multicenter, noninferiority study was conducted to evaluate the safety and effectiveness of transdermal fentanyl solution (TFS) compared with oxymorphone for the control of postoperative pain in dogs. Five hundred and two (502) client-owned dogs were assigned to a single dose of TFS (2.7 mg/kg) applied 2-4 h prior to surgery or oxymorphone hydrochloride (0.22 mg/kg) administered subcutaneously 2-4 h prior to surgery and q6h through 90 h. Pain was evaluated over 4 days by blinded observers using a modified Glasgow composite pain scale, and the a priori criteria for treatment failure was a pain score ≥ 8 or adverse event necessitating withdrawal. Four TFS- and eight oxymorphone-treated dogs were withdrawn due to lack of pain control. Eighteen oxymorphone-treated, but no TFS-treated dogs were withdrawn due to severe adverse events. The one-sided upper 95% confidence interval of the difference between TFS and oxymorphone treatment failure rates was -5.3%. Adverse events associated with oxymorphone were greater in number and severity compared with TFS. It was concluded that a single administration of TFS was safe and noninferior to repeated injections of oxymorphone for the control of postoperative pain over 4 days at the dose rates of both formulations used in this study.

Single vs composite measures of pain intensity: relative sensitivity for detecting treatment effects.

Assay sensitivity remains a significant issue in pain clinical trials. One possible method for increasing assay sensitivity for detecting changes in pain intensity is to increase the reliability of pain intensity assessment by increasing the number of intensity ratings obtained, and combining these ratings into composite scores. The current study performed secondary analyses from a published clinical trial to test this possibility. The reliability and assay sensitivity pain intensity scores made up of 1 to 9 24-hour pain intensity recall ratings were compared. Although the reliability of the outcome measures improved as the number of items increased, this increase in reliability was not associated with an increase in assay sensitivity. A single 24-hour recall rating was about as valid (sensitive) for detecting treatment effects as composite scores made up of 2 to 9 different ratings. If this finding replicates in other pain populations, it has significant implications for the design and conduct of pain clinical trials. Specifically, it suggests the possibility that assessment burden (and associated costs and problems related to missing data) might be greatly reduced by specifying a single recall rating as the primary outcome variable. Research is needed to explore this possibility further.

Clinical applications of oxymorphone.

Oxymorphone (14-hydroxydihydromorphinone), a pyridine ring unsubstituted pyridomorphinan, a semisynthetic opioid analgesic derived from thebaine, first developed in the year 1914 and has been available as oxymorphone hydrochloride parenteral forms in the United States since 1959, when the US Food and Drug Administration approved it. Over the years, it has been used for the alleviation of moderate-to-severe pain. Pharmacological considerations, new and traditional formulations, clinical indications, and recent study populations are examined in this review. Specific considerations for oxymorphone interactions are focused on as well as specific side effects and end organ considerations. Although discovered many decades ago and used as parenteral formulation, the newer oral preparations of oxymorphone (immediate release and extended release) that were approved in 2006 can provide additional options for customizing therapy to accommodate various patient needs. This newer oral formulation could make this powerful agent an important drug in the armamentarium of the healthcare provider caring for patients with pain.

The meaning of global outcome measures in pain clinical trials: more than just change in pain intensity.

OBJECTIVES: To understand the factors that contribute to patient and physician global outcome ratings and the extent to which receiving different doses of opioids or placebo might influence the importance of these factors better. METHODS: A secondary analysis was performed using data from a prospective, multicenter, double-blind placebo-controlled, and active-controlled parallel group dose-ranging study comparing the efficacy of oxymorphone extended release (ER) 20 mg (ER20, N=121); oxymorphone ER 40 mg (ER40, N=121); oxycodone controlled release 20 mg (Oxy20, N=125); and placebo (N=124) in a sample of patients with osteoarthritis. We performed 2 regression analyses to identify the predictors of pretreatment to posttreatment improvement in patient and physician global ratings of arthritis status. RESULTS: Improvement in global ratings of arthritis status was strongly associated with a decrease in pain intensity. Pretreatment to posttreatment improvement in physical and psychological functioning made independent contributions to the prediction of both criterion variables. DISCUSSION: The findings underscore the importance of change in pain intensity as a key correlate of ratings of global improvement. However, pain intensity is not the only important factor. In the current sample, improvement in both physical and psychological functioning made independent contributions to improvements in ratings of osteoarthritis status, supporting global ratings as assessing multicomponent domains. Overall, the findings suggest that when a patient or physician reports that the patient is "doing better," the patient is likely reporting less pain intensity and engaging in more physical activity and feeling better emotionally.

Tolerability of concomitant use of selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors and oxymorphone extended release.

BACKGROUND: Opioids and antidepressants are frequently prescribed for chronic low back pain (cLBP). This post hoc analysis was conducted to assess the tolerability of oxymorphone extended release (ER) for cLBP in patients taking selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) compared with patients not taking SSRIs/SNRIs. METHODS: Patients in 2 clinical trials (NCT00225797, November 22, 2004 to July 18, 2005; NCT00226421, October 13, 2004 to August 19, 2005) aged ≥ 18 years with moderate to severe cLBP were titrated to a stabilized dose of oxymorphone ER during an open-label titration phase and then randomized to treatment with this dose or placebo every 12 hours for 12 weeks. In a post hoc analysis, adverse events (AEs) were compared between patients taking versus not taking SSRIs/SNRIs. Treatment efficacy was assessed as change from baseline in average daily pain intensity on a 100-mm visual analog scale. RESULTS: Of 575 patients enrolled, 45 of 89 (50.6%) taking SSRIs/SNRIs and 303 of 486 (62.3%) not taking SSRIs/SNRIs successfully titrated to oxymorphone ER. The frequency of any AE did not differ significantly between the 2 subpopulations. During the titration phase, serious AEs occurred more frequently in patients taking SSRIs/SNRIs (3/89; 3.4%) compared with those not taking SSRIs/SNRIs (4/486; 0.8%; P = 0.04); however, during the double-blind treatment phase, there was no significant difference in the frequency of serious AEs in patients treated with oxymorphone ER taking (1/29; 3.4%) versus those not taking (3/146; 2.0%) SSRIs/SNRIs. Visual analog scale scores were similar in patients taking versus those not taking SSRIs/SNRIs throughout the study. CONCLUSION: The concomitant use of oxymorphone ER with SSRIs or SNRIs was well tolerated in patients with cLBP.

Negligible analgesic tolerance seen with extended release oxymorphone: a post hoc analysis of open-label longitudinal data.

OBJECTIVE: To examine the development of analgesic tolerance in patients on oxymorphone extended-release (OxymER). DESIGN: Post hoc analysis of data from a previously conducted prospective 1 year multi-center open-label extension study in which patients were able to titrate as needed. PATIENTS: Sample of 153 hip and knee osteoarthritis (OA) subjects on OxymER. Primary analyses were limited to study completers (n = 62) due to the large amount of missing data for the noncompleters (n = 91). OUTCOME MEASURES: Main outcome measures included OxymER doses (pill counts) and pain intensity ratings using a visual analog scale at monthly visits. RESULTS: There were significant dose increases from weeks 1 to 2 and 2 to 6 (P < 0.05). Doses stabilized around week 6, suggesting the completion of what we defined as "titration." Both doses and pain ratings were stable when this titration phase was excluded from the analysis (P = 0.751; P = 0.056, respectively). Only 28% of the patients had any dose changes following this titration. While there was a significantly greater dose at week 52 compared with week 10 (P = 0.010), the increase in dose became insignificant after excluding four subjects who required two dose increases (P = 0.103). CONCLUSIONS: The results showed that most of the titration/dose stabilization changes occurred within the first 10 weeks. A minority (28%) of subjects required dosage increases after this (defined) titration period. Pain reports stabilized statistically after 2 weeks. The findings of this post hoc analysis suggest a lack of opioid tolerance in the majority (72%) of these OA patients who completed this study following a defined titration period on OxymER. SUMMARY: This post hoc analysis of oxymorphone ER consumption in osteoarthritis pain vs pain report showed that most dose changes occurred during an initial "titration period" as defined. Following this titration few subjects increased dose and analgesia remained stable. These findings suggest a lack of longitudinal opioid tolerance in the majority of those OA subjects who completed the trial.