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Deaths from opioid overdoses have increased dramatically over the past few years. Given that immediate-release (IR) opioids account for most of the U.S. market share, and that abusers generally prefer IR opioids over extended-release (ER) opioids, it is not surprising that rates of abuse are higher for IR than ER opioids. IR opioids are widely prescribed, often without consideration for risks of abuse, misuse, and diversion. Prescription opioid abuse and misuse often begins through oral administration and progresses into non-oral routes (e.g. snorting, injecting) as abusers gain more experience; non-oral routes carry heightened safety concerns. Current approaches used for reducing opioid abuse include U.S. Food and Drug Administration regulations, state legislation, insurance company policies, the use of multimodal analgesic therapy, patient risk assessment and monitoring, limiting access to opioids by reducing IR opioid prescription quantity and length, prescription drug monitoring programs, patient education on proper disposal of unused medication and risks of diversion, as well as abuse-deterrent formulations. Albeit, most abuse-deterrent formulations have focused on ways to prevent the circumvention of ER characteristics rather than placing obstacles to abuse of IR opioid formulations. Reducing opioid abuse requires the combined efforts of multiple stakeholders, including prescribing clinicians, patients, pharmacists, nurses, insurance companies, government agencies, and pharmaceutical companies.

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PURPOSE: The purpose of this study was to assess how patient-reported pain is related to osteoarthritis (OA) treatment patterns in routine clinical practice. PATIENTS AND METHODS: Data were collected between February and May 2017 from 153 United States (US) primary care physicians, rheumatologists, and orthopedic surgeons. Each invited up to nine consecutive patients to rate their OA pain in the last week. Physicians provided demographic, clinical, and treatment information for patients, including nonpharmacologic therapies ever recommended, currently recommended over-the-counter (OTC) medications, and currently and ever prescribed medications for the management of OA. Findings for patients with mild (0─3), moderate (4─6), and severe current pain (7─10) were compared using appropriate statistics. RESULTS: Among the 841 patients (61% female; mean 65 years; 57% knee OA), 45% reported mild, 36% moderate, and 19% severe current OA pain. Current treatment modalities differed by pain severity (P<0.05). Most patients (70%) had been recommended nonpharmacologic therapy and 40% were currently recommended OTC medications. More patients with moderate (81%) or severe pain (78%) currently received prescription medications, with or without nonpharmacologic therapy, versus those with mild pain (67%). Overall, 47% of patients currently received just one prescription drug, while 49% had received one prescription drug ever. Nonsteroidal anti-inflammatory drugs (NSAIDs) were the most common current (58%) and ever received (88%) prescriptions. Current NSAID prescriptions were not associated with pain severity. Acetaminophen recommendations, opioid prescriptions (current and ever), and multiple prescription medications tried were numerically highest in the severe pain group (all P<0.05 by pain severity). In all groups, >80% of treatment switches were due to lack of efficacy. CONCLUSION: Real-life treatment patterns for OA in the US are significantly associated with current patient-reported pain. Combining nonpharmacologic and pharmacologic treatments is common but higher pain ratings are associated with multiple failed prescription treatments. Current use of acetaminophen and opioids, but not NSAIDs, increases alongside pain severity.

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The Centers for Disease Control and Prevention has classified prescription drug abuse and overdose deaths as an epidemic. Prescription drug overdose is now the leading cause of injury death, with rates that have more than doubled since 1999. This crisis has developed concurrently with the increased prescribing and availability analgesic drugs, especially opioids, resulting from an effort on the part of clinicians to address a critical need for improved pain assessment and treatment. Clinicians have recognized that oftentimes, opioid analgesics are one of the few remaining options for patients who suffer with severe pain. A 2015 fact sheet issued by the Office of National Drug Policy stated: "While we must ensure better access to prescription medications to alleviate suffering, it is also vital that we do all we can to reduce the diversion and abuse of pharmaceuticals." The US Food and Drug Administration has issued guidance that encourages the research and development of abuse-deterrent formulation of opioids which have the potential to curtail abuse. Included among the recommended formulations for development of abuse-deterrent opioids are prodrugs. Prodrugs are chemically modified versions of pharmacological agents that must undergo a biochemical conversion following administration, often by enzymatic cleavage, to free the active drug. Prodrugs may be inherently abuse-deterrent because they are inactive or significantly less active until conversion to the active drug. This requirement for conversion in the GI tract can modify the pharmacokinetic profile and eliminate or reduce the euphoria when abusers change the route of administration. Abusers often attempt to extract the active drug for injection or insufflation. Prodrugs can be designed to be resistant to crushing or dissolving. In this article, we review the concept of prodrugs and introduce and examine the potential of abuse-deterrent opioid prodrugs.

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BACKGROUND: Subcutaneous methylnaltrexone is efficacious and well tolerated in inducing bowel movements in patients with advanced illness and opioid-induced constipation (OIC); factors determining optimal responsiveness to OIC treatment, however, have not been elucidated. This post hoc responder analysis examined the influence of demographic and baseline characteristics on methylnaltrexone efficacy and tolerability in this population. METHODS: Data were pooled from 2 randomized, double-blind, placebo-controlled, phase 3 studies of subcutaneous methylnaltrexone (0.15 and 0.30 mg/kg) [ClinicalTrials.gov identifiers: Study 301 - NCT00401362; Study 302 - NCT00402038]. Subgroup analyses of the primary outcome, percentage of patients with rescue medication-free bowel movements (RFBM) within 4 hours of first dose, were conducted for age, sex, primary diagnosis, baseline constipation-related distress score, and baseline oral morphine equivalent dose. RESULTS: More than 50% of 165 patients treated with either methylnaltrexone dose experienced a RFBM within 4 hours vs. 14.6% of 123 placebo-treated patients (P < 0.0001 for both methylnaltrexone doses vs. placebo). Methylnaltrexone response was significantly greater than placebo response in all subgroups (P < 0.01). The largest differences vs. placebo were observed for patients taking methylnaltrexone 0.30 mg/kg with a noncancer primary diagnosis (70.0% [methylnaltrexone] vs. 12.8% [placebo]; P < 0.001) and for patients taking methylnaltrexone 0.30 mg/kg maintained on ≥ 150 mg/day baseline morphine equivalent doses (73.3% vs. 16.7%; P < 0.0001). Common adverse events were abdominal pain (pooled methylnaltrexone: 27.9%, placebo: 9.8%), flatulence (13.3%, 5.7%), and nausea (10.9%, 4.9%). Tolerability was comparable across subgroups. CONCLUSION: Subcutaneous methylnaltrexone provides a rapid, robust, and consistent RFBM response in patients with advanced illness and OIC. Methylnaltrexone 0.30 mg/kg may elicit particularly favorable responses in select patient populations.

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OBJECTIVE: To examine the relationship between the dose of fentanyl sublingual spray needed to control breakthrough cancer pain (BTCP) and the dose of around-the-clock (ATC) opioid used to control background pain. DESIGN: Analysis was based on the open-label, dose-titration phase (up to 26 days) of a randomized, double-blind, placebo-controlled trial. PATIENTS: Opioid-tolerant cancer patients (aged ≥18 years) with chronic pain of ≤moderate severity in the 24 hours before screening while receiving stable doses of scheduled ATC opioid therapy for ≥1 week and 1 to 4 episodes of BTCP per day. INTERVENTIONS: Fentanyl sublingual spray was initiated at 100 µg. Dose titration proceeded until a dose was reached that provided adequate pain relief for two consecutive BTCP episodes without intolerable adverse effects (AEs). RESULTS: Overall, 98/130 (75.4 percent) patients completed the dose-titration phase and achieved pain relief, and 73.5 percent of those who completed the titration period attained an effective dose of ≥600 µg (median effective dose, 800 µg). No clinically relevant correlation was found between effective doses of fentanyl sublingual spray for the treatment of BTCP and the ATC opioid doses used to control persistent pain (Spearman rank correlation [rs]=0.351, n=98). Sixty percent of patients reported ≥1 AE during the dose-titration phase. The most common AEs considered related to study treatment were nausea (6.2 percent), somnolence (4.6 percent), dizziness (3.8 percent), and vomiting (3.8 percent). CONCLUSIONS: These findings highlight the importance of titrating the dose of fentanyl sublingual spray to optimize dosing for individual patients.

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PURPOSE: To describe the efficacy and safety of hydromorphone extended-release tablets (OROS hydromorphone ER) during dose conversion and titration. PATIENTS AND METHODS: A total of 459 opioid-tolerant adults with chronic moderate to severe low back pain participated in an open-label, 2- to 4-week conversion/titration phase of a double-blind, placebo-controlled, randomized withdrawal trial, conducted at 70 centers in the United States. Patients were converted to once-daily OROS hydromorphone ER at 75% of the equianalgesic dose of their prior total daily opioid dose (5:1 conversion ratio), and titrated as frequently as every 3 days to a maximum dose of 64 mg/day. The primary outcome measure was change in pain intensity numeric rating scale; additional assessments included the Patient Global Assessment and the Roland-Morris Disability Questionnaire scores. Safety assessments were performed at each visit and consisted of recording and monitoring all adverse events (AEs) and serious AEs. RESULTS: Mean (standard deviation) final daily dose of OROS hydromorphone ER was 37.5 (17.8) mg. Mean (standard error of the mean [SEM]) numeric rating scale scores decreased from 6.6 (0.1) at screening to 4.3 (0.1) at the final titration visit (mean [SEM] change, -2.3 [0.1], representing a 34.8% reduction). Mean (SEM) change in Patient Global Assessment was -0.6 (0.1), and mean change (SEM) in the Roland-Morris Disability Questionnaire was -2.8 (0.3). Patients achieving a stable dose showed greater improvement than patients who discontinued during titration for each of these measures (P < 0.001). Almost 80% of patients achieving a stable dose (213/268) had a ≥30% reduction in pain. Commonly reported AEs were constipation (15.4%), nausea (11.9%), somnolence (8.7%), headache (7.8%), and vomiting (6.5%); 13.0% discontinued from the study due to AEs. CONCLUSION: The majority of opioid-tolerant patients with chronic low back pain were successfully converted to effective doses of OROS hydromorphone ER within 2 to 4 weeks.

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INTRODUCTION: Although chronic opioid therapy is usually initiated using short-acting opioids, many patients with chronic pain are subsequently converted to long-acting and extended-release preparations. In clinical practice, optimal management requires careful individualization of dosage in order to achieve an appropriate balance of efficacy and adverse effects. After successful initiation and stabilization of opioid treatment, subsequent changes in regimen may still be required to maintain efficacy with an acceptable adverse effect profile. METHODS: This is a qualitative review of the available literature from June 2012 or earlier on opioid rotation for the management of chronic pain in the clinical setting. The PubMed database was searched using various search terms, and additional articles were identified through manual search of the bibliographies of articles identified through the PubMed search. Papers were selected based on relevance to the topic. RESULTS: When considering opioid rotation, clinicians must take into account not only the significant differences in potency among opioid drugs but also the considerable interpatient variability in response to opioids. The estimate of relative potency used in calculating an appropriate starting dose when switching from one opioid to another has been codified on equianalgesic dose tables. To reduce the risk of unintentional overdose, a two-step calculation has been proposed, which incorporates an initial reduction (typically 25-50%) in the equianalgesic dose followed by a second evaluation based on the severity of pain at the time of rotation along with other medical or psychosocial factors that might alter the effectiveness and tolerability of the new drug. Given the uncertainty of accurately predicting a patient's response to treatment, each initial exposure to a new opioid should be considered a discrete clinical trial to assess the degree of response. Systematic reviews of opioid rotation have documented the re-establishment of adequate pain control or reduced adverse effects in 50-80% of patients. CONCLUSIONS: Although continued research is needed to refine equianalgesic doses further, opioid rotation is an important and necessary practice in patients with chronic cancer or noncancer pain that is refractory to the initially used opioid.

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CONTEXT: The efficacy and tolerability of once-daily hydromorphone extended release (ER) (OROS(®) hydromorphone ER, Exalgo(®), Mallinckrodt Brand Pharmaceuticals, Inc., Hazelwood, MO) in patients with chronic cancer and noncancer pain have been reported in previous studies. OBJECTIVES: The objective of this analysis was to assess the pooled safety data of OROS hydromorphone ER in opioid-tolerant patients with chronic cancer and noncancer pain. METHODS: Safety results were pooled from 11 clinical studies in opioid-tolerant patients: one 12-week, double-blind, placebo-controlled study; three active-controlled studies; and seven uncontrolled studies (durations of three to 52 weeks). Patients were included in this analysis if they took ≥1 dose of study medication. Descriptive statistics were used to analyze baseline and demographic characteristics, supplemental analgesic use, and incidence of adverse events (AEs). RESULTS: In total, 1251 opioid-tolerant patients received ≥1 dose of OROS hydromorphone ER. Mean (SD) duration of exposure was 43.1 (67.8) days (range 1-396 days), and mean (SD) daily dose was 43.4 (47.1) mg. Overall, 1081 patients (86.4%) used supplemental rescue analgesics. The overall incidence of AEs was 76.9%. The most frequently reported AEs were nausea (23.2%), constipation (22.4%), vomiting (14.4%), somnolence (12.9%), and headache (12.8%). Treatment-related constipation occurred in 20.5% of patients, nausea in 16.8%, somnolence in 11.8%, vomiting in 8.2%, and headache in 7.0%. Serious adverse events occurred in 13.5% of patients, with the most frequently reported serious adverse events being dehydration, nausea, and vomiting. No treatment-related deaths occurred. CONCLUSION: Once-daily OROS hydromorphone ER demonstrated a safety and tolerability profile in opioid-tolerant patients that is consistent with the known safety profiles of opioids.

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OBJECTIVE: This analysis was conducted to determine the likelihood of identifying an effective dose of fentanyl sublingual tablet during the initial titration phase of 2 clinical trials, to characterize the actual effective dose in patients achieving successful titration, and to examine the relationship between baseline characteristics and likelihood of achieving an effective dose. METHODS: Data were derived from 2 clinical trials (Study 1, n=131; Study 2, n=139) of fentanyl sublingual tablet in patients with cancer-associated breakthrough pain (BTP). Both trials comprised a 2-week titration phase and 12-month maintenance phase. The initial dose was 100 µg, titrated to an effective dose (producing effective relief of all BTP episodes on 2 consecutive days) of 100 to 800 µg. RESULTS: A total of 270 patients entered the titration phase. Mean (SD) baseline BTP opioid dose was 25.7 (88.9) mg morphine equivalent, and mean baseline around-the-clock opioid dose was 196.5 (151.6) mg morphine equivalent. Using conservative criteria for determining effective dose, 174 patients (64.4%) were successfully titrated to an effective dose (mean [SD], 498.2 [234.8] µg). The most frequent (27.6%) effective dose was 800 µg, and more than 85% of patients required an effective dose ≥300 µg. There were no significant relationships between any baseline characteristics and titration success. CONCLUSION: Despite stringent criteria, 64.4% of patients achieved an effective dose of fentanyl sublingual tablet within the dose range of 100 to 800 µg. Baseline characteristics were not identified to be associated with the likelihood of successful titration or with the actual effective dose of fentanyl sublingual tablet.

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UNLABELLED: The Neuropathic Pain Scale (NPS) is a valid measure of the pain qualities and perceived depth of neuropathic pain. However, it does not include a number of pain qualities commonly seen in some neuropathic and non-neuropathic pain conditions. To address this limitation, additional items were added to the NPS to create a 20-item measure (Pain Quality Assessment Scale, PQAS) that would be even more useful for assessing neuropathic pain and also would be used to assess pain qualities associated with non-neuropathic pain. To evaluate the responsivity of the PQAS items to pain treatment, secondary analyses were conducted on data from a trial that compared the efficacy of lidocaine patch 5% versus a single steroid injection in 40 patients with carpal tunnel syndrome. Statistically significant (P < .0025) decreases in 10 of the 20 PQAS pain descriptor ratings occurred with both treatments, and 8 ratings showed nonsignificant trends (.0025 < P < .05) for decreasing before treatment to after treatment. No significant differences were found between the 2 treatment conditions on any of the items. The results support the validity of the PQAS items for assessing the effects of pain treatment on pain qualities of carpal tunnel syndrome. PERSPECTIVE: Clinical trials that include measures of pain qualities can be used to identify the effects of treatments on distinct pain qualities. Measures such as the PQAS can potentially be used to help clinicians target analgesics more efficiently.

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