Since the initial reports of an emerging opioid epidemic in the early 2000s, intense focus on improving opioid prescribing in outpatient settings has culminated in new guidelines for chronic pain.^1,2 Although opioid stewardship in the setting of chronic pain is of paramount importance in curbing the ongoing epidemic, long-term prescription opioid use often begins with treatment of acute pain.¹ In addition to differences in recommended management strategies for acute and chronic pain, there are unique aspects and challenges to pain management in the acute-care setting.

Opioids are commonly used for the treatment of acute pain in hospitalized patients, often at high doses.³ Recent reports highlight that hospital use of opioids impacts downstream use.^4-6 Additionally, opioid prescribing practices vary between hospital-based providers and hospitals,^3,7 highlighting the need for prescribing standards and guidance. To our knowledge, there are no existing guidelines for improving the safety of opioid use in hospitalized patients outside of the intensive care or immediate perioperative settings.

The Society of Hospital Medicine (SHM) convened a working group to systematically review existing guidelines and develop a consensus statement to assist clinicians in safe opioid use for acute, noncancer pain in hospitalized adults.

Consensus Statement Purpose and Scope

The purpose of this Consensus Statement is to present clinical recommendations on the safe use of opioids for the treatment of acute, noncancer pain in hospitalized adults. The guidance is intended for clinicians practicing medicine in the inpatient setting (eg, hospitalists, primary care physicians, family physicians, nurse practitioners, and physician assistants) and is intended to apply to hospitalized adults with acute, noncancer pain (ie, pain that typically lasts <3 months or during the period of normal tissue healing) outside of the palliative, end-of-life, and intensive care settings.

Consensus Statement Development

Our working group included experts in opioid use in the hospital setting, defined by 1) engagement in the clinical practice of hospital medicine and 2) involvement in clinical research related to usage patterns and clinical outcomes of opioid use in hospitalized patients (see Appendix Table 1). The SHM provided administrative assistance with the project and funded the in-person working group meeting, but it had no role in formulating the recommendations. The SHM Board of Directors provided approval of the Consensus Statement without modification.

An overview of the sequential steps in the Consensus Statement development process is described below; details of the methods and results can be found in the Appendix (eMethods).

Performing the Systematic Review

Drafting the Consensus Statement

After performing the systematic review, the working group drafted and iteratively revised a set of recommendations using a variation of the Delphi Method⁸ to identify consensus among group members.

External Review

Following agreement on a draft set of recommendations, we obtained feedback from external groups, including 1) individuals involved in the SHM’s Reducing Adverse Drug Events Related to Opioids (RADEO) initiative, including those involved in the development of the implementation guide and site leads for the Mentored Implementation program, 2) SHM members, SHM Patient-Family Advisory Council (PFAC) members, and leaders of other relevant professional societies, and 3) peer-reviewers at the Journal of Hospital Medicine.

Deciding Whether to Use Opioids During Hospitalization

1. SHM recommends that clinicians limit the use of opioids to patients with 1) severe pain or 2) moderate pain that has not responded to nonopioid therapy, or where nonopioid therapy is contraindicated or anticipated to be ineffective.

Opioids are associated with several well-recognized risks ranging from mild to severe, including nausea, constipation, urinary retention, falls, delirium, sedation, physical dependence, addiction, respiratory depression, and death. Given these risks, the risk-to-benefit ratio is generally not favorable at lower levels of pain severity. Furthermore, for most painful conditions, including those causing severe pain, nonopioid analgesics, including acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), have been demonstrated to be equally or more effective with less risk of harm than opioids.^9-13 Clinicians should consider drug–drug and drug–disease associations when deciding between these different therapies and make a determination in each patient regarding whether the benefits outweigh the risks. Often, drug–disease interactions do not represent absolute contraindications, and risks can be mitigated by adhering to dosage limits and, with respect to NSAIDs, 1) monitoring renal function, 2) monitoring volume status in patients with congestive heart failure, and 3) considering a selective cyclooxygenase-2 (COX-2) inhibitor rather than a nonselective NSAID or pairing the NSAID with an acid-suppressive medication in patients with a history of peptic ulcer disease or at elevated risk for gastroduodenal disease. For these reasons, a trial of nonopioid therapy (including pharmacologic and nonpharmacologic modalities) should always be considered before using opioids for pain of any severity. This does not imply that a trial of nonopioid therapy must be performed in all patients, but rather, that the likelihood of benefit and associated risks of opioid and nonopioid therapy should be considered for all patients in determining the best initial management strategy.

2. SHM recommends that clinicians use extra caution when administering opioids to patients with risk factors for opioid-related adverse events.

Several factors have been consistently demonstrated to increase the risk of opioid-related adverse events–most importantly, respiratory depression and overdose–in varied patient populations and settings, including age 65 years and older,^1,14-17 renal insufficiency,^1,14,18 hepatic insufficiency,^1,14 chronic respiratory failure (including chronic obstructive pulmonary disease, sleep apnea, etc.), and receipt of other central nervous system (CNS) depressant medications (including, but not limited to, benzodiazepines).^1,18-20 History of any substance use disorder and psychiatric disorders have been associated with an increased risk for the development of opioid use disorder.^21-24 These factors should be weighed against the benefits when deciding on opioid appropriateness in a given patient. However, identification of these risks should not preclude opioids as part of pain management. When a decision is made to use opioids in patients with these risk factors, clinicians should 1) use a reduced starting dose (generally, at least a 50% reduction in the usual starting dose) and 2) consider closer monitoring for adverse effects (eg, more frequent nursing assessments, capnography, or more frequent outpatient visits).

3. SHM recommends that clinicians review the information contained in the prescription drug monitoring program (PDMP) database to inform decision-making around opioid therapy.

Although data on the impact of use of the state PDMP database on prescribing practices or patient outcomes are limited, PDMP use has been advocated by multiple guidelines on acute pain management.^25-27 The PDMP provides information that can be useful in several ways, including 1) confirmation of prior opioid exposure and dosage, which should be used to guide appropriate dosage selection in the hospital, 2) identification of existing controlled substance prescriptions, which should be considered in prescribing decisions in the hospital and on discharge, and 3) identification of signs of aberrant behavior. For example, the identification of controlled substance prescriptions written by multiple different clinicians can facilitate early identification of potential diversion or evolving or existing opioid use disorder and the opportunity for intervention,²⁸ which may include referral to support services, initiation of medication-assisted treatment, and/or pain specialist consultation when available. Concerns regarding evolving or existing opioid use disorder should prompt further discussion between the clinician and the patient, both to clarify their understanding of their recent prescription history and to discuss concerns for patient safety related to the increased risk of opioid-related adverse effects (including respiratory depression and overdose) among patients with controlled substance prescriptions written by multiple providers. Although such concerns should not automatically preclude the use of opioids for acute pain in the hospital setting, they should be considered in the assessment of whether the benefits of opioid therapy outweigh the risks for a given patient.

4. SHM recommends that clinicians educate patients and families or caregivers about the potential risks and side effects of opioid therapy as well as alternative pharmacologic and nonpharmacologic therapies for managing pain.

Patients are often unaware of the risks of opioid therapy (see Consensus Statement 1 for key risks),²⁹ or that there are often equally effective alternative therapies. As with any therapy associated with substantial risk, clinicians should discuss these risks with patients and/or caregivers at the outset of therapy, as well as the potential benefits of nonopioid pharmacologic and nonpharmacologic therapies for managing pain. Patients should be informed that they may request nonopioid therapy in lieu of opioids, even for severe pain.

Once a Decision Has Been Made to Use Opioids During Hospitalization

5. SHM recommends that clinicians use the lowest effective opioid dose for the shortest duration possible.

Higher opioid doses are associated with an increased incidence of opioid-related adverse events, particularly overdose, in studies of both inpatient and outpatient populations.^{1,17,19,30,31} Studies in the inpatient and outpatient settings consistently demonstrate that risk increases with dosage.^19,30,31 Clinicians should reduce the usual starting dose by at least 50% among patients with conditions that increase susceptibility to opioid-related adverse events (see Consensus Statement 2). The ongoing need for opioids should be re-assessed regularly-at least daily-during the hospitalization, with attempts at tapering as healing occurs and/or pain and function improve.

6. SHM recommends that clinicians use immediate-release opioid formulations and avoid initiation of long-acting or extended-release formulations (including transdermal fentanyl) for treatment of acute pain.

Studies in outpatient settings demonstrate that the use of long-acting opioids is associated with greater risk for overdose–especially in opioid-naïve patients–and long-term use.^32,33 Further, hospitalized patients frequently have fluctuating renal function and rapidly changing pain levels. We therefore recommend that initiation of long-acting opioids be avoided for the treatment of acute, noncancer pain in hospitalized medical patients. It is important to note that although we recommend avoiding initiation of long-acting opioids for the treatment of acute, noncancer pain, there are circumstances outside of the scope of this Consensus Statement for which initiation of long-acting opioids may be indicated, including the treatment of opioid withdrawal. We also do not recommend discontinuation of long-acting or extended-release opioids in patients who are taking these medications for chronic pain at the time of hospital admission (unless there are concerns regarding adverse effects or drug–disease interactions).

7. SHM recommends that clinicians use the oral route of administration whenever possible. Intravenous opioids should be reserved for patients who cannot take food or medications by mouth, patients suspected of gastrointestinal malabsorption, or when immediate pain control and/or rapid dose titration is necessary.

Intravenous opioid administration is associated with an increased risk of side effects, adverse events, and medication errors.^34-36 Additionally, studies demonstrate that in general, the addiction potential of medications is greater the more rapid the onset of action (the onset of action is 5–10 min for intravenous and 15–30 minutes for oral administration).^37,38 Furthermore, the duration of action is greater for oral compared to that of intravenous administration, potentially allowing for more consistent pain relief and less frequent administrations. As such, intravenous administration should be reserved for situations when oral administration is not possible or likely to be ineffective, or when immediate pain control and/or rapid titration is necessary.

8. SHM recommends that clinicians use an opioid equivalency table or calculator to understand the relative potency of different opioids 1) when initiating opioid therapy, 2) when changing from one route of administration to another, and 3) when changing from one opioid to another. When changing from one opioid to another, clinicians should generally reduce the dose of the new opioid by at least 25%–50% of the calculated equianalgesic dose to account for interindividual variability in the response to opioids as well as possible incomplete cross-tolerance.

Most errors causing preventable adverse drug events in hospitals occur at the ordering stage.^39,40 Clinicians are often unaware of the potency of different types of opioids relative to each other or to morphine (ie, morphine equivalent dose), which can lead to inadvertent overdose when initiating therapy with nonmorphine opioids and when converting from one opioid to another. To facilitate safe opioid use, we recommend that clinicians use one of several available opioid equivalency tables or calculators to better understand the relative potencies of opioids and to inform both starting dose calculations and conversions between opioids and routes of administration. When converting from one opioid to another, we caution clinicians to reduce the dose of the new opioid by at least 25%–50% of the calculated equianalgesic dose to account for interindividual variability in the response to opioids and the potential for incomplete cross-tolerance, wherein tolerance to a currently administered opioid does not extend completely to other opioids. Clinicians should use extreme caution when performing conversions to and from methadone and consider consultation with a hospital pharmacist or a pain management specialist, when available, to assist with conversion decisions and calculations.

9. SHM recommends that clinicians pair opioids with scheduled nonopioid analgesic medications, unless contraindicated, and always consider pairing with nonpharmacologic pain management strategies (ie, multimodal analgesia).

Concurrent receipt of opioids and nonopioid analgesic medications (including acetaminophen, NSAIDs, and gabapentin or pregabalin, depending on the underlying pathophysiology of the pain) has been demonstrated to reduce total opioid requirements and improve pain management.^41,42 Clinicians should be familiar with contraindications and maximum dosage recommendations for each of these adjunctive nonopioid medications. We recommend separate orders for each, rather than using drug formulations that combine opioids and nonopioid analgesics in the same pill, due to the risk of inadvertently exceeding the maximum recommended doses of the nonopioid analgesic (particularly acetaminophen) with combination products. We recommend that nonopioid analgesics be ordered at a scheduled frequency, rather than as needed, to facilitate consistent administration that is not dependent on opioid administration. Topical agents, including lidocaine and capsaicin, should also be considered. Nonpharmacologic pain management strategies can include procedure-based (eg, regional and local anesthesia) and nonprocedure-based therapies depending on the underlying condition and institutional availability. Although few studies have assessed the benefit of nonpharmacologic, nonprocedure-based therapies for the treatment of acute pain in hospitalized patients, the lack of harm associated with their use argues for their adoption. Simple nonpharmacologic therapies that can usually be provided to patients in any hospital setting include music therapy, cold or hot packs, chaplain or social work visits (possibly including mindfulness training),⁴³ and physical therapy, among others.

10. SHM recommends that, unless contraindicated, clinicians order a bowel regimen to prevent opioid-induced constipation in patients receiving opioids.

Constipation is a common adverse effect of opioid therapy and results from the activation of mu opioid receptors in the colon, resulting in decreased peristalsis. Hospitalized patients are already prone to constipation due to their often-limited physical mobility. To mitigate this complication, we recommend the administration of a bowel regimen to all hospitalized medical patients receiving opioid therapy, provided the patient is not having diarrhea. Given the mechanism of opioid-induced constipation, stimulant laxatives (eg, senna, bisacodyl) have been recommended for this purpose.⁴⁴ Osmotic laxatives (eg, polyethylene glycol, lactulose) have demonstrated efficacy for the treatment of constipation more generally (ie, not necessarily opioid-induced constipation). Stool softeners, although frequently used in the inpatient setting, are not recommended due to limited and conflicting evidence for efficacy in prevention or treatment of constipation.⁴⁵ Bowel movements should be tracked during hospitalization, and the bowel regimen modified accordingly.

11. SHM recommends that clinicians limit co-administration of opioids with other central nervous system depressant medications to the extent possible.

This combination has been demonstrated to increase the risk of opioid-related adverse events in multiple settings of care, including during hospitalization.^1,18,19 Although benzodiazepines have received the most attention in this respect, other medications with CNS depressant properties may also increase the risk, including, but not limited to, nonbenzodiazepine sedative-hypnotics (eg, zolpidem, zaleplon, zopiclone), muscle relaxants, sedating antidepressants, antipsychotics, and antihistamines.^18,19,46 For some patients, the combination will be unavoidable, and we do not suggest routine discontinuation of longstanding medications that preexisted hospitalization, given the risks of withdrawal and/or worsening of the underlying condition for which these medications are prescribed. Rather, clinicians should carefully consider the necessity of each medication class with input from the patient’s outpatient providers, taper the frequency and/or the dose of CNS depressants when appropriate and feasible, and avoid new coprescriptions to the extent possible, both during hospitalization and on hospital discharge.

12. SHM recommends that clinicians work with patients and families or caregivers to establish realistic goals and expectations of opioid therapy and the expected course of recovery.

Discussing expectations at the start of therapy is important to facilitate a clear understanding of how meaningful improvement will be defined and measured during the hospitalization and how long the patient is anticipated to require opioid therapy. Meaningful improvement should be defined to include improvement in both pain and function. Clinicians should discuss with patients 1) that the goal of opioid therapy is tolerability of pain such that meaningful improvement in function can be achieved and 2) that a decrease in pain intensity in the absence of improved function is not considered meaningful improvement in most situations and should prompt reevaluation of the appropriateness of continued opioid therapy as well as close follow-up with a clinician following hospital discharge. Discussions regarding the expected course of recovery should include that acute pain is expected to resolve as the underlying medical condition improves and that although pain may persist beyond the hospitalization, pain that is severe enough to require opioids will often be resolved or almost resolved by the time of hospital discharge.

13. SHM recommends that clinicians monitor the response to opioid therapy, including assessment for functional improvement and development of adverse effects.

Pain severity and function should be assessed at least daily, and improvement in reported pain severity without improvement in function over several days should, in most circumstances, prompt reconsideration of ongoing opioid therapy and reconsideration of the underlying etiology of pain. Although hospital-specific functional measures in the setting of acute pain have not yet been validated, we suggest that such measures and goals should be individualized based on preexisting function and may include the ability to sit up or move in bed, move to a chair, work with physical therapy, or ambulate in the hallway. Protocols for the assessment for adverse effects are not well established. Because sedation typically precedes respiratory depression, it is generally recommended that patients are evaluated (eg, by nursing staff) for sedation after each opioid administration (10–20 minutes for intravenous and 30–60 minutes for oral administration based on the time-to-peak effect). Whether certain patients may benefit from more intensive respiratory monitoring, such as pulse oximetry or capnography, is an area of active investigation and not yet established.

Prescribing at the Time of Hospital Discharge

14. SHM recommends that clinicians ask patients about any existing opioid supply at home and account for any such supply when issuing an opioid prescription on discharge.

Even in the setting of acute pain, patients may have previously received an opioid prescription from an outpatient clinician prior to hospitalization. Unused prescription opioids create the possibility of both overdose (when patients take multiple opioids concurrently, intentionally or inadvertently) and diversion (many adults with prescription opioid misuse obtained their opioids from a friend or a relative who may or may not have known that this occurred⁴⁷). The PDMP database can provide information related to the potential existence of any prior opioid supplies, which should be confirmed with the patient and considered when providing a new prescription on hospital discharge. Information on proper disposal should be provided if use of the preexisting opioid is no longer intended.

15. SHM recommends that clinicians prescribe the minimum quantity of opioids anticipated to be necessary based on the expected course and duration of pain that is severe enough to require opioid therapy after hospital discharge.

For many patients, the condition causing their acute pain will be mostly or completely resolved by the time of hospital discharge. When pain is still present at the time of discharge, most pain can be completely managed with nonopioid therapies. For those with ongoing pain that is severe enough to require opioids after hospital discharge, decisions regarding the duration of therapy should be made on a case-by-case basis; generally, however, provision of a 3- to 5-day supply will be sufficient, and provision of more than a 7-day supply of opioids should generally be avoided for several reasons. These include 1) acute pain lasting longer than 7 days after appropriate treatment of any existing underlying conditions should prompt re-evaluation of the working diagnosis and/or reconsideration of the management approach, 2) receiving higher intensity opioid therapy (including longer courses) in the setting of acute pain has been associated with an increased risk of long-term disability and long-term opioid use,^33,48,49 and 3) unused opioids create the possibility of intentional or unintentional opioid diversion (see Consensus Statement 14).⁴⁷ Accordingly, clinicians should attempt to arrange an outpatient follow-up appointment for re-evaluation within 7 days, rather than providing an extended opioid prescription on hospital discharge. In situations where this is not feasible, and pain that is severe enough to require opioids is expected to persist longer than 7 days, an extended prescription may be indicated. However, some states have begun enacting legislation to limit the duration of first-time opioid prescriptions, typically using a 5-to-7 day supply as an upper limit; clinicians should be aware of and adhere to individual state laws governing their practice.

16. SHM recommends that clinicians ensure that patients and families or caregivers receive information regarding how to minimize the risks of opioid therapy for themselves, their families, and their communities. This includes but is not limited to 1) how to take their opioids correctly (the planned medications, doses, schedule); 2) that they should take the minimum quantity necessary to achieve tolerable levels of pain and meaningful functional improvement, reducing the dose and/or frequency as pain and function improve; 3) how to safeguard their supply and dispose of any unused supply; 4) that they should avoid agents that may potentiate the sedative effect of opioids, including sleeping medication and alcohol; 5) that they should avoid driving or operating heavy machinery while taking opioids; and 6) that they should seek help if they begin to experience any potential adverse effects, with inclusion of information on early warning signs.

Clear and concise patient instructions on home opioid dosing and administration will limit opioid-related adverse events and dosing errors upon hospital discharge. Each of these recommendations derive from one or more of the existing guidelines and reflect the transfer of responsibility for safe opioid use practices that occurs as patients transition from a closely monitored inpatient setting to the more self-regulated home environment.

This Consensus Statement reflects a synthesis of the key recommendations from a systematic review of existing guidelines on acute pain management, adapted for a hospital-specific scope of practice. Despite a paucity of data on the comparative effectiveness of different management strategies for acute pain, several areas of expert consensus emerged across existing guidelines, which were felt to be relevant and applicable to the hospital setting. The objective of these recommendations is to provide information that can be used to inform and support opioid-related management decisions for acute pain by clinicians practicing medicine in the inpatient setting.

Although these recommendations are not intended to apply to the immediate perioperative setting (ie, care in the postanesthesia care unit), many of the recommendations in the existing guidelines upon which this Consensus Statement was based were intended for the postoperative setting, and, as others have noted, recommendations in this setting are mostly comparable to those for treating acute pain more generally.²⁷ Those interested in pain management in the postoperative setting specifically may wish to review the recent guidelines released by the American Pain Society,⁵⁰ the content of which is in close alignment with our Consensus Statement.

Several important issues were raised during the extensive external feedback process undertaken as part of the development of this Consensus Statement. Although many issues were incorporated into the recommendations, there were several suggestions for which we felt the evidence base was not sufficient to allow a clear or valid recommendation to be made. For example, several reviewers requested endorsement of specific patient education tools and opioid equivalency calculators. In the absence of tools specifically validated for this purpose, we felt that the evidence was insufficient to make specific recommendations. Validating such tools for use in the inpatient setting should be an area of future investigation. In the meantime, we note that there are several existing and widely available resources for both patient education (ie, opioid information sheets, including opioid risks, safe containment and disposal, and safe use practices) and opioid equivalency calculations that clinicians and hospitals can adapt for their purposes.

Several individuals suggested recommendations on communication with outpatient continuity providers around opioid management decisions during hospitalization and on discharge. Although we believe that it is of paramount importance for outpatient providers to be aware of and have input into these decisions, the optimal timing and the method for such communication are unclear and likely to be institution-specific depending on the availability and integration of electronic records across care settings. We recommend that clinicians use their judgment as to the best format and timing for assuring that outpatient physicians are aware of and have input into these important management decisions with downstream consequences.

Concerns were also raised about the time required to complete the recommended practices and the importance of emphasizing the need for a team-based approach in this realm. We agree wholeheartedly with this sentiment and believe that many of the recommended practices can and should be automated and/or shared across the care team. For example, PDMPs allow prescribers to appoint delegates to check the PDMP on their behalf. Additionally, we suggest that hospitals work to develop systems to assist care teams with performance of these tasks in a standardized and streamlined manner (eg, integrating access to the PDMP and opioid equivalency tables within the electronic health record and developing standard patient educational handouts). Provision of written materials on opioid risks, side effects, and safety practices may be helpful in facilitating consistent messaging and efficient workflow for members of the care team.

Finally, the working group carefully considered whether to include a recommendation regarding naloxone prescribing at the time of hospital discharge. The provision of naloxone kits to laypersons through Overdose Education and Naloxone Distribution Programs has been shown to reduce opioid overdose deaths^51,52 and hospitalizations^53,54 and is both safe and cost-effective.⁵⁵ The Centers for Disease Control and Preventionrecommend that clinicians “consider offering naloxone to patients with a history of overdose, a current or past substance use disorder, receipt of ≥50 mg of morphine equivalents per day or concurrent benzodiazepine use.”¹ However, these recommendations are intended for patients on chronic opioid therapy; presently, no clear evidence exists to guide decisions about the benefits and costs associated with prescribing naloxone in the setting of short-term opioid therapy for acute pain. Further research in this area is warranted.

The greatest limitation of this Consensus Statement is the lack of high-quality studies informing most of the recommendations in the guidelines upon which our Consensus Statement was based. The majority of recommendations in the existing guidelines were based on expert opinion alone. Additional research is necessary before evidence-based recommendations can be formulated.

Accordingly, the working group identified several key areas for future research, in addition to those noted above. First, ongoing efforts to develop and evaluate the effectiveness of nonopioid and nonpharmacologic management strategies for acute pain in hospitalized patients are necessary. Second, studies identifying the risk factors for opioid-related adverse events in hospitalized patients would help inform management decisions and allow deployment of resources and specialized monitoring strategies to patients at heightened risk. The working group also noted the need for research investigating the impact of PDMP use on management decisions and downstream outcomes among hospitalized patients. Finally, conversations around pain management and concerns related to aberrant behaviors are often challenging in the hospital setting owing to the brief, high-intensity nature of the care and the lack of a longstanding therapeutic alliance. There is a great need to develop strategies and language to facilitate these conversations.

In conclusion, until more high-quality evidence becomes available, clinicians can use the recommendations contained in this Consensus Statement along with their clinical judgment and consultation with pharmacists, interventional pain specialists, and other staff (eg, social work, nursing) to help facilitate consistent, high-quality care across providers and hospitals. We believe that doing so will help increase the appropriateness of opioid therapy, minimize adverse events, facilitate shared decision-making, and foster stronger therapeutic alliances at the outset of the hospitalization for patients suffering from acute pain.

The authors would like to acknowledge and thank Kevin Vuernick, Jenna Goldstein, Meghan Mallouk, and Chris Frost, MD, from the SHM for their facilitation of this project and dedication to this purpose.

The authors would also like to thank the many individuals who provided comments on the draft recommendations, including the participants in the SHM RADEO program; the SHM members; the representatives of specialty societies, including the American Academy of Family Physicians, the American College of Physicians, the American Hospital Association, the American Society of Addiction Medicine, the American Society of Anesthesiologists, the American Society of Health-System Pharmacists, the Society of Critical Care Medicine, and the Society of General Internal Medicine; and the representatives of patient advocacy groups, including SHM PFAC, Regions Hospital Patient and Family Advisory Committee, Patient and Family Centered Care Council of St. Louis Children’s Hospital, Missouri Family Partnership, and Parent and Family Care.

Disclosures: Dr. Herzig reports receiving compensation from the Society of Hospital Medicine for her editorial role at the Journal of Hospital Medicine (unrelated to the present work). Dr. Jena reports receiving consulting fees from Pfizer, Inc., Hill Rom Services, Inc., Bristol Myers Squibb, Novartis Pharmaceuticals, Vertex Pharmaceuticals, and Precision Health Economics, a consultancy to the life sciences industry (all unrelated to the present work). None of the other authors have any conflicts of interest to disclose.

Funding: The Society of Hospital Medicine (SHM) provided administrative assistance with the project and funded the in-person working group meeting but had no role in or influence on developing the content of the recommendations themselves. The SHM Board of Directors provided approval to submit the manuscript for publication without modification. Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging. Dr. Mosher was supported in part by the Department of Veterans Affairs Office of Academic Affiliations and Office of Research and Development and Health Services Research and Development Service (HSR&D) through the Comprehensive Access and Delivery Research and Evaluation Center (CIN 13-412). None of the funding agencies had involvement in any aspect of the study, including design, conduct, and reporting of the study

Since the initial reports of an emerging opioid epidemic in the early 2000s, intense focus on improving opioid prescribing in outpatient settings has culminated in new guidelines for chronic pain.^1,2 Although opioid stewardship in the setting of chronic pain is of paramount importance in curbing the ongoing epidemic, long-term prescription opioid use often begins with treatment of acute pain.¹ In addition to differences in recommended management strategies for acute and chronic pain, there are unique aspects and challenges to pain management in the acute-care setting.

Opioids are commonly used for the treatment of acute pain in hospitalized patients, often at high doses.³ Recent reports highlight that hospital use of opioids impacts downstream use.^4-6 Additionally, opioid prescribing practices vary between hospital-based providers and hospitals,^3,7 highlighting the need for prescribing standards and guidance. To our knowledge, there are no existing guidelines for improving the safety of opioid use in hospitalized patients outside of the intensive care or immediate perioperative settings.

The Society of Hospital Medicine (SHM) convened a working group to systematically review existing guidelines and develop a consensus statement to assist clinicians in safe opioid use for acute, noncancer pain in hospitalized adults.

Consensus Statement Purpose and Scope

The purpose of this Consensus Statement is to present clinical recommendations on the safe use of opioids for the treatment of acute, noncancer pain in hospitalized adults. The guidance is intended for clinicians practicing medicine in the inpatient setting (eg, hospitalists, primary care physicians, family physicians, nurse practitioners, and physician assistants) and is intended to apply to hospitalized adults with acute, noncancer pain (ie, pain that typically lasts <3 months or during the period of normal tissue healing) outside of the palliative, end-of-life, and intensive care settings.

Consensus Statement Development

Our working group included experts in opioid use in the hospital setting, defined by 1) engagement in the clinical practice of hospital medicine and 2) involvement in clinical research related to usage patterns and clinical outcomes of opioid use in hospitalized patients (see Appendix Table 1). The SHM provided administrative assistance with the project and funded the in-person working group meeting, but it had no role in formulating the recommendations. The SHM Board of Directors provided approval of the Consensus Statement without modification.

An overview of the sequential steps in the Consensus Statement development process is described below; details of the methods and results can be found in the Appendix (eMethods).

Performing the Systematic Review

Drafting the Consensus Statement

After performing the systematic review, the working group drafted and iteratively revised a set of recommendations using a variation of the Delphi Method⁸ to identify consensus among group members.

External Review

Following agreement on a draft set of recommendations, we obtained feedback from external groups, including 1) individuals involved in the SHM’s Reducing Adverse Drug Events Related to Opioids (RADEO) initiative, including those involved in the development of the implementation guide and site leads for the Mentored Implementation program, 2) SHM members, SHM Patient-Family Advisory Council (PFAC) members, and leaders of other relevant professional societies, and 3) peer-reviewers at the Journal of Hospital Medicine.

Deciding Whether to Use Opioids During Hospitalization

1. SHM recommends that clinicians limit the use of opioids to patients with 1) severe pain or 2) moderate pain that has not responded to nonopioid therapy, or where nonopioid therapy is contraindicated or anticipated to be ineffective.

Opioids are associated with several well-recognized risks ranging from mild to severe, including nausea, constipation, urinary retention, falls, delirium, sedation, physical dependence, addiction, respiratory depression, and death. Given these risks, the risk-to-benefit ratio is generally not favorable at lower levels of pain severity. Furthermore, for most painful conditions, including those causing severe pain, nonopioid analgesics, including acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), have been demonstrated to be equally or more effective with less risk of harm than opioids.^9-13 Clinicians should consider drug–drug and drug–disease associations when deciding between these different therapies and make a determination in each patient regarding whether the benefits outweigh the risks. Often, drug–disease interactions do not represent absolute contraindications, and risks can be mitigated by adhering to dosage limits and, with respect to NSAIDs, 1) monitoring renal function, 2) monitoring volume status in patients with congestive heart failure, and 3) considering a selective cyclooxygenase-2 (COX-2) inhibitor rather than a nonselective NSAID or pairing the NSAID with an acid-suppressive medication in patients with a history of peptic ulcer disease or at elevated risk for gastroduodenal disease. For these reasons, a trial of nonopioid therapy (including pharmacologic and nonpharmacologic modalities) should always be considered before using opioids for pain of any severity. This does not imply that a trial of nonopioid therapy must be performed in all patients, but rather, that the likelihood of benefit and associated risks of opioid and nonopioid therapy should be considered for all patients in determining the best initial management strategy.

2. SHM recommends that clinicians use extra caution when administering opioids to patients with risk factors for opioid-related adverse events.

Several factors have been consistently demonstrated to increase the risk of opioid-related adverse events–most importantly, respiratory depression and overdose–in varied patient populations and settings, including age 65 years and older,^1,14-17 renal insufficiency,^1,14,18 hepatic insufficiency,^1,14 chronic respiratory failure (including chronic obstructive pulmonary disease, sleep apnea, etc.), and receipt of other central nervous system (CNS) depressant medications (including, but not limited to, benzodiazepines).^1,18-20 History of any substance use disorder and psychiatric disorders have been associated with an increased risk for the development of opioid use disorder.^21-24 These factors should be weighed against the benefits when deciding on opioid appropriateness in a given patient. However, identification of these risks should not preclude opioids as part of pain management. When a decision is made to use opioids in patients with these risk factors, clinicians should 1) use a reduced starting dose (generally, at least a 50% reduction in the usual starting dose) and 2) consider closer monitoring for adverse effects (eg, more frequent nursing assessments, capnography, or more frequent outpatient visits).

3. SHM recommends that clinicians review the information contained in the prescription drug monitoring program (PDMP) database to inform decision-making around opioid therapy.

Although data on the impact of use of the state PDMP database on prescribing practices or patient outcomes are limited, PDMP use has been advocated by multiple guidelines on acute pain management.^25-27 The PDMP provides information that can be useful in several ways, including 1) confirmation of prior opioid exposure and dosage, which should be used to guide appropriate dosage selection in the hospital, 2) identification of existing controlled substance prescriptions, which should be considered in prescribing decisions in the hospital and on discharge, and 3) identification of signs of aberrant behavior. For example, the identification of controlled substance prescriptions written by multiple different clinicians can facilitate early identification of potential diversion or evolving or existing opioid use disorder and the opportunity for intervention,²⁸ which may include referral to support services, initiation of medication-assisted treatment, and/or pain specialist consultation when available. Concerns regarding evolving or existing opioid use disorder should prompt further discussion between the clinician and the patient, both to clarify their understanding of their recent prescription history and to discuss concerns for patient safety related to the increased risk of opioid-related adverse effects (including respiratory depression and overdose) among patients with controlled substance prescriptions written by multiple providers. Although such concerns should not automatically preclude the use of opioids for acute pain in the hospital setting, they should be considered in the assessment of whether the benefits of opioid therapy outweigh the risks for a given patient.

4. SHM recommends that clinicians educate patients and families or caregivers about the potential risks and side effects of opioid therapy as well as alternative pharmacologic and nonpharmacologic therapies for managing pain.

Patients are often unaware of the risks of opioid therapy (see Consensus Statement 1 for key risks),²⁹ or that there are often equally effective alternative therapies. As with any therapy associated with substantial risk, clinicians should discuss these risks with patients and/or caregivers at the outset of therapy, as well as the potential benefits of nonopioid pharmacologic and nonpharmacologic therapies for managing pain. Patients should be informed that they may request nonopioid therapy in lieu of opioids, even for severe pain.

Once a Decision Has Been Made to Use Opioids During Hospitalization

5. SHM recommends that clinicians use the lowest effective opioid dose for the shortest duration possible.

Higher opioid doses are associated with an increased incidence of opioid-related adverse events, particularly overdose, in studies of both inpatient and outpatient populations.^{1,17,19,30,31} Studies in the inpatient and outpatient settings consistently demonstrate that risk increases with dosage.^19,30,31 Clinicians should reduce the usual starting dose by at least 50% among patients with conditions that increase susceptibility to opioid-related adverse events (see Consensus Statement 2). The ongoing need for opioids should be re-assessed regularly-at least daily-during the hospitalization, with attempts at tapering as healing occurs and/or pain and function improve.

6. SHM recommends that clinicians use immediate-release opioid formulations and avoid initiation of long-acting or extended-release formulations (including transdermal fentanyl) for treatment of acute pain.

Studies in outpatient settings demonstrate that the use of long-acting opioids is associated with greater risk for overdose–especially in opioid-naïve patients–and long-term use.^32,33 Further, hospitalized patients frequently have fluctuating renal function and rapidly changing pain levels. We therefore recommend that initiation of long-acting opioids be avoided for the treatment of acute, noncancer pain in hospitalized medical patients. It is important to note that although we recommend avoiding initiation of long-acting opioids for the treatment of acute, noncancer pain, there are circumstances outside of the scope of this Consensus Statement for which initiation of long-acting opioids may be indicated, including the treatment of opioid withdrawal. We also do not recommend discontinuation of long-acting or extended-release opioids in patients who are taking these medications for chronic pain at the time of hospital admission (unless there are concerns regarding adverse effects or drug–disease interactions).

7. SHM recommends that clinicians use the oral route of administration whenever possible. Intravenous opioids should be reserved for patients who cannot take food or medications by mouth, patients suspected of gastrointestinal malabsorption, or when immediate pain control and/or rapid dose titration is necessary.

Intravenous opioid administration is associated with an increased risk of side effects, adverse events, and medication errors.^34-36 Additionally, studies demonstrate that in general, the addiction potential of medications is greater the more rapid the onset of action (the onset of action is 5–10 min for intravenous and 15–30 minutes for oral administration).^37,38 Furthermore, the duration of action is greater for oral compared to that of intravenous administration, potentially allowing for more consistent pain relief and less frequent administrations. As such, intravenous administration should be reserved for situations when oral administration is not possible or likely to be ineffective, or when immediate pain control and/or rapid titration is necessary.

8. SHM recommends that clinicians use an opioid equivalency table or calculator to understand the relative potency of different opioids 1) when initiating opioid therapy, 2) when changing from one route of administration to another, and 3) when changing from one opioid to another. When changing from one opioid to another, clinicians should generally reduce the dose of the new opioid by at least 25%–50% of the calculated equianalgesic dose to account for interindividual variability in the response to opioids as well as possible incomplete cross-tolerance.

Most errors causing preventable adverse drug events in hospitals occur at the ordering stage.^39,40 Clinicians are often unaware of the potency of different types of opioids relative to each other or to morphine (ie, morphine equivalent dose), which can lead to inadvertent overdose when initiating therapy with nonmorphine opioids and when converting from one opioid to another. To facilitate safe opioid use, we recommend that clinicians use one of several available opioid equivalency tables or calculators to better understand the relative potencies of opioids and to inform both starting dose calculations and conversions between opioids and routes of administration. When converting from one opioid to another, we caution clinicians to reduce the dose of the new opioid by at least 25%–50% of the calculated equianalgesic dose to account for interindividual variability in the response to opioids and the potential for incomplete cross-tolerance, wherein tolerance to a currently administered opioid does not extend completely to other opioids. Clinicians should use extreme caution when performing conversions to and from methadone and consider consultation with a hospital pharmacist or a pain management specialist, when available, to assist with conversion decisions and calculations.

9. SHM recommends that clinicians pair opioids with scheduled nonopioid analgesic medications, unless contraindicated, and always consider pairing with nonpharmacologic pain management strategies (ie, multimodal analgesia).

Concurrent receipt of opioids and nonopioid analgesic medications (including acetaminophen, NSAIDs, and gabapentin or pregabalin, depending on the underlying pathophysiology of the pain) has been demonstrated to reduce total opioid requirements and improve pain management.^41,42 Clinicians should be familiar with contraindications and maximum dosage recommendations for each of these adjunctive nonopioid medications. We recommend separate orders for each, rather than using drug formulations that combine opioids and nonopioid analgesics in the same pill, due to the risk of inadvertently exceeding the maximum recommended doses of the nonopioid analgesic (particularly acetaminophen) with combination products. We recommend that nonopioid analgesics be ordered at a scheduled frequency, rather than as needed, to facilitate consistent administration that is not dependent on opioid administration. Topical agents, including lidocaine and capsaicin, should also be considered. Nonpharmacologic pain management strategies can include procedure-based (eg, regional and local anesthesia) and nonprocedure-based therapies depending on the underlying condition and institutional availability. Although few studies have assessed the benefit of nonpharmacologic, nonprocedure-based therapies for the treatment of acute pain in hospitalized patients, the lack of harm associated with their use argues for their adoption. Simple nonpharmacologic therapies that can usually be provided to patients in any hospital setting include music therapy, cold or hot packs, chaplain or social work visits (possibly including mindfulness training),⁴³ and physical therapy, among others.

10. SHM recommends that, unless contraindicated, clinicians order a bowel regimen to prevent opioid-induced constipation in patients receiving opioids.

Constipation is a common adverse effect of opioid therapy and results from the activation of mu opioid receptors in the colon, resulting in decreased peristalsis. Hospitalized patients are already prone to constipation due to their often-limited physical mobility. To mitigate this complication, we recommend the administration of a bowel regimen to all hospitalized medical patients receiving opioid therapy, provided the patient is not having diarrhea. Given the mechanism of opioid-induced constipation, stimulant laxatives (eg, senna, bisacodyl) have been recommended for this purpose.⁴⁴ Osmotic laxatives (eg, polyethylene glycol, lactulose) have demonstrated efficacy for the treatment of constipation more generally (ie, not necessarily opioid-induced constipation). Stool softeners, although frequently used in the inpatient setting, are not recommended due to limited and conflicting evidence for efficacy in prevention or treatment of constipation.⁴⁵ Bowel movements should be tracked during hospitalization, and the bowel regimen modified accordingly.

11. SHM recommends that clinicians limit co-administration of opioids with other central nervous system depressant medications to the extent possible.

This combination has been demonstrated to increase the risk of opioid-related adverse events in multiple settings of care, including during hospitalization.^1,18,19 Although benzodiazepines have received the most attention in this respect, other medications with CNS depressant properties may also increase the risk, including, but not limited to, nonbenzodiazepine sedative-hypnotics (eg, zolpidem, zaleplon, zopiclone), muscle relaxants, sedating antidepressants, antipsychotics, and antihistamines.^18,19,46 For some patients, the combination will be unavoidable, and we do not suggest routine discontinuation of longstanding medications that preexisted hospitalization, given the risks of withdrawal and/or worsening of the underlying condition for which these medications are prescribed. Rather, clinicians should carefully consider the necessity of each medication class with input from the patient’s outpatient providers, taper the frequency and/or the dose of CNS depressants when appropriate and feasible, and avoid new coprescriptions to the extent possible, both during hospitalization and on hospital discharge.

12. SHM recommends that clinicians work with patients and families or caregivers to establish realistic goals and expectations of opioid therapy and the expected course of recovery.

Discussing expectations at the start of therapy is important to facilitate a clear understanding of how meaningful improvement will be defined and measured during the hospitalization and how long the patient is anticipated to require opioid therapy. Meaningful improvement should be defined to include improvement in both pain and function. Clinicians should discuss with patients 1) that the goal of opioid therapy is tolerability of pain such that meaningful improvement in function can be achieved and 2) that a decrease in pain intensity in the absence of improved function is not considered meaningful improvement in most situations and should prompt reevaluation of the appropriateness of continued opioid therapy as well as close follow-up with a clinician following hospital discharge. Discussions regarding the expected course of recovery should include that acute pain is expected to resolve as the underlying medical condition improves and that although pain may persist beyond the hospitalization, pain that is severe enough to require opioids will often be resolved or almost resolved by the time of hospital discharge.

13. SHM recommends that clinicians monitor the response to opioid therapy, including assessment for functional improvement and development of adverse effects.

Pain severity and function should be assessed at least daily, and improvement in reported pain severity without improvement in function over several days should, in most circumstances, prompt reconsideration of ongoing opioid therapy and reconsideration of the underlying etiology of pain. Although hospital-specific functional measures in the setting of acute pain have not yet been validated, we suggest that such measures and goals should be individualized based on preexisting function and may include the ability to sit up or move in bed, move to a chair, work with physical therapy, or ambulate in the hallway. Protocols for the assessment for adverse effects are not well established. Because sedation typically precedes respiratory depression, it is generally recommended that patients are evaluated (eg, by nursing staff) for sedation after each opioid administration (10–20 minutes for intravenous and 30–60 minutes for oral administration based on the time-to-peak effect). Whether certain patients may benefit from more intensive respiratory monitoring, such as pulse oximetry or capnography, is an area of active investigation and not yet established.

Prescribing at the Time of Hospital Discharge

14. SHM recommends that clinicians ask patients about any existing opioid supply at home and account for any such supply when issuing an opioid prescription on discharge.

Even in the setting of acute pain, patients may have previously received an opioid prescription from an outpatient clinician prior to hospitalization. Unused prescription opioids create the possibility of both overdose (when patients take multiple opioids concurrently, intentionally or inadvertently) and diversion (many adults with prescription opioid misuse obtained their opioids from a friend or a relative who may or may not have known that this occurred⁴⁷). The PDMP database can provide information related to the potential existence of any prior opioid supplies, which should be confirmed with the patient and considered when providing a new prescription on hospital discharge. Information on proper disposal should be provided if use of the preexisting opioid is no longer intended.

15. SHM recommends that clinicians prescribe the minimum quantity of opioids anticipated to be necessary based on the expected course and duration of pain that is severe enough to require opioid therapy after hospital discharge.

For many patients, the condition causing their acute pain will be mostly or completely resolved by the time of hospital discharge. When pain is still present at the time of discharge, most pain can be completely managed with nonopioid therapies. For those with ongoing pain that is severe enough to require opioids after hospital discharge, decisions regarding the duration of therapy should be made on a case-by-case basis; generally, however, provision of a 3- to 5-day supply will be sufficient, and provision of more than a 7-day supply of opioids should generally be avoided for several reasons. These include 1) acute pain lasting longer than 7 days after appropriate treatment of any existing underlying conditions should prompt re-evaluation of the working diagnosis and/or reconsideration of the management approach, 2) receiving higher intensity opioid therapy (including longer courses) in the setting of acute pain has been associated with an increased risk of long-term disability and long-term opioid use,^33,48,49 and 3) unused opioids create the possibility of intentional or unintentional opioid diversion (see Consensus Statement 14).⁴⁷ Accordingly, clinicians should attempt to arrange an outpatient follow-up appointment for re-evaluation within 7 days, rather than providing an extended opioid prescription on hospital discharge. In situations where this is not feasible, and pain that is severe enough to require opioids is expected to persist longer than 7 days, an extended prescription may be indicated. However, some states have begun enacting legislation to limit the duration of first-time opioid prescriptions, typically using a 5-to-7 day supply as an upper limit; clinicians should be aware of and adhere to individual state laws governing their practice.

16. SHM recommends that clinicians ensure that patients and families or caregivers receive information regarding how to minimize the risks of opioid therapy for themselves, their families, and their communities. This includes but is not limited to 1) how to take their opioids correctly (the planned medications, doses, schedule); 2) that they should take the minimum quantity necessary to achieve tolerable levels of pain and meaningful functional improvement, reducing the dose and/or frequency as pain and function improve; 3) how to safeguard their supply and dispose of any unused supply; 4) that they should avoid agents that may potentiate the sedative effect of opioids, including sleeping medication and alcohol; 5) that they should avoid driving or operating heavy machinery while taking opioids; and 6) that they should seek help if they begin to experience any potential adverse effects, with inclusion of information on early warning signs.

Clear and concise patient instructions on home opioid dosing and administration will limit opioid-related adverse events and dosing errors upon hospital discharge. Each of these recommendations derive from one or more of the existing guidelines and reflect the transfer of responsibility for safe opioid use practices that occurs as patients transition from a closely monitored inpatient setting to the more self-regulated home environment.

This Consensus Statement reflects a synthesis of the key recommendations from a systematic review of existing guidelines on acute pain management, adapted for a hospital-specific scope of practice. Despite a paucity of data on the comparative effectiveness of different management strategies for acute pain, several areas of expert consensus emerged across existing guidelines, which were felt to be relevant and applicable to the hospital setting. The objective of these recommendations is to provide information that can be used to inform and support opioid-related management decisions for acute pain by clinicians practicing medicine in the inpatient setting.

Although these recommendations are not intended to apply to the immediate perioperative setting (ie, care in the postanesthesia care unit), many of the recommendations in the existing guidelines upon which this Consensus Statement was based were intended for the postoperative setting, and, as others have noted, recommendations in this setting are mostly comparable to those for treating acute pain more generally.²⁷ Those interested in pain management in the postoperative setting specifically may wish to review the recent guidelines released by the American Pain Society,⁵⁰ the content of which is in close alignment with our Consensus Statement.

Several important issues were raised during the extensive external feedback process undertaken as part of the development of this Consensus Statement. Although many issues were incorporated into the recommendations, there were several suggestions for which we felt the evidence base was not sufficient to allow a clear or valid recommendation to be made. For example, several reviewers requested endorsement of specific patient education tools and opioid equivalency calculators. In the absence of tools specifically validated for this purpose, we felt that the evidence was insufficient to make specific recommendations. Validating such tools for use in the inpatient setting should be an area of future investigation. In the meantime, we note that there are several existing and widely available resources for both patient education (ie, opioid information sheets, including opioid risks, safe containment and disposal, and safe use practices) and opioid equivalency calculations that clinicians and hospitals can adapt for their purposes.

Several individuals suggested recommendations on communication with outpatient continuity providers around opioid management decisions during hospitalization and on discharge. Although we believe that it is of paramount importance for outpatient providers to be aware of and have input into these decisions, the optimal timing and the method for such communication are unclear and likely to be institution-specific depending on the availability and integration of electronic records across care settings. We recommend that clinicians use their judgment as to the best format and timing for assuring that outpatient physicians are aware of and have input into these important management decisions with downstream consequences.

Concerns were also raised about the time required to complete the recommended practices and the importance of emphasizing the need for a team-based approach in this realm. We agree wholeheartedly with this sentiment and believe that many of the recommended practices can and should be automated and/or shared across the care team. For example, PDMPs allow prescribers to appoint delegates to check the PDMP on their behalf. Additionally, we suggest that hospitals work to develop systems to assist care teams with performance of these tasks in a standardized and streamlined manner (eg, integrating access to the PDMP and opioid equivalency tables within the electronic health record and developing standard patient educational handouts). Provision of written materials on opioid risks, side effects, and safety practices may be helpful in facilitating consistent messaging and efficient workflow for members of the care team.

Finally, the working group carefully considered whether to include a recommendation regarding naloxone prescribing at the time of hospital discharge. The provision of naloxone kits to laypersons through Overdose Education and Naloxone Distribution Programs has been shown to reduce opioid overdose deaths^51,52 and hospitalizations^53,54 and is both safe and cost-effective.⁵⁵ The Centers for Disease Control and Preventionrecommend that clinicians “consider offering naloxone to patients with a history of overdose, a current or past substance use disorder, receipt of ≥50 mg of morphine equivalents per day or concurrent benzodiazepine use.”¹ However, these recommendations are intended for patients on chronic opioid therapy; presently, no clear evidence exists to guide decisions about the benefits and costs associated with prescribing naloxone in the setting of short-term opioid therapy for acute pain. Further research in this area is warranted.

The greatest limitation of this Consensus Statement is the lack of high-quality studies informing most of the recommendations in the guidelines upon which our Consensus Statement was based. The majority of recommendations in the existing guidelines were based on expert opinion alone. Additional research is necessary before evidence-based recommendations can be formulated.

Accordingly, the working group identified several key areas for future research, in addition to those noted above. First, ongoing efforts to develop and evaluate the effectiveness of nonopioid and nonpharmacologic management strategies for acute pain in hospitalized patients are necessary. Second, studies identifying the risk factors for opioid-related adverse events in hospitalized patients would help inform management decisions and allow deployment of resources and specialized monitoring strategies to patients at heightened risk. The working group also noted the need for research investigating the impact of PDMP use on management decisions and downstream outcomes among hospitalized patients. Finally, conversations around pain management and concerns related to aberrant behaviors are often challenging in the hospital setting owing to the brief, high-intensity nature of the care and the lack of a longstanding therapeutic alliance. There is a great need to develop strategies and language to facilitate these conversations.

In conclusion, until more high-quality evidence becomes available, clinicians can use the recommendations contained in this Consensus Statement along with their clinical judgment and consultation with pharmacists, interventional pain specialists, and other staff (eg, social work, nursing) to help facilitate consistent, high-quality care across providers and hospitals. We believe that doing so will help increase the appropriateness of opioid therapy, minimize adverse events, facilitate shared decision-making, and foster stronger therapeutic alliances at the outset of the hospitalization for patients suffering from acute pain.

The authors would like to acknowledge and thank Kevin Vuernick, Jenna Goldstein, Meghan Mallouk, and Chris Frost, MD, from the SHM for their facilitation of this project and dedication to this purpose.

The authors would also like to thank the many individuals who provided comments on the draft recommendations, including the participants in the SHM RADEO program; the SHM members; the representatives of specialty societies, including the American Academy of Family Physicians, the American College of Physicians, the American Hospital Association, the American Society of Addiction Medicine, the American Society of Anesthesiologists, the American Society of Health-System Pharmacists, the Society of Critical Care Medicine, and the Society of General Internal Medicine; and the representatives of patient advocacy groups, including SHM PFAC, Regions Hospital Patient and Family Advisory Committee, Patient and Family Centered Care Council of St. Louis Children’s Hospital, Missouri Family Partnership, and Parent and Family Care.

Disclosures: Dr. Herzig reports receiving compensation from the Society of Hospital Medicine for her editorial role at the Journal of Hospital Medicine (unrelated to the present work). Dr. Jena reports receiving consulting fees from Pfizer, Inc., Hill Rom Services, Inc., Bristol Myers Squibb, Novartis Pharmaceuticals, Vertex Pharmaceuticals, and Precision Health Economics, a consultancy to the life sciences industry (all unrelated to the present work). None of the other authors have any conflicts of interest to disclose.

Funding: The Society of Hospital Medicine (SHM) provided administrative assistance with the project and funded the in-person working group meeting but had no role in or influence on developing the content of the recommendations themselves. The SHM Board of Directors provided approval to submit the manuscript for publication without modification. Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging. Dr. Mosher was supported in part by the Department of Veterans Affairs Office of Academic Affiliations and Office of Research and Development and Health Services Research and Development Service (HSR&D) through the Comprehensive Access and Delivery Research and Evaluation Center (CIN 13-412). None of the funding agencies had involvement in any aspect of the study, including design, conduct, and reporting of the study

Since the initial reports of an emerging opioid epidemic in the early 2000s, intense focus on improving opioid prescribing in outpatient settings has culminated in new guidelines for chronic pain.^1,2 Although opioid stewardship in the setting of chronic pain is of paramount importance in curbing the ongoing epidemic, long-term prescription opioid use often begins with treatment of acute pain.¹ In addition to differences in recommended management strategies for acute and chronic pain, there are unique aspects and challenges to pain management in the acute-care setting.

Opioids are commonly used for the treatment of acute pain in hospitalized patients, often at high doses.³ Recent reports highlight that hospital use of opioids impacts downstream use.^4-6 Additionally, opioid prescribing practices vary between hospital-based providers and hospitals,^3,7 highlighting the need for prescribing standards and guidance. To our knowledge, there are no existing guidelines for improving the safety of opioid use in hospitalized patients outside of the intensive care or immediate perioperative settings.

The Society of Hospital Medicine (SHM) convened a working group to systematically review existing guidelines and develop a consensus statement to assist clinicians in safe opioid use for acute, noncancer pain in hospitalized adults.

Consensus Statement Purpose and Scope

The purpose of this Consensus Statement is to present clinical recommendations on the safe use of opioids for the treatment of acute, noncancer pain in hospitalized adults. The guidance is intended for clinicians practicing medicine in the inpatient setting (eg, hospitalists, primary care physicians, family physicians, nurse practitioners, and physician assistants) and is intended to apply to hospitalized adults with acute, noncancer pain (ie, pain that typically lasts <3 months or during the period of normal tissue healing) outside of the palliative, end-of-life, and intensive care settings.

Consensus Statement Development

Our working group included experts in opioid use in the hospital setting, defined by 1) engagement in the clinical practice of hospital medicine and 2) involvement in clinical research related to usage patterns and clinical outcomes of opioid use in hospitalized patients (see Appendix Table 1). The SHM provided administrative assistance with the project and funded the in-person working group meeting, but it had no role in formulating the recommendations. The SHM Board of Directors provided approval of the Consensus Statement without modification.

An overview of the sequential steps in the Consensus Statement development process is described below; details of the methods and results can be found in the Appendix (eMethods).

Performing the Systematic Review

Drafting the Consensus Statement

After performing the systematic review, the working group drafted and iteratively revised a set of recommendations using a variation of the Delphi Method⁸ to identify consensus among group members.

External Review

Following agreement on a draft set of recommendations, we obtained feedback from external groups, including 1) individuals involved in the SHM’s Reducing Adverse Drug Events Related to Opioids (RADEO) initiative, including those involved in the development of the implementation guide and site leads for the Mentored Implementation program, 2) SHM members, SHM Patient-Family Advisory Council (PFAC) members, and leaders of other relevant professional societies, and 3) peer-reviewers at the Journal of Hospital Medicine.

Deciding Whether to Use Opioids During Hospitalization

1. SHM recommends that clinicians limit the use of opioids to patients with 1) severe pain or 2) moderate pain that has not responded to nonopioid therapy, or where nonopioid therapy is contraindicated or anticipated to be ineffective.

Opioids are associated with several well-recognized risks ranging from mild to severe, including nausea, constipation, urinary retention, falls, delirium, sedation, physical dependence, addiction, respiratory depression, and death. Given these risks, the risk-to-benefit ratio is generally not favorable at lower levels of pain severity. Furthermore, for most painful conditions, including those causing severe pain, nonopioid analgesics, including acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), have been demonstrated to be equally or more effective with less risk of harm than opioids.^9-13 Clinicians should consider drug–drug and drug–disease associations when deciding between these different therapies and make a determination in each patient regarding whether the benefits outweigh the risks. Often, drug–disease interactions do not represent absolute contraindications, and risks can be mitigated by adhering to dosage limits and, with respect to NSAIDs, 1) monitoring renal function, 2) monitoring volume status in patients with congestive heart failure, and 3) considering a selective cyclooxygenase-2 (COX-2) inhibitor rather than a nonselective NSAID or pairing the NSAID with an acid-suppressive medication in patients with a history of peptic ulcer disease or at elevated risk for gastroduodenal disease. For these reasons, a trial of nonopioid therapy (including pharmacologic and nonpharmacologic modalities) should always be considered before using opioids for pain of any severity. This does not imply that a trial of nonopioid therapy must be performed in all patients, but rather, that the likelihood of benefit and associated risks of opioid and nonopioid therapy should be considered for all patients in determining the best initial management strategy.

2. SHM recommends that clinicians use extra caution when administering opioids to patients with risk factors for opioid-related adverse events.

Several factors have been consistently demonstrated to increase the risk of opioid-related adverse events–most importantly, respiratory depression and overdose–in varied patient populations and settings, including age 65 years and older,^1,14-17 renal insufficiency,^1,14,18 hepatic insufficiency,^1,14 chronic respiratory failure (including chronic obstructive pulmonary disease, sleep apnea, etc.), and receipt of other central nervous system (CNS) depressant medications (including, but not limited to, benzodiazepines).^1,18-20 History of any substance use disorder and psychiatric disorders have been associated with an increased risk for the development of opioid use disorder.^21-24 These factors should be weighed against the benefits when deciding on opioid appropriateness in a given patient. However, identification of these risks should not preclude opioids as part of pain management. When a decision is made to use opioids in patients with these risk factors, clinicians should 1) use a reduced starting dose (generally, at least a 50% reduction in the usual starting dose) and 2) consider closer monitoring for adverse effects (eg, more frequent nursing assessments, capnography, or more frequent outpatient visits).

3. SHM recommends that clinicians review the information contained in the prescription drug monitoring program (PDMP) database to inform decision-making around opioid therapy.

Although data on the impact of use of the state PDMP database on prescribing practices or patient outcomes are limited, PDMP use has been advocated by multiple guidelines on acute pain management.^25-27 The PDMP provides information that can be useful in several ways, including 1) confirmation of prior opioid exposure and dosage, which should be used to guide appropriate dosage selection in the hospital, 2) identification of existing controlled substance prescriptions, which should be considered in prescribing decisions in the hospital and on discharge, and 3) identification of signs of aberrant behavior. For example, the identification of controlled substance prescriptions written by multiple different clinicians can facilitate early identification of potential diversion or evolving or existing opioid use disorder and the opportunity for intervention,²⁸ which may include referral to support services, initiation of medication-assisted treatment, and/or pain specialist consultation when available. Concerns regarding evolving or existing opioid use disorder should prompt further discussion between the clinician and the patient, both to clarify their understanding of their recent prescription history and to discuss concerns for patient safety related to the increased risk of opioid-related adverse effects (including respiratory depression and overdose) among patients with controlled substance prescriptions written by multiple providers. Although such concerns should not automatically preclude the use of opioids for acute pain in the hospital setting, they should be considered in the assessment of whether the benefits of opioid therapy outweigh the risks for a given patient.

4. SHM recommends that clinicians educate patients and families or caregivers about the potential risks and side effects of opioid therapy as well as alternative pharmacologic and nonpharmacologic therapies for managing pain.

Patients are often unaware of the risks of opioid therapy (see Consensus Statement 1 for key risks),²⁹ or that there are often equally effective alternative therapies. As with any therapy associated with substantial risk, clinicians should discuss these risks with patients and/or caregivers at the outset of therapy, as well as the potential benefits of nonopioid pharmacologic and nonpharmacologic therapies for managing pain. Patients should be informed that they may request nonopioid therapy in lieu of opioids, even for severe pain.

Once a Decision Has Been Made to Use Opioids During Hospitalization

5. SHM recommends that clinicians use the lowest effective opioid dose for the shortest duration possible.

Higher opioid doses are associated with an increased incidence of opioid-related adverse events, particularly overdose, in studies of both inpatient and outpatient populations.^{1,17,19,30,31} Studies in the inpatient and outpatient settings consistently demonstrate that risk increases with dosage.^19,30,31 Clinicians should reduce the usual starting dose by at least 50% among patients with conditions that increase susceptibility to opioid-related adverse events (see Consensus Statement 2). The ongoing need for opioids should be re-assessed regularly-at least daily-during the hospitalization, with attempts at tapering as healing occurs and/or pain and function improve.

6. SHM recommends that clinicians use immediate-release opioid formulations and avoid initiation of long-acting or extended-release formulations (including transdermal fentanyl) for treatment of acute pain.

Studies in outpatient settings demonstrate that the use of long-acting opioids is associated with greater risk for overdose–especially in opioid-naïve patients–and long-term use.^32,33 Further, hospitalized patients frequently have fluctuating renal function and rapidly changing pain levels. We therefore recommend that initiation of long-acting opioids be avoided for the treatment of acute, noncancer pain in hospitalized medical patients. It is important to note that although we recommend avoiding initiation of long-acting opioids for the treatment of acute, noncancer pain, there are circumstances outside of the scope of this Consensus Statement for which initiation of long-acting opioids may be indicated, including the treatment of opioid withdrawal. We also do not recommend discontinuation of long-acting or extended-release opioids in patients who are taking these medications for chronic pain at the time of hospital admission (unless there are concerns regarding adverse effects or drug–disease interactions).

7. SHM recommends that clinicians use the oral route of administration whenever possible. Intravenous opioids should be reserved for patients who cannot take food or medications by mouth, patients suspected of gastrointestinal malabsorption, or when immediate pain control and/or rapid dose titration is necessary.

Intravenous opioid administration is associated with an increased risk of side effects, adverse events, and medication errors.^34-36 Additionally, studies demonstrate that in general, the addiction potential of medications is greater the more rapid the onset of action (the onset of action is 5–10 min for intravenous and 15–30 minutes for oral administration).^37,38 Furthermore, the duration of action is greater for oral compared to that of intravenous administration, potentially allowing for more consistent pain relief and less frequent administrations. As such, intravenous administration should be reserved for situations when oral administration is not possible or likely to be ineffective, or when immediate pain control and/or rapid titration is necessary.

8. SHM recommends that clinicians use an opioid equivalency table or calculator to understand the relative potency of different opioids 1) when initiating opioid therapy, 2) when changing from one route of administration to another, and 3) when changing from one opioid to another. When changing from one opioid to another, clinicians should generally reduce the dose of the new opioid by at least 25%–50% of the calculated equianalgesic dose to account for interindividual variability in the response to opioids as well as possible incomplete cross-tolerance.

Most errors causing preventable adverse drug events in hospitals occur at the ordering stage.^39,40 Clinicians are often unaware of the potency of different types of opioids relative to each other or to morphine (ie, morphine equivalent dose), which can lead to inadvertent overdose when initiating therapy with nonmorphine opioids and when converting from one opioid to another. To facilitate safe opioid use, we recommend that clinicians use one of several available opioid equivalency tables or calculators to better understand the relative potencies of opioids and to inform both starting dose calculations and conversions between opioids and routes of administration. When converting from one opioid to another, we caution clinicians to reduce the dose of the new opioid by at least 25%–50% of the calculated equianalgesic dose to account for interindividual variability in the response to opioids and the potential for incomplete cross-tolerance, wherein tolerance to a currently administered opioid does not extend completely to other opioids. Clinicians should use extreme caution when performing conversions to and from methadone and consider consultation with a hospital pharmacist or a pain management specialist, when available, to assist with conversion decisions and calculations.

9. SHM recommends that clinicians pair opioids with scheduled nonopioid analgesic medications, unless contraindicated, and always consider pairing with nonpharmacologic pain management strategies (ie, multimodal analgesia).

Concurrent receipt of opioids and nonopioid analgesic medications (including acetaminophen, NSAIDs, and gabapentin or pregabalin, depending on the underlying pathophysiology of the pain) has been demonstrated to reduce total opioid requirements and improve pain management.^41,42 Clinicians should be familiar with contraindications and maximum dosage recommendations for each of these adjunctive nonopioid medications. We recommend separate orders for each, rather than using drug formulations that combine opioids and nonopioid analgesics in the same pill, due to the risk of inadvertently exceeding the maximum recommended doses of the nonopioid analgesic (particularly acetaminophen) with combination products. We recommend that nonopioid analgesics be ordered at a scheduled frequency, rather than as needed, to facilitate consistent administration that is not dependent on opioid administration. Topical agents, including lidocaine and capsaicin, should also be considered. Nonpharmacologic pain management strategies can include procedure-based (eg, regional and local anesthesia) and nonprocedure-based therapies depending on the underlying condition and institutional availability. Although few studies have assessed the benefit of nonpharmacologic, nonprocedure-based therapies for the treatment of acute pain in hospitalized patients, the lack of harm associated with their use argues for their adoption. Simple nonpharmacologic therapies that can usually be provided to patients in any hospital setting include music therapy, cold or hot packs, chaplain or social work visits (possibly including mindfulness training),⁴³ and physical therapy, among others.

10. SHM recommends that, unless contraindicated, clinicians order a bowel regimen to prevent opioid-induced constipation in patients receiving opioids.

Constipation is a common adverse effect of opioid therapy and results from the activation of mu opioid receptors in the colon, resulting in decreased peristalsis. Hospitalized patients are already prone to constipation due to their often-limited physical mobility. To mitigate this complication, we recommend the administration of a bowel regimen to all hospitalized medical patients receiving opioid therapy, provided the patient is not having diarrhea. Given the mechanism of opioid-induced constipation, stimulant laxatives (eg, senna, bisacodyl) have been recommended for this purpose.⁴⁴ Osmotic laxatives (eg, polyethylene glycol, lactulose) have demonstrated efficacy for the treatment of constipation more generally (ie, not necessarily opioid-induced constipation). Stool softeners, although frequently used in the inpatient setting, are not recommended due to limited and conflicting evidence for efficacy in prevention or treatment of constipation.⁴⁵ Bowel movements should be tracked during hospitalization, and the bowel regimen modified accordingly.

11. SHM recommends that clinicians limit co-administration of opioids with other central nervous system depressant medications to the extent possible.

This combination has been demonstrated to increase the risk of opioid-related adverse events in multiple settings of care, including during hospitalization.^1,18,19 Although benzodiazepines have received the most attention in this respect, other medications with CNS depressant properties may also increase the risk, including, but not limited to, nonbenzodiazepine sedative-hypnotics (eg, zolpidem, zaleplon, zopiclone), muscle relaxants, sedating antidepressants, antipsychotics, and antihistamines.^18,19,46 For some patients, the combination will be unavoidable, and we do not suggest routine discontinuation of longstanding medications that preexisted hospitalization, given the risks of withdrawal and/or worsening of the underlying condition for which these medications are prescribed. Rather, clinicians should carefully consider the necessity of each medication class with input from the patient’s outpatient providers, taper the frequency and/or the dose of CNS depressants when appropriate and feasible, and avoid new coprescriptions to the extent possible, both during hospitalization and on hospital discharge.

12. SHM recommends that clinicians work with patients and families or caregivers to establish realistic goals and expectations of opioid therapy and the expected course of recovery.

Discussing expectations at the start of therapy is important to facilitate a clear understanding of how meaningful improvement will be defined and measured during the hospitalization and how long the patient is anticipated to require opioid therapy. Meaningful improvement should be defined to include improvement in both pain and function. Clinicians should discuss with patients 1) that the goal of opioid therapy is tolerability of pain such that meaningful improvement in function can be achieved and 2) that a decrease in pain intensity in the absence of improved function is not considered meaningful improvement in most situations and should prompt reevaluation of the appropriateness of continued opioid therapy as well as close follow-up with a clinician following hospital discharge. Discussions regarding the expected course of recovery should include that acute pain is expected to resolve as the underlying medical condition improves and that although pain may persist beyond the hospitalization, pain that is severe enough to require opioids will often be resolved or almost resolved by the time of hospital discharge.

13. SHM recommends that clinicians monitor the response to opioid therapy, including assessment for functional improvement and development of adverse effects.

Pain severity and function should be assessed at least daily, and improvement in reported pain severity without improvement in function over several days should, in most circumstances, prompt reconsideration of ongoing opioid therapy and reconsideration of the underlying etiology of pain. Although hospital-specific functional measures in the setting of acute pain have not yet been validated, we suggest that such measures and goals should be individualized based on preexisting function and may include the ability to sit up or move in bed, move to a chair, work with physical therapy, or ambulate in the hallway. Protocols for the assessment for adverse effects are not well established. Because sedation typically precedes respiratory depression, it is generally recommended that patients are evaluated (eg, by nursing staff) for sedation after each opioid administration (10–20 minutes for intravenous and 30–60 minutes for oral administration based on the time-to-peak effect). Whether certain patients may benefit from more intensive respiratory monitoring, such as pulse oximetry or capnography, is an area of active investigation and not yet established.

Prescribing at the Time of Hospital Discharge

14. SHM recommends that clinicians ask patients about any existing opioid supply at home and account for any such supply when issuing an opioid prescription on discharge.

Even in the setting of acute pain, patients may have previously received an opioid prescription from an outpatient clinician prior to hospitalization. Unused prescription opioids create the possibility of both overdose (when patients take multiple opioids concurrently, intentionally or inadvertently) and diversion (many adults with prescription opioid misuse obtained their opioids from a friend or a relative who may or may not have known that this occurred⁴⁷). The PDMP database can provide information related to the potential existence of any prior opioid supplies, which should be confirmed with the patient and considered when providing a new prescription on hospital discharge. Information on proper disposal should be provided if use of the preexisting opioid is no longer intended.

15. SHM recommends that clinicians prescribe the minimum quantity of opioids anticipated to be necessary based on the expected course and duration of pain that is severe enough to require opioid therapy after hospital discharge.

For many patients, the condition causing their acute pain will be mostly or completely resolved by the time of hospital discharge. When pain is still present at the time of discharge, most pain can be completely managed with nonopioid therapies. For those with ongoing pain that is severe enough to require opioids after hospital discharge, decisions regarding the duration of therapy should be made on a case-by-case basis; generally, however, provision of a 3- to 5-day supply will be sufficient, and provision of more than a 7-day supply of opioids should generally be avoided for several reasons. These include 1) acute pain lasting longer than 7 days after appropriate treatment of any existing underlying conditions should prompt re-evaluation of the working diagnosis and/or reconsideration of the management approach, 2) receiving higher intensity opioid therapy (including longer courses) in the setting of acute pain has been associated with an increased risk of long-term disability and long-term opioid use,^33,48,49 and 3) unused opioids create the possibility of intentional or unintentional opioid diversion (see Consensus Statement 14).⁴⁷ Accordingly, clinicians should attempt to arrange an outpatient follow-up appointment for re-evaluation within 7 days, rather than providing an extended opioid prescription on hospital discharge. In situations where this is not feasible, and pain that is severe enough to require opioids is expected to persist longer than 7 days, an extended prescription may be indicated. However, some states have begun enacting legislation to limit the duration of first-time opioid prescriptions, typically using a 5-to-7 day supply as an upper limit; clinicians should be aware of and adhere to individual state laws governing their practice.

16. SHM recommends that clinicians ensure that patients and families or caregivers receive information regarding how to minimize the risks of opioid therapy for themselves, their families, and their communities. This includes but is not limited to 1) how to take their opioids correctly (the planned medications, doses, schedule); 2) that they should take the minimum quantity necessary to achieve tolerable levels of pain and meaningful functional improvement, reducing the dose and/or frequency as pain and function improve; 3) how to safeguard their supply and dispose of any unused supply; 4) that they should avoid agents that may potentiate the sedative effect of opioids, including sleeping medication and alcohol; 5) that they should avoid driving or operating heavy machinery while taking opioids; and 6) that they should seek help if they begin to experience any potential adverse effects, with inclusion of information on early warning signs.

Clear and concise patient instructions on home opioid dosing and administration will limit opioid-related adverse events and dosing errors upon hospital discharge. Each of these recommendations derive from one or more of the existing guidelines and reflect the transfer of responsibility for safe opioid use practices that occurs as patients transition from a closely monitored inpatient setting to the more self-regulated home environment.

This Consensus Statement reflects a synthesis of the key recommendations from a systematic review of existing guidelines on acute pain management, adapted for a hospital-specific scope of practice. Despite a paucity of data on the comparative effectiveness of different management strategies for acute pain, several areas of expert consensus emerged across existing guidelines, which were felt to be relevant and applicable to the hospital setting. The objective of these recommendations is to provide information that can be used to inform and support opioid-related management decisions for acute pain by clinicians practicing medicine in the inpatient setting.

Although these recommendations are not intended to apply to the immediate perioperative setting (ie, care in the postanesthesia care unit), many of the recommendations in the existing guidelines upon which this Consensus Statement was based were intended for the postoperative setting, and, as others have noted, recommendations in this setting are mostly comparable to those for treating acute pain more generally.²⁷ Those interested in pain management in the postoperative setting specifically may wish to review the recent guidelines released by the American Pain Society,⁵⁰ the content of which is in close alignment with our Consensus Statement.

Several important issues were raised during the extensive external feedback process undertaken as part of the development of this Consensus Statement. Although many issues were incorporated into the recommendations, there were several suggestions for which we felt the evidence base was not sufficient to allow a clear or valid recommendation to be made. For example, several reviewers requested endorsement of specific patient education tools and opioid equivalency calculators. In the absence of tools specifically validated for this purpose, we felt that the evidence was insufficient to make specific recommendations. Validating such tools for use in the inpatient setting should be an area of future investigation. In the meantime, we note that there are several existing and widely available resources for both patient education (ie, opioid information sheets, including opioid risks, safe containment and disposal, and safe use practices) and opioid equivalency calculations that clinicians and hospitals can adapt for their purposes.

Several individuals suggested recommendations on communication with outpatient continuity providers around opioid management decisions during hospitalization and on discharge. Although we believe that it is of paramount importance for outpatient providers to be aware of and have input into these decisions, the optimal timing and the method for such communication are unclear and likely to be institution-specific depending on the availability and integration of electronic records across care settings. We recommend that clinicians use their judgment as to the best format and timing for assuring that outpatient physicians are aware of and have input into these important management decisions with downstream consequences.

Concerns were also raised about the time required to complete the recommended practices and the importance of emphasizing the need for a team-based approach in this realm. We agree wholeheartedly with this sentiment and believe that many of the recommended practices can and should be automated and/or shared across the care team. For example, PDMPs allow prescribers to appoint delegates to check the PDMP on their behalf. Additionally, we suggest that hospitals work to develop systems to assist care teams with performance of these tasks in a standardized and streamlined manner (eg, integrating access to the PDMP and opioid equivalency tables within the electronic health record and developing standard patient educational handouts). Provision of written materials on opioid risks, side effects, and safety practices may be helpful in facilitating consistent messaging and efficient workflow for members of the care team.

Finally, the working group carefully considered whether to include a recommendation regarding naloxone prescribing at the time of hospital discharge. The provision of naloxone kits to laypersons through Overdose Education and Naloxone Distribution Programs has been shown to reduce opioid overdose deaths^51,52 and hospitalizations^53,54 and is both safe and cost-effective.⁵⁵ The Centers for Disease Control and Preventionrecommend that clinicians “consider offering naloxone to patients with a history of overdose, a current or past substance use disorder, receipt of ≥50 mg of morphine equivalents per day or concurrent benzodiazepine use.”¹ However, these recommendations are intended for patients on chronic opioid therapy; presently, no clear evidence exists to guide decisions about the benefits and costs associated with prescribing naloxone in the setting of short-term opioid therapy for acute pain. Further research in this area is warranted.

The greatest limitation of this Consensus Statement is the lack of high-quality studies informing most of the recommendations in the guidelines upon which our Consensus Statement was based. The majority of recommendations in the existing guidelines were based on expert opinion alone. Additional research is necessary before evidence-based recommendations can be formulated.

Accordingly, the working group identified several key areas for future research, in addition to those noted above. First, ongoing efforts to develop and evaluate the effectiveness of nonopioid and nonpharmacologic management strategies for acute pain in hospitalized patients are necessary. Second, studies identifying the risk factors for opioid-related adverse events in hospitalized patients would help inform management decisions and allow deployment of resources and specialized monitoring strategies to patients at heightened risk. The working group also noted the need for research investigating the impact of PDMP use on management decisions and downstream outcomes among hospitalized patients. Finally, conversations around pain management and concerns related to aberrant behaviors are often challenging in the hospital setting owing to the brief, high-intensity nature of the care and the lack of a longstanding therapeutic alliance. There is a great need to develop strategies and language to facilitate these conversations.

In conclusion, until more high-quality evidence becomes available, clinicians can use the recommendations contained in this Consensus Statement along with their clinical judgment and consultation with pharmacists, interventional pain specialists, and other staff (eg, social work, nursing) to help facilitate consistent, high-quality care across providers and hospitals. We believe that doing so will help increase the appropriateness of opioid therapy, minimize adverse events, facilitate shared decision-making, and foster stronger therapeutic alliances at the outset of the hospitalization for patients suffering from acute pain.

The authors would like to acknowledge and thank Kevin Vuernick, Jenna Goldstein, Meghan Mallouk, and Chris Frost, MD, from the SHM for their facilitation of this project and dedication to this purpose.

The authors would also like to thank the many individuals who provided comments on the draft recommendations, including the participants in the SHM RADEO program; the SHM members; the representatives of specialty societies, including the American Academy of Family Physicians, the American College of Physicians, the American Hospital Association, the American Society of Addiction Medicine, the American Society of Anesthesiologists, the American Society of Health-System Pharmacists, the Society of Critical Care Medicine, and the Society of General Internal Medicine; and the representatives of patient advocacy groups, including SHM PFAC, Regions Hospital Patient and Family Advisory Committee, Patient and Family Centered Care Council of St. Louis Children’s Hospital, Missouri Family Partnership, and Parent and Family Care.

Disclosures: Dr. Herzig reports receiving compensation from the Society of Hospital Medicine for her editorial role at the Journal of Hospital Medicine (unrelated to the present work). Dr. Jena reports receiving consulting fees from Pfizer, Inc., Hill Rom Services, Inc., Bristol Myers Squibb, Novartis Pharmaceuticals, Vertex Pharmaceuticals, and Precision Health Economics, a consultancy to the life sciences industry (all unrelated to the present work). None of the other authors have any conflicts of interest to disclose.

Funding: The Society of Hospital Medicine (SHM) provided administrative assistance with the project and funded the in-person working group meeting but had no role in or influence on developing the content of the recommendations themselves. The SHM Board of Directors provided approval to submit the manuscript for publication without modification. Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging. Dr. Mosher was supported in part by the Department of Veterans Affairs Office of Academic Affiliations and Office of Research and Development and Health Services Research and Development Service (HSR&D) through the Comprehensive Access and Delivery Research and Evaluation Center (CIN 13-412). None of the funding agencies had involvement in any aspect of the study, including design, conduct, and reporting of the study

Clinicians at Centro Hospitalar do Porto in Portugal reported on the case to highlight risk factors for tumor lysis syndrome (TLS).  After 3 cycles of folinic acid, 5-fluorouracil and oxaliplatin (FOLFOX), the patient developed nausea, mild asthenia, tremors, and hyperkalemia that did not respond to standard measures. The differential diagnosis included dehydration, hypotension, exposure to nephrotoxic drugs, and obstructive uropathy, as well as TLS. The patient was diagnosed with acute kidney injury and TLS.

Tumor lysis syndrome is common after the beginning of antineoplastic treatments. As massive amounts of tumor cells are killed, intracellular electrolytes and metabolites flood into the bloodstream. If the metabolites exceed the renal clearance threshold, serious complications ensue, including cardiac arrhythmias or seizures and death. Mortality rates related to TLS in solid tumors can be as high as 35%, the clinicians say. Acute kidney injury during chemotherapy should raise warning flags about TLS, they add, particularly because prompt diagnosis is crucial for short-term outcomes.

The patient was admitted immediately to the intensive care unit with the main aim of preventing severe cardiac events and reversing crystal nephropathy. Adding targeted therapy might have worsened the TLS, so the clinicians opted for high-risk prophylaxis. They advise having rasburicase readily available for treating TLS to degrade urate crystals and reverse nephropathy, reducing the need for renal replacement therapy. However, the clinicians caution that rasburicase and allopurinol (another option) are not free of toxicity.

After a reevaluation computer tomography scan showed that the hepatomegaly was reduced with smaller liver metastases, the clinicians switched the patient to low-risk prophylaxis. The TLS did not recur.

Chemosensitivity, which raises the risk of TLS, is low in colon cancer, the clinicians say. High tumor burden and high proliferation rates seem to be better predictors for TLS.

Source:
Gouveia HS, Lopes SO, Faria AL. BMJ Case Rep. 2018;2018. pii: bcr-2017-223474.
doi: 10.1136/bcr-2017-223474.

Clinicians at Centro Hospitalar do Porto in Portugal reported on the case to highlight risk factors for tumor lysis syndrome (TLS).  After 3 cycles of folinic acid, 5-fluorouracil and oxaliplatin (FOLFOX), the patient developed nausea, mild asthenia, tremors, and hyperkalemia that did not respond to standard measures. The differential diagnosis included dehydration, hypotension, exposure to nephrotoxic drugs, and obstructive uropathy, as well as TLS. The patient was diagnosed with acute kidney injury and TLS.

Tumor lysis syndrome is common after the beginning of antineoplastic treatments. As massive amounts of tumor cells are killed, intracellular electrolytes and metabolites flood into the bloodstream. If the metabolites exceed the renal clearance threshold, serious complications ensue, including cardiac arrhythmias or seizures and death. Mortality rates related to TLS in solid tumors can be as high as 35%, the clinicians say. Acute kidney injury during chemotherapy should raise warning flags about TLS, they add, particularly because prompt diagnosis is crucial for short-term outcomes.

The patient was admitted immediately to the intensive care unit with the main aim of preventing severe cardiac events and reversing crystal nephropathy. Adding targeted therapy might have worsened the TLS, so the clinicians opted for high-risk prophylaxis. They advise having rasburicase readily available for treating TLS to degrade urate crystals and reverse nephropathy, reducing the need for renal replacement therapy. However, the clinicians caution that rasburicase and allopurinol (another option) are not free of toxicity.

After a reevaluation computer tomography scan showed that the hepatomegaly was reduced with smaller liver metastases, the clinicians switched the patient to low-risk prophylaxis. The TLS did not recur.

Chemosensitivity, which raises the risk of TLS, is low in colon cancer, the clinicians say. High tumor burden and high proliferation rates seem to be better predictors for TLS.

Source:
Gouveia HS, Lopes SO, Faria AL. BMJ Case Rep. 2018;2018. pii: bcr-2017-223474.
doi: 10.1136/bcr-2017-223474.

Clinicians at Centro Hospitalar do Porto in Portugal reported on the case to highlight risk factors for tumor lysis syndrome (TLS).  After 3 cycles of folinic acid, 5-fluorouracil and oxaliplatin (FOLFOX), the patient developed nausea, mild asthenia, tremors, and hyperkalemia that did not respond to standard measures. The differential diagnosis included dehydration, hypotension, exposure to nephrotoxic drugs, and obstructive uropathy, as well as TLS. The patient was diagnosed with acute kidney injury and TLS.

Tumor lysis syndrome is common after the beginning of antineoplastic treatments. As massive amounts of tumor cells are killed, intracellular electrolytes and metabolites flood into the bloodstream. If the metabolites exceed the renal clearance threshold, serious complications ensue, including cardiac arrhythmias or seizures and death. Mortality rates related to TLS in solid tumors can be as high as 35%, the clinicians say. Acute kidney injury during chemotherapy should raise warning flags about TLS, they add, particularly because prompt diagnosis is crucial for short-term outcomes.

The patient was admitted immediately to the intensive care unit with the main aim of preventing severe cardiac events and reversing crystal nephropathy. Adding targeted therapy might have worsened the TLS, so the clinicians opted for high-risk prophylaxis. They advise having rasburicase readily available for treating TLS to degrade urate crystals and reverse nephropathy, reducing the need for renal replacement therapy. However, the clinicians caution that rasburicase and allopurinol (another option) are not free of toxicity.

After a reevaluation computer tomography scan showed that the hepatomegaly was reduced with smaller liver metastases, the clinicians switched the patient to low-risk prophylaxis. The TLS did not recur.

Chemosensitivity, which raises the risk of TLS, is low in colon cancer, the clinicians say. High tumor burden and high proliferation rates seem to be better predictors for TLS.

Source:
Gouveia HS, Lopes SO, Faria AL. BMJ Case Rep. 2018;2018. pii: bcr-2017-223474.
doi: 10.1136/bcr-2017-223474.

Photo by Don Boomer

New research indicates that non-muscle myosin II-A (NMIIA) plays a key role in maintaining red blood cell (RBC) shape and deformability.

Researchers found evidence to suggest that NMIIA forms filaments in RBCs, and specialized regions at both ends of the filaments can pull on actin to control the stiffness of the cell membrane.

“You need active contraction on the cell membrane, similar to how muscles contract,” explained study author Velia Fowler, PhD, of The Scripps Research Institute in La Jolla, California.

“The myosin pulls on the actin to provide tension in the membrane, and then that tension maintains the biconcave shape.”

Dr Fowler and her colleagues described these findings in PNAS.

The researchers noted that RBC shape and deformability depend upon the membrane skeleton—a network of actin filaments (F-actin) cross-linked by spectrin tetramers.

And although NMII motors are known to exert force on F-actin networks to control cell shapes, no one had investigated a function for NMII contractility in the spectrin–F-actin network of RBCs. So Dr Fowler and her colleagues did just that.

The researchers said their work suggests NMIIA is the predominant RBC NMII isoform, and NMIIA motor activity regulates interactions with the spectrin–F-actin network to control RBCs’ shape and deformability.

Specifically, NMIIA forms bipolar filaments in RBCs, and these filaments associate with F-actins via their motor domains. It is through these interactions that NMIIA contractile forces promote membrane tension to maintain RBC shape and deformability.

To test these findings, the researchers treated RBCs with a compound called blebbistatin, which inhibits NMII motor activity.

After treatment, the team observed a decrease in NMIIA filaments associated with the RBC membrane and evidence of decreased membrane tension. The treated RBCs became elongated and showed a reduction in biconcavity as well as an increase in deformability.

The researchers believe this work could have applications for diseases in which RBCs are deformed. In fact, the team thinks inhibiting NMIIA in RBCs might prove useful for treating patients with sickle cell disease, as it could restore some elasticity to the patients’ RBCs.

Going forward, the researchers hope to learn more about what regulates NMIIA’s activity in RBCs and other cells.

Photo by Don Boomer

New research indicates that non-muscle myosin II-A (NMIIA) plays a key role in maintaining red blood cell (RBC) shape and deformability.

Researchers found evidence to suggest that NMIIA forms filaments in RBCs, and specialized regions at both ends of the filaments can pull on actin to control the stiffness of the cell membrane.

“You need active contraction on the cell membrane, similar to how muscles contract,” explained study author Velia Fowler, PhD, of The Scripps Research Institute in La Jolla, California.

“The myosin pulls on the actin to provide tension in the membrane, and then that tension maintains the biconcave shape.”

Dr Fowler and her colleagues described these findings in PNAS.

The researchers noted that RBC shape and deformability depend upon the membrane skeleton—a network of actin filaments (F-actin) cross-linked by spectrin tetramers.

And although NMII motors are known to exert force on F-actin networks to control cell shapes, no one had investigated a function for NMII contractility in the spectrin–F-actin network of RBCs. So Dr Fowler and her colleagues did just that.

The researchers said their work suggests NMIIA is the predominant RBC NMII isoform, and NMIIA motor activity regulates interactions with the spectrin–F-actin network to control RBCs’ shape and deformability.

Specifically, NMIIA forms bipolar filaments in RBCs, and these filaments associate with F-actins via their motor domains. It is through these interactions that NMIIA contractile forces promote membrane tension to maintain RBC shape and deformability.

To test these findings, the researchers treated RBCs with a compound called blebbistatin, which inhibits NMII motor activity.

After treatment, the team observed a decrease in NMIIA filaments associated with the RBC membrane and evidence of decreased membrane tension. The treated RBCs became elongated and showed a reduction in biconcavity as well as an increase in deformability.

The researchers believe this work could have applications for diseases in which RBCs are deformed. In fact, the team thinks inhibiting NMIIA in RBCs might prove useful for treating patients with sickle cell disease, as it could restore some elasticity to the patients’ RBCs.

Going forward, the researchers hope to learn more about what regulates NMIIA’s activity in RBCs and other cells.

Photo by Don Boomer

New research indicates that non-muscle myosin II-A (NMIIA) plays a key role in maintaining red blood cell (RBC) shape and deformability.

Researchers found evidence to suggest that NMIIA forms filaments in RBCs, and specialized regions at both ends of the filaments can pull on actin to control the stiffness of the cell membrane.

“You need active contraction on the cell membrane, similar to how muscles contract,” explained study author Velia Fowler, PhD, of The Scripps Research Institute in La Jolla, California.

“The myosin pulls on the actin to provide tension in the membrane, and then that tension maintains the biconcave shape.”

Dr Fowler and her colleagues described these findings in PNAS.

The researchers noted that RBC shape and deformability depend upon the membrane skeleton—a network of actin filaments (F-actin) cross-linked by spectrin tetramers.

And although NMII motors are known to exert force on F-actin networks to control cell shapes, no one had investigated a function for NMII contractility in the spectrin–F-actin network of RBCs. So Dr Fowler and her colleagues did just that.

The researchers said their work suggests NMIIA is the predominant RBC NMII isoform, and NMIIA motor activity regulates interactions with the spectrin–F-actin network to control RBCs’ shape and deformability.

Specifically, NMIIA forms bipolar filaments in RBCs, and these filaments associate with F-actins via their motor domains. It is through these interactions that NMIIA contractile forces promote membrane tension to maintain RBC shape and deformability.

To test these findings, the researchers treated RBCs with a compound called blebbistatin, which inhibits NMII motor activity.

After treatment, the team observed a decrease in NMIIA filaments associated with the RBC membrane and evidence of decreased membrane tension. The treated RBCs became elongated and showed a reduction in biconcavity as well as an increase in deformability.

The researchers believe this work could have applications for diseases in which RBCs are deformed. In fact, the team thinks inhibiting NMIIA in RBCs might prove useful for treating patients with sickle cell disease, as it could restore some elasticity to the patients’ RBCs.

Going forward, the researchers hope to learn more about what regulates NMIIA’s activity in RBCs and other cells.

showing multiple myeloma

Targeted screening could potentially reduce the prevalence of multiple myeloma (MM), according to research published in JCO Clinical Cancer Informatics.

Researchers found that screening for monoclonal gammopathy of undetermined significance (MGUS) might reduce the risk of MM in individuals with a high lifetime risk of MGUS, which includes men, African Americans, and people with a family history of MM.

The researchers said patients who screen positive for MGUS could seek medical care early and try strategies such as aspirin, metformin, or weight reduction to potentially reduce their risk of progression from MGUS to MM.

However, additional studies are needed to confirm the effectiveness of aspirin, metformin, and weight-loss strategies in preventing MGUS progression.

“Screening for MGUS may have significant benefits by lowering the incidence of multiple myeloma, provided that effective and non-toxic interventions can be identified,” said study author Philipp Altrock, PhD, of Moffitt Cancer Center in Tampa, Florida.

Dr Altrock and his colleagues performed a series of computational modeling experiments to determine the best screening strategies in different groups of patients. The goal was to determine when screening should begin, how often it should occur, and in which individuals it could be most effective.

The researchers designed their model to predict the progression of MGUS to MM, the changes in MGUS and MM prevalence, and the annual follow-up mortality due to disease.

The team found evidence to suggest that screening strategies could reduce the risk of progression and the prevalence of MM. This effect was more pronounced in individuals who had a higher risk of MGUS.

Modeling suggested the prevalence of MM could be reduced by 19% in patients who begin screening at age 55 and have follow-up screening every 6 years.

A similar reduction in prevalence could also be achieved by starting screening at age 65 and following up every 2 years.

“Regular screening of MGUS candidates should start as early as possible, with biannual follow-up, and focus on high-risk individuals, especially with a family history of multiple myeloma or in groups with a strong indication of MGUS progression,” Dr Altrock said.

showing multiple myeloma

Targeted screening could potentially reduce the prevalence of multiple myeloma (MM), according to research published in JCO Clinical Cancer Informatics.

Researchers found that screening for monoclonal gammopathy of undetermined significance (MGUS) might reduce the risk of MM in individuals with a high lifetime risk of MGUS, which includes men, African Americans, and people with a family history of MM.

The researchers said patients who screen positive for MGUS could seek medical care early and try strategies such as aspirin, metformin, or weight reduction to potentially reduce their risk of progression from MGUS to MM.

However, additional studies are needed to confirm the effectiveness of aspirin, metformin, and weight-loss strategies in preventing MGUS progression.

“Screening for MGUS may have significant benefits by lowering the incidence of multiple myeloma, provided that effective and non-toxic interventions can be identified,” said study author Philipp Altrock, PhD, of Moffitt Cancer Center in Tampa, Florida.

Dr Altrock and his colleagues performed a series of computational modeling experiments to determine the best screening strategies in different groups of patients. The goal was to determine when screening should begin, how often it should occur, and in which individuals it could be most effective.

The researchers designed their model to predict the progression of MGUS to MM, the changes in MGUS and MM prevalence, and the annual follow-up mortality due to disease.

The team found evidence to suggest that screening strategies could reduce the risk of progression and the prevalence of MM. This effect was more pronounced in individuals who had a higher risk of MGUS.

Modeling suggested the prevalence of MM could be reduced by 19% in patients who begin screening at age 55 and have follow-up screening every 6 years.

A similar reduction in prevalence could also be achieved by starting screening at age 65 and following up every 2 years.

“Regular screening of MGUS candidates should start as early as possible, with biannual follow-up, and focus on high-risk individuals, especially with a family history of multiple myeloma or in groups with a strong indication of MGUS progression,” Dr Altrock said.

showing multiple myeloma

Targeted screening could potentially reduce the prevalence of multiple myeloma (MM), according to research published in JCO Clinical Cancer Informatics.

Researchers found that screening for monoclonal gammopathy of undetermined significance (MGUS) might reduce the risk of MM in individuals with a high lifetime risk of MGUS, which includes men, African Americans, and people with a family history of MM.

The researchers said patients who screen positive for MGUS could seek medical care early and try strategies such as aspirin, metformin, or weight reduction to potentially reduce their risk of progression from MGUS to MM.

However, additional studies are needed to confirm the effectiveness of aspirin, metformin, and weight-loss strategies in preventing MGUS progression.

“Screening for MGUS may have significant benefits by lowering the incidence of multiple myeloma, provided that effective and non-toxic interventions can be identified,” said study author Philipp Altrock, PhD, of Moffitt Cancer Center in Tampa, Florida.

Dr Altrock and his colleagues performed a series of computational modeling experiments to determine the best screening strategies in different groups of patients. The goal was to determine when screening should begin, how often it should occur, and in which individuals it could be most effective.

The researchers designed their model to predict the progression of MGUS to MM, the changes in MGUS and MM prevalence, and the annual follow-up mortality due to disease.

The team found evidence to suggest that screening strategies could reduce the risk of progression and the prevalence of MM. This effect was more pronounced in individuals who had a higher risk of MGUS.

Modeling suggested the prevalence of MM could be reduced by 19% in patients who begin screening at age 55 and have follow-up screening every 6 years.

A similar reduction in prevalence could also be achieved by starting screening at age 65 and following up every 2 years.

“Regular screening of MGUS candidates should start as early as possible, with biannual follow-up, and focus on high-risk individuals, especially with a family history of multiple myeloma or in groups with a strong indication of MGUS progression,” Dr Altrock said.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for moxetumomab pasudotox, an investigational anti-CD22 recombinant immunotoxin.

With this BLA, AstraZeneca is seeking approval for moxetumomab pasudotox for the treatment of adults with hairy cell leukemia (HCL) who have received at least 2 prior lines of therapy.

The FDA expects to make a decision on the BLA in the third quarter of this year.

The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The agency grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

About moxetumomab pasudotox

Moxetumomab pasudotox (formerly CAT-8015 or HA22) is composed of a binding portion of an anti-CD22 antibody fused to a toxin. After binding to CD22, the molecule is internalized, processed, and releases its modified protein toxin, which inhibits protein translation and leads to apoptosis.

In addition to priority review, moxetumomab pasudotox has received orphan drug designation from the FDA.

Moxetumomab pasudotox has been tested in a phase 1 trial. Initial results from this trial were published in the Journal of Clinical Oncology in 2012. Long-term follow-up was presented at the 2017 ASH Annual Meeting.

The ASH data included 49 patients with relapsed/refractory HCL. Their median age was 57 (range, 40-77), most (n=41) were male, and they had a median of 35 (range, 1-60,444) circulating HCL cells/mm³ at baseline (in 48 evaluable patients).

Twenty-eight patients received moxetumomab pasudotox in the dose-escalation portion of the study—at 5, 10, 20, 30, 40, or 50 µg/kg—and 21 received the drug at 50 µg/kg for the extension portion of the study.

Among the 33 patients who received moxetumomab pasudotox at 50 µg/kg, the overall response rate was 88%, and the complete response (CR) rate was 64% (n=21). The median time to CR was 3.6 months, and the median duration of CR was 70.3 months.

The median follow-up was 75 months for the entire study population. At 72 months, the progression-free survival (PFS) rate was 77%.

The researchers found that minimal residual disease (MRD) negativity (via immunohistochemistry) was associated with extended response duration and prolonged PFS.

The MRD evaluation included 19 MRD+ patients and 18 MRD- patients. Forty-seven percent of the MRD+ patients (n=9) and 94% of the MRD- patients (n=17) had a CR as their best response.

The median duration of CR was 13.1 months among the MRD+ patients and was not reached among the MRD- patients (P=0.0002). The median PFS was 82.1 months among the MRD+ patients and not reached among the MRD- patients (P=0.0031).

Moxetumomab pasudotox did not undergo phase 2 testing but proceeded to a phase 3 trial. In this single-arm study, researchers evaluated the drug in HCL patients who had received at least 2 prior therapies.

According to AstraZeneca, the study’s primary endpoint—durable CR—was met. The company said the phase 3 results will be presented at an upcoming medical meeting.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for moxetumomab pasudotox, an investigational anti-CD22 recombinant immunotoxin.

With this BLA, AstraZeneca is seeking approval for moxetumomab pasudotox for the treatment of adults with hairy cell leukemia (HCL) who have received at least 2 prior lines of therapy.

The FDA expects to make a decision on the BLA in the third quarter of this year.

The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The agency grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

About moxetumomab pasudotox

Moxetumomab pasudotox (formerly CAT-8015 or HA22) is composed of a binding portion of an anti-CD22 antibody fused to a toxin. After binding to CD22, the molecule is internalized, processed, and releases its modified protein toxin, which inhibits protein translation and leads to apoptosis.

In addition to priority review, moxetumomab pasudotox has received orphan drug designation from the FDA.

Moxetumomab pasudotox has been tested in a phase 1 trial. Initial results from this trial were published in the Journal of Clinical Oncology in 2012. Long-term follow-up was presented at the 2017 ASH Annual Meeting.

The ASH data included 49 patients with relapsed/refractory HCL. Their median age was 57 (range, 40-77), most (n=41) were male, and they had a median of 35 (range, 1-60,444) circulating HCL cells/mm³ at baseline (in 48 evaluable patients).

Twenty-eight patients received moxetumomab pasudotox in the dose-escalation portion of the study—at 5, 10, 20, 30, 40, or 50 µg/kg—and 21 received the drug at 50 µg/kg for the extension portion of the study.

Among the 33 patients who received moxetumomab pasudotox at 50 µg/kg, the overall response rate was 88%, and the complete response (CR) rate was 64% (n=21). The median time to CR was 3.6 months, and the median duration of CR was 70.3 months.

The median follow-up was 75 months for the entire study population. At 72 months, the progression-free survival (PFS) rate was 77%.

The researchers found that minimal residual disease (MRD) negativity (via immunohistochemistry) was associated with extended response duration and prolonged PFS.

The MRD evaluation included 19 MRD+ patients and 18 MRD- patients. Forty-seven percent of the MRD+ patients (n=9) and 94% of the MRD- patients (n=17) had a CR as their best response.

The median duration of CR was 13.1 months among the MRD+ patients and was not reached among the MRD- patients (P=0.0002). The median PFS was 82.1 months among the MRD+ patients and not reached among the MRD- patients (P=0.0031).

Moxetumomab pasudotox did not undergo phase 2 testing but proceeded to a phase 3 trial. In this single-arm study, researchers evaluated the drug in HCL patients who had received at least 2 prior therapies.

According to AstraZeneca, the study’s primary endpoint—durable CR—was met. The company said the phase 3 results will be presented at an upcoming medical meeting.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for moxetumomab pasudotox, an investigational anti-CD22 recombinant immunotoxin.

With this BLA, AstraZeneca is seeking approval for moxetumomab pasudotox for the treatment of adults with hairy cell leukemia (HCL) who have received at least 2 prior lines of therapy.

The FDA expects to make a decision on the BLA in the third quarter of this year.

The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The agency grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

About moxetumomab pasudotox

Moxetumomab pasudotox (formerly CAT-8015 or HA22) is composed of a binding portion of an anti-CD22 antibody fused to a toxin. After binding to CD22, the molecule is internalized, processed, and releases its modified protein toxin, which inhibits protein translation and leads to apoptosis.

In addition to priority review, moxetumomab pasudotox has received orphan drug designation from the FDA.

Moxetumomab pasudotox has been tested in a phase 1 trial. Initial results from this trial were published in the Journal of Clinical Oncology in 2012. Long-term follow-up was presented at the 2017 ASH Annual Meeting.

The ASH data included 49 patients with relapsed/refractory HCL. Their median age was 57 (range, 40-77), most (n=41) were male, and they had a median of 35 (range, 1-60,444) circulating HCL cells/mm³ at baseline (in 48 evaluable patients).

Twenty-eight patients received moxetumomab pasudotox in the dose-escalation portion of the study—at 5, 10, 20, 30, 40, or 50 µg/kg—and 21 received the drug at 50 µg/kg for the extension portion of the study.

Among the 33 patients who received moxetumomab pasudotox at 50 µg/kg, the overall response rate was 88%, and the complete response (CR) rate was 64% (n=21). The median time to CR was 3.6 months, and the median duration of CR was 70.3 months.

The median follow-up was 75 months for the entire study population. At 72 months, the progression-free survival (PFS) rate was 77%.

The researchers found that minimal residual disease (MRD) negativity (via immunohistochemistry) was associated with extended response duration and prolonged PFS.

The MRD evaluation included 19 MRD+ patients and 18 MRD- patients. Forty-seven percent of the MRD+ patients (n=9) and 94% of the MRD- patients (n=17) had a CR as their best response.

The median duration of CR was 13.1 months among the MRD+ patients and was not reached among the MRD- patients (P=0.0002). The median PFS was 82.1 months among the MRD+ patients and not reached among the MRD- patients (P=0.0031).

Moxetumomab pasudotox did not undergo phase 2 testing but proceeded to a phase 3 trial. In this single-arm study, researchers evaluated the drug in HCL patients who had received at least 2 prior therapies.

According to AstraZeneca, the study’s primary endpoint—durable CR—was met. The company said the phase 3 results will be presented at an upcoming medical meeting.

The FP recognized this to be a Becker's nevus, also known as a Becker nevus.

This nevus, which tends to occur in adolescent males, presents as a brown patch (often with hair) that is located on the shoulder, back, or submammary area. The lesion may enlarge to cover an entire shoulder or upper arm. While the nevus in this case did not have hair, it did have increased acne within the area—another feature of Becker nevus.

Although it is called a nevus, it does not actually have nevus cells and has no malignant potential. It is a type of hamartoma—an abnormal mixture of cells and tissues normally found in the area of the body where the growth occurs. Becker nevi do not become melanoma because they lack melanocytes. Therefore, there is no reason to excise them. Generally, these lesions are large and the risks of excision for cosmetic reasons outweigh the benefits.

In this case, the patient and his mother were reassured that no treatment was needed and they opted to leave it alone.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith M, Usatine R. Benign nevi. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:945-952.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.

The FP recognized this to be a Becker's nevus, also known as a Becker nevus.

This nevus, which tends to occur in adolescent males, presents as a brown patch (often with hair) that is located on the shoulder, back, or submammary area. The lesion may enlarge to cover an entire shoulder or upper arm. While the nevus in this case did not have hair, it did have increased acne within the area—another feature of Becker nevus.

Although it is called a nevus, it does not actually have nevus cells and has no malignant potential. It is a type of hamartoma—an abnormal mixture of cells and tissues normally found in the area of the body where the growth occurs. Becker nevi do not become melanoma because they lack melanocytes. Therefore, there is no reason to excise them. Generally, these lesions are large and the risks of excision for cosmetic reasons outweigh the benefits.

In this case, the patient and his mother were reassured that no treatment was needed and they opted to leave it alone.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith M, Usatine R. Benign nevi. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:945-952.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.

The FP recognized this to be a Becker's nevus, also known as a Becker nevus.

This nevus, which tends to occur in adolescent males, presents as a brown patch (often with hair) that is located on the shoulder, back, or submammary area. The lesion may enlarge to cover an entire shoulder or upper arm. While the nevus in this case did not have hair, it did have increased acne within the area—another feature of Becker nevus.

Although it is called a nevus, it does not actually have nevus cells and has no malignant potential. It is a type of hamartoma—an abnormal mixture of cells and tissues normally found in the area of the body where the growth occurs. Becker nevi do not become melanoma because they lack melanocytes. Therefore, there is no reason to excise them. Generally, these lesions are large and the risks of excision for cosmetic reasons outweigh the benefits.

In this case, the patient and his mother were reassured that no treatment was needed and they opted to leave it alone.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith M, Usatine R. Benign nevi. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:945-952.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.

Patients with malignant pleural effusion treated with an indwelling pleural catheter have an improved chance of a positive outcome when talc administration is part of their procedure, suggest the results of a randomized, placebo-controlled study.

Malignant pleural effusion, which is usually caused by the spread of metastatic cancer, is typically treated by inducement of pleurodesis. Talc is probably the most effective agent for achieving this result, but there are drawbacks to using talc to induce pleurodesis. Patients who receive this treatment often need to stay in the hospital for 4-7 days, according to Rahul Bhatnagar, PhD, and the coauthors of a study published in the New England Journal of Medicine). Indwelling pleural catheters provide an “ambulatory alternative” for fluid management, they noted. In a noncomparative series of 22 patients, administering talc through such a catheter produced high rates of pleurodesis, they added.

In the new study, Dr. Bhatnagar of the Academic Respiratory Unit, University of Bristol, England, and his coauthors evaluated the use of an indwelling catheter, with or without talc, in patients with malignant pleural effusion recruited at 18 centers in the United Kingdom over 4 years.

“Our primary-outcome results, which were backed up by robust sensitivity analyses, strongly suggest that the administration of talc through an indwelling pleural catheter was significantly more efficacious than the use of an indwelling pleural catheter alone among patients without substantial lung entrapment,” the authors wrote.

A total of 154 patients underwent randomization to the talc or placebo group, and 139 had sufficient data to evaluate the primary outcome of successful pleurodesis at 35 days after randomization. The researchers excluded patients with evidence of lung entrapment, or nonexpandable lung, according to the study report.

In the talc group, pleurodesis was successful at day 35 in 30 of 69 patients (43%) versus 16 of 70 patients (23%) in the placebo group (P = .008).

At day 70, the success rate was 51% for the talc group vs. 27% for the placebo group, respectively.

The rate of pleurodesis was significantly higher when talc was administered through an indwelling pleural catheter, Dr. Bhatnagar and his colleagues noted.

“Success rates at day 70 suggested that pleurodesis was maintained to a point that is clinically relevant for patients with short median survival,” they added.

No excess of side effects or catheter blockages were associated with talc vs. placebo administration through a catheter. Additionally, no differences were seen between the talc and placebo groups in the number of adverse events, number of inpatient days, mortality, or other outcomes tracked by the researchers.

Dr. Bhatnagar reported he had no disclosures related to the study. Study coauthors reported disclosures related to Becton Dickinson – CareFusion, Rosetrees Trust, GE Medical, and Rocket Medical. Becton Dickinson supported the trial with an unrestricted research grant and supplied catheters and drainage bottles for the study’s participants.

SOURCE: Bhatnagar R et al. N Engl J Med. 2018;378:1313-22.

Patients with malignant pleural effusion treated with an indwelling pleural catheter have an improved chance of a positive outcome when talc administration is part of their procedure, suggest the results of a randomized, placebo-controlled study.

Malignant pleural effusion, which is usually caused by the spread of metastatic cancer, is typically treated by inducement of pleurodesis. Talc is probably the most effective agent for achieving this result, but there are drawbacks to using talc to induce pleurodesis. Patients who receive this treatment often need to stay in the hospital for 4-7 days, according to Rahul Bhatnagar, PhD, and the coauthors of a study published in the New England Journal of Medicine). Indwelling pleural catheters provide an “ambulatory alternative” for fluid management, they noted. In a noncomparative series of 22 patients, administering talc through such a catheter produced high rates of pleurodesis, they added.

In the new study, Dr. Bhatnagar of the Academic Respiratory Unit, University of Bristol, England, and his coauthors evaluated the use of an indwelling catheter, with or without talc, in patients with malignant pleural effusion recruited at 18 centers in the United Kingdom over 4 years.

“Our primary-outcome results, which were backed up by robust sensitivity analyses, strongly suggest that the administration of talc through an indwelling pleural catheter was significantly more efficacious than the use of an indwelling pleural catheter alone among patients without substantial lung entrapment,” the authors wrote.

A total of 154 patients underwent randomization to the talc or placebo group, and 139 had sufficient data to evaluate the primary outcome of successful pleurodesis at 35 days after randomization. The researchers excluded patients with evidence of lung entrapment, or nonexpandable lung, according to the study report.

In the talc group, pleurodesis was successful at day 35 in 30 of 69 patients (43%) versus 16 of 70 patients (23%) in the placebo group (P = .008).

At day 70, the success rate was 51% for the talc group vs. 27% for the placebo group, respectively.

The rate of pleurodesis was significantly higher when talc was administered through an indwelling pleural catheter, Dr. Bhatnagar and his colleagues noted.

“Success rates at day 70 suggested that pleurodesis was maintained to a point that is clinically relevant for patients with short median survival,” they added.

No excess of side effects or catheter blockages were associated with talc vs. placebo administration through a catheter. Additionally, no differences were seen between the talc and placebo groups in the number of adverse events, number of inpatient days, mortality, or other outcomes tracked by the researchers.

Dr. Bhatnagar reported he had no disclosures related to the study. Study coauthors reported disclosures related to Becton Dickinson – CareFusion, Rosetrees Trust, GE Medical, and Rocket Medical. Becton Dickinson supported the trial with an unrestricted research grant and supplied catheters and drainage bottles for the study’s participants.

SOURCE: Bhatnagar R et al. N Engl J Med. 2018;378:1313-22.

Patients with malignant pleural effusion treated with an indwelling pleural catheter have an improved chance of a positive outcome when talc administration is part of their procedure, suggest the results of a randomized, placebo-controlled study.

Malignant pleural effusion, which is usually caused by the spread of metastatic cancer, is typically treated by inducement of pleurodesis. Talc is probably the most effective agent for achieving this result, but there are drawbacks to using talc to induce pleurodesis. Patients who receive this treatment often need to stay in the hospital for 4-7 days, according to Rahul Bhatnagar, PhD, and the coauthors of a study published in the New England Journal of Medicine). Indwelling pleural catheters provide an “ambulatory alternative” for fluid management, they noted. In a noncomparative series of 22 patients, administering talc through such a catheter produced high rates of pleurodesis, they added.

In the new study, Dr. Bhatnagar of the Academic Respiratory Unit, University of Bristol, England, and his coauthors evaluated the use of an indwelling catheter, with or without talc, in patients with malignant pleural effusion recruited at 18 centers in the United Kingdom over 4 years.

“Our primary-outcome results, which were backed up by robust sensitivity analyses, strongly suggest that the administration of talc through an indwelling pleural catheter was significantly more efficacious than the use of an indwelling pleural catheter alone among patients without substantial lung entrapment,” the authors wrote.

A total of 154 patients underwent randomization to the talc or placebo group, and 139 had sufficient data to evaluate the primary outcome of successful pleurodesis at 35 days after randomization. The researchers excluded patients with evidence of lung entrapment, or nonexpandable lung, according to the study report.

In the talc group, pleurodesis was successful at day 35 in 30 of 69 patients (43%) versus 16 of 70 patients (23%) in the placebo group (P = .008).

At day 70, the success rate was 51% for the talc group vs. 27% for the placebo group, respectively.

The rate of pleurodesis was significantly higher when talc was administered through an indwelling pleural catheter, Dr. Bhatnagar and his colleagues noted.

“Success rates at day 70 suggested that pleurodesis was maintained to a point that is clinically relevant for patients with short median survival,” they added.

No excess of side effects or catheter blockages were associated with talc vs. placebo administration through a catheter. Additionally, no differences were seen between the talc and placebo groups in the number of adverse events, number of inpatient days, mortality, or other outcomes tracked by the researchers.

Dr. Bhatnagar reported he had no disclosures related to the study. Study coauthors reported disclosures related to Becton Dickinson – CareFusion, Rosetrees Trust, GE Medical, and Rocket Medical. Becton Dickinson supported the trial with an unrestricted research grant and supplied catheters and drainage bottles for the study’s participants.

SOURCE: Bhatnagar R et al. N Engl J Med. 2018;378:1313-22.

Overweight boys were more likely to develop type 2 diabetes in adulthood unless their weight normalized by the onset of puberty, a time marked by decreased insulin sensitivity, or by early adulthood, according to data from a study of Danish men.

“This large-scale longitudinal study showed that men who had remission of overweight between 7 and 13 years of age and had subsequently maintained a normal weight in early adulthood had a risk of type 2 diabetes similar to that among men with normal weights at all of these ages,” Lise G. Bjerregaard, PhD, of the Center for Clinical Research and Prevention in Copenhagen and her colleagues wrote in the New England Journal of Medicine.

Studies in adults have shown that lowering body weights and body mass indexes delayed the onset of type 2 diabetes. While correcting body mass index seems to benefit adults, little is known about how being overweight or obese as children and young adults can affect the risk for type 2 diabetes. This is a particularly pressing issue because almost a quarter of children in developed countries are either overweight or obese.

The investigators looked at the heights and weights of 62,565 Danish men during childhood, measured at 7 and 13 years of age, and during early adulthood between 17 and 26 years of age. The height and weight data were obtained from two national health databases. The Copenhagen School Health Record Register (CSHRR) contains information on most of the children in Copenhagen who attended school during 1930-1989. The researchers then corroborated the information from this database and connected it with data from the Danish Conscription Database, which included heights and weights of men born during 1939-1959 that was taken at conscription examinations. In addition, diagnoses of type 2 diabetes were obtained from the Danish National Patient Register.

A little more than 10% (6,710) of the 62,565 men in the study were diagnosed with type 2 diabetes during the course of the 2 million person-years of follow-up. The prevalence of being overweight increased from 5.4% to 8.2% from age 7 years of age to early adulthood.

The risk of developing type 2 diabetes was heavily dependent on how old patients were when they were overweight and at what age they reduced their bodyweight. Being overweight at any age corresponded to an increased risk of type 2 diabetes. Men who were overweight during early adulthood had the highest incidence of type 2 diabetes. An encouraging finding was that men who had been overweight at age 7 years but had reduced their bodyweight by age 13 years and maintained a stable bodyweight as young men had a risk of being diagnosed similar to men who had never been overweight (hazard ratio, 0.96; 95% confidence interval, 0.75-1.21). Similarly, men who had been overweight only at age 13 years or between ages 7 and 13 years had a lower risks of developing type 2 diabetes than did men who had been persistently overweight, but the risks were still higher than in men who had never been overweight (overweight only at 7 and 13 years of age vs. never overweight: HR , 1.47; 95% CI, 1.10-1.9; persistently overweight vs. never overweight: HR, 4.14; 95% CI, 3.57-4.79). Men who had been overweight later in life had a higher risk of type 2 diabetes, compared with men who were only overweight as young adults, but the risk was similar to men who had been overweight at all ages.

The findings from this study are supported by the large sample size and the length of follow-up. Unfortunately, the researchers analyzed exclusively men and no information was available for early-life explanatory factors like pubertal timing and parental socioeconomic class or later-life body mass index.

SOURCE: Bjerregaard L et al. N Engl J Med. 2018 Apr 04. doi: 10.1056/NEJMoa1713231.

Overweight boys were more likely to develop type 2 diabetes in adulthood unless their weight normalized by the onset of puberty, a time marked by decreased insulin sensitivity, or by early adulthood, according to data from a study of Danish men.

“This large-scale longitudinal study showed that men who had remission of overweight between 7 and 13 years of age and had subsequently maintained a normal weight in early adulthood had a risk of type 2 diabetes similar to that among men with normal weights at all of these ages,” Lise G. Bjerregaard, PhD, of the Center for Clinical Research and Prevention in Copenhagen and her colleagues wrote in the New England Journal of Medicine.

Studies in adults have shown that lowering body weights and body mass indexes delayed the onset of type 2 diabetes. While correcting body mass index seems to benefit adults, little is known about how being overweight or obese as children and young adults can affect the risk for type 2 diabetes. This is a particularly pressing issue because almost a quarter of children in developed countries are either overweight or obese.

The investigators looked at the heights and weights of 62,565 Danish men during childhood, measured at 7 and 13 years of age, and during early adulthood between 17 and 26 years of age. The height and weight data were obtained from two national health databases. The Copenhagen School Health Record Register (CSHRR) contains information on most of the children in Copenhagen who attended school during 1930-1989. The researchers then corroborated the information from this database and connected it with data from the Danish Conscription Database, which included heights and weights of men born during 1939-1959 that was taken at conscription examinations. In addition, diagnoses of type 2 diabetes were obtained from the Danish National Patient Register.

A little more than 10% (6,710) of the 62,565 men in the study were diagnosed with type 2 diabetes during the course of the 2 million person-years of follow-up. The prevalence of being overweight increased from 5.4% to 8.2% from age 7 years of age to early adulthood.

The risk of developing type 2 diabetes was heavily dependent on how old patients were when they were overweight and at what age they reduced their bodyweight. Being overweight at any age corresponded to an increased risk of type 2 diabetes. Men who were overweight during early adulthood had the highest incidence of type 2 diabetes. An encouraging finding was that men who had been overweight at age 7 years but had reduced their bodyweight by age 13 years and maintained a stable bodyweight as young men had a risk of being diagnosed similar to men who had never been overweight (hazard ratio, 0.96; 95% confidence interval, 0.75-1.21). Similarly, men who had been overweight only at age 13 years or between ages 7 and 13 years had a lower risks of developing type 2 diabetes than did men who had been persistently overweight, but the risks were still higher than in men who had never been overweight (overweight only at 7 and 13 years of age vs. never overweight: HR , 1.47; 95% CI, 1.10-1.9; persistently overweight vs. never overweight: HR, 4.14; 95% CI, 3.57-4.79). Men who had been overweight later in life had a higher risk of type 2 diabetes, compared with men who were only overweight as young adults, but the risk was similar to men who had been overweight at all ages.

The findings from this study are supported by the large sample size and the length of follow-up. Unfortunately, the researchers analyzed exclusively men and no information was available for early-life explanatory factors like pubertal timing and parental socioeconomic class or later-life body mass index.

SOURCE: Bjerregaard L et al. N Engl J Med. 2018 Apr 04. doi: 10.1056/NEJMoa1713231.

Overweight boys were more likely to develop type 2 diabetes in adulthood unless their weight normalized by the onset of puberty, a time marked by decreased insulin sensitivity, or by early adulthood, according to data from a study of Danish men.

“This large-scale longitudinal study showed that men who had remission of overweight between 7 and 13 years of age and had subsequently maintained a normal weight in early adulthood had a risk of type 2 diabetes similar to that among men with normal weights at all of these ages,” Lise G. Bjerregaard, PhD, of the Center for Clinical Research and Prevention in Copenhagen and her colleagues wrote in the New England Journal of Medicine.

Studies in adults have shown that lowering body weights and body mass indexes delayed the onset of type 2 diabetes. While correcting body mass index seems to benefit adults, little is known about how being overweight or obese as children and young adults can affect the risk for type 2 diabetes. This is a particularly pressing issue because almost a quarter of children in developed countries are either overweight or obese.

The investigators looked at the heights and weights of 62,565 Danish men during childhood, measured at 7 and 13 years of age, and during early adulthood between 17 and 26 years of age. The height and weight data were obtained from two national health databases. The Copenhagen School Health Record Register (CSHRR) contains information on most of the children in Copenhagen who attended school during 1930-1989. The researchers then corroborated the information from this database and connected it with data from the Danish Conscription Database, which included heights and weights of men born during 1939-1959 that was taken at conscription examinations. In addition, diagnoses of type 2 diabetes were obtained from the Danish National Patient Register.

A little more than 10% (6,710) of the 62,565 men in the study were diagnosed with type 2 diabetes during the course of the 2 million person-years of follow-up. The prevalence of being overweight increased from 5.4% to 8.2% from age 7 years of age to early adulthood.

The risk of developing type 2 diabetes was heavily dependent on how old patients were when they were overweight and at what age they reduced their bodyweight. Being overweight at any age corresponded to an increased risk of type 2 diabetes. Men who were overweight during early adulthood had the highest incidence of type 2 diabetes. An encouraging finding was that men who had been overweight at age 7 years but had reduced their bodyweight by age 13 years and maintained a stable bodyweight as young men had a risk of being diagnosed similar to men who had never been overweight (hazard ratio, 0.96; 95% confidence interval, 0.75-1.21). Similarly, men who had been overweight only at age 13 years or between ages 7 and 13 years had a lower risks of developing type 2 diabetes than did men who had been persistently overweight, but the risks were still higher than in men who had never been overweight (overweight only at 7 and 13 years of age vs. never overweight: HR , 1.47; 95% CI, 1.10-1.9; persistently overweight vs. never overweight: HR, 4.14; 95% CI, 3.57-4.79). Men who had been overweight later in life had a higher risk of type 2 diabetes, compared with men who were only overweight as young adults, but the risk was similar to men who had been overweight at all ages.

The findings from this study are supported by the large sample size and the length of follow-up. Unfortunately, the researchers analyzed exclusively men and no information was available for early-life explanatory factors like pubertal timing and parental socioeconomic class or later-life body mass index.

SOURCE: Bjerregaard L et al. N Engl J Med. 2018 Apr 04. doi: 10.1056/NEJMoa1713231.

Cutaneous angiosarcoma is a rare malignant tumor of vascular endothelial cells that has the propensity to arise in various clinical settings. This tumor predominantly occurs in the head and neck region in elderly patients, but it also has been reported to develop postradiotherapy or in the setting of chronic lymphedema in the extremities.^1-3 In all settings, the diagnosis carries a very poor prognosis with a high likelihood of local recurrence and rapid dissemination. The mortality rate typically is 80% or higher.^2,4-6

Making the correct clinical diagnosis of cutaneous angiosarcoma may be difficult given the variety of patient symptoms and clinical appearances that can be demonstrated on presentation. Lesions can appear as bluish or violaceous plaques, macules, or nodules, and ulceration may be present in some advanced cases.^5,7 Clinical misdiagnosis is common, as cutaneous angiosarcomas may be mistaken for infectious processes, benign vascular malformations, and other cutaneous malignancies.¹ Biopsy often is delayed given the initial benign appearance of the lesions, and this frequently results in aggressive and extensive disease at the time of diagnosis, which is unfortunate given that small tumor size has been shown to be one of the only favorable prognostic indicators in cutaneous angiosarcoma.^1,2,6,8

Microscopically, diagnosis of cutaneous angiosarcoma can present a challenge, as the histology varies between a well-differentiated vascular neoplasm and a considerably anaplastic and poorly differentiated malignancy. On low power, some areas may appear as benign hemangiomas with other areas showing frank sarcomatous features.⁹ As a result, these tumors can be mistaken for a variety of other diseases including melanomas, carcinomas, or other vascular tumors.^6,8,9 Previously, electron microscopy has been utilized on undifferentiated tumors to help distinguish cutaneous angiosarcomas from other potential diagnoses. The atypical tumor cells of cutaneous angiosarcoma display common features of endothelial cells (eg, pinocytotic vesicles, tubulated bodies).⁷ Historically, it has been noted that the histologic findings and tumor grade provide little evidence regarding the aggressiveness of the tumor, and all cutaneous angiosarcoma diagnoses receive a poor prognosis.^6,8

Classically, the histologic findings of cutaneous angiosarcoma include a highly infiltrative neoplasm forming irregular vascular channels that penetrate through the cutaneous soft tissues and frequently extend into the subcutaneous fat. The vascular spaces are lined by hyperchromatic endothelial cells with varying degrees of atypia.^1,2,4,6,7,10 Occasionally, prominent endothelial cells lining a papillary structure within the lumen of the neoformed vessel may also be observed. Currently, immunohistochemical staining for MYC, Ki-67, D2-40, and various other markers complement the histologic findings to aid in the diagnosis of cutaneous angiosarcoma.^11,12 An additional diagnostic clue that has been described in cases of postirradiation cutaneous angiosarcoma shows free-floating or tufted pleomorphic spindle cells within the vascular lumen (Figure). This finding has been described as “fish in the creek.”¹¹ In this study, we aimed to determine the frequency and subsequent diagnostic utility of the fish-in-the-creek finding in cases of cutaneous angiosarcoma.

Methods

A natural language search of our institutional archives over a 20-year period (1997–2017) using the term angiosarcoma was performed. Fifteen cases of cutaneous angiosarcoma were identified. Fifteen additional benign and malignant vascular tumors with cutaneous angiosarcoma in the histologic differential diagnosis were selected from the archives over a similar time frame. The additional lesions included Kaposi sarcoma (n=3), atypical vascular lesion (n=6), atypical hemangioma (n=1), tufted angioma (n=1), epithelioid hemangioma (n=1), epithelioid hemangioendothelioma (n=1), sinusoidal hemangioma (n=1), and angiofibroma (n=1). The pathologists were blinded to the original diagnosis of each case and were instructed to evaluate the histology slides for the sole feature of free-floating intraluminal spindle cells or spindle cells tufting off the endothelium. Epithelial cells lining papillae found within the vessel lumen were not counted as a positive finding, as they do not fit the criteria described for the histologic pattern of fish in the creek. Following microscopic evaluation, the original diagnoses were reassigned to their respective cases to evaluate the diagnostic utility of this feature.

Results

The histologic pattern of fish in the creek was identified in all 15 cases of cutaneous angiosarcoma and was absent in the other 15 malignancies examined in this study. This finding shows the potential for the fish-in-the-creek pattern to be used as an additional diagnostic tool for dermatopathologists.

Comment

Cutaneous angiosarcoma is a rare but aggressive malignancy that proves difficult to diagnose both clinically and histologically as well as to treat effectively.^1,5-8 Our results indicate that fish in the creek may be a useful and salient histologic feature in cutaneous angiosarcoma. It is important to recognize, however, that this finding should not be the sole feature upon which a diagnosis of cutaneous angiosarcoma is made, as it requires corroboration with positivity of MYC and D2-40 as well as a high Ki-67 proliferation index (>20%).^11,12 Finding a fish-in-the-creek pattern should prompt dermatopathologists to consider a diagnosis of cutaneous angiosarcoma in the appropriate clinical and histologic settings.

The chief limitation of this study was the small sample size, with only 15 cases of cutaneous angiosarcoma available in the last 20 years at our institution. The limited sample size did not allow us to make claims on sensitivity and specificity regarding this histologic feature; however, with a larger sample size, the true diagnostic potential could be elucidated. Although the pathologists were blinded to the original diagnoses as they examined it for fish in the creek, it is possible they were able to make the correct diagnosis based on other histopathologic clues and therefore were biased.

Although the fish-in-the-creek pattern is present in cutaneous angiosarcoma, there may be other mimickers to consider. Intraluminal papillary projections lined by endothelial cells may be sectioned in a manner imitating this finding.³ In such a case, these endothelial cells must be differentiated from the free-floating or tufted spindle cells in order to have a positive finding for fish in the creek. There can be confusion if the biopsy cuts through a section of spindled cells, resulting in difficulty differentiating cutaneous angiosarcoma from other spindle tumors such as spindle cell melanoma or spindle cell squamous cell carcinoma.⁶ In such cases, immunohistochemistry may be helpful, as spindle cell melanoma would stain positive for S100 and SOX10 and spindle cell squamous cell carcinoma would stain positive for p63 and cytokeratin.

Various treatment strategies for cutaneous angiosarcoma have been employed, with the majority still resulting in poor outcomes.^2,4-6 The recommended treatment is radical surgical excision of the primary tumor with lymph node clearance if possible. Following excision, the patient should undergo high-dose, wide-field radiotherapy to the region.^5,8 Cutaneous angiosarcomas also have the ability to spread extensively through the dermis and can result in subclinical or clinically obvious widespread disease with multifocal or satellite lesions present. Distant metastases occur most frequently in the cervical lymph nodes and lungs.⁷ In cases where the disease is too extensive for surgery, palliative radiation monotherapy can be used.^5,6

As atypical vascular lesions are considered to be a precursor to cutaneous angiosarcoma, it is important to note that the fish-in-the-creek feature was absent in all 6 of the atypical vascular lesions observed in the study. The differentiation generally is made based on MYC, which is present in cutaneous angiosarcomas and absent in atypical vascular lesions.¹⁰ The feature of fish in the creek may now be an additional clue for dermatopathologists to differentiate between angiosarcomas and other similar-appearing tumors.

Conclusion

Our study aimed to highlight an important histologic feature of cutaneous angiosarcomas that can aid in the diagnosis of this deceptive malignancy. Our findings warrant further study of the fish-in-the-creek histologic pattern in a larger sample size to determine its success as a diagnostic tool for cutaneous angiosarcomas. As noted previously, tumor grade does not impact survival outcome, but small tumor size has been one of the only features found to result in a more favorable prognosis.^1,6,8 Future studies to identify a correlation between the histologic finding of fish in the creek and disease outcome in cutaneous angiosarcoma may be helpful to determine if these histologic findings provide prognostic significance in cases of cutaneous angiosarcoma.

Cutaneous angiosarcoma is a rare malignant tumor of vascular endothelial cells that has the propensity to arise in various clinical settings. This tumor predominantly occurs in the head and neck region in elderly patients, but it also has been reported to develop postradiotherapy or in the setting of chronic lymphedema in the extremities.^1-3 In all settings, the diagnosis carries a very poor prognosis with a high likelihood of local recurrence and rapid dissemination. The mortality rate typically is 80% or higher.^2,4-6

Making the correct clinical diagnosis of cutaneous angiosarcoma may be difficult given the variety of patient symptoms and clinical appearances that can be demonstrated on presentation. Lesions can appear as bluish or violaceous plaques, macules, or nodules, and ulceration may be present in some advanced cases.^5,7 Clinical misdiagnosis is common, as cutaneous angiosarcomas may be mistaken for infectious processes, benign vascular malformations, and other cutaneous malignancies.¹ Biopsy often is delayed given the initial benign appearance of the lesions, and this frequently results in aggressive and extensive disease at the time of diagnosis, which is unfortunate given that small tumor size has been shown to be one of the only favorable prognostic indicators in cutaneous angiosarcoma.^1,2,6,8

Microscopically, diagnosis of cutaneous angiosarcoma can present a challenge, as the histology varies between a well-differentiated vascular neoplasm and a considerably anaplastic and poorly differentiated malignancy. On low power, some areas may appear as benign hemangiomas with other areas showing frank sarcomatous features.⁹ As a result, these tumors can be mistaken for a variety of other diseases including melanomas, carcinomas, or other vascular tumors.^6,8,9 Previously, electron microscopy has been utilized on undifferentiated tumors to help distinguish cutaneous angiosarcomas from other potential diagnoses. The atypical tumor cells of cutaneous angiosarcoma display common features of endothelial cells (eg, pinocytotic vesicles, tubulated bodies).⁷ Historically, it has been noted that the histologic findings and tumor grade provide little evidence regarding the aggressiveness of the tumor, and all cutaneous angiosarcoma diagnoses receive a poor prognosis.^6,8

Classically, the histologic findings of cutaneous angiosarcoma include a highly infiltrative neoplasm forming irregular vascular channels that penetrate through the cutaneous soft tissues and frequently extend into the subcutaneous fat. The vascular spaces are lined by hyperchromatic endothelial cells with varying degrees of atypia.^1,2,4,6,7,10 Occasionally, prominent endothelial cells lining a papillary structure within the lumen of the neoformed vessel may also be observed. Currently, immunohistochemical staining for MYC, Ki-67, D2-40, and various other markers complement the histologic findings to aid in the diagnosis of cutaneous angiosarcoma.^11,12 An additional diagnostic clue that has been described in cases of postirradiation cutaneous angiosarcoma shows free-floating or tufted pleomorphic spindle cells within the vascular lumen (Figure). This finding has been described as “fish in the creek.”¹¹ In this study, we aimed to determine the frequency and subsequent diagnostic utility of the fish-in-the-creek finding in cases of cutaneous angiosarcoma.

Methods

A natural language search of our institutional archives over a 20-year period (1997–2017) using the term angiosarcoma was performed. Fifteen cases of cutaneous angiosarcoma were identified. Fifteen additional benign and malignant vascular tumors with cutaneous angiosarcoma in the histologic differential diagnosis were selected from the archives over a similar time frame. The additional lesions included Kaposi sarcoma (n=3), atypical vascular lesion (n=6), atypical hemangioma (n=1), tufted angioma (n=1), epithelioid hemangioma (n=1), epithelioid hemangioendothelioma (n=1), sinusoidal hemangioma (n=1), and angiofibroma (n=1). The pathologists were blinded to the original diagnosis of each case and were instructed to evaluate the histology slides for the sole feature of free-floating intraluminal spindle cells or spindle cells tufting off the endothelium. Epithelial cells lining papillae found within the vessel lumen were not counted as a positive finding, as they do not fit the criteria described for the histologic pattern of fish in the creek. Following microscopic evaluation, the original diagnoses were reassigned to their respective cases to evaluate the diagnostic utility of this feature.

Results

The histologic pattern of fish in the creek was identified in all 15 cases of cutaneous angiosarcoma and was absent in the other 15 malignancies examined in this study. This finding shows the potential for the fish-in-the-creek pattern to be used as an additional diagnostic tool for dermatopathologists.

Comment

Cutaneous angiosarcoma is a rare but aggressive malignancy that proves difficult to diagnose both clinically and histologically as well as to treat effectively.^1,5-8 Our results indicate that fish in the creek may be a useful and salient histologic feature in cutaneous angiosarcoma. It is important to recognize, however, that this finding should not be the sole feature upon which a diagnosis of cutaneous angiosarcoma is made, as it requires corroboration with positivity of MYC and D2-40 as well as a high Ki-67 proliferation index (>20%).^11,12 Finding a fish-in-the-creek pattern should prompt dermatopathologists to consider a diagnosis of cutaneous angiosarcoma in the appropriate clinical and histologic settings.

The chief limitation of this study was the small sample size, with only 15 cases of cutaneous angiosarcoma available in the last 20 years at our institution. The limited sample size did not allow us to make claims on sensitivity and specificity regarding this histologic feature; however, with a larger sample size, the true diagnostic potential could be elucidated. Although the pathologists were blinded to the original diagnoses as they examined it for fish in the creek, it is possible they were able to make the correct diagnosis based on other histopathologic clues and therefore were biased.

Although the fish-in-the-creek pattern is present in cutaneous angiosarcoma, there may be other mimickers to consider. Intraluminal papillary projections lined by endothelial cells may be sectioned in a manner imitating this finding.³ In such a case, these endothelial cells must be differentiated from the free-floating or tufted spindle cells in order to have a positive finding for fish in the creek. There can be confusion if the biopsy cuts through a section of spindled cells, resulting in difficulty differentiating cutaneous angiosarcoma from other spindle tumors such as spindle cell melanoma or spindle cell squamous cell carcinoma.⁶ In such cases, immunohistochemistry may be helpful, as spindle cell melanoma would stain positive for S100 and SOX10 and spindle cell squamous cell carcinoma would stain positive for p63 and cytokeratin.

Various treatment strategies for cutaneous angiosarcoma have been employed, with the majority still resulting in poor outcomes.^2,4-6 The recommended treatment is radical surgical excision of the primary tumor with lymph node clearance if possible. Following excision, the patient should undergo high-dose, wide-field radiotherapy to the region.^5,8 Cutaneous angiosarcomas also have the ability to spread extensively through the dermis and can result in subclinical or clinically obvious widespread disease with multifocal or satellite lesions present. Distant metastases occur most frequently in the cervical lymph nodes and lungs.⁷ In cases where the disease is too extensive for surgery, palliative radiation monotherapy can be used.^5,6

As atypical vascular lesions are considered to be a precursor to cutaneous angiosarcoma, it is important to note that the fish-in-the-creek feature was absent in all 6 of the atypical vascular lesions observed in the study. The differentiation generally is made based on MYC, which is present in cutaneous angiosarcomas and absent in atypical vascular lesions.¹⁰ The feature of fish in the creek may now be an additional clue for dermatopathologists to differentiate between angiosarcomas and other similar-appearing tumors.

Conclusion

Our study aimed to highlight an important histologic feature of cutaneous angiosarcomas that can aid in the diagnosis of this deceptive malignancy. Our findings warrant further study of the fish-in-the-creek histologic pattern in a larger sample size to determine its success as a diagnostic tool for cutaneous angiosarcomas. As noted previously, tumor grade does not impact survival outcome, but small tumor size has been one of the only features found to result in a more favorable prognosis.^1,6,8 Future studies to identify a correlation between the histologic finding of fish in the creek and disease outcome in cutaneous angiosarcoma may be helpful to determine if these histologic findings provide prognostic significance in cases of cutaneous angiosarcoma.

Cutaneous angiosarcoma is a rare malignant tumor of vascular endothelial cells that has the propensity to arise in various clinical settings. This tumor predominantly occurs in the head and neck region in elderly patients, but it also has been reported to develop postradiotherapy or in the setting of chronic lymphedema in the extremities.^1-3 In all settings, the diagnosis carries a very poor prognosis with a high likelihood of local recurrence and rapid dissemination. The mortality rate typically is 80% or higher.^2,4-6

Making the correct clinical diagnosis of cutaneous angiosarcoma may be difficult given the variety of patient symptoms and clinical appearances that can be demonstrated on presentation. Lesions can appear as bluish or violaceous plaques, macules, or nodules, and ulceration may be present in some advanced cases.^5,7 Clinical misdiagnosis is common, as cutaneous angiosarcomas may be mistaken for infectious processes, benign vascular malformations, and other cutaneous malignancies.¹ Biopsy often is delayed given the initial benign appearance of the lesions, and this frequently results in aggressive and extensive disease at the time of diagnosis, which is unfortunate given that small tumor size has been shown to be one of the only favorable prognostic indicators in cutaneous angiosarcoma.^1,2,6,8

Microscopically, diagnosis of cutaneous angiosarcoma can present a challenge, as the histology varies between a well-differentiated vascular neoplasm and a considerably anaplastic and poorly differentiated malignancy. On low power, some areas may appear as benign hemangiomas with other areas showing frank sarcomatous features.⁹ As a result, these tumors can be mistaken for a variety of other diseases including melanomas, carcinomas, or other vascular tumors.^6,8,9 Previously, electron microscopy has been utilized on undifferentiated tumors to help distinguish cutaneous angiosarcomas from other potential diagnoses. The atypical tumor cells of cutaneous angiosarcoma display common features of endothelial cells (eg, pinocytotic vesicles, tubulated bodies).⁷ Historically, it has been noted that the histologic findings and tumor grade provide little evidence regarding the aggressiveness of the tumor, and all cutaneous angiosarcoma diagnoses receive a poor prognosis.^6,8

Classically, the histologic findings of cutaneous angiosarcoma include a highly infiltrative neoplasm forming irregular vascular channels that penetrate through the cutaneous soft tissues and frequently extend into the subcutaneous fat. The vascular spaces are lined by hyperchromatic endothelial cells with varying degrees of atypia.^1,2,4,6,7,10 Occasionally, prominent endothelial cells lining a papillary structure within the lumen of the neoformed vessel may also be observed. Currently, immunohistochemical staining for MYC, Ki-67, D2-40, and various other markers complement the histologic findings to aid in the diagnosis of cutaneous angiosarcoma.^11,12 An additional diagnostic clue that has been described in cases of postirradiation cutaneous angiosarcoma shows free-floating or tufted pleomorphic spindle cells within the vascular lumen (Figure). This finding has been described as “fish in the creek.”¹¹ In this study, we aimed to determine the frequency and subsequent diagnostic utility of the fish-in-the-creek finding in cases of cutaneous angiosarcoma.

Methods

A natural language search of our institutional archives over a 20-year period (1997–2017) using the term angiosarcoma was performed. Fifteen cases of cutaneous angiosarcoma were identified. Fifteen additional benign and malignant vascular tumors with cutaneous angiosarcoma in the histologic differential diagnosis were selected from the archives over a similar time frame. The additional lesions included Kaposi sarcoma (n=3), atypical vascular lesion (n=6), atypical hemangioma (n=1), tufted angioma (n=1), epithelioid hemangioma (n=1), epithelioid hemangioendothelioma (n=1), sinusoidal hemangioma (n=1), and angiofibroma (n=1). The pathologists were blinded to the original diagnosis of each case and were instructed to evaluate the histology slides for the sole feature of free-floating intraluminal spindle cells or spindle cells tufting off the endothelium. Epithelial cells lining papillae found within the vessel lumen were not counted as a positive finding, as they do not fit the criteria described for the histologic pattern of fish in the creek. Following microscopic evaluation, the original diagnoses were reassigned to their respective cases to evaluate the diagnostic utility of this feature.

Results

The histologic pattern of fish in the creek was identified in all 15 cases of cutaneous angiosarcoma and was absent in the other 15 malignancies examined in this study. This finding shows the potential for the fish-in-the-creek pattern to be used as an additional diagnostic tool for dermatopathologists.

Comment

Cutaneous angiosarcoma is a rare but aggressive malignancy that proves difficult to diagnose both clinically and histologically as well as to treat effectively.^1,5-8 Our results indicate that fish in the creek may be a useful and salient histologic feature in cutaneous angiosarcoma. It is important to recognize, however, that this finding should not be the sole feature upon which a diagnosis of cutaneous angiosarcoma is made, as it requires corroboration with positivity of MYC and D2-40 as well as a high Ki-67 proliferation index (>20%).^11,12 Finding a fish-in-the-creek pattern should prompt dermatopathologists to consider a diagnosis of cutaneous angiosarcoma in the appropriate clinical and histologic settings.

The chief limitation of this study was the small sample size, with only 15 cases of cutaneous angiosarcoma available in the last 20 years at our institution. The limited sample size did not allow us to make claims on sensitivity and specificity regarding this histologic feature; however, with a larger sample size, the true diagnostic potential could be elucidated. Although the pathologists were blinded to the original diagnoses as they examined it for fish in the creek, it is possible they were able to make the correct diagnosis based on other histopathologic clues and therefore were biased.

Although the fish-in-the-creek pattern is present in cutaneous angiosarcoma, there may be other mimickers to consider. Intraluminal papillary projections lined by endothelial cells may be sectioned in a manner imitating this finding.³ In such a case, these endothelial cells must be differentiated from the free-floating or tufted spindle cells in order to have a positive finding for fish in the creek. There can be confusion if the biopsy cuts through a section of spindled cells, resulting in difficulty differentiating cutaneous angiosarcoma from other spindle tumors such as spindle cell melanoma or spindle cell squamous cell carcinoma.⁶ In such cases, immunohistochemistry may be helpful, as spindle cell melanoma would stain positive for S100 and SOX10 and spindle cell squamous cell carcinoma would stain positive for p63 and cytokeratin.

Various treatment strategies for cutaneous angiosarcoma have been employed, with the majority still resulting in poor outcomes.^2,4-6 The recommended treatment is radical surgical excision of the primary tumor with lymph node clearance if possible. Following excision, the patient should undergo high-dose, wide-field radiotherapy to the region.^5,8 Cutaneous angiosarcomas also have the ability to spread extensively through the dermis and can result in subclinical or clinically obvious widespread disease with multifocal or satellite lesions present. Distant metastases occur most frequently in the cervical lymph nodes and lungs.⁷ In cases where the disease is too extensive for surgery, palliative radiation monotherapy can be used.^5,6

As atypical vascular lesions are considered to be a precursor to cutaneous angiosarcoma, it is important to note that the fish-in-the-creek feature was absent in all 6 of the atypical vascular lesions observed in the study. The differentiation generally is made based on MYC, which is present in cutaneous angiosarcomas and absent in atypical vascular lesions.¹⁰ The feature of fish in the creek may now be an additional clue for dermatopathologists to differentiate between angiosarcomas and other similar-appearing tumors.

Conclusion

Our study aimed to highlight an important histologic feature of cutaneous angiosarcomas that can aid in the diagnosis of this deceptive malignancy. Our findings warrant further study of the fish-in-the-creek histologic pattern in a larger sample size to determine its success as a diagnostic tool for cutaneous angiosarcomas. As noted previously, tumor grade does not impact survival outcome, but small tumor size has been one of the only features found to result in a more favorable prognosis.^1,6,8 Future studies to identify a correlation between the histologic finding of fish in the creek and disease outcome in cutaneous angiosarcoma may be helpful to determine if these histologic findings provide prognostic significance in cases of cutaneous angiosarcoma.

CHICAGO – Levothyroxine treatment is associated with increased mortality in patients 65 years and older with subclinical hypothyroidism, according to a study presented at the annual meeting of the Endocrine Society.

With increased mortality and similar prevalence of atrial fibrillation and femoral fractures between study and control groups, physicians may want to reevaluate giving their elderly patients levothyroxine until more information is available, according to presenter Joseph Meyerovitch, MD, of Schneider Children’s Medical Center, Ramat Hasharon, Israel.

The case-control study included 416 patients 65 years or older with TSH levels of 4.2-10 mIU/L who died between 2012 and 2016, and 1,461 patients with comparable TSH levels who did not die during that time.

Most of the patients in both the control and study group were women. The average age of the patients was 84 years, and most had some form of dementia or senility (86.4%).

Mortality was 19% more likely in the group taking levothyroxine, according to an analysis by Dr. Meyerovitch and his fellow investigators.

When broken down further, presence of certain comorbidities increased mortality dramatically, including dementia (odds ratio, 1.61), heart failure (OR, 2.67), chronic renal failure (OR, 1.89), and cerebrovascular disease (OR, 1.94).

There was no significant difference in prevalence of atrial fibrillation between the test and control groups with thyroid stimulating hormone (TSH) testing, nor any difference in femur fracture prevalence.

Patients were given a TSH test three times during follow-up and showed significantly lower TSH levels compared with controls, according to Dr. Meyerovitch.

Dr. Meyerovitch acknowledged that the data he and his team used did not include the reason for a TSH evaluation, nor why patients began levothyroxine treatment. This leaves unanswered questions about the initial baseline mortality risk in patients included in the study.

“This may have resulted in treatment of patients with a higher risk, since we don’t know the reason for the treatment,” he said. “There may have been other reasons that were not included in the database that caused the physician to treat with levothyroxine.”

Details on the cause of death were not included.

Despite these limitations, Dr. Meyerovitch and his team stressed the need for more research before continuing to recommend this treatment to their elderly patients.

Dr. Meyerovitch reported no relevant financial disclosures.

[email protected]

Source: Meyerovitch J et al. ENDO 2018 Abstract OR34-2.

CHICAGO – Levothyroxine treatment is associated with increased mortality in patients 65 years and older with subclinical hypothyroidism, according to a study presented at the annual meeting of the Endocrine Society.

With increased mortality and similar prevalence of atrial fibrillation and femoral fractures between study and control groups, physicians may want to reevaluate giving their elderly patients levothyroxine until more information is available, according to presenter Joseph Meyerovitch, MD, of Schneider Children’s Medical Center, Ramat Hasharon, Israel.

The case-control study included 416 patients 65 years or older with TSH levels of 4.2-10 mIU/L who died between 2012 and 2016, and 1,461 patients with comparable TSH levels who did not die during that time.

Most of the patients in both the control and study group were women. The average age of the patients was 84 years, and most had some form of dementia or senility (86.4%).

Mortality was 19% more likely in the group taking levothyroxine, according to an analysis by Dr. Meyerovitch and his fellow investigators.

When broken down further, presence of certain comorbidities increased mortality dramatically, including dementia (odds ratio, 1.61), heart failure (OR, 2.67), chronic renal failure (OR, 1.89), and cerebrovascular disease (OR, 1.94).

There was no significant difference in prevalence of atrial fibrillation between the test and control groups with thyroid stimulating hormone (TSH) testing, nor any difference in femur fracture prevalence.

Patients were given a TSH test three times during follow-up and showed significantly lower TSH levels compared with controls, according to Dr. Meyerovitch.

Dr. Meyerovitch acknowledged that the data he and his team used did not include the reason for a TSH evaluation, nor why patients began levothyroxine treatment. This leaves unanswered questions about the initial baseline mortality risk in patients included in the study.

“This may have resulted in treatment of patients with a higher risk, since we don’t know the reason for the treatment,” he said. “There may have been other reasons that were not included in the database that caused the physician to treat with levothyroxine.”

Details on the cause of death were not included.

Despite these limitations, Dr. Meyerovitch and his team stressed the need for more research before continuing to recommend this treatment to their elderly patients.

Dr. Meyerovitch reported no relevant financial disclosures.

[email protected]

Source: Meyerovitch J et al. ENDO 2018 Abstract OR34-2.

CHICAGO – Levothyroxine treatment is associated with increased mortality in patients 65 years and older with subclinical hypothyroidism, according to a study presented at the annual meeting of the Endocrine Society.

With increased mortality and similar prevalence of atrial fibrillation and femoral fractures between study and control groups, physicians may want to reevaluate giving their elderly patients levothyroxine until more information is available, according to presenter Joseph Meyerovitch, MD, of Schneider Children’s Medical Center, Ramat Hasharon, Israel.

The case-control study included 416 patients 65 years or older with TSH levels of 4.2-10 mIU/L who died between 2012 and 2016, and 1,461 patients with comparable TSH levels who did not die during that time.

Most of the patients in both the control and study group were women. The average age of the patients was 84 years, and most had some form of dementia or senility (86.4%).

Mortality was 19% more likely in the group taking levothyroxine, according to an analysis by Dr. Meyerovitch and his fellow investigators.

When broken down further, presence of certain comorbidities increased mortality dramatically, including dementia (odds ratio, 1.61), heart failure (OR, 2.67), chronic renal failure (OR, 1.89), and cerebrovascular disease (OR, 1.94).

There was no significant difference in prevalence of atrial fibrillation between the test and control groups with thyroid stimulating hormone (TSH) testing, nor any difference in femur fracture prevalence.

Patients were given a TSH test three times during follow-up and showed significantly lower TSH levels compared with controls, according to Dr. Meyerovitch.

Dr. Meyerovitch acknowledged that the data he and his team used did not include the reason for a TSH evaluation, nor why patients began levothyroxine treatment. This leaves unanswered questions about the initial baseline mortality risk in patients included in the study.

“This may have resulted in treatment of patients with a higher risk, since we don’t know the reason for the treatment,” he said. “There may have been other reasons that were not included in the database that caused the physician to treat with levothyroxine.”

Details on the cause of death were not included.

Despite these limitations, Dr. Meyerovitch and his team stressed the need for more research before continuing to recommend this treatment to their elderly patients.

Dr. Meyerovitch reported no relevant financial disclosures.

[email protected]

Source: Meyerovitch J et al. ENDO 2018 Abstract OR34-2.