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.

Current topics in opioid therapy for pain management: addressing the problem of abuse.

Opioids are an established therapy for cancer pain and have become an accepted therapy for chronic noncancer pain. However, increased prescribing of opioids in recent years has been accompanied by an increase in prescription opioid abuse. All opioids have inherent potential for abuse, but gaps in healthcare provider understanding of or adherence to best prescribing practices may facilitate the misdirection of opioids for abuse. To address these concerns, the US Food and Drug Administration has required pharmaceutical manufacturers to develop Risk Evaluation and Mitigation Strategies (REMS) for prescribers of extended-release/long-acting (ER/LA) opioids and has encouraged research to develop opioid formulations that are less easily abused or less attractive for abuse. The ER/LA opioid REMS require a partnership between the pharmaceutical industry, regulators, and healthcare providers to develop educational materials for physicians and patients that are not promotional. This article addresses challenges associated with improving the quality of pain care through support of prescriber education, developing formulations that combine efficacy with tamper-resistant properties, and encouraging collaborative efforts by regulatory bodies, legislators, healthcare providers, and patient advocacy groups to achieve these ends.

Validity testing of patient objections to acceptance of tamper-resistant opioid formulations.

BACKGROUND: Tamper-resistant formulations (TRFs) of oral opioid drugs are intended to prevent certain types of abuse (eg, intranasal, intravenous). Patients raising objections to receiving a TRF may have valid concerns or may be seeking a formulation that can be more easily misused. METHODS: US clinicians experienced in pain management met in October 2011 to discuss common patient objections to being switched from a non-TRF opioid to a TRF of the same opioid. Retail pharmacy, health insurance, and scientific data were used to assess the potential validity of these patient objections. RESULTS: Clinical experience switching patients from a non-TRF to a TRF opioid was limited to oxycodone controlled release (CR), as it was the only TRF available at that time; knowledge of other TRFs was limited to the scientific literature. Common objections from patients included "costs more," "not covered by insurance," "can't feel it working," and "causes adverse events." Objective retail pharmacy and insurance coverage information for oxycodone CR was accessible and indicated that patient objections were based on cost and coverage varied by insurer. Unpublished trial results (ClinicalTrials.gov) revealed that TRF oxycodone CR has a slower initial release than the non-TRF formulation, which may reduce positive subjective effects. The complaint "I can't feel it working" may reflect lessened positive subjective effects rather than reduced analgesic efficacy. Most tolerability complaints lacked objective support. CONCLUSION: The general process used to assess the validity of patient objections to TRF oxycodone CR may be applied to other TRFs once they become available. Publication of clinical data on TRFs would help clinicians to appropriately weigh patient concerns.

Tolerability of diclofenac sodium 1% gel with concomitant medications known to interact with diclofenac.

BACKGROUND: Topical diclofenac sodium 1% gel (DSG) has demonstrated efficacy and tolerability in patients with osteoarthritis (OA) of the knees or hands, including elderly patients and those with an increased risk of gastrointestinal, cardiovascular, and renal adverse events (AEs). Medications known to interact with diclofenac were disallowed in a clinical trial of DSG for knee OA; however, patients were not to be discontinued for intake of disallowed treatment, unless there was a safety issue. This post hoc analysis examined the frequency and type of AEs in patients who received DSG concomitantly with drugs known to have potential interactions with diclofenac. MATERIALS AND METHODS: This was a post hoc analysis of a randomized controlled trial of DSG for knee OA pain. Patients (n = 254) aged ≥ 35 years with OA in one or both knees, but with clinical OA symptoms in only one knee, administered DSG topically to the target knee four times daily (total dose, 16 g/d) for 12 weeks. Drugs with the potential for major or moderate drug-drug interactions (DDIs) were identified via Drugs.com. AE rates were compared in patients with versus those without ≥1 potential DDI. RESULTS: At least one AE was experienced by 62.6% (107/171) of patients with ≥1 DDI and by 55.4% (46/83) of patients with no DDIs. Gastrointestinal AEs (upper and lower) were reported in 5.3% (9/171) and 7.2% (6/83), cardiovascular AEs in 4.7% (8/171) and 1.2% (1/83), renal AEs in 1.2% (2/171) and 0%, and hepatic AEs in 0% and 1.2% (1/83) of patients with ≥1 DDI compared with patients with no DDIs, respectively. CONCLUSION: Concurrent use of DSG with medications that had potential for major to moderate DDIs had little impact on the frequency of AEs in this population. Further research is needed to consider how factors such as dose, duration, and timing of concomitant drug administration may affect the likelihood of clinically evident AEs resulting from a potential DDI.

Drug Development in the 21st Century: The Synergy of Public, Private, and International Collaboration.

The traditional economic model for drug development by leading pharmaceutical companies in the developed world has yielded diminishing returns in recent years, with large pharmaceutical companies relying less on research and development and more on cost cutting and obtaining promising drug candidates through mergers and acquisitions. Concurrently, drug companies in emerging markets have flourished under a different economic model characterized by public-private partnerships, government subsidy, and profitable marketing of generic drugs. These companies are now focusing on research and development of innovative drug candidates, including drugs that treat neglected diseases such as tuberculosis and hepatitis. However, drug companies in developing countries may lack the expertise of leading drug companies to navigate the complicated regulatory system. This article highlights an opportunity for companies with drug development expertise to partner with companies in the developing world with innovative pipeline drugs.

Long-term tolerability of topical diclofenac sodium 1% gel for osteoarthritis in seniors and patients with comorbidities.

BACKGROUND: Adverse events associated with nonsteroidal anti-inflammatory drugs (NSAIDs) used to treat knee and hand osteoarthritis may be more frequent in certain patient populations. Topical NSAIDs, such as diclofenac sodium 1% gel (DSG), have equivalent efficacy and fewer adverse events compared with oral NSAIDs. This post hoc analysis assessed the long-term tolerability of DSG in elderly patients and patients with an elevated risk of gastrointestinal, cardiovascular, and renal adverse events. METHODS: Patients ≥ 35 years of age with knee osteoarthritis applied DSG (4 g) to one or both knees for 12 weeks during either of two primary studies and for 9 months during a long-term extension study. Other patients entered the long-term extension study directly and applied DSG for 12 months. Safety was assessed by reported adverse events. Subpopulations were defined based on age, or the comorbidities of hypertension, type 2 diabetes mellitus, and cerebrovascular or cardiovascular disease. RESULTS: The safety population consisted of 947 patients who received at least one dose of DSG during the primary or extension study. Patients aged < 65 years (68.2%) and ≥65 years (67.2%) experienced any adverse event at similar rates. The percentage of patients who experienced any adverse event was similar between patients with and without hypertension (65.5% versus 69.7%, respectively), type 2 diabetes mellitus (64.0% versus 68.2%), or cerebrovascular or cardiovascular disease (61.9% versus 68.5%). Among the 15 patients with all three comorbidities, the percentage of patients with any adverse event (53.3%) was less than that of patients who did not have all three comorbidities (68.0%). CONCLUSION: These results suggest that long-term DSG treatment is safe in patient subpopulations with an elevated risk of NSAID-related adverse events, such as the elderly and those with the comorbidities of hypertension, type 2 diabetes mellitus, and cerebrovascular or cardiovascular disease.

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.

Tolerability of topical diclofenac sodium 1% gel for osteoarthritis in seniors and patients with comorbidities.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a dose-related risk of cardiovascular, renal, and gastrointestinal adverse events (AEs). Topical NSAIDs produce lower systemic NSAID exposure compared with oral NSAIDs, offering potential benefits. OBJECTIVE: To evaluate the safety of topical diclofenac sodium 1% gel (DSG) for knee and hand osteoarthritis (OA) in older and younger patients and in patients with versus without comorbid hypertension, type 2 diabetes, or cerebrovascular or cardiovascular disease. METHODS: Post hoc analysis of pooled data from 5 randomized, double-blind, placebo-controlled trials involving 1426 patients (aged ≥35 years) with mild to moderate OA of the knee and 783 patients (aged ≥40 years) with mild to moderate OA of the hand. Patients applied 4 g of DSG or vehicle to affected knees QID for 12 weeks or 2 g of DSG or vehicle to affected hands QID for 8 weeks. RESULTS: In patients with knee OA, the percentage with ≥1 adverse event was similar in patients aged <65 years (56.6%) versus ≥65 years (55.8%) and was similar in patients with versus without comorbid hypertension (53.4% vs 59.0%, respectively), type 2 diabetes mellitus (50.0% vs 57.2%), or cerebrovascular or cardiovascular disease (53.8% vs 56.5%). In patients with hand OA, the percentage with ≥1 AE was similar in patients aged ≥65 years (42.7%) versus <65 years (39.1%) and was similar in patients with versus without hypertension (39.6% vs 41.7%, respectively), lower in patients with versus without type 2 diabetes mellitus (28.0% vs 41.6%), and higher in patients with versus without cerebrovascular or cardiovascular disease (48.5% vs 39.2%). Gastrointestinal, cardiovascular, and renal AEs were rare and did not differ according to age or comorbidity. Application site reactions were the primary cause for the greater frequency of AEs with DSG versus vehicle. CONCLUSION: The similar and low rates of AEs in DSG-treated patients aged ≥65 years and <65 years and in those with and without comorbid hypertension, type 2 diabetes, or cerebrovascular or cardiovascular disease suggest that DSG treatment is generally well tolerated.