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Lynn Webster,1 Jeffrey Gudin2 1Dr. Vince Clinical Research, Overland Park, KS, USA; 2Department of Anesthesiology and Pain Management, University of Miami, Miller School of Medicine, Miami, FL, USACorrespondence: Lynn Webster, Dr. Vince Clinical Research, 1285 3rd Avenue, Salt Lake City, UT, 84103, USA, Tel +1 801-560-1707, Email LRWebsterMD@gmail.comAbstract: The misuse and abuse of opioid analgesics continue to pose a serious public health concern, but for some patients, opioids remain an important analgesic option. Extended-release (ER) opioid formulations are effective for treating chronic pain and are supported by multiple 12-week efficacy studies. ER opioids often contain a high opioid content, and similar to immediate-release (IR) formulations, are subject to abuse, misuse, and diversion. Unintentional misuse may also occur when ER formulations are manipulated for medicinal administration, such as crushing a dose for easier oral intake. As part of a multipronged strategy designed to fight the opioid epidemic, abuse-deterrent formulations (ADFs) were developed to deter misuse, abuse, and diversion of opioids by making manipulation more difficult and nonoral routes of administration less rewarding. Although ADF opioids have been shown to decrease rates of abuse and diversion, they are not equally effective in terms of deterring manipulation for abuse or misuse. Xtampza ER utilizes DETERx technology, which allows it to retain ER characteristics when chewed or crushed, making it the only ER opioid without a boxed warning against these types of manipulation. OxyContin was also developed as an ADF but uses RESISTEC technology, making the tablet hard to crush and viscous in aqueous solutions. ADF utilization has been hampered by patient access issues, including high prices due to lack of insurance coverage. Postmarket real-world studies demonstrate lower rates of abuse, misuse, and diversion for ADF ER opioids compared with non-ADF formulations. However, similar studies comparing abuse-related effectiveness and health care costs for ADF opioids are warranted if clinicians are expected to utilize these potentially safer opioid formulations. These studies would support further education surrounding the benefits and utilization of ADFs and manipulation potential of different ADFs.Keywords: opioid analgesics, opioid crisis, chronic pain, tamper, abuse-deterrent, extended release

William D Chey,1 Darren M Brenner,2 Brooks D Cash,3 Martin Hale,4 Jeremy Adler,5 Mansi S Jamindar,6 Carol B Rockett,6 June S Almenoff,6 Enoch Bortey,7 Jeffrey Gudin8 1Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, MI, USA; 2Departments of Medicine and Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 3Division of Gastroenterology, Hepatology, and Nutrition at the University of Texas Health Science Center at Houston, Houston, TX, USA; 4Gold Coast Research, L.L.C, Miami, FL, USA; 5Pacific Pain Medicine Consultants, Encinitas, CA, USA; 6Medical Affairs, RedHill Biopharma, Inc, Raleigh, NC, USA; 7Pharmaceutical Development Strategies, L.L.C, Chapel Hill, NC, USA; 8Department of Anesthesiology and Pain Management, University of Miami, Miami, FL, USACorrespondence: June S Almenoff, Email jalmenoff@redhillus.comObjective: This study evaluates the onset, magnitude, and consistency of improvement of opioid-induced constipation (OIC) symptoms with naloxegol treatment.Methods: This was a pooled analysis of two Phase 3, double-blind, randomized, placebo-controlled studies (KODIAC-04/05, NCT01309841/NCT01323790) in patients with chronic non-cancer pain and OIC treated with naloxegol 25mg or 12.5mg daily. This analysis assessed improvements in response rates, frequency of spontaneous bowel movement (SBM) and complete SBMs (CSBM), OIC constipation symptoms (straining, stool consistency), time to first post-dose SBM and CSBM, and onset of adverse events over the 12-week period.Subjects: The population of 1337 subjects had a mean age of 52 years and mean duration of opioid use of 3.6 years at baseline. Mean SBM frequency was 1.4/week.Results: Naloxegol 25mg and 12.5mg demonstrated significantly higher response rates vs placebo (PBO) [41.9% (P < 0.001), 37.8% (P = 0.008), 29.4% respectively]. Rapid (within 1 week) and sustained (over 12 weeks) symptom improvement was significantly greater for naloxegol vs PBO (P < 0.05). Both doses showed statistically significant and clinically meaningful improvements in straining, stool consistency, number of SBMs and CSBMs/wk. Significantly shorter times to first post-dose SBM and CSBM were observed with naloxegol vs PBO (SBM HR: 25mg = 1.90, 12.5mg= 1.60; CSBM HR: 25mg = 1.42, 12.5mg = 1.36; P < 0.001 for each regimen). Adverse events occurred more frequently in the naloxegol 25mg group and were most frequently reported during the first week.Conclusion: In patients with chronic non-cancer pain, naloxegol 25mg and 12.5mg demonstrated significantly higher response rates and rapid and sustained improvements in OIC symptoms compared with PBO.Keywords: opioid-induced constipation, naloxegol, clinical trials

Evan Peskin,1 Jeffrey Gudin,2 Michael E Schatman3,4 1Department of Pain Management - Insight Institute of Neurosurgery & Neuroscience, Flint, MI, USA; 2Professor of Anesthesiology, Perioperative Medicine and Pain Management - University of Miami, Miller School of Medicine, Miami, Fl, USA; 3Department of Anesthesiology, Perioperative Care and Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 4Department of Population Health – Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USACorrespondence: Michael E Schatman, Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU Grossman School of Medicine, 550 1st Ave, New York, NY, 10016, USA, Tel +1 425-647-4880, Email Michael.Schatman@NYULangone.org

Joyce McSwan,1,* Jeffrey Gudin,2,* Xue-Jun Song,3 Perola Grinberg Plapler,4 Neil John Betteridge,5 Hayet Kechemir,6 Iva Igracki-Turudic,7 Gisele Pickering8 1GCPHN Persistent Pain Program, PainWISE, Gold Coast, QLD, Australia; 2Department of Anesthesiology, University of Miami, Miller School of Medicine, Miami, FL, USA; 3SUSTech Center of Pain Medicine, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, People’s Republic of China; 4Division of Physical Medicine, Institute of Orthopedics and Traumatology, Hospital das Clínicas, Faculty of Medicine, University of São Paulo, São Paulo, Brazil; 5Neil Betteridge Associates Ltd, London, UK; 6Consumer Healthcare Medical Affairs Department, Sanofi CHC, Paris, France; 7Consumer Healthcare Medical Affairs Department, Sanofi CHC, Frankfurt, Germany; 8Clinical Investigation Center CIC Inserm 1405, University Hospital Clermont-Ferrand, Clermont-Ferrand, France*These authors contributed equally to this workCorrespondence: Gisele PickeringClinical Investigation Center CIC Inserm 1405, University Hospital Clermont-Ferrand, rue Montalembert, CHU G Montpied, Clermont-Ferrand, 63000, FranceTel +33 4 73 17 84 16Fax +33 4 73 17 84 12Email gisele.pickering@uca.frAbstract: Traditionally, musculoskeletal pain management has focused on the use of conventional treatments to relieve pain. However, multi-modal integrative medicine including alternative/complementary treatments is becoming more widely used and integrated into treatment guidelines around the world. The uptake of this approach varies according to country, with generally a higher uptake in developed countries and in females aged more than 40 years. Integral to the concept described here, is that the body has an innate ability to self-heal, which can be optimized by the use of integrative medical strategies. Stress triggers for acute or recurring musculoskeletal pain are diverse and can range from physical to psychological. The mechanism by which the body responds to triggers and initiates the self-healing processes is complex, but five body networks or processes are thought to be integral: the nervous system, microcirculation/vasodilation, immune modulation, muscular relaxation/contraction and psychological balance. Multi-modal integrative medicine approaches include nutritional/dietary modification, postural/muscular training exercises, and cognitive behavioral mind/body techniques. This article will review the self-healing concept and provide plausible scientific evidence where available.Keywords: innate, complementary, intrinsic ability, multi-modal, acute, equilibrium

Jeffrey Gudin,1,2 Lynn R Webster,3 Emileigh Greuber,4 Kip Vought,4 Kalpana Patel,4 Louis Kuritzky5 1Department of Anesthesiology, Rutgers New Jersey Medical School, Newark, NJ, USA; 2Department of Anesthesiology and Pain Management, Englewood Hospital and Medical Center, Englewood, NJ, USA; 3Scientific Affairs Neurosciences, PRA Health Sciences, Salt Lake City, UT, USA; 4Global Research and Development and Medical Affairs, Scilex Pharmaceuticals Inc, Palo Alto, CA, USA; 5Community Health and Family Medicine, University of Florida Community Health & Family Medicine, Gainesville, FL, USACorrespondence: Lynn R WebsterVice President Scientific Affairs, PRA Health Sciences, Salt Lake City, UT, 84103, USATel +1 801 904 4593Email WebsterLynn@Prahs.comPurpose: The primary objective was to evaluate adhesion performance of the lidocaine topical system 1.8% for 12 hours in healthy human subjects in three studies: as a single product (Study 1) and versus other lidocaine topical products (lidocaine patch 5% and lidocaine medicated plaster 5% [Study 2] and generic lidocaine patch 5% [Study 3]). Safety of the lidocaine topical system 1.8%, with a skin irritation focus, was a secondary objective.Patients and Methods: All three studies were open-label, randomized, Phase 1 adhesion performance studies in healthy adult volunteers (N=125). Lidocaine topical products were applied for 12 hours per test, per study arm. Adhesion of all test products was scored at 0, 3, 6, 9, and 12 hours post-application. Skin irritation was scored after product removal or when a product detached.Results: Overall, the majority (≥ 75%) of subjects treated with the lidocaine topical system 1.8% demonstrated ≥ 90% adhesion (FDA adhesion score 0) throughout the 12-hour administration period versus 13.6% of subjects treated with lidocaine patch 5%, 15.9% of subjects treated with lidocaine medicated plaster 5%, and 0% of subjects treated with the generic lidocaine patch 5%. There were no complete detachments with the lidocaine topical system 1.8%, whereas 4.5% of lidocaine patch 5% and lidocaine medicated plaster 5% detached, and 29% of generic lidocaine patch 5% detached. Minimal skin irritation was observed with each lidocaine topical product.Conclusion: Across three studies, lidocaine topical system 1.8% demonstrated superior adhesion performance versus the three other products tested. Skin irritation was minimal across products and studies.Clinicaltrials.gov: NCT04312750, NCT04320173, NCT04319926.Keywords: lidocaine topical system, lidocaine patch, lidocaine medicated plaster, adhesion, postherpetic neuralgia

Srinivas Nalamachu,1,2 Jeffrey Gudin3,4 1Mid America PolyClinic, Overland Park, KS, USA; 2Kansas City University of Medicine and Biosciences, Kansas City, MO, USA; 3Department of Anesthesiology and Pain Management, Englewood Hospital and Medical Center, Englewood, NJ, USA; 4Department of Anesthesiology and Perioperative Medicine, Rutgers New Jersey School of Medicine, Newark, NJ, USACorrespondence: Srinivas Nalamachu Tel +1 913-317-5300Fax +1 913-317-5301Email nalamachu@yahoo.comAbstract: 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.Keywords: topical, transdermal, lidocaine, capsaicin, patch adhesion

Jeffrey Gudin,1 Charles Argoff,2 Jeffrey Fudin,3 Emileigh Greuber,4 Kip Vought,4 Kalpana Patel,4 Sri Nalamachu5 1Department of Anesthesiology, Englewood Hospital and Medical Center, Englewood, NJ, USA; 2Department of Neurology, Albany Medical Center, Albany, NY, USA; 3Professional Practice, Albany College of Pharmacy and Health Sciences, Albany, NY, USA; 4Scilex Pharmaceuticals Inc., Palo Alto, CA, USA; 5Mid America PolyClinic, Overland Park, KS, USACorrespondence: Jeffrey FudinProfessional Practice, Albany College of Pharmacy and Health Sciences, Albany, NY, USATel +1 518-772-4100Fax +1 518-734-0288Email jeff@paindr.comPurpose: This study was designed to characterize drug delivery with lidocaine topical system 1.8% vs lidocaine patch 5% through 2 PK studies.Patients and Methods: Two Phase 1, single-center, open-label, randomized PK studies were performed in healthy adults. In Study 1, 56 subjects received a single intravenous bolus of 0.7 mg/kg of lidocaine as a lead-in to allow for the accurate determination of apparent dose of both products. After a 7-day washout period, subjects were randomized to receive either lidocaine topical system 1.8% or lidocaine patch 5% for 12 hours followed by another 7-day washout period, after which subjects crossed over to receive the other treatment for 12 hours. In Study 2, 54 subjects were randomized to receive either lidocaine topical system 1.8% or lidocaine patch 5% for 12 hours. After a 7-day washout period, subjects crossed over to receive the other treatment. Adhesion and skin irritation assessments were performed after application of the products in Study 2. In both studies, serial blood samples were collected to measure the plasma concentration of lidocaine after product application. Safety assessments and adverse events were monitored in both studies.Results: The comparative PK analysis demonstrated that the two products, despite their difference in drug load and strength, are bioequivalent. Both products were well tolerated. In Study 2, dermal response scores (skin tolerability after removal) were similar between lidocaine topical system 1.8% and lidocaine patch 5%, with a mean irritation score per patch < 1 (barely perceptible erythema), which is not considered to be clinically significant.Conclusion: Bioequivalence was demonstrated between lidocaine topical system 1.8% and lidocaine patch 5%. A comparison of the single-time adhesion scores at 12 hours in Study 2 favored lidocaine topical system 1.8% over lidocaine patch 5%. Both products were well tolerated as a single application in healthy adult human subjects.ClinicalTrials.gov: NCT04144192, NCT04149938.Keywords: postherpetic neuralgia, topical, lidocaine, pharmacokinetics

Razmic Gregorian,1 Elizabeth Marrett,2 Vivek Sivathanu,1 Mariana Torgal,1 Sejal Shah,1 Winghan Jacqueline Kwong,2 Jeffrey Gudin3 1Simon-Kucher & Partners, Cambridge, MA, USA; 2Daiichi Sankyo, Inc., Basking Ridge, NJ, USA; 3Department of Anesthesia and Perioperative Care, Rutgers New Jersey Medical School, Newark, NJ, USACorrespondence: Razmic GregorianSimon-Kucher & Partners, Strategy and Marketing Consultants, LLC, 201 Washington Street, Suite 3301, Boston, MA 02108, USATel +1617-231-4500Fax +1617-576-2751Email Razmic.Gregorian@simon-kucher.comObjective: To evaluate knowledge, practices, and beliefs of US patients receiving prescription opioids regarding opioid storage, disposal, and diversion.Design: Internet-based, cross-sectional survey conducted between September and October 2018. Fisher’s exact tests and Kendall’s Tau-c were used to assess associations with storage and disposal outcomes.Participants: Patients aged ≥ 18 years with acute (n=250) or chronic noncancer (n=250) pain were prescribed an oral opioid within 90 days of the survey.Results: Mean (SD) patient age was 48 (14.7) years, 57.2% were female, 82.6% lived with ≥ 1 person in the home, and 28.0% had remaining/unused pills. One-third of all patients received safe opioid storage (35.2%) and/or disposal (31.4%) counseling from a healthcare provider, while 50.0% received neither storage nor disposal information. Only 27.4% of all patients stored their opioids in a locked location, and 17.9% of those with remaining/unused pills disposed of their medication. Patients who received any opioid counseling were more likely to keep their medication in a locked location compared with those who did not (42.4% vs 12.4%, respectively; P< 0.0001), as were those who perceived any risk of opioid diversion in the home compared with those who perceived no risk or were unsure (53.7% vs 24.2%, respectively; P< 0.0001). Disposal rates did not differ based on counseling received (20.8% counseled vs 16.1% not counseled; P=0.5011) or perceived diversion risk (27.8% perceived any risk vs 16.4% perceived no risk or unsure; P=0.3166).Conclusion: The proportion of patients receiving prescription opioids who receive safe storage/disposal counseling from a healthcare provider appears suboptimal. Further research is warranted to develop effective ways to improve patient opioid storage/disposal education and practices.Keywords: surveys, misuse, diversion, abuse, opioids

Jeffrey Gudin,1 Seferina Mavroudi,2,3 Aigli Korfiati,3 Konstantinos Theofilatos,3 Derek Dietze,4 Peter Hurwitz5 1Rutgers New Jersey Medical School, Newark, NJ, USA; 2Department of Nursing, School of Health Rehabilitation Sciences, University of Patras, Pátrai, Greece; 3InSyBio Ltd, Winchester, UK; 4Metrics for Learning LLC, Queen Creek, Arizona, USA; 5Clarity Science LLC, Narragansett, Rhode Island, USACorrespondence: Peter HurwitzClarity Science LLC, 750 Boston Neck Road, Suite 11, Narragansett, RI 02882, USATel +1917 757 0521Fax +1855-891-8303Email peterh@claritysciences.orgPurpose: Chronic pain is a life changing condition, and non-opioid treatments have been lately introduced to overcome the addictive nature of opioid therapies and their side effects. In the present study, we explore the potential of machine learning methods to discriminate chronic pain patients into ones who will benefit from such a treatment and ones who will not, aiming to personalize their treatment.Patients and Methods: In the current study, data from the OPERA study were used, with 631 chronic pain patients answering the Brief Pain Inventory (BPI) validated questionnaire along with supplemental questions before and after a follow-up period. A novel machine learning approach combining multi-objective optimization and support vector regression was used to build prediction models which can predict, using responses in the baseline, the four different outcomes of the study: total drugs change, total interference change, total severity change, and total complaints change. Data were split to training (504 patients) and testing (127 patients) sets and all results are measured on the independent test set.Results: The machine learning models extracted in the present study significantly overcame other state of the art machine learning methods which were deployed for comparative purposes. The experimental results indicated that the machine learning models can predict the outcomes of this study with considerably high accuracy (AUC 73.8– 87.2%) and this allowed their incorporation in a decision support system for the selection of the treatment of chronic pain patients.Conclusion: Results of this study revealed the potential of machine learning for an individualized medicine application for chronic pain therapies. Topical analgesics treatment were proven to be, in general, beneficial but carefully selecting with the suggested individualized medicine decision support system was able to decrease by approximately 10% the patients which would have been subscribed with topical analgesics without having benefits from it.Keywords: individualized medicine, pain therapy, non-opioid treatment, machine learning, predictive analytics, regression, multi-objective optimization, support vector regression

Jeffrey Gudin,1,2 Andrew G Kaufman,1 Samyadev Datta1,3 1Department of Anesthesiology, Rutgers New Jersey Medical School, Newark, NJ, USA; 2Department of Anesthesiology, Englewood Hospital and Medical Center, Englewood, NJ, USA; 3Center for Pain Management, Hackensack, NJ, USACorrespondence: Jeffrey GudinEnglewood Hospital and Medical Center, 350 Engle St #1808, Englewood, NJ 07631, USATel +1 201-894-3322Email healthmd@optonline.netAbstract: The continued prevalence of chronic low back pain (CLBP) is a testament to our lack of understanding of the potential causes, leading to significant treatment challenges. CLBP is the leading cause of years lived with disability and the fifth leading cause of disability-adjusted life-years. No single non-pharmacologic, pharmacologic, or interventional therapy has proven effective as treatment for the majority of patients with CLBP. Although non-pharmacologic therapies are generally helpful, they are often ineffective as monotherapy and many patients lack adequate access to these treatments. Noninvasive treatment measures supported by evidence include physical and chiropractic therapy, yoga, acupuncture, and non-opioid and opioid pharmacologic therapy; data suggest a moderate benefit, at most, for any of these therapies. Until our understanding of the pathophysiology and treatment of CLBP advances, clinicians must continue to utilize rational multimodal treatment protocols. Recent Centers for Disease Control and Prevention guidelines for opioid prescribing recommend that opioids not be utilized as first-line therapy and to limit the doses when possible for fear of bothersome or dangerous adverse effects. In combination with the current opioid crisis, this has caused providers to minimize or eliminate opioid therapy when treating patients with chronic pain, leaving many patients suffering despite optimal nonopioid therapies. Therefore, there remains an unmet need for effective and tolerable opioid receptor agonists for the treatment of CLBP with improved safety properties over legacy opioids. There are several such agents in development, including opioids and other agents with novel mechanisms of action. This review critiques non-pharmacologic and pharmacologic treatment modalities for CLBP and examines the potential of novel opioids and other analgesics that may be a useful addition to the treatment options for patients with chronic pain.Keywords: non-pharmacologic, opioid, chronic low back pain, analgesia

Jeffrey Gudin, 1, 2 Jeffrey Fudin 3–6 1Department of Anesthesiology, Rutgers New Jersey Medical School, Newark, NJ, USA; 2Department of Anesthesiology, Englewood Hospital and Medical Center, Englewood, NJ, USA; 3Albany College of Pharmacy and Health Sciences, Albany, NY, USA; 4Western New England University College of Pharmacy, Springfield, MA, USA; 5Remitigate, LLC, Delmar, NY, USA; 6Stratton Veterans Affairs Medical Center, Albany, NY, USACorrespondence: Jeffrey GudinDepartment of Anesthesiology, Englewood Hospital and Medical Center, 350 Engle Street, Englewood, NJ 07631, USAEmail jeff@paindr.comAbstract: Opioid analgesics remain a treatment option for refractory acute and chronic pain, despite their potential risk for abuse and adverse events (AEs). Opioids are associated with several common AEs, but the most bothersome is opioid-induced constipation (OIC). OIC is often overlooked but has the potential to affect patient quality of life, increase associated symptom burden, and impede long-term opioid compliance. The peripherally acting μ-receptor antagonists (PAMORAs) are a class of drugs that include methylnaltrexone, naloxegol, and naldemedine. Collectively, each is approved for the treatment of OIC. PAMORAs work peripherally in the gastrointestinal tract, without impacting the central analgesic effects of opioids. However, each has unique pharmacokinetic properties that may be impacted by coadministered drugs or food. This review focuses on important metabolic and pharmacokinetic principals that are pertinent to drug interactions involving μ-opioid receptor antagonists prescribed for OIC. It highlights subtle differences among the PAMORAs that may have clinical significance. For example, unlike naloxegol or naldemedine, methylnaltrexone is not a substrate for CYP3A4 or p-glycoprotein; therefore, its plasma concentration is not altered when coadministered with concomitant medications that are CYP3A4 or p-glycoprotein inducers or inhibitors. With a better understanding of pharmacokinetic nuances of each PAMORA, clinicians will be better equipped to identify potential safety and efficacy considerations that may arise when PAMORAs are coadministered with other medications.Keywords: drug-related side effects and adverse reactions, opioid or opiate mu (μ)-receptor antagonists, opioid analgesics, pharmacokinetics; opioid-induced constipation

Byline: P. Morales (1), E. Cases (1), J. Gudin (2) Keywords: Key words: Diaphragmatic myopathy--Diaphragmatic paralysis--Idiopathic diaphragmatic paralysis. Abstract: Bilateral diaphragmatic paralysis (BDP) is an uncommon entity among neuromuscular diseases. We present a young female with no triggering factors who developed progressive dyspnea with respiratory failure. Further studies led to the diagnosis of BDP. Author Affiliation: (1) Servicio de Neumologia, Hospital Universitario La Fe, Valencia 46009, Espana, ES (2) Unidad de Cuidados Intensivos, Hospital Universitario La Fe, Valencia 46009, Espana, ES Article note: Accepted for publication: 1 February 1997

Jeffrey A Gudin,1 Derek T Dietze,2 Peter L Hurwitz3 1Englewood Hospital Medical Center, Englewood, NJ; Rutgers New Jersey Medical School, Department of Anesthesiology, Newark, NJ, USA; 2Metrics for Learning LLC, Queen Creek, AZ, USA; 3Clarity Science LLC, Narragansett, RI, USACorrespondence: Peter L HurwitzClarity Science LLC, 750 Boston Neck Road, Suite 11, Narragansett, RI 02882, USATel +1917-757-0521Fax +1855-891-8303Email peterh@claritysciences.orgPurpose: Pain is the most common reason for patients to consult primary care providers. Identification of effective treatments with minimal adverse events is critical to safer opioid-sparing and multi-modal approaches to pain treatment. Topical analgesic patches target medication to peripheral sites of pain while potentially avoiding adverse effects associated with systemic medications. Opioids, prescription nonsteroidal anti-inflammatory drugs, and over-the-counter oral medications are associated with systemic toxicities, increasing morbidity and mortality. This study evaluated a topical analgesic pain-relieving patch in reducing pain severity and improving function in patients with mild to moderate arthritic, neurological, or musculoskeletal pain.Patients and Methods: This Institutional Review Board-approved study evaluated the effectiveness of a topical pain-relieving patch in reducing Brief Pain Inventory (BPI) scores in patients. The treatment group (TG) (n=152) received patches for 14 days. A control group (CG) (n=47) did not receive the patch. After day 14, 34 CG patients crossed over to treatment (CROSSG) with the patch. Surveys were administered to patients at baseline and 14 days to assess changes in pain severity and interference. Changes in oral pain medication use, side effects, and satisfaction use were also assessed.Results: Paired data were collected in the CG, TG and CROSSG. At day 14, TG pain severity score and pain interference score decreased (49% and 58.1%, respectively). Pain severity and interference scores decreased less in the CG (12.3% and 14.8%, respectively). In the study, 60.5% of the TG were using concomitant oral pain medications “a lot less”, and 90.8% were very/extremely satisfied with the patch. CROSSG patients showed similar reductions in pain severity and interference scores after patch treatment. No side effects of treatment were reported.Conclusion: Results indicate that this topical analgesic pain-relieving patch can reduce BPI pain severity and interference scores in adult patients with mild to moderate arthritic, neurological, and musculoskeletal pain and should be considered as a treatment option.Keywords: methyl salicylate, menthol, analgesic, Salonpas

Jeffrey A Gudin,1 Michael J Brennan,2 E Dennis Harris,3 Peter L Hurwitz,3 Derek T Dietze,4 James D Strader5 1Pain Medicine and Palliative Care, Englewood Hospital and Medical Center, Englewood, NJ, 2The Pain Center of Fairfield, Fairfield, CT, 3Clarity Science, Austin, TX, 4Metrics for Learning, LLC, Queen Creek, AZ, 5Safe Harbor Compliance and Clinical Services, LLC, Austin, TX, USA Background: Opioids and other controlled substances prescribed for chronic pain are associated with abuse, addiction, and death, prompting national initiatives to identify safe and effective pain management strategies including topical analgesics.Methods: This prospective, observational study evaluated changes from baseline in overall mean severity and interference scores on the Brief Pain Inventory scale and the use of concurrent pain medications at 3- and 6-month follow-up assessments in chronic pain patients treated with topical analgesics. Changes in pain severity and interference and medication usage were compared between treated patients and unmatched and matched controls.Results: The unmatched intervention group (unmatched-IG) included 631 patients who completed baseline and 3-month follow-up surveys (3-month unmatched-IG) and 158 who completed baseline and 6-month follow-up assessments (6-month unmatched-IG). Baseline and 3-month follow-up data were provided by 76 unmatched controls and 76 matched controls (3-month unmatched-CG and matched-CG), and 51 unmatched and 36 matched patients completed baseline and 6-month follow-up surveys (6-month unmatched-CG and matched-CG). Baseline demographic characteristics and mean pain severity and interference scores were similar between groups. There were statistically significant decreases from baseline in mean pain severity and interference scores within the 3- and 6-month unmatched-IG (all P

Jeffrey A GudinEnglewood Hospital and Medical Center, Englewood, NJ, USAAbstract: Prescriptions for opioid analgesics to manage moderate-to-severe chronic noncancer pain have increased markedly over the last decade, as have postmarketing reports of adverse events associated with opioids. As an unintentional consequence of greater prescription opioid utilization, there has been the parallel increase in misuse, abuse, and overdose, which are serious risks associated with all opioid analgesics. In response to these concerns, the Food and Drug Administration announced the requirement for a class-wide Risk Evaluation and Mitigation Strategy (REMS) for long-acting and extended-release (ER) opioid analgesics in April 2011. An understanding of the details of this REMS will be of particular importance to primary care providers. The class-wide REMS is focused on educating health care providers and patients on appropriate prescribing and safe use of ER opioids. Support from primary care will be necessary for the success of this REMS, as these clinicians are the predominant providers of care and the main prescribers of opioid analgesics for patients with chronic pain. Although currently voluntary, future policy will likely dictate that providers undergo mandatory training to continue prescribing medications within this class. This article outlines the elements of the class-wide REMS for ER opioids and clarifies the impact on primary care providers with regard to training, patient education, and clinical practice.Keywords: long-acting opioid, extended-release opioid, risk, REMS, FDA, primary care

The ongoing important debate about the relative benefits/risks of COX ‐ 1 or COX ‐ 2 NSAIDs is hampered by the use of a measure of ‘selectivity’ that is inherently flawed. An alternative measure provides more meaningful and clinically relevant information. [ABSTRACT FROM AUTHOR]

Importance: No safe level of exposure to lead has been identified., Objective: To evaluate individual- and community-level factors associated with detectable and elevated blood lead levels (BLLs) in children., Design, Setting, and Participants: This cross-sectional, retrospective study analyzed deidentified results from blood lead tests performed at a large clinical laboratory from October 1, 2018, to February 29, 2020. Participants were 1 141 441 children younger than 6 years living in all 50 US states and the District of Columbia who underwent blood lead testing during the study period. Children who underwent lead testing of unknown source and those with elevated BLLs who received capillary blood lead testing without confirmatory venous testing were excluded., Exposures: Individual demographic categories included sex, age, and insurance type; community-level demographic categories included pre-1950s housing, poverty, predominant race and ethnicity, and geographical regions., Main Outcomes and Measures: Proportions of children with detectable (≥1.0 μg/dL) and elevated (≥5.0 μg/dL) BLLs, by exposure category., Results: Of the 1 141 441 children (586 703 boys [51.4%]; mean [SD] age, 2.3 [1.4] years) in the study, more than half of the children tested (576 092 [50.5%; 95% CI, 50.4%-50.6%]) had detectable BLLs, and 21 172 children (1.9% [95% CI, 1.8%-1.9%]) had BLLs of 5.0 μg/dL or more. In multivariable analyses, children with public insurance had greater odds of having detectable BLLs (adjusted odds ratio [AOR], 2.01 [95% CI, 1.99-2.04]) and elevated BLLs (AOR, 1.08 [95% CI, 1.04-1.12]). The proportion of children with detectable and elevated BLLs increased significantly for progressive pre-1950s housing and poverty quintiles (P < .001). The odds of detectable BLLs were significantly higher among children in the highest vs lowest quintile of pre-1950s housing (AOR, 1.65 [95% CI, 1.62-1.68]) and of poverty (AOR, 1.89 [95% CI, 1.86-1.93]). A similar association was found for those with elevated BLLs, with an AOR of 3.06 (95% CI, 2.86-3.27) for the highest vs lowest quintile of pre-1950 housing and 1.99 (95% CI, 1.88-2.11) for the highest quintile of poverty. Children residing in zip codes with predominantly Black non-Hispanic and non-Latinx populations had higher odds of detectable BLLs (AOR, 1.13 [95% CI, 1.11-1.15]) but lower odds for elevated BLL (AOR, 0.83 [95% CI, 0.80-0.88])., Conclusions and Relevance: This study suggests that, despite progress in reducing pediatric lead exposure, substantial individual- and community-level disparities persist.

Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Jeffrey Gudin reports consulting fees from Quest Diagnostics. Harvey W. Kaufman reports stock holdings in Quest Diagnostics. No other potential conflicts of interest were disclosed.

The convergence of the opioid epidemic and the coronavirus disease 2019 (COVID-19) pandemic has created new health care challenges. The authors analyzed changes in clinical drug testing patterns and results at a national clinical laboratory, comparing data obtained before and during the pandemic. Testing for prescription and illicit drugs declined rapidly during the pandemic, with weekly test volumes falling by approximately 70% from the baseline period to the trough (the week beginning March 29) before rising in subsequent weeks. Among individuals tested, positivity increased by 35% for non-prescribed fentanyl and 44% for heroin during the pandemic. Positivity for non-prescribed fentanyl increased significantly among patients positive for other drugs: by 89% for specimens positive for amphetamines; 48% for benzodiazepines; 34% for cocaine; and 39% for opiates ( P  < 0.01 for all comparisons). These findings suggest significant increases in dangerous drug combinations. Positivity for non-prescribed use of many other drugs remained consistent or declined for some drugs, relative to pre-pandemic patterns. Models adjusting for potential confounding variables, including medication-assisted treatment and treatment at a substance use disorder facility indicated that the risk for non-prescribed fentanyl positivity rose by more than 50% during the pandemic. In summary, these findings demonstrate decreased drug testing overall, with increased positivity for high-risk drugs and dangerous drug combinations. The convergence of the drug abuse epidemic and COVID-19 pandemic has led to an increased need for health care and public health resources dedicated to supporting vulnerable patients and addressing the underlying causes of these disturbing trends.

Objective: To evaluate the long-term safety of NKTR-181, a novel mu-opioid receptor agonist that may have reduced human abuse potential, in patients with moderate to severe chronic low back pain (CLBP) or other chronic noncancer pain (CNP)., Design: Uncontrolled, multicenter, open-label, long-term study of NKTR-181 comprised of three periods: screening (≤21 days), treatment (52 weeks), and safety follow-up (∼14 days after the last dose of NKTR-181)., Setting: Multicenter, long-term clinical research study., Methods: NKTR-181 administered at doses of 100-600 mg twice daily (BID) was evaluated in opioid-naïve and opioid-experienced patients. Patients were enrolled de novo or following completion of the randomized, placebo-controlled phase 3 efficacy study (SUMMIT-07). Safety assessments included adverse event documentation, measurements of opioid withdrawal, and clinical laboratory tests. Effectiveness was assessed using the modified Brief Pain Inventory Short Form (mBPI-SF)., Results: The study enrolled 638 patients. The most frequently reported treatment-emergent adverse events (TEAEs) were constipation (26%) and nausea (12%). Serious TEAEs, reported in 5% of patients, were deemed by investigators to be unrelated to NKTR-181. There were no deaths or reported cases of respiratory depression. A sustained reduction in mBPI-SF pain intensity and pain interference from baseline to study termination was observed throughout treatment. Only 2% of patients discontinued NKTR-181 due to lack of efficacy, and 11% discontinued due to treatment-related AEs. NKTR-181 doses of up to 600 mg BID were generally well tolerated, and patients experienced low rates of opioid-related adverse events., Conclusions: The study results support the premise that NKTR-181 is a safe and effective option for patients with moderate to severe CLBP or CNP., (© 2019 American Academy of Pain Medicine.)

Objective: The Centers for Disease Control and Prevention (CDC) recommend that clinicians prescribing opioids for chronic pain should consider at least annual urine drug testing (UDT). We evaluated whether shorter intervals for repeat UDT are associated with decreased rates of drug misuse., Design: Retrospective analysis of deidentified serial UDT and matched prescribing data., Setting: We analyzed Quest Diagnostics 2016-2017 UDT results from new patients being monitored for prescription drug adherence, in nonsubstance use disorder (SUD) treatment environments., Main Outcome Measures: Drug misuse was defined as the absence of a prescribed substance or the presence of a nonprescribed substance. Patients with ≥3 sets of the UDT results were included., Results: UDT results from 49,601 patients (148,803 specimens) were tested. Declines in misuse between the first and second UDT were highest for those tested at the shortest intervals: approximately weekly, 19 percent; monthly, 15 percent; bimonthly, 12 percent; quarterly, 9 percent; semiannually, 3 percent; misuse rates increased by 1 percent for patients tested annually. Declines in misuse were more pronounced for opioids than other drug groups. Substantial declines in positivity were noted for heroin (32 percent) and nonprescribed fentanyl (10 percent). Declines in misuse between the second and third UDT followed a similar pattern., Conclusions: UDT intervals of ≤ quarterly were associated with marked declines, but testing annually or semiannually was not associated with consistent decreases. Our findings suggest that clinical strategies that include serial testing conducted quarterly or sooner may be instrumental in decreasing drug misuse. Testing more frequently than "at least once annually" should be considered by clinicians monitoring potential drug misuse.

Objective: To evaluate the SUMMIT-07 trial opioid withdrawal results of NKTR-181 (oxycodegol), a new molecular entity mu-opioid receptor agonist., Design: Phase 3, enriched-enrollment, double-blind, randomized-withdrawal study in patients with chronic low back pain (CLBP)., Setting: Conducted in the United States at multiple sites., Methods: SUMMIT-07 was comprised of five periods: screening; NKTR-181 open-label titration (100 to 400 mg twice daily); 12-week randomized, double-blind study drug (NKTR-181 or placebo); one-week study drug taper; and two-week safety follow-up. Permitted rescue medication included hydrocodone 5 mg/acetaminophen 300 mg (two tablets daily) for two weeks after randomization, then acetaminophen 1.0 gm daily for the remainder of the trial. Signs and symptoms of drug withdrawal were evaluated using the Clinical Opiate Withdrawal Scale (COWS); Subjective Opiate Withdrawal Scale (SOWS); Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS); and withdrawal-related adverse events., Results: Of 1,190 patients entering titration, one patient had moderate withdrawal (COWS score 13/48 maximum) three days after discontinuing NKTR-181. Of 610 patients randomized (N = 309, NKTR-181; N = 301, placebo), no COWS scores indicating withdrawal at a moderate level or greater (i.e., score ≥13) were observed at any time point. At day 8 after randomization, week 12, and the end of tapering, COWS scores indicating mild withdrawal (<13) were observed in seven (2.4%), one (0.4%), and one (0.5%) placebo patients, respectively, and three (1.0%), one (0.4%), and five (2.3%) NKTR-181 patients, respectively. Mean SOWS scores in both arms were ≤2.8 of 64 possible points at all time points. During the randomized period, of 35 events identified by MADDERS, adjudicators identified 20 possible "withdrawal" events (9 [2.9%] NKTR-181 and 11 [3.7%] placebo)., Conclusions: NKTR-181 exhibited a low rate and severity of opioid withdrawal in SUMMIT-07 patients with CLBP., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.)

Buprenorphine is a Schedule III opioid analgesic with unique pharmacodynamic and pharmacokinetic properties that may be preferable to those of Schedule II full μ-opioid receptor agonists. The structure of buprenorphine allows for multimechanistic interactions with opioid receptors μ, δ, κ, and opioid receptor-like 1. Buprenorphine is considered a partial agonist with very high binding affinity for the μ-opioid receptor, an antagonist with high binding affinity for the δ- and κ-opioid receptors, and an agonist with low binding affinity for the opioid receptor-like 1 receptor. Partial agonism at the μ-opioid receptor does not provide partial analgesia, but rather analgesia equivalent to that of full μ-opioid receptor agonists. In addition, unlike full μ-opioid receptor agonists, buprenorphine may have a unique role in mediating analgesic signaling at spinal opioid receptors while having less of an effect on brain receptors, potentially limiting classic opioid-related adverse events such as euphoria, addiction, or respiratory depression. The pharmacokinetic properties of buprenorphine are also advantageous in a clinical setting, where metabolic and excretory pathways allow for use in patients requiring concomitant medications, the elderly, and those with renal or hepatic impairment. The unique pharmacodynamic and pharmacokinetic properties of buprenorphine translate to an effective analgesic with a potentially favorable safety profile compared with that of full μ-opioid receptor agonists for the treatment of chronic pain.

Objective: An expert panel convened to reach a consensus on common misconceptions surrounding buprenorphine, a Schedule III partial µ-opioid receptor agonist indicated for chronic pain. The panel also provided clinical recommendations on the appropriate use of buprenorphine and conversion strategies for switching to buprenorphine from a full µ-opioid receptor agonist for chronic pain management., Methods: The consensus panel met on March 25, 2019, to discuss relevant literature and provide recommendations on interpreting buprenorphine as a partial µ-opioid receptor agonist, prescribing buprenorphine before some Schedule II, III, or IV options, perioperative/trauma management of patients taking buprenorphine, and converting patients from a full µ-opioid receptor agonist to buprenorphine., Results: The panel recommended that buprenorphine's classification as a partial µ-opioid receptor agonist not be clinically translated to mean partial analgesic efficacy. The panel also recommended that buprenorphine be considered before some Schedule II, III, or IV opioids in patients with a favorable risk/benefit profile on the basis of metabolic factors, abuse potential, and tolerability and that buprenorphine be continued during the perioperative/trauma period. In addition, switching patients from a full µ-opioid receptor agonist to buprenorphine should be considered with no weaning period at starting doses that are based on the previous opioid dose., Conclusions: These recommendations provide a framework for clinicians to address most clinical scenarios regarding buprenorphine use. The overall consensus of the panel was that buprenorphine is a unique Schedule III opioid with favorable pharmacologic properties and a safety profile that may be desirable for chronic pain management., (© 2020 American Academy of Pain Medicine.)

Opioids can be an effective treatment option for appropriate patients with chronic pain for whom nonpharmacological or nonopioid treatment does not provide adequate pain relief. However, extended-release (ER) opioid formulations, because of their high drug content, are attractive options for nonmedical use and abuse. Xtampza ® ER (oxycodone DETERx ® ) capsules, an ER abuse-deterrent formulation (ADF), contain microspheres that combine oxycodone with inactive ingredients to increase the difficulty of tampering with the ER mechanism. The aim of this article is to review five previously published studies highlighting the impact of physical manipula-tion (ie, crushing and chewing) on the pharmacokinetic (PK) properties of orally administered Xtampza ER compared with immedi-ate-release (IR) oxycodone and/or reformulated OxyContin ® (the first approved oxycodone ER ADF). Across five studies, manipulated (crushed or chewed) Xtampza ER retained an ER PK profile similar to that of intact Xtampza ER, with respect to maximum plasma con-centration (Cmax) and time to Cmax. Additionally, bioequivalence was established between manipulated and intact Xtampza ER, based on Cmax and area under the concentration-time curve values in healthy volunteers and nondependent recreational opioid users. In contrast, crushed OxyContin failed to retain the ER PK profile of intact OxyContin and was bioequivalent to IR oxycodone, based on Cmax in healthy volunteers. The retention of ER PK properties when capsule contents are physically manipulated before oral administra-tion suggests Xtampza ER has lower potential to be manipulated for oral abuse when compared with IR oxycodone or OxyContin.

Interest in and use of topical analgesics has been increasing, presumably due to their potential utility for relief of acute and chronic pain. Topically applied agents with analgesic properties can target peripheral nociceptive pathways while minimizing absorption into the plasma that leads to potential systemic adverse effects.Clinical trials have found 5% lidocaine patches to be effective and well tolerated for the treatment of post-herpetic neuralgia (PHN) with a minimal risk of toxicity or drug-drug interactions. With this patch formulation, the penetration of lidocaine into the skin produces an analgesic effect without producing a complete sensory block. Use of topical lidocaine is supported by clinical practice guidelines, including first-line treatment by the American Academy of Neurology (guidelines retired 2018), the European Federation of Neurological Societies and second-line by the Canadian Pain Society.FDA approved 5% lidocaine patches in 1999, and a 1.8% topical lidocaine system in 2018 - both indicated for the treatment of pain secondary to PHN. The 1.8% system offers a more efficient delivery of lidocaine that is bioequivalent to 5% lidocaine patches, but with a 19-fold decrease in drug load (i.e., 36 mg versus 700 mg) as well as superior adhesion that allows the patch to maintain contact with the skin during the 12-h administration period.Although topical lidocaine formulations have advanced over time and play an important role in the treatment of PHN, a variety of other conditions that respond to topical lidocaine have been reported in the literature including PHN, lower back pain, carpal tunnel syndrome, diabetic peripheral neuropathy, and osteoarthritis joint pain. Other neuropathic or nociceptive pain syndromes may respond to topical lidocaine in select cases and warrant further study. Clinicians should consider local anesthetics and other topical agents as part of their multimodal treatments of acute and chronic pain.

Background: Postherpetic neuralgia (PHN) is a chronic, painful condition characterized by persistent pain following resolution of a herpes zoster (HZ) infection. Epidemiologic data demonstrate that the risks for HZ infections and the development of PHN increase with age., Objective: To characterize prescribing patterns, health care utilization, and treatment costs for adults with PHN based on real-world data., Methods: This study analyzed medical and pharmacy claims from 2010 to 2014 in the MarketScan Commercial and Medicare Supplemental databases. PHN patients were identified based on criteria from a published algorithm. PHN treatment patterns were analyzed by age and reported descriptively for patients aged < 65 or ≥ 65 years. Excess incremental health care costs were calculated for PHN patients by comparing expenditures for a cohort of PHN patients to expenditures of a propensity score-matched control group of patients with HZ alone., Results: Approximately 0.4% of patients aged < 65 years were diagnosed with HZ versus 1.3% of patients aged ≥ 65 years; approximately 15.3% of HZ patients aged < 65 years and 26.4% of patients aged ≥ 65 years were diagnosed with PHN. Overall, opioids remained the most frequently prescribed initial treatment. Approximately 21.6% of PHN patients received an opioid as an initial treatment for PHN, 15.1% received gabapentin; 8.9% received a prescription nonsteroidal anti-inflammatory drug (NSAID); 8.3% received a lidocaine patch; 3.3% received pregabalin; 2.5% received a tricyclic antidepressants (TCAs); 0.8% received other topical lidocaine; and < 1% received capsaicin. Observed first-line use of the lidocaine patch and gabapentin was higher in patients aged ≥ 65 years relative to patients aged < 65 years. When separated by age group, only 24.6% of patients aged < 65 years and 38.5% of patients aged ≥ 65 years were prescribed a recommended first-line treatment for initial PHN therapy (gabapentin, lidocaine patch, pregabalin, and TCAs). Comparisons of treatment costs of PHN patients to matched HZ patients without PHN indicated that PHN patients initiated on opioids had the highest mean additional health care expenditure compared with PHN patients initiated on other medications. On average, PHN patients initiated on opioids had $7,601 additional health care expenditure compared with HZ patients with no PHN; additional expenditures were $6,428 for pregabalin, $4,213 for lidocaine patches, $3,478 for gabapentin, $3,304 for NSAIDs, and $2,797 for TCAs, respectively., Conclusions: Management of PHN is associated with substantial utilization of opioid-based therapies across all ages. Medications supported by evidence either as first-line therapies or as part of a multimodal regimen for the management of PHN are underused relative to opioid-based PHN therapies. Improving adherence to evidence-based PHN treatment regimens offers the potential to reduce opioid prescribing first line and reduce overall treatment costs. Given the emphasis to reduce opioid prescribing to minimize the risk of dependence, abuse, and diversion, multimodal analgesic treatments that can avoid or reduce opioid use should be considered., Disclosures: Research funding was provided by SCILEX Pharmaceuticals. The sponsor reviewed and approved the research plan and provided support for manuscript preparation through Patel's role as a coauthor of this manuscript. The sponsor's product (lidocaine patch) was not used in this study. Patel is a paid employee of SCILEX Pharmaceuticals. Goss is an employee and minority owner of Boston Healthcare Associates, which received a research grant from SCILEX Pharmaceuticals to conduct this study. Gudin reports advisory board fees from AcelRx Pharmaceuticals and BioDelivery Sciences International and consulting fees from Averitas, Daiichi, Hisumitsu, Nektar, Purdue, Quest Diagnostics, SCILEX Pharmaceuticals, and US WorldMeds, unrelated to this study. Fudin reports advisory board fees from AcelRx Pharmaceuticals, Human Half-Cell, Quest Diagnostics, GlaxoSmithKline, SCILEX Pharmaceuticals, BioDelivery Sciences, Daiichi Sankyo, and Salix Pharmaceuticals; speaker fees from Daiichi Sankyo, Salix Pharmaceuticals, Abbott Laboratories, Acutis Diagnostics, and AstraZeneca; and consulting fees from Firstox Laboratories, unrelated to this study. The other authors have nothing to disclose. Parts of this research were presented at the AMCP Managed Care & Specialty Pharmacy Annual Meeting; April 22, 2016; San Francisco, CA, and at the 35th Annual Scientific Meeting of the American Pain Society; May 11-14, 2016; Austin, TX.

Objective: To prospectively evaluate the abuse potential of NKTR-181, a novel opioid analgesic, in two phase 3 clinical trials using a newly developed reporting system: the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS®). Methods: SUMMIT-07 was an enriched enrollment randomized withdrawal study that examined the safety and efficacy of NKTR-181 across 12 weeks in opioid-naïve subjects with chronic low back pain. SUMMIT-LTS was a 52 week open-label study in opioid-naïve and experienced subjects with chronic low back pain or noncancer pain rolled over from SUMMIT-07 or enrolled de novo . System evaluations were triggered by adverse events of interest and drug accountability discrepancies signaling potentially abuse-related events. Each event was assigned a primary classification and supplementary classification(s) by investigators and by a blinded, independent committee of substance abuse experts (adjudicators). At the final study visit, investigators administered a survey to subjects to identify overlooked events of interest. Results: Seventy-nine (6.6%) of 1189 subjects were associated with 86 events in SUMMIT-07 and 51 (8.0%) of 638 subjects were associated with 59 events in SUMMIT-LTS. Most events were attributed to "Withdrawal" and, primarily in SUMMIT-07, "Therapeutic Error" (unintentional overuse) or "Misuse" (intentional overuse for a therapeutic purpose) of study medication. Adjudicators identified five possible "Abuse" events (three NKTR-181, two placebo) in SUMMIT-07 and four possible "Abuse" events (all NKTR-181) in SUMMIT-LTS. Conclusions: The MADDERS® system discerns potentially abuse-related events and identified low rates of withdrawal and a low risk of abuse potential, diversion or addiction associated with NKTR-181 in phase 3 trials.