Oxycodone

“This behavior is disturbing but not surprising,” Robert Steinbrook, M.D., director of the Health Research Group of the consumer rights advocacy nonprofit Public Citizen, said in the report. “It’s like they used every trick in the book.” In an analysis of thousands of Mallinckrodt’s internal documents, a pair of researchers uncovered a host of strategies that the pharma allegedly utilized to help sway doctors to prescribe its opioids. Throughout the last decade, Mallinckrodt has faced thousands of lawsuits accusing it of engaging in misleading marketing tactics to boost sales of its pain pills; the company was reportedly the U.S.’s largest producer of opioids, including hydrocodone, hydromorphone and oxycodone, for several years from 2006 to the early 2010s. The company has denied all wrongdoing, but the resulting settlements and fines have led it to file for bankruptcy twice, in 2020 and 2023. More than 1 million of the drugmaker’s internal documents were made public in the initial bankruptcy case, the 2022 settlement of which concluded with Mallinckrodt agreeing to pay $1.7 billion to local and state governments and individual victims of the opioid crisis—$1 billion of which was erased in the second bankruptcy filing. A report published in The BMJ on Monday details two researchers’ findings from digging through nearly 900 contracts included in that trove of documents, which “reflect concrete efforts backed up by payments.” According to Sergio Sismondo, Ph.D., and Maud Bernisson, Ph.D., the docs “outline a smorgasbord of tactics to achieve greater sales.” Tying those tactics together was an apparent effort to convince medical professionals that opioids like those sold by Mallinckrodt were not only effective treatments for acute and chronic pain but also safe for prolonged use. Mallinckrodt did not respond to requests for comment from Fierce Pharma Marketing nor from Sismondo and Bernisson. Among the strategies outlined in the contracts was Mallinckrodt’s recruitment of physicians to serve as key opinion leaders. After undergoing training at reportedly lavish weekend getaways, those KOLs would then be dispatched across the country to give presentations to their fellow doctors reiterating Mallinckrodt’s selling points for its opioid products. Those KOLs were also used to help carry out the pharma’s other marketing efforts. For example, some served as co-chairs of the continuing medical education course that Mallinckrodt developed to tout the benefits of opioids for pain management. The course, which ultimately reached more than 88,000 physicians by 2017, provided education on raising doses of long-acting opioids and quoted the company’s paid doctors as downplaying the risks of addiction, according to the report. Meanwhile, Mallinckrodt reportedly also worked with the doctors to place articles in medical journals—often ghostwritten by contracted agencies—aimed at persuading scientists and medical professionals of the safety and necessity of opioids to treat pain. For example, one such 2013 review article cited by the report’s authors discussed how acute pain is “commonly undertreated” and, if left untreated, can develop into chronic pain. It went on to suggest not only that prescribing opioids on a preventive basis could stop chronic pain in its tracks but also that “efforts to prevent chronic pain may eliminate extended exposure to opioids, which could, in turn, minimize drug abuse.” However, a chronic pain and opioid researcher cited by Sismondo and Bernisson noted that there’s no “good research” supporting the idea that acute pain can be prevented from turning into chronic pain, but that stopping opioid use promptly can help avoid dependence. A recurring theme in the presentations Mallinckrodt’s KOLs gave and the literature they put their names on was the minimizing of the possibility of addiction. According to the report, many of those materials relied on the concept of “pseudoaddiction,” which claims that patients’ increased tolerance of and physical dependence on opioids, and their resulting need for higher doses over time, is different from “true addiction,” despite their near-identical and easily confused presentations. Separately, a 2015 analysis of medical literature concluded that “no empirical evidence yet exists” to support the concept of pseudoaddiction as distinct from addiction. Nevertheless, bolstered by that nebulous distinction, the company went on to market its longer-acting, extended-release opioids—including novel versions of hydromorphone and oxycodone—as “abuse-deterrent.” The tactics that Sismondo and Bernisson found detailed in Mallinckrodt’s contracts were employed as opioid overdose deaths were skyrocketing in the U.S. and doctors were becoming more wary of the drugs and their potential for addiction. The medical literature and physician endorsements cultivated by the drugmaker would therefore have lent a reassuring measure of credibility to Mallinckrodt’s offerings, especially, as the authors noted, to particularly “busy physicians.” “This behavior is disturbing but not surprising,” Robert Steinbrook, M.D., director of the Health Research Group of the consumer rights advocacy nonprofit Public Citizen, said in the report. “It’s like they used every trick in the book.”

Double-blind, placebo-controlled study aims to measure safety and efficacy of INDV-2000 over 3 months in participants with moderate to severe Opioid Use Disorder. INDV-2000 is an investigational non-opioid treatment that acts through the orexin pathway, shown to play a key role in the neurobiology of substance use disorder in animals. Recent animal studies have demonstrated that selective Orexin-1 receptor antagonism can reduce self-administration of opioids and synthetic opioids such as fentanyl and remifentanil. RICHMOND, Va., June 10, 2024 /PRNewswire/ -- Indivior PLC (LSE/Nasdaq: INDV) today announced the dosing of the first subject with INDV-2000 in a Phase 2 double-blind, placebo controlled, randomized, dose-ranging study to assess the safety and efficacy of INDV-2000 over 3 months in treatment-seeking individuals with Opioid Use Disorder (OUD) (NCT06384157). The purpose of this proof-of-concept study is to measure safety and efficacy and to determine the dose-response relationship for INDV-2000 in participants with moderate to severe OUD who are treatment-naïve, have recently initiated or completed short-term medically supervised opioid withdrawal with transmucosal (TM) buprenorphine, and are interested in transitioning to a non-opioid treatment. This milestone is another step in Indivior's mission to develop new treatment options for patients with OUD and other substance use disorders. With the support of an NIH-HEAL grant (1R01DA043898-01A1) titled "Clinical Evaluation of INDV-2000 (C4X3256), a Non-Opioid, Highly Selective Orexin-1 Receptor Antagonist for the Treatment of Opioid Use Disorder" the study was initiated for the clinical development of INDV-2000, a potent and selective oral orexin-1 receptor (OX1R) antagonist, with demonstrated activity in rodent models of addiction and a safety profile suitable for therapeutic administration in clinical studies.1 More recently, animal studies also have shown that selective antagonism of the OX1R can reduce heroin intake and oxycodone self-administration2 and reduce the consumption of synthetic opioids including remifentanil3 and fentanyl.4 "INDV-2000 provides Indivior with a unique opportunity to further address unmet patient needs in the treatment of OUD with potentially the first non-opioid orexin-targeted therapy," said Christian Heidbreder, Chief Scientific Officer. "By providing a potential therapeutic option for patients who might benefit from a non-opioid alternative, INDV-2000 may broaden the spectrum of care for OUD treatment." The orexin-A and orexin-B neuropeptides are agonists of the orexin-1 receptor (OX1R) and orexin-2 receptor (OX2R), respectively. The OX1R and OX2R are thought to play differential physiological roles with the OX1R mainly involved in motivation and reward and the OX2R in the modulation of the sleep/wake cycle and energy homeostasis.3 The completion of clinical Phase 1 Single Ascending Dose (NCT04413552) and Multiple Ascending Dose (NCT04976855) studies happened after an end-of-Phase 1 meeting with the FDA on November 3, 2023, paving the way for the preparation and initiation of this clinical Phase 2 proof-of-concept (PoC) study. Opioid use disorder (OUD) involves disruption of brain circuits engaged in reward, decision-making, learning, and self-control. The magnitude of OUD worldwide highlights the need for novel molecular entities ultimately translating into new medications for the treatment of OUD. In the United States, among people aged 12 or older in 2022, 3.2% (or 8.9 million people) misused opioids in the past year.5 "As the opioid epidemic continues to escalate, it is important to develop more treatment options," said Dr. Heidbreder. "This milestone highlights Indivior's commitment to developing a wider range of therapeutics in both the opioid and non-opioid treatment category, ultimately providing more choices for the patient." About the Study The purpose of this Phase 2 study is to measure safety and efficacy and to determine the dose-response relationship for INDV-2000 in participants with moderate to severe Opioid Use Disorder (OUD) who are new to treatment, have recently initiated or completed short-term medically supervised opioid withdrawal with TM buprenorphine, and are interested in transitioning to a non-opioid treatment. On Day 1, trial participants will be randomized to the INDV-2000 or placebo group and receive the treatment in conjunction with TM buprenorphine until Day 7. From Day 8 onward, INDV-2000 or placebo will be administered as a standalone. The randomized treatment period starts when the participant receives randomized treatment (at Day 1) and ends at his/her last study visit after 3 months on INDV-2000 or placebo. Alternatively, the treatment period ends when participants initiate buprenorphine rescue therapy due to a relapse in illicit opioid use. About Indivior Indivior is a global pharmaceutical company working to help change patients' lives by developing medicines to treat substance use disorders (SUD), opioid overdose and serious mental illnesses. Our vision is that all patients around the world will have access to evidence-based treatment for the chronic conditions and co-occurring disorders of SUD. Indivior is dedicated to transforming SUD from a global human crisis to a recognized and treated chronic disease. Building on its global portfolio of opioid use disorder treatments, Indivior has a pipeline of product candidates designed to both expand on its heritage in this category and potentially address other chronic conditions and cooccurring disorders of SUD. Headquartered in the United States in Richmond, VA, Indivior employs more than 1,100 individuals globally and its portfolio of products is available in 37 countries worldwide. Visit to learn more. Connect with Indivior on LinkedIn by visiting . Important Cautionary Note Regarding Forward-Looking Statements This news release contains certain statements that are forward-looking. Forward-looking statements include, among other things, statements regarding potential new productor or therapies, express or implied statements about their safety and efficacy, and other statements containing the words "believe", "anticipate", "plan", "expect", "intend", "estimate", "forecast," "strategy," "target," "guidance," "outlook," "potential", "project", "priority," "may", "will", "should", "would", "could", "can", "outlook," "guidance", the negatives thereof, and variations thereon and similar expressions. By their nature, forward-looking statements involve risks and uncertainties as they relate to events or circumstances that may or may not occur in the future. Actual results may differ materially from those expressed or implied in such statements because they relate to future events. Various factors may cause differences between Indivior's expectations and actual results, including, among others, the risk that the clinical trial may fail to demonstrate the safety or efficacy of the treatment; that the FDA will require one or more Phase 3 trials before approving INDV-2000 for individuals with opioid use disorder; that the FDA may decline to approve INDV-2000 for individuals with opioid use disorder for many other reasons; and the material risks described in the most recent Indivior PLC Annual Report and in subsequent releases. Forward-looking statements speak only as of the date that they are made and should be regarded solely as our current plans, estimates and beliefs. Except as required by law, we do not undertake and specifically decline any obligation to update, republish or revise forward-looking statements to reflect future events or circumstances or to reflect the occurrences of unanticipated events. References Murray CM, Fox JC, Heidbreder C, Young M. A Novel, Non-Opioid, Selective Orexin-1 Receptor Antagonist for the Treatment of Substance Use Disorders. Neuroscience Applied, Volume 3, 2024, 104053. . Epub ahead of print. Smith, R.J., Aston-Jones, G., 2012. Orexin / hypocretin 1 receptor antagonist reduces heroin self-administration and cue-induced heroin seeking. Eur. J. Neurosci. 35, 798–804. Mohammadkhani, A., James, M.H., Pantazis, C.B., Aston-Jones, G., 2020. Persistent effects of the orexin-1 receptor antagonist SB-334867 on motivation for the fast-acting opioid remifentanil. Brain Res. 1731:146461. Fragale, J E., Pantazis, C.B., James, M.H., and Aston-Jones, G., 2019. The role of orexin-1 receptor signaling in demand for the opioid fentanyl. Neuropsychopharmacology. 44, 1690–1697. Substance Abuse and Mental Health Services Administration. (2022) Highlights for the 2022 National Survey on Drug Use and Health1. Retrieved from Highlights for the 2022 National Survey on Drug Use and Health (samhsa.gov) SOURCE Indivior PLC