Why is there a nationwide hospital shortage of injectable opioids? – follow the money. (part 3 of a continuing case study on the opioid crisis)

“The incident command system kicked in at Brigham and Women’s Hospital about a week ago. A large team of doctors, pharmacists, and nurses began assembling every morning to confront an emerging crisis with the potential to severely undermine care for patients.
The challenge was different than it was during the Boston Marathon bombing, another event that triggered the command response. This one wasn’t rushing toward caregivers as fast. But it was similarly daunting and logistically demanding: Amid a nationwide crisis caused by too-easy access to medical painkillers, hospitals are now struggling to find enough of that same class of drugs to keep their patients’ pain controlled.
That is the reality now facing Brigham and Women’s and other medical providers across the country. Production of injectable opioids has nearly ground to a halt due to manufacturing problems, creating a shortage of staple medications used to treat a wide array of patients. Alarms are now ringing at all kinds of medical providers, from sprawling academic hospitals to small hospice programs, and many are launching efforts to conserve injectable opioids and institute safeguards to prevent dosing errors that can result from rapid changes in medication regimens.” (A)

“The shortage, though more significant in some places than others, has left many hospitals and surgical centers scrambling to find enough injectable morphine, Dilaudid and fentanyl — drugs needed for patients undergoing surgery, fighting cancer or suffering traumatic injuries. The shortfall, which has intensified since last summer, was triggered by manufacturing setbacks and a government effort to reduce addiction by restricting drug production.
As a result, hospital pharmacists are working long hours to find alternatives, forcing nurses to administer second-choice drugs or deliver standard drugs differently. That raises the risk of mistakes — and already has led to at least a few instances in which patients received potentially harmful doses, according to the nonprofit Institute for Safe Medication Practices, which works with health care providers to promote patient safety.
In the institute’s survey of hospital pharmacists last year, one provider reported that a patient received five times the appropriate amount of morphine when a smaller-dose vial was out of stock. In another case, a patient was mistakenly given too much sufentanil, which is about 10 times more powerful than fentanyl, which was the ideal medication for that situation.
In response to the shortages, doctors in states as far-flung as California, Illinois and Alabama are improvising the best they can. Some patients are receiving less potent medications like acetaminophen or muscle relaxants as hospitals direct their scant supplies to higher-priority cases. Others patients are languishing in pain because preferred, more powerful medications aren’t available, or because they have to wait for substitute oral drugs to kick in.” (B)

The shortages involve prefilled syringes of these drugs, as well as small ampules and vials of liquid medication that can be added to bags of intravenous fluids.
Drug shortages are common, especially of certain injectable drugs, because few companies make them. But experts say opioid shortages carry a higher risk than other medications.
Giving the wrong dose of morphine, for example, “can lead to severe harm or fatalities,” explained Mike Ganio, a medication safety expert at the American Society of Health-System Pharmacists.
Calculating dosages can be difficult and seemingly small mistakes by pharmacists, doctors or nurses can make a big difference, experts said.
Marchelle Bernell, a nurse at St. Louis University Hospital in Missouri, said it would be easy for medical mistakes to occur during a shortage. For instance, in a fast-paced environment, a nurse could forget to program an electronic pump for the appropriate dose when given a mix of intravenous fluids and medication to which she was unaccustomed.
“The system has been set up safely for the drugs and the care processes that we ordinarily use,”…“You change those drugs, and you change those care processes, and the safety that we had built in is just not there anymore.”
Chicago-based Marti Smith, a nurse and spokeswoman for the National Nurses United union, offered an example.
“If your drug comes in a prefilled syringe and at 1 milligram, and you need to give 1 milligram, it’s easy,” she said. “But if you have to pull it out of a 25-milligram vial, you know, it’s not that we’re not smart enough to figure it out, it just adds another layer of possible error.” (C)

Experts say opioid pills are most often the culprits behind this abuse. It is not those drugs, but the liquid form that hospitals depend upon for general surgery, sedation, trauma treatment and pain management. And it is those drugs — namely ketamine, fentanyl and hydromorphone — that are in critically low supply.
Pfizer, a major injectable drug supplier, had to stop production of the medications after the Food and Drug Administration found problems at a manufacturing facility in Kansas. Work to upgrade the facility took longer than expected, Pfizer wrote in a letter to its customers in November.
In that letter, Pfizer said syringes would not be available until 2019.
Roper St. Francis’ medication safety officer, Kim Gaillard, said the system gets 60 percent of its IV opioid drugs from Pfizer…
Clinicians have had to find solutions. Gaillard was sure to stress there are other medications in many cases. Other types of painkillers have worked just as well in some surgeries, she said. The shortage has led the hospital system to speed up its review of different ways to deal with pain.
“I know that this is alarming,” Gaillard said, “but we have other strategies.”
Leaders at MUSC restricted ketamine, fentanyl and hydromophone to the system’s intensive care unit, emergency department and operating rooms. An email circulated to MUSC prescribers cited “critical shortages.”
Clinicians were told they need to convert all patients to morphine, if possible. The email warned further restrictions are possible.
Heather Easterling, administrator of pharmacy services at MUSC Medical Center, said in a statement the pharmacy team is working with wholesalers every day to order more of the medications. The DEA’s restrictions are at the heart of the issue, she said.
The DEA’s quotas are quarterly, so Easterling said the shortages hospitals are seeing may continue at least until mid-April.” (D)

“This fact sheet provides an outline of potential actions for organizations to consider in managing the acute shortages of injectable hydromorphone, morphine, and fentanyl. Healthcare professionals should use their professional judgment in deciding how to use the information in this document, taking into account the needs and resources of their individual organizations.
Critical importance
Shortages of injectable opioids can be particularly challenging due to the range of uses in various healthcare settings, including emergency response, ambulatory surgery centers, and hospitals. Injectable opioids are used for acute, acute-on-chronic, or chronic pain that cannot be controlled by other pain management options. Some injectable opioids are used for sedation or anesthesia. Intermittent shortages of specific injectable opioids may require institutions to convert temporarily to a more available product. Not all injectable opioids are interchangeable for all indications. Improper conversion between morphine and hydromorphone caused two deaths during a similar shortage in 2010.
ISMP Medication Error Reporting
ASHP encourages the reporting of any medication errors related to drug shortages to the Medication Error Reporting page on the Institute for Safe Medication Practices (ISMP) website.
What can clinicians do to mitigate the impact?
• Switch therapy to a clinically appropriate oral or enteral opioid whenever possible. o The Pharmacy and Therapeutics (P&T) committee should review current IV-to-oral policies; there may be an opportunity to expand policies to include drug classes affected by shortages.
• Provide multimodal pain management by using parenteral and enteral alternatives to opioids. Consider nonpharmacologic treatments, local nerve blocks, or other pharmacologic adjuncts, as appropriate.
• Engage the institution’s experts in anesthesia and pain and palliative medicine to further develop guidance and formulate strategies for dealing with intermittent shortages.
• Ensure relevant institutional pain medication guidelines are up to date. o To reduce the risk of conversion errors, use a uniform opioid conversion tool that is approved by the anesthesia team and the P&T committee and distributed throughout the entire health system. o Resources like the ASHP Demystifying Opioid Conversion Calculations reference may be helpful in establishing guidelines.
• Product availability can vary by wholesaler and may change from week to week. Guiding prescribers to choose between the available injectable opioids can help institutions reserve certain opioids for specific populations or indications (for example, reserve fentanyl for operating-room use). Use systemwide communications to alert all clinicians who prescribe, dispense, or administer injectable opioids.
• Ensure the electronic health record (EHR) displays opioid options that match the products currently in stock. Do not underestimate the informatics resources that will be needed during this shortage. Inventory control strategies
• Consider reserving supplies of specific injectable opioids for specific indications and limiting the placement.” (E)

“Regrettably, we believe the forecast for drug shortages is grim. There is little relief in sight to halt the rapid escalation of shortages in large part because the conditions that lead to shortages are varied and FDA lacks the necessary regulatory authority to proactively manage potential shortages. It is not always clear what causes drug shortages, as drug companies are not required to disclose the underlying reason or notify FDA regarding a decision to stop production unless they are the sole-provider of the product and it is a medically necessary product. Few manufacturers will supply letters to healthcare providers regarding the reason behind the shortage and the anticipated duration, which is very frustrating to healthcare personnel. The drug shortage lists maintained on the ASHP and FDA Web sites attempt to provide a reason for the shortage in very general terms.
Some of the more common reasons for drug shortages include the following:
– Unavailability of bulk and raw materials used to produce pharmaceuticals, of which 80% come from outside the US
– A delay or halt of production in response to an FDA enforcement action regarding noncompliance with good manufacturing practices identified during an inspection
– Voluntary recall of a drug after the manufacturer discovers a problem with the medication, such as inadvertent bacterial or fungal contamination
– Change in the manufacturer or product formulation (e.g., inhalers without chlorofluorocarbons) that delays production
– Manufacturer’s business decision to halt production of a drug due to availability of generic products, patent expiration, market size, drug approval status, regulatory compliance requirements, anticipated clinical demand, and/or reallocation of resources to other products (FDA does not have authority to require a company to continue manufacturing a medically necessary product)
– Manufacturer mergers that narrow the focus of product lines, causing discontinuation of certain products, or move production of a drug to a new facility, causing production delays
– Poor inventory ordering practices, stockpiling before price increases, and hoarding caused by rumors of an impending shortage
– Unexpected increases in demand for a drug when a new indication has been approved, usage changes due to new therapeutic guidelines, or a substantial disease outbreak occurs
– Natural disasters that involve manufacturing facilities or that lead to demands for certain classes of medications to treat disaster victims.” (F)

“Other companies can’t make up the difference because they don’t have the capacity. Even if they did, the Drug Enforcement Administration is unwilling to give them large amounts of raw materials. The DEA implements annual caps on the amount of raw material a manufacturer can use to make opioids—one mechanism it has to try to limit the diversion of the addictive drugs amid the addiction epidemic.
The DEA has not shifted those caps to allow other manufacturers to produce enough to offset the shortage of injectable narcotics, according to Premier, which has advocated for the agency to loosen its quota restrictions.
“We understand and support the DEA’s goal to be judicious about the production of narcotics, but we believe we are in the midst of a public health crisis,” Mike Alkire, chief operating officer of Premier, said in a statement. “A temporary reallocation of supply quotas would allow others to step into the void, potentially addressing a multi-year shortage in a matter of months.”
Injectable opioids aren’t the ones getting diverted, said Scott Knoer, chief pharmacy officer at Cleveland Clinic.
“We have to do something to try to limit controlled substances, but limiting injectable opioids is not helpful for patients who need them,” he said. “ (G)

“The Drug Enforcement Administration has raised production quotas for drug manufacturers Fresenius Kabi and West-Ward Pharmaceuticals to mitigate the shortage of opioid injectables, but relief is likely months away…
Providers, lawmakers, group purchasing organizations and industry groups like the American Hospital Association have been lobbying the DEA to raise production quotas amid the shortage. In a survey of 116 member health systems, GPO and consulting group Premier found that nearly all of them are experiencing moderate-to-severe shortages of injectable opioids. More than half reported that the shortage affected patient care, including delaying or canceling surgeries or lowering patient satisfaction scores.
“We are encouraged that the DEA did transfer raw material allocations to the three other companies, and we applaud Pfizer for recognizing the need to transfer some of their excess raw material allocation to other suppliers to help meet the inpatient needs for injectable narcotics,” Todd Ebert, CEO of the Healthcare Supply Chain Association, said in an email. “However, we hope that the DEA will develop processes and procedures to recognize and respond to these market issues much more quickly in the future, as three months seems to be too long.”…
The DEA has been under immense pressure to rein in production as the opioid epidemic has worsened.
The agency reduced its production quota of opioids by at least 25% in 2016, which was the first reduction of its kind in more than two decades. But DEA-approved opioid production volumes remain high—including a 55% increase in oxycodone levels in 2017 compared with 2007, according to a July 2017 letter to the DEA signed by 16 senators…
Between 1993 and 2015, the DEA allowed production of oxycodone to increase 39-fold, along with drastic increases for other opioids, the letter said. The number of opioid prescriptions increased from 76 million in 1991 to more than 245 million prescriptions in 2014, resulting in a dramatic rise in overdoses. More than 42,000 people died from opioid overdoses in 2016, according to the Centers for Disease Control and Prevention, a five-fold increase from 1999… (H)

“Hydrocodone and oxycodone are semi-synthetic opioids, manufactured in labs with natural and synthetic ingredients. Between 2007 and 2016, the most widely prescribed opioid was hydrocodone (Vicodin). In 2016, 6.2 billion hydrocodone pills were distributed nationwide. The second most prevalent opioid was oxycodone (Percocet). In 2016, 5 billion oxycodone tablets were distributed in the United States.
The International Narcotics Control Board reported that in 2015, Americans represented about 99.7% of the world’s hydrocodone consumption.” (I)

“Governments allege that opioid companies unreasonably interfered with the public’s health by oversaturating the market with drugs and failing to implement controls against misuse and diversion, thereby creating a public nuisance.” (J)

So why didn’t manufacturers switch to a higher percentage of injectable opioids?
“Part of the issue is that there are a limited number of manufacturers that produce syringes of opioids. The products are heavily regulated given the complexity of making a syringe and the return on investment is slim.” (H)

(A) Hospitals are confronting a new opioid crisis: an alarming shortage of pain meds, by Casey Ross, https://www.statnews.com/2018/03/15/hospitals-opioid-shortage/
(B) Opioid shortages leave US hospitals scrambling, by Pauline Bartolone, https://www.cnn.com/2018/03/19/health/hospital-opioid-shortage-partner/index.html
(C) The Other Opioid Crisis: Hospital Shortages Lead To Patient Pain, Medical Errors , by Pauline Bartolone, https://www.washingtonpost.com/national/health-science/the-other-opioid-crisis-hospital-shortages-lead-to-patient-pain-medical-errors/2018/03/16/91d2c6fe-28fa-11e8-a227-fd2b009466bc_story.html?noredirect=on&utm_term=.d44201ad0fd6
(D) South Carolina hospitals dealing with ‘critical shortage’ of opioids, by Mary Katherine Wildeman, https://www.postandcourier.com/health/south-carolina-hospitals-dealing-with-critical-shortage-of-opioids/article_33c49db6-2c7a-11e8-b468-eb78b128b456.html
(E) Injectable Opioid Shortages Suggestions for Management and Conservation (Compiled by ASHP and the University of Utah Drug Information Service, March 20, 2018), https://www.ashp.org/-/media/assets/drug-shortages/docs/drug-shortages-iv-opioids-faq-march2018.ashx
(F) Drug Shortages Threaten Patient Safety, https://www.medscape.com/viewarticle/727958,
(G) Injectable opioid shortage compromises care, by Alex Kacik, http://www.modernhealthcare.com/article/20180321/TRANSFORMATION03/180329986
(H) DEA lifts production quotas to ease injectable opioid shortage, by Alex Kacik, http://www.modernhealthcare.com/article/20180414/NEWS/180419944
(I) Opioid Crisis Fast Facts, https://www.cnn.com/2017/09/18/health/opioid-crisis-fast-facts/index.html
(J) Drug Companies’ Liability for the Opioid Epidemic, by Rebecca L. Haffajee and Michelle M. Mello, http://www.nejm.org/doi/full/10.1056/NEJMp1710756

Part 1
CASE STUDY ON THE OPIOID CRISIS. “We still have lacked the insight that this is a crisis, a cataclysmic crisis”

Part 2
“In 2016, more than 40 percent of opioid overdose deaths in the U.S. involved a prescription opioid.”

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