Your probably tired of our frequent columns on the dangers of IV opiates (see our May 17, 2011 Patient Safety Tip of the Week “Opioid-Induced Respiratory Depression – Again!” which has links to all the other columns as well). But the opiate category (which should rank near the top on your high alert medication list) should also include opiates that are delivered in ways other than by the IV route. And, in fact, the newer opiate formulations are either more potent or designed to produce a longer peak action, two characteristics that lead to some of the greatest dangers that have been popping up. We are referring to the long-acting and extended-release forms of opiates. These have been designed to be used in patients who are opioid-tolerant and have pain of a chronic nature that has not been controlled with more conventional opiates. They were not intended to be used for treatment of acute pain nor to be used as first line agents in patients with pain. But in practice they are often being (mis)used in that way.
The rate of prescription opioid–related overdose deaths increased substantially in the United States over the past decade (Bohnert 2011) and the higher death rate correlates with higher opioid doses. The problem has become so severe that the FDA has recently announced a risk evaluation and mitigation strategies (REMS) campaign to reduce risks associated with prescribing these agents.
ISMP’s Michael Cohen has warned of the dangers and the risks taken by providers who prescribe transdermal fentanyl patches for acute pain (Cohen 2010). Though reports of deaths related to transdermal fentanyl patches have been accumulating for years, he became very concerned when 3 deaths in young adults related to these patches were reported in 2010, each in relation to acute pain (eg. dental pain, post-tonsillectomy pain, etc.). ISMP has had a series of alerts in the newsletters regarding the dangers (ISMP 2007). Though they noted the importance of educating physicians, nurses and pharmacists about the dangers, they stressed that additional measures are necessary to prevent such disastrous outcomes (see below).
And Cohen also warned that children commonly mistake such transdermal patches for Band-Aids, tattoos or stickers and may put them on their skin with devastating, even fatal, outcomes (Cohen 2011). Discarded used fentanyl patches may contain substantial amounts of active drug and there have been deaths reported after children applied these to their skin (and pets that have died after retrieving them from the trash).
ISMP Canada also reviewed multiple incidents related to fentanyl patches reported through the International Medication Safety Network (ISMP Canada 2009). They analyzed over 3000 incidents, including 271 resulting in harm and 8 resulting in death. They found 3 basic themes: (1) dose was higher than required or patch was replaced too soon (2) patient should not have received the medication (3) dose was lower than required or patch was replaced too late or omitted. They found that lack of knowledge or awareness of the potency applied to both providers and patients/caregivers. Complex dosing was especially error-prone and lack of communication at handoffs and transitions of care led to many incidents. They also identified issues with product design. They recommended development of real-time aids, such as manual checklists or electronic decision support tools, that could assist providers and patients/caregivers. Verifying appropriate indications for use and confirming opiate tolerance are two of the most important elements of a safe prescribing program for fentanyl patches.
ISMP (US) provides a very good brochure for patients on fentanyl patches with not just warnings but advice on use, storage, and disposal of the patches.
And don’t forget that many transdermal drug patches contain metal or ferromagnetic elements that may lead to burns during MRI scanning (see our March 2009 What’s New in the Patient Safety World column “Risk of Burns during MRI Scans from Transdermal Drug Patches”). Fentanyl patches do appear on the FDA list of transdermal drug patches with metal backings (FDA 2009).
And then there are the transmucosal formulations of opiates. A 2007 FDA warning on Fentora, a potent opioid pain medication, is used only for treatment of breakthrough pain in cancer patients receiving opioid treatment and who have become tolerant to it. Breakthrough pain is an intense increase in pain that occurs with rapid onset, even when opioid pain-control medication is being used. Patients who take narcotic pain medications daily and around-the-clock develop tolerance and are more resistant to the dangerous side effects of these medications than patients who take narcotic pain medication on a less frequent basis. The FDA alert noted serious adverse effects and deaths occurring in patients treated with Fentora, often patients who had acute pain and were not opioid-tolerant.
In addition, FDA is concerned about the improper substitution of Fentora, a quick acting pain drug, for other pain medicines. Fentora is not the same as other fentanyl products and cannot be substituted for Actiq, another transmucosal fentanyl product used to treat breakthrough cancer pain. Because Fentora delivers more fentanyl to the blood than Actiq, substituting Fentora for Actiq using the same dose can result in a fatal overdose.
Off-label use of these drugs to treat acute pain has been increasing. The California Workers’ Compensation Institute reports more than 14 percent of claims with minor back injury had at least one prescription for Actiq or Fentora. The newest transmucosal opiate on the market is Onsolis. These drugs are big business. It’s estimated that the overall U.S. market for transmucosal fentanyl products for breakthrough pain, including generics, totaled $375 million in 2009 (Vinluan 2011).
Sustained-release or extended-release tablets are also problematic and switching from one opiate to another is often problematic (AHRQ Web M&M 2006). In the AHRQ case a young man with low back pain was switched from Vicodin to MS Contin and after one dose of the latter became obtunded with respiratory depression necessitating intubation and a long, complicated ICU stay. The dose of MS Contin far exceeded the dose of Vicodin that he had been receiving. It is very common to see misunderstandings of the relative potencies of the various opiate preparations. Therefore, equianalgesic conversion tables should be used when making such switches, keeping in mind that even those provide only approximations. As in the AHRQ article, reducing the calculated dose of the new drug 25-50% is often a good strategy when making such conversions. We’ve also seen a case where a patient who took an intentional overdose of MS Contin developed respiratory failure almost 24 hours after ingestion. So understanding the potential delayed effects of ingested longer-acting opiates is critical.
Concentrated liquid preparations also give rise to problems. Another ISMP Alert (ISMP 2008) described two cases in which patients were mistakenly given 20 mg/ml solutions of oxycodone oral solutions rather than the intended 1 mg/ml, both with devastating results. Most such errors occur when the prescriber orders the medicine in ml rather than mg. That ISMP Alert has good recommendations about ways to help avert such errors. In addition to prescribing in mg rather than ml, they stress restricting use of these agents to patients who require higher than usual doses because of severe chronic pain or who are unable to swallow larger volumes of liquids. They describe using CPOE systems to alert prescribers (eg. adding the word “concentrated” to the drug name, showing warnings about the potential adverse effects) and barcoding systems to help verify the correct solution (eg. creating a hard stop that requires the nurse check with a pharmacist before dispensing). They also have advice for dispensing community pharmacists, such as printing warnings on the patient’s receipts or linking mandatory pharmacist counseling of patients to these preparations. They also warn against covering the concentration on the manufacturer’s label with a pharmacy label. And creating awareness of the risks among patients and caregivers plus healthcare staff is very important.
And remember that all the patients at high risk for respiratory depression from IV opiates are also at risk with these alternative opiate preparations. That includes patients with conditions such as COPD and sleep apnea. One of the deaths referred to in the 2007 ISMP alert on fentanyl patches occurred in a patient with sleep apnea (ISMP 2007).
Hospitals and health systems need to standardize on a short list of conventional opiates. Only the more conventional ones should appear in standardized order sets. Yes, they do need to provide access to the alternate formulations for individual cases (such as patients with intractable pain from cancer) but should restrict prescribing access for the latter to those providers who have established special competencies in using such drugs for managing complex pain (eg. pain specialists, palliative care specialists, or physicians specifically credentialed by your organization based on their training and/or competencies). And they need to put in place constraining functions that prevent use of these drugs for inappropriate purposes. For example, CPOE alerts can require a valid indication and clarification as to whether a patient is opiate-tolerant or opiate-naive (with hard stops in some cases). And access to equianalgesic dose conversion tables must be readily available, whether linked to CPOE or provided elsewhere. At all times be aware of all the opiates a patient may be receiving and any other drugs that may produce drowsiness or depress respiration. Tying warnings to bardcoding verification prior to administration is also advisable, as are independent double checks. Be especially wary at transitions of care. Medication reconciliation at those vulnerable times is critical. And make sure that the patient and family or caregivers understand the potent nature of these agents and risks involved and know what signs of potential toxicity to watch for. Lastly, be aware that, at least theoretically, patients on such potent agents may be at risk for withdrawal symptoms when there is a substantial reduction in dosage. We’ve also seen a patient on chronic opiate therapy develop acute withdrawal when naloxone was administered to treat a likely overdose.
See also our prior Patient Safety Tips of the Week pertaining to opioid-induced respiratory depression:
Bohnert ASB, Valenstein M, Bair MJ, et al. Association Between Opioid Prescribing Patterns and Opioid Overdose-Related Deaths. JAMA. 2011; 305(13): 1315-1321
FDA. Opioid Drugs and Risk Evaluation and Mitigation Strategies (REMS).
Cohen M. Doctors risk patient safety by prescribing fentanyl painkiller for short-term pain. Philly.com November 8, 2010
ISMP. Ongoing, Preventable Fatal Events With Fentanyl Transdermal Patches Are Alarming! ISMP Medication Safety Alert! Acute Care Edition. June 28, 2007
Cohen M. Warning! Kids may mistake drug patches as Band-Aids, tattoos or stickers. Philly.com January 3, 2011
ISMP Canada. Analysis of International Findings from Incidents Involving Fentanyl Transdermal Patches. ISMP Canada Safety Bulletin 2009; 10: 1-2 (December 30, 2009)
ISMP. Fentanyl patches brochure. 2011
FDA. Public Health Advisory: Risk of Burns during MRI Scans from Transdermal Drug Patches with Metallic Backings. 3/5/2009; updated 3/9/2009
FDA MedWatch Safety Alert. Fentora (fentanyl buccal tablet). September 26, 2007
New report shows growing off-label narcotic use in California. RiskandInsurance.com May 26, 2011
Vinluan F. FDA’s REMS program puts BDSI at a disadvantage in cancer drug market. MEDCITY News June 8, 2011
AHRQ (Strassels SA discussant). AHRQ Web M&M. Miscalculated Risk. August 2006.
ISMP. Tragic events with concentrated opiate oral solutions. ISMP Medication Safety Alert! Community/Ambulatory Care Edition. July 2008