Establishing Minimal Clinically Important Differences in Quality of Life Measures in Opioid-Induced Constipation.

BACKGROUND & AIMS: Opioids have a role in chronic pain management. However, opioid-induced constipation may cause patients to skip or reduce opioid doses, leading to inadequate pain relief and negatively impacting quality of life. We sought to establish a minimal clinically important difference to understand whether changes in quality of life scores are of value to patients. METHODS: Integrated data from the double-blind, controlled, phase 3 COMPOSE-1 and COMPOSE-2 trials of naldemedine in chronic noncancer pain and opioid-induced constipation were used to determine minimal clinically important differences using Patient Assessment of Constipation Symptoms (PAC-SYM) and Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaires. Patients completed the questionnaires (5-point Likert scale; predose, Weeks 2, 4, and 12), kept a daily log of Bowel Movement and Constipation Assessment, and rated satisfaction at end of study. Minimal clinically important differences were computed using an anchor-based method with 6 anchors: 5 from the Bowel Movement and Constipation Assessment and 1 from patient satisfaction. Threshold values for each anchor were set to define responders versus nonresponders based on score definitions. Clinically meaningful cutoff values for changes in PAC-SYM and PAC-QOL scores were determined using receiver operating characteristic curves. RESULTS: Data from 1095 patients (549, naldemedine; 546, placebo) were analyzed. The area under the curve for the receiver operating characteristic curves (ranges, 0.719 to 0.798 for PAC-SYM and 0.734 to 0.833 for PAC-QOL) indicated that both instruments can discriminate responders and nonresponders for each anchor. PAC-SYM cutoff values ranged from -1.04 to -0.83; PAC-QOL cutoff values ranged from -0.93 to -0.82. CONCLUSIONS: Based on data derived from the anchor method, reductions in PAC-SYM and PAC-QOL scores of >1.0 in patients with chronic noncancer pain and opioid-induced constipation are clinically meaningful. CLINICALTRIALS: gov Registration: NCT01965158; NCT01993940.

Abuse of immediate-release opioids and current approaches to reduce misuse, abuse and diversion.

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.

Efficacy and Safety of Cryoneurolysis for Treatment of Chronic Head Pain Secondary to Occipital Neuralgia: A Pilot Study.

PURPOSE: Treatment of chronic pain associated with occipital neuralgia (ON) is complex, and no consensus statement or guidelines have been published for ON management. This pilot study evaluated the efficacy and safety of cryoneurolysis for management of ON-associated chronic pain. PATIENTS AND METHODS: The study was a prospective, multicenter, nonrandomized cohort study assessing the degree and duration of clinical effect of cryoneurolysis therapy for reducing pain in patients diagnosed with unilateral or bilateral ON. The primary outcome measure was improvement in pain due to ON from baseline to day 7, measured on an 11-point numeric rating scale for pain. Secondary outcome measures included duration of treatment effects and safety events, including anticipated observations and adverse events. Treatment effect was assessed at days 7, 30, and 56 by asking the patient if they were continuing to experience a treatment effect, with potential responses of "effect," "no effect," or "no longer effective." A posttreatment questionnaire evaluated patient satisfaction. RESULTS: Twenty-six patients (9 men, 17 women) with a mean age of 49.1 years enrolled and completed the study. A total of 64% (16/25) of participants reported a clinically important improvement of ≥2 points in numeric rating scale pain scores at day 7; similar results persisted to day 30. Treatment effects were reported by 50% (13/26) of participants at day 30, with a continued effect reported by 35% (9/26) of participants at day 56. Overall, ~70% of participants were satisfied with treatment at 7, 30, and 56 days. No serious anticipated observations, adverse events, or unanticipated adverse device effects were reported. CONCLUSION: Cryoneurolysis provided significant relief from pain associated with ON ≤30 days after treatment and had an acceptable safety profile.

Multimodal Treatment Patterns for Osteoarthritis and Their Relationship to Patient-Reported Pain Severity: A Cross-Sectional Survey in the United States.

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.

Tolperisone for the Treatment of Acute Muscle Spasm of the Back: Results from the Dose-Ranging Phase 2 STAR Study (NCT03802565).

OBJECTIVE: Use of skeletal muscle relaxants (SMRs) for acute muscle spasm is confounded by central nervous system adverse events (AEs), including somnolence. Tolperisone is an SMR that does not appear to be associated with somnolence. The aim of this study was to assess the safety and efficacy of tolperisone versus placebo in subjects with acute muscle spasm of the back. METHODS: STAR (NCT03802565) was a double-blind, randomized, placebo-controlled phase 2 study in subjects with back pain due to acute muscle spasm. Subjects were randomized 1:1:1:1:1 to tolperisone 50, 100, 150, or 200 mg three times daily (TID) or placebo for 14 days. The primary efficacy endpoint was subject-rated pain "right now" using a numeric rating scale on day 14. RESULTS: Subjects (tolperisone, n=337; placebo, n=78) were enrolled at 38 US clinical sites. Tolperisone was well tolerated, with AEs in 18.1% of subjects receiving tolperisone versus 14.1% of subjects receiving placebo. Headache (7.1%) and diarrhea (2.4%) were the most frequent AEs in tolperisone-treated subjects versus 3.8% and 0%, respectively, in placebo-treated subjects. Somnolence was reported in 1.2% and 2.6% of subjects treated with tolperisone and placebo, respectively. Mean change from baseline in numeric rating scale score of pain "right now" on day 14 was -3.5 for placebo versus -4.2, -4.0, -3.7, and -4.4 for tolperisone 50, 100, 150, and 200 mg TID, respectively (linear test of trend on the least-squares mean difference [treatment-placebo]; p=0.0539). In an analysis of pairwise estimates (treatment-placebo), the greatest numerical difference and significance were observed for tolperisone 200 mg TID (p=0.0040). Several secondary endpoints trended toward significance for tolperisone 200 mg TID versus placebo. CONCLUSION: Tolperisone 200 mg TID may be a promising treatment for acute muscle spasm, without the somnolence associated with SMRs. The safety and efficacy of tolperisone should be evaluated in a phase 3 trial.

Characteristics of Analgesic Patch Formulations.

Topical and transdermal formulations are a common means of pharmaceutical drug delivery. If a drug is able to penetrate transcutaneously, the skin is an ideal site for the delivery of medications for both local (topical) and systemic (transdermal) effects. The administration of analgesics through the skin poses several potential advantages to those administered orally including compliance, the ability to deliver a drug to a peripheral target site and more stable and sustained plasma levels. One method of drug delivery is with the use of patch formulations - also known as patch systems. Typically, transdermal patches deliver medications intended to reach the systemic circulation, whereas topical patches are designed to keep medication localized for targeted delivery in proximity to the application site. There are a variety of technologies and materials utilized in patches, as well as penetration and formulation enhancers that ultimately affect the performance, efficacy and safety of the patch system. The degree of adherence to the skin is also of critical importance in drug delivery. Patches that lift up or fall off before the prescribed time period may represent a therapeutic failure and must be replaced, increasing patch utilization and cost to the healthcare system or to the patient. The added risk from accidental exposure makes poor patch adhesion a safety issue as well. A variety of analgesics are currently available as patch formulations including local anesthetics, capsaicin, nonsteroidal anti-inflammatory drugs and opioids. This review will highlight each of those patch delivery systems and introduce newer patch technologies that lend towards improved adhesion and compliance. Understanding the designs, limitations and benefits of patch systems will allow clinicians to select between these therapies when appropriate for their patients.

Evolving Pharmacotherapies for Pain: Drug Development.

The Chronic pain epidemic is a pressing public health crises facing the United States. Currently, more than 100 million Americans suffer from chronic pain, with chronic pain being among the most prevalent conditions and the leading cause of disability. Chronic pain disproportionately affects certain populations including women, low-income individuals, and older adults. This article focuses primarily on new molecular entities in development targeting various chronic pain receptors and new delivery technologies.

Efficacy and safety of naloxegol for opioid-induced constipation assessed by specific opioid medication, opioid dose, and duration of opioid use.

OBJECTIVE: Efficacy and safety of naloxegol, a peripherally acting µ-opioid receptor antagonist that significantly reduces opioid-induced constipation (OIC), were assessed for patient subgroups defined post hoc by baseline maintenance opioid characteristics. DESIGN: Post hoc, pooled analysis of data from two 12-week, randomized, double-blind, placebo-controlled, phase 3 studies. SETTING: Two hundred fifty-seven outpatient centers in the United States and Europe. PATIENTS: Patients with noncancer pain and OIC. INTERVENTIONS: Naloxegol (12.5 or 25 mg daily) or placebo. MAIN OUTCOMES MEASURES: The primary efficacy endpoint was the proportion of patients meeting response criteria at 12 weeks: at least three spontaneous bowel movements (SBMs)/wk and an increase from baseline of at least one SBM for ≥9 of 12 weeks and ≥3 of the last 4 weeks. No adjustments were made for multiplicity; all p values are descriptive. RESULTS: This analysis included 1,337 patients. Increases in the proportion of patients who achieved response at 12 weeks were observed with naloxegol 25 mg versus placebo in patients taking maintenance oxycodone, hydrocodone, morphine, or fentanyl (p ≤ 0.038); patients taking either ≥120 or <120 morphine-equivalent units at baseline (p ≤ 0.032); and patients treated with their current opioid for >6 months (p ≤ 0.035). Efficacy results were less robust with naloxegol 12.5 mg versus placebo. Adverse event incidences were generally comparable across treatment groups, regardless of opioid dose or duration of therapy but were numerically higher with some specific baseline opioids. CONCLUSION: In this post hoc, exploratory analysis, naloxegol 25 mg showed similar efficacy in treating OIC regardless of maintenance opioid type, dose, or duration of opioid use at baseline.

Pharmacokinetics of Fentanyl Sublingual Spray in Opioid-Naïve Participants: Results of a Phase 1, Multiple Ascending Dose Study.

BACKGROUND AND OBJECTIVES: Fentanyl sublingual spray may be a viable alternative to intravenous (IV) opioids for the treatment of acute pain. As patients with acute pain may include those who have limited prior exposure to opioids, this phase 1, open-label, randomized, multiple ascending-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of multiple doses of fentanyl sublingual spray in opioid-naïve participants. This article primarily reports the pharmacokinetics results. METHODS: Study drugs were administered in four dosing cohorts: every 0.5, 1, 2, or 4 h for a maximum of three doses per cohort. Eight fasted individuals per cohort were randomized to either fentanyl sublingual spray (100, 200, or 400 µg) or fentanyl citrate IV 50 µg (6:2 ratio). Blood samples were collected pre-dose through 24 h post first dose. RESULTS: A total of 98 healthy adults were enrolled and 96 completed the study. Mean plasma fentanyl concentrations increased with increasing doses of fentanyl sublingual spray administered every 0.5-4 h. With multiple doses, systemic exposure increased relative to the first dose; shorter dosing intervals resulted in higher concentrations. Analysis of dose proportionality suggested that systemic exposure increased in a linear but slightly greater than dose-proportional manner. Accumulation between the first and last doses of fentanyl sublingual spray was more pronounced with shorter dosing intervals. CONCLUSION: Dose-dependent fentanyl pharmacokinetics following multiple doses of fentanyl sublingual spray were well characterized in an opioid-naïve population. CLINICALTRIALS. GOV IDENTIFIER: NCT02641340.

Long-term use of naldemedine in the treatment of opioid-induced constipation in patients with chronic noncancer pain: a randomized, double-blind, placebo-controlled phase 3 study.

The long-term safety of naldemedine, a peripherally acting µ-opioid receptor antagonist, was evaluated in patients with opioid-induced constipation and chronic noncancer pain in a 52-week, randomized, double-blind, phase 3 study. Eligible adults who could be on a routine laxative regimen were randomized 1:1 to receive once-daily oral naldemedine 0.2 mg (n = 623) or placebo (n = 623). The primary endpoint was summary measures of treatment-emergent adverse events (AEs). Additional endpoints included opioid withdrawal on the Clinical Opiate Withdrawal Scale and the Subjective Opiate Withdrawal Scale, pain intensity on Numeric Rating Scale, frequency of bowel movements, and constipation-related symptoms and quality of life on the Patient Assessment of Constipation Symptoms and Patient Assessment of Constipation Quality of Life scales, respectively. Treatment-emergent AEs (naldemedine, 68.4% vs placebo, 72.1%; difference: -3.6% [95% confidence interval: -8.7 to 1.5]) and treatment-emergent AEs leading to study discontinuation (6.3% vs 5.8%; difference: 0.5% [-2.2 to 3.1)] were reported for similar proportions of patients. Diarrhea was reported more frequently with naldemedine (11.0%) vs placebo (5.3%; difference: 5.6% [2.6-8.6]). There were no meaningful differences between groups in opioid withdrawal or pain intensity. Sustained significant improvements in bowel movement frequency and overall constipation-related symptoms and quality of life were observed with naldemedine (P ≤ 0.0001 vs placebo at all time points). Naldemedine was generally well tolerated for 52 weeks and did not interfere with opioid-mediated analgesia or precipitate opioid withdrawal. Naldemedine significantly increased bowel movement frequency, improved symptomatic burden of opioid-induced constipation, and increased patients' quality of life vs placebo.

Pharmacokinetics and safety of fentanyl sublingual spray and fentanyl citrate intravenous: a multiple ascending dose study in opioid-naïve healthy volunteers.

OBJECTIVE: Fentanyl sublingual spray, with its rapid onset for pain relief, may be efficacious in the management of acute or post-operative pain. Because patients in these settings may be opioid-naïve, the study was conducted to determine the safety, tolerability, and pharmacokinetics of multiple dose administration of fentanyl sublingual spray in an opioid-naïve population. METHODS: Fentanyl sublingual spray (100 mcg, 200 mcg, and 400 mcg) and fentanyl citrate intravenous (IV; 50 mcg) were administered every 0.5, 1.0, 2.0, and 4.0 h for up to three doses per cohort in opioid-naïve subjects (ClinicalTrials.gov identifier: NCT02641340). Eight subjects in each cohort were randomly assigned (six subjects received fentanyl sublingual spray; two subjects received fentanyl citrate IV). Pharmacokinetic and safety-related pharmacodynamic assessments were performed through 24 h post-first dose. Safety assessments were collected through Day 7. RESULTS: Ninety-six opioid-naïve subjects, aged 20-55 years, with a body mass index of 18.7-31.5 kg/m2, participated in the study. Multiple doses of fentanyl sublingual spray (100, 200, and 400 mcg) were generally well tolerated. Hypoxia, observed in the 200-mcg and 400-mcg dose groups, increased with increasing doses and higher dosing frequency, but was readily managed by nasal cannula oxygenation. Overall, nausea increased with increasing doses, and ∼52.6% (10 out of 19) cases of nausea that occurred at the highest dose of 400 mcg were treated with concomitant medication. Overall, the reported adverse events were consistent with the known safety profile of fentanyl. CONCLUSION: Fentanyl sublingual spray (100 mcg, 200 mg, and 400 mcg) administered every 0.5, 1, 2, and 4 h was generally well tolerated in an opioid-naïve population. The results suggest that doses of 200 mcg or lower may be safe for use in an opioid-naïve population.

Pharmacokinetics and safety of fentanyl sublingual spray and fentanyl citrate intravenous: a single ascending dose study in opioid-naïve healthy volunteers.

OBJECTIVE: Fentanyl sublingual spray offers rapid pain relief in opioid-tolerant cancer patients, and may be useful in acute or post-operative pain. Both opioid-naïve and non-tolerant patients are likely to receive opioids in these settings. Understanding the relationship between systemic exposure of fentanyl sublingual spray and effects on respiratory function in opioid-naïve or non-tolerant populations is important to ensure patient safety. This study evaluated single-dose fentanyl sublingual spray in opioid-naïve participants. RESEARCH DESIGN: Participants were randomized to receive single-dose fentanyl sublingual spray (100, 200, 400, 600, 800 mcg) or fentanyl citrate IV in one of five cohorts. Dosing occurred following a 10-h fast, with fasting continuing for 4 h post-dose. Dose proportionality was assessed using analysis of variance and linear regression techniques. PK assessments and safety monitoring were performed through 24 h post-dose. Safety assessments, including adverse event (AE) monitoring, occurred from dosing through Day 7. RESULTS: Fifty participants (19-53 years) received fentanyl sublingual spray or fentanyl citrate IV. Mean maximum plasma concentrations were reached between 0.27-0.60 h post-dose for fentanyl sublingual spray. Peak (Cmax) and total (AUC0-t, AUC0-∞) fentanyl exposures increased in a linear, but more than dose-proportional manner, with higher doses. The most common AEs were somnolence, nausea, and vomiting. All AEs were mild or moderate in severity. Doses at 400, 600, and 800 mcg were associated with nausea and vomiting, requiring pharmacologic intervention. Hypoxia episodes requiring nasal cannula oxygenation were observed with 600mcg and 800mcg doses. CONCLUSIONS: Overall, single-dose fentanyl sublingual spray (100-800 mcg) was generally well tolerated, with greater incidences of AEs (e.g. nausea, vomiting, hypoxia) at higher doses. Doses up to 200 mcg may be safely administered to healthy opioid-naïve individuals with routine monitoring; doses between 400-800 mcg may be administered in settings with nasal cannula oxygenation.

Application of human factors engineering (HFE) to the design of a naloxone auto-injector for the treatment of opioid emergencies.

The increased use of opioids for chronic treatment of pain and the resulting epidemic of opioid overdoses have created a major public health challenge. Parenteral naloxone has been used since the 1970's to treat opioid overdose. Recently, a novel naloxone auto-injector device (EVZIO, kaleo, Inc., Richmond, VA) was approved by the Food and Drug Administration. In this article, we review the Human Factors Engineering (HFE) process used in the development and testing of this novel naloxone auto-injector currently used in nonmedical settings for the emergency treatment of known or suspected opioid overdose. HFE methods were employed throughout the product development process for the naloxone auto-injector including formative and summative studies in order to optimize the auto-injector's user interface, mitigate use-related hazards and increase reliability during an opioid emergency use scenario. HFE was also used to optimize the product's design and user interface in order to reduce or prevent user confusion and misuse. The naloxone auto-injector went through a rigorous HFE process that included perceptual, cognitive, and physical action analysis; formative usability evaluations; use error analysis and summative design validation studies. Applying HFE resulted in the development of a product that is safe, fast, easy and predictably reliable to deliver a potentially life-saving dose of naloxone during an opioid overdose emergency. The naloxone auto-injector may be considered as a universal precaution option for at-risk patients prescribed opioids or those who are at increased risk for an opioid overdose emergency.

Evaluation of the durability of pain relief throughout a 12 hour dosing interval of a novel, extended-release, abuse-deterrent formulation of oxycodone.

BACKGROUND: Abuse deterrent formulations (ADF) are designed to prevent the misuse of opioids by tampering (e.g. physical and chemical manipulation) in order to ingest the opioid in a manner other than intended. Extended-release (ER) formulations are formulated with a larger drug load than immediate-release (IR) formulations, which makes ER opioids more desirable to drug abusers than I.R. formulations. ADFs, therefore, are particularly useful with ER opioid agents, which are designed to produce consistent analgesia over prolonged dosing intervals. However, the drug release properties of these formulations vary and sometimes may not provide adequate pain relief throughout the intended dosing interval, requiring patients to take additional medication for pain relief. Oxycodone DETERx* (Xtampza ER * ) is a novel, microsphere-in-capsule opioid formulation, which allows for twice daily dosing (i.e. every 12 hours) and mitigates the ability to tamper with the formulation. OBJECTIVE: To evaluate the durability of pain relief of a novel formulation of oxycodone throughout the 12 hour dosing interval. RESEARCH DESIGN AND METHODS: This study is a post-hoc analysis of 193 subjects in a Phase 3 randomized withdrawal, double-blind, placebo-controlled, enriched-enrollment, parallel-group, multicenter, 12-week clinical study. MAIN OUTCOME MEASURES: The analysis evaluated the frequency and distribution of use of oxycodone ER and rescue medication during the Double-blind Maintenance Phase of the study. RESULTS: Usage patterns captured by an electronic diary indicated limited overall and limited per-day use of rescue medication with no increase in rescue medication consumption 8 to 12 hours post-dose, suggesting that subjects did not experience end-of-dose failure during this time period. LIMITATIONS: This study is limited in that it is a post-hoc analysis based on data gathered electronically from a large, prospective, double-blind, randomized, placebo-controlled, Phase 3 clinical study. CONCLUSION: The evaluation of dosing patterns indicates that this ER oxycodone capsule formulation has durability of effect over the entire 12-hour dosing interval. These data support the use of abuse-deterrent oxycodone ER as a 12-hour dosing formulation.

SoluMatrix® Diclofenac: Sustained Opioid-Sparing Effects in a Phase 3 Study in Patients with Postoperative Pain.

OBJECTIVES: To evaluate opioid rescue medication usage and the opioid-sparing effect of low-dose SoluMatrix® diclofenac developed using SoluMatrix Fine Particle Technology™ in a phase 3 study in patients experiencing pain following bunionectomy surgery. DESIGN: Multicenter, randomized, double-blind, parallel-group study (NCT01462435). SETTING: Four clinical research centers in the United States. SUBJECTS: Four hundred twenty-eight patients aged 18 to 65 years who experienced moderate-to-severe pain following bunionectomy surgery. METHODS: Patients were randomized to receive low-dose SoluMatrix diclofenac 35 mg or 18 mg capsules three times daily (35-mg group or 18-mg group), celecoxib 400 mg loading dose followed by 200-mg capsules twice daily (celecoxib 200-mg group), or placebo capsules postsurgery. Patients were permitted to receive opioid-containing rescue medication as needed. RESULTS: Significantly fewer patients who received SoluMatrix diclofenac 35 mg or 18 mg or celecoxib required rescue medication during 0-24 h and >24-48 h postsurgery compared with placebo. Patients in the SoluMatrix diclofenac 35 mg or 18 mg groups or in the celecoxib group used fewer mean rescue medication tablets over 0-24 h and >24-48 h compared with placebo-treated patients. Patients in the SoluMatrix diclofenac 35 mg and 18 mg groups and in the celecoxib group also required rescue medication at later times and at slower rates compared with placebo-treated patients. No serious adverse effects occurred in patients receiving SoluMatrix diclofenac. CONCLUSIONS: SoluMatrix diclofenac at two dosage strengths demonstrated an opioid-sparing effect postoperatively in this phase 3 study. SUMMARY: The opioid-sparing effect following low-dose SoluMatrix diclofenac (35 mg or 18 mg three times daily) administration was evaluated in patients experiencing pain following bunionectomy. Significantly fewer patients receiving SoluMatrix diclofenac or celecoxib (400 mg loading, 200 mg twice daily) required rescue medication during 0-24 h and >24-48 h following bunionectomy compared with placebo. No serious adverse events were reported among patients who received SoluMatrix diclofenac. SoluMatrix diclofenac may reduce opioid usage in the postoperative setting in patients with acute pain.

Evolution to low-dose NSAID therapy.

All NSAIDs are to varying degrees associated with gastrointestinal, cardiovascular and renal adverse effects (AEs). Differences in selectivity for inhibition of the COX isozymes (COX-1/COX-2) have been used as an indicator of the likelihood of experiencing an AE, but the measure of 'selectivity' commonly used is less than desirable, and selectivity has not yielded unequivocal superior safety. Recent guidelines recommend that NSAIDs be used at the lowest effective dose and for the shortest period of time. In response, 'low-dose' NSAID formulations have been developed. Such formulations may help by reducing overall systemic exposure, thereby reducing the frequency or severity of AEs. It seems timely to review the need, rationale and application of such an approach.

Levorphanol use: past, present and future.

Levorphanol is a potent opioid analgesic that was first approved for use in the United States in 1953. Levorphanol is approved for use in moderate to severe pain where an opioid analgesic is appropriate. Levorphanol has a wide range of activities including mu opioid agonism, delta agonism, kappa1 and kappa3 receptor agonism, N-methyl-d-aspartate receptor antagonism and reuptake inhibition of both norepinephrine and serotonin. This multimodal profile might prove effective for pain syndromes that are refractory to other opioid analgesics, such as central and neuropathic pain and opioid-induced hyperalgesia. Levorphanol is well suited as a first-line opioid and can also be used during opioid rotation. It has no known effect on the cardiac QT interval or drug-drug interactions involving hepatic cytochrome P450s enzymes. In these regards, levorphanol may offer a superior safety profile over methadone and other long-acting opioids. Despite its prospective value of multiple mechanisms of action and the potential for treating various types of pain, levorphanol use has been largely supplanted by other recently approved opioids. Its waning use over the years has caused it to be referred to as the "Forgotten Opioid" and resulted in what some consider its underutilization. In fact, levorphanol is relatively unfamiliar to most prescribers. The purpose of this review is to inform practitioners about the attributes of this opioid and reintroduce it to clinicians as an option for treating moderate to severe pain when alternative treatment options are inadequate, not indicated or contraindicated.

An overview of prodrug technology and its application for developing abuse-deterrent opioids.

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.

Safety and Tolerability of Biphasic Immediate-Release/Extended-Release Oxycodone/Acetaminophen Tablets: Analysis of 11 Clinical Trials.

OBJECTIVES: To characterize the safety of immediate-release (IR)/extended-release (ER) oxycodone (OC)/acetaminophen (APAP). METHODS: Data were assessed from 9 phase 1 trials in healthy volunteers and recreational users of prescription opioids (N = 405), including 5 single-dose and 3 multidose open-label pharmacokinetic studies of IR/ER OC/APAP and active comparators; and 1 randomized, controlled, single-dose human abuse potential (HAP) study comparing IR/ER OC/APAP, IR OC/APAP, and placebo in recreational users of opioids; and 2 phase 3 trials (N = 701) including a 48-hour placebo-controlled safety and efficacy study in patients with moderate to severe postbunionectomy pain with a 14-day open-label safety extension and a long-term (≤ 35 days) open-label safety study in patients with chronic osteoarthritis pain or chronic low back pain. RESULTS: Adverse events (AEs) experienced by ≥ 10% of participants receiving IR/ER OC/APAP in all trials were pruritus, nausea, vomiting, dizziness, headache, and somnolence; these AEs occurred with similar frequency for equianalgesic doses of IR OC/APAP and IR OC but less frequently for IR tramadol HCl/APAP. In the HAP study, crushing IR/ER or IR OC/APAP tablets did not increase frequency of AEs. Constipation was experienced by < 10% of participants receiving IR/ER OC/APAP. No serious (SAE) or severe AEs were reported in phase 1 trials. In phase 3 trials of 8 reported SAEs, only 1 treatment-related SAE (hypersensitivity to placebo) required treatment discontinuation. No clinically meaningful changes in vital signs, oxygen saturation, electrocardiograms, or laboratory values were reported. CONCLUSIONS: Safety and tolerability of IR/ER OC/APAP are similar to other low-dose opioid/APAP analgesics.

Burden of HIV-Related Neuropathic Pain in the United States.

BACKGROUND: HIV-related neuropathic pain (HIV-NeP) is common; however, the burden of HIV-NeP is not well-understood. METHODS: The cross-sectional study aimed to characterize the HIV-NeP burden. A total of 103 patients with HIV-NeP recruited during routine office visits completed a questionnaire to assess patient-reported outcomes, including pain severity, health status, sleep, mood, and lost productivity. Physicians completed a 6-month retrospective chart review. RESULTS: The sample was predominantly male and not employed for pay. A majority (75.7%) of patients experienced moderate or severe pain. Pain interference, general health, physical health, and depression were worse among patients with more severe pain (all Ps < .006). Most (87.4%) patients were prescribed at least 1 medication for NeP. HIV-related neuropathic pain was associated with 36.1% work impairment. Adjusted annualized costs increased with increasing pain severity (P < .0001). CONCLUSION: The impact of HIV-NeP on health status, physical function, and depression increases with severity, resulting in substantial clinical and economic burden.