Jeffrey A. Gudin

Risks, management, and monitoring of combination opioid, benzodiazepines, and/or alcohol use.

Abstract The concurrent use of opioids, benzodiazepines (BZDs), and/or alcohol poses a formidable challenge for clinicians who manage chronic pain. While the escalating use of opioid analgesics for the treatment of chronic pain and the concomitant rise in opioid-related abuse and misuse are widely recognized trends, the contribution of combination use of BZDs, alcohol, and/or other sedative agents to opioid-related morbidity and mortality is underappreciated, even when these agents are used appropriately. Patients with chronic pain who use opioid analgesics along with BZDs and/or alcohol are at higher risk for fatal/nonfatal overdose and have more aberrant behaviors. Few practice guidelines for BZD treatment are readily available, especially when they are combined clinically with opioid analgesics and other central nervous system-depressant agents. However, coadministration of these agents produces a defined increase in rates of adverse events, overdose, and death, warranting close monitoring and consideration when treating patients with pain. To improve patient outcomes, ongoing screening for aberrant behavior, monitoring of treatment compliance, documentation of medical necessity, and the adjustment of treatment to clinical changes are essential. In this article, we review the prevalence and pharmacologic consequences of BZDs and/or alcohol use among patients with pain on chronic opioid therapy, as well as the importance of urine drug testing, an indispensable tool for therapeutic drug monitoring, which helps to ensure the continued safety of patients. Regardless of risk or known aberrant drug-related behaviors, patients on chronic opioid therapy should periodically undergo urine drug testing to confirm adherence to the treatment plan.

Consensus Recommendations on Initiating Prescription Therapies for Opioid-Induced Constipation

Abstract Objective Aims of this consensus panel were to determine (1) an optimal symptom‐based method for assessing opioid‐induced constipation in clinical practice and (2) a threshold of symptom severity to prompt consideration of prescription therapy. Methods A multidisciplinary panel of 10 experts with extensive knowledge/experience with opioid‐associated adverse events convened to discuss the literature on assessment methods used for opioid‐induced constipation and reach consensus on each objective using the nominal group technique. Results Five validated assessment tools were evaluated: the Patient Assessment of Constipation–Symptoms (PAC‐SYM), Patient Assessment of Constipation–Quality of Life (PAC‐QOL), Stool Symptom Screener (SSS), Bowel Function Index (BFI), and Bowel Function Diary (BF‐Diary). The 3‐item BFI and 4‐item SSS, both clinician administered, are the shortest tools. In published trials, the BFI and 12‐item PAC‐SYM are most commonly used. The 11‐item BF‐Diary is highly relevant in opioid‐induced constipation and was developed and validated in accordance with US Food and Drug Administration guidelines. However, the panel believes that the complex scoring for this tool and the SSS, PAC‐SYM, and 28‐item PAC‐QOL may be unfeasible for clinical practice. The BFI is psychometrically validated and responsive to changes in symptom severity; scores range from 0 to 100, with higher scores indicating greater severity and scores >28.8 points indicating constipation. Conclusions The BFI is a simple assessment tool with a validated threshold of clinically significant constipation. Prescription treatments for opioid‐induced constipation should be considered for patients who have a BFI score of ≥30 points and an inadequate response to first‐line interventions.

Opioid Therapies and Cytochrome P450 Interactions

Adverse drug reactions are common and associated with substantial economic and human costs. Particularly among older adult populations, preventable adverse drug reactions are often caused by drug-drug interactions. All analgesics have side effect profiles and many have known drug-drug interactions. Opioids are recognized as a necessary option for managing moderate-to-severe pain, yet many opioid side effects can be enhanced by metabolic interactions within the liver, involving other drugs, diseases, or genetics.

Assessment of Extended-Release Opioid Analgesics for the Treatment of Chronic Pain

ABSTRACT Approximately 3.8 million patients annually receive extended-release (ER) or long-acting opioid prescriptions in the outpatient setting, around half of which are written by primary care physicians. Compared with short-acting, immediate-release (IR) formulations, ER and oral long-acting opioid analgesics are associated with clinical advantages, such as extended periods of time during which drug plasma levels are within the therapeutic range, decreased peak-to-trough fluctuations, and prolonged analgesia over the dosing period. Additionally, ER opioids offer a more convenient, less frequent dosing regimen to chronic pain patients who are often taking several concomitant medications. The increased utilization of ER opioids has been accompanied by a rise in the misuse and abuse of these formulations. Certain pharmacokinetic parameters (e.g., longer time to maximum drug plasma concentration, lower maximum drug plasma concentration) may decrease the abuse potential of intact ER opioids by limiting the positive subjective and reinforcing effects relative to IR formulations. Putative abuse-deterrent formulations have also recently been introduced to impede physical manipulation of these formulations, or reduce the harm resulting from such behavior. Such formulations may represent an incremental advance to reduce non-oral forms of abuse. This article reviews the pharmacokinetic profiles and abuse-deterrent features of newer ER opioid analgesics for the treatment of moderate to severe chronic pain.

Risk Evaluation and Mitigation Strategies (REMS) for Extended-Release and Long-Acting Opioid Analgesics: Considerations for Palliative Care Practice

ABSTRACT Prescription opioid analgesics are an essential treatment option for patients with moderate to severe pain. Over the last decade the increased medical use of these agents has contributed to a public health epidemic of abuse, addiction, and overdose-related deaths. These medications remain mainstays in both primary care and pain management practices. As palliative services are incorporated at earlier stages of the disease process and the number of individuals with chronic illness increases, palliative care specialists may encounter an increasing number of patients with opioid abuse and addiction problems. Extended-release (ER) and long-acting (LA) opioid formulations are administered to patients with moderate to severe chronic pain requiring around-the-clock analgesia. Given the large quantity of active ingredient contained within some dosage strengths, this medication class is associated with serious risks when taken improperly. In response to growing reports of abuse and overdose deaths, the US Food and Drug Administration (FDA) announced the need for a risk mitigation strategy for the entire class of medication. The class-wide Risk Evaluation and Mitigation Strategy (REMS) for ER/LA opioids will emphasize prescriber training and patient education to ensure that the therapeutic benefits outweigh the risks of addiction, unintentional overdose, and death. As primary care, pain management, and palliative care clinicians often encounter patients who require ER/LA opioids, an understanding of the suggested requirements and potential impact of this regulation is essential.

Acute Pain: Effective Management Requires Comprehensive Assessment

Abstract Pain is among the most common reasons that patients seek medical care, and inadequate assessment may result in suboptimal management. Acute pain in response to trauma or surgery can be complex, variable, and dynamic, but its assessment is often simplistic and brief. One-dimensional rating scale measures of pain severity facilitate rapid evaluation and often form the basis of treatment algorithms. However, additional features of pain should inform the selection of a treatment regimen, and can include pain qualities, duration, impact on functional capabilities, and underlying cause. Patient age, sex, psychosocial features, and comorbid conditions are also important features to consider. Use of a multidimensional tool is recommended for assessing many of these features if time permits. Additionally, clinicians often fail to recognize or consider the potentially detrimental long-term effects of acute pain. As the United States continues to experience a prescription drug crisis, a “universal precautions” approach including abuse risk assessment and abuse deterrence strategies should be implemented for patients receiving opioids. Increased efforts and research are necessary to enhance the utility of available acute pain assessment tools. Developing more comprehensive tools for patient assessment is the first step in achieving the ultimate goal of effective acute pain management. The objectives of this review are to summarize issues regarding the complexity of acute pain and to provide suggestions for its evaluation.

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

Abstract 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.

Clinical Strategies for the Primary Health Care Professional to Minimize Prescription Opioid Abuse

Abstract Prescription opioid analgesic therapy can be effective in managing chronic noncancer pain in appropriately selected patients. However, the risks and benefits of prescription opioids should be carefully considered when treating this patient population. A dramatic increase in opioid–related morbidity and mortality has been observed in the United States in the past decade. Therefore, health care providers must balance the treatment of chronic pain with the need to minimize the risks of opioid misuse, abuse, addiction, and diversion. Current literature suggests that most patients with chronic pain are managed at the primary care level. However, many of these practitioners are not skilled in risk assessment, stratification, and monitoring. This article reviews strategies and tools that providers may implement to help identify appropriate patients for chronic opioid therapy and recognize signs of drug–related aberrant behaviors and abuse. In addition, the potential role of abuse–deterrent, extended–release opioid formulations to reduce risk in patients and nonmedical users of opioids is introduced. Collectively, these preventative measures may effectively reduce opioid misuse, abuse, and diversion without denying adequate analgesia in appropriate patients.

Opioid abuse-deterrent strategies: role of clinicians in acute pain management

Abstract Opioid abuse is a healthcare and societal problem that burdens individuals, their families and the healthcare professionals who care for them. Restricting access to opioid analgesics is one option to deter abuse, but this may prevent pain patients in need from obtaining effective analgesics. Therefore, strategies that mitigate the risk of opioid abuse while maintaining access are being pursued by several stakeholders including federal agencies, state governments, payors, researchers, the pharmaceutical industry and clinicians. Federal agency efforts have included required licensure and documentation for prescribing opioids, implementation of risk evaluation and mitigation strategies, and guidance on assessment and labeling of opioid abuse-deterrent formulations. In addition, state governments and payors have enacted monitoring programs, and pharmaceutical companies continue to develop abuse-deterrent opioid formulations. Strategies for clinicians to mitigate opioid abuse include comprehensive patient assessment and universal precautions (e.g. use of multimodal analgesia and abuse-deterrent opioid formulations, urine toxicology screening, participation in prescription drug monitoring and risk evaluation and mitigation strategy programs).

Development of Federally Mandated Risk Evaluation and Mitigation Strategies (REMS) for Transmucosal Immediate-Release Fentanyl Products

The potential adverse health consequences of prescription opioid analgesics are well documented and include abuse, addiction, and death due to overdose.1–3 In 2007, the US Congress passed the Food and Drug Administration Amendments Act (FDAAA), which authorized the Food and Drug Administration (FDA) to require that drug manufacturers implement a Risk Evaluation and Mitigation Strategy (REMS) for pharmaceuticals with known or suspected risks of abuse and overdose, although REMS were not required for short-acting opioids (eg, combination oxycodone/acetaminophen).4–7 FDAAA required that the REMS for each drug be designed with the purpose of evaluating and mitigating the risks of adverse events. This editorial briefly describes the development of a shared REMS for transmucosal immediate-release fentanyl (TIRF) products from individual REMS (with examples from a previous, separate program for sublingual TIRF tablets [Abstral®]), implementation of the shared REMS, and remaining challenges. The goals of the TIRF REMS, which is required by the FDA, are to ensure patient access to important medications and to “mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors.” In 2009, the FDA released a draft “Guidance for Industry” describing the requirements for how a REMS should attempt to achieve these goals.9 Although problems with opioid analgesics range from accidental medical misuse (eg, through treatment noncompliance) to intentional illegal use, the new REMS policies for opioids focus primarily on safe and appropriate medical use. The FDAAA and the 2009 Guidance recommended “Elements to Assure Safe Use” (ETASU); this document refers to a variety of methods to promote safe medication access. However, a REMS program that imposes undue restrictions on appropriate opioid treatment could negatively affect the adequate care of all patients who may need these medications.10 The law therefore also obligates the FDA to ensure, via periodic evaluations, that REMS requirements do not limit medication access or create an undue burden on the healthcare system. A separate REMS for sublingual TIRF tablets, which received final approval from the US FDA in January 2011, served as one model for the shared REMS that has now been implemented for all TIRF products. These sublingual fentanyl tablets are a Schedule II controlled substance with an abuse liability similar to that of other legal or illicit opioid agonists.12 They are approved only for the management of breakthrough pain in patients, 18 years of age and older, who are already receiving and are tolerant to opioid therapy for underlying persistent cancer pain. The stated goals of the REMS for the sublingual TIRF tablets, identical to those of the current shared TIRF REMS Access program (hereafter referred to as TIRF REMS), were to “mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors.” As with the shared TIRF REMS, the goals of the sublingual TIRF tablets REMS were to be achieved by the following actions: Prescribing and dispensing only to appropriate patients, which includes use only in patients with cancer who are opioid tolerant. Preventing inappropriate conversion between fentanyl products. Preventing accidental exposure to children and others for whom it was not prescribed (ie, reducing the incidence of adverse events associated with accidental exposures and use by nontolerant individuals). Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose. Although an ETASU plan can suggest various methods to address these issues, the available strategies are open to some criticism. For example, a REMS program may limit opioid distribution to certain healthcare settings, specially certified registrant pharmacies, or patients listed in a registry.14 However, although opioid-associated misuse, abuse, addiction, and mortality have increased contemporaneously with prescribing, the exact relationship between medical and nonmedical prescription opioid use remains unclear.15 Training can be required, but there is limited evidence for the efficacy of educational efforts. The components of the TIRF REMS that attempt to modify illegal behavior by patients represent an extension of FDA authority that has not been seen previously. The complexity of nonmedical use of prescription opioids, coupled with the unproven and unknown effects of a REMS, have led to skepticism that there is sufficient understanding of how to develop an effective and safe REMS.5 Although the FDA is mandating these mitigation strategies now in an attempt to reduce adverse events related to the use of prescription opioids, close attention to their intended and unintended consequences is warranted in the future.