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Analgesic Alternatives to Opioid Drug Shortages

Kimberly E. Levasseur-Franklin, PharmD, BCPS, BCCCP; Dragos M. Galusca, MD, FCCP, FASA

Opioid epidemics and opioid overdose-related deaths have been commonly reported in the media for more than a decade. Although injectable opioid shortages are prevalent, little has been mentioned about the shortages or their impact on the critical care community. The shortage affecting injectable formulations, such as fentanyl, morphine, and hydromorphone, has intensified in recent months, necessitating strategic implementation of therapeutic alternatives.

Opioid shortages pose a challenge to critical care clinicians, pharmacists, and other critical care professionals, particularly in practices that rely primarily on opioids for analgesia control as part of their pain, agitation, and delirium intensive care unit (ICU) protocols.1 Nationwide, pharmacy and therapeutics committees routinely face opioid shortages, ultimately using significant resources to identify alternative medications and/or analgesic routes for critically ill patients.

Based on our institutional experiences, we present some pharmacologic alternatives to injectable opioids. These have been grouped into three categories: noninjectable opioid analgesics, nonopioid analgesics, and analgesic adjuncts.

Noninjectable Opioid Analgesics​
Nonparenteral opioids such as oral oxycodone and oral morphine are commonly available in most critical care practices. For nonopioid-naive patients or those with chronic pain, fentanyl patch therapy may be a reasonable option. All opioids have equivalent analgesic efficacy without clinically significant differences in patient outcomes. Special attention should be paid to dosing equivalence between opioids because it differs significantly and may lead to deleterious dosing errors affecting patient safety. In addition, when evaluating patients as candidates for fentanyl patch therapy, the pharmacokinetic and pharmacodynamic properties need to be appreciated. Particular attention should be paid to whether or not patients will absorb the fentanyl in the intended amount. Specifically, does the patient have intact skin? Is the patient febrile or hypothermic? Is the patient obese or cachectic? These are some of the elements that must be evaluated before fentanyl patch therapy is started. Also note that a fentanyl patch will not treat pain acutely; it takes several hours before it begins to take effect.

Nonopioid Analgesics​
Nonsteroidal antiinflammatory drugs
Nonsteroidal antiinflammatory drugs (NSAIDs) (intravenous [IV] or intramuscular ketorolac, oral ibuprofen) provide analgesic effect without the respiratory depression or hemodynamic compromise that can potentially occur with other medication classes. With that in mind, the analgesic benefits of NSAIDs has not been well studied in critically ill patients, so it is unclear whether the potential benefits of NSAID therapy outweigh the known risks. In a retrospective study conducted in ICU patients, IV ketorolac use was associated with decreased pneumonia and increased ICU-free days. NSAIDs should be avoided in patients who are at risk for renal injury, gastrointestinal bleeding, coagulopathy or aspirin-sensitive asthma.

Acetaminophen
Acetaminophen is a commonly used analgesic alternative in the ICU. In patients with sufficient gastrointestinal absorption and motility, there is a lack of evidence to support the use of IV acetaminophen over oral formulations. In our institution, oral or rectal acetaminophen use is encouraged in most situations unless contraindications are present. IV acetaminophen has been reserved for postsurgical critically ill patients who have contraindications to NSAIDs (e.g., bleeding) and strict nothing-bymouth status required by the surgical procedure. In our institution, the Pharmacy and Therapeutics Committee monitors the use of IV acetaminophen monthly; however, utilization monitoring and restrictions vary from site to site.

Local anesthetics
Lidocaine therapy has a reliable analgesic benefit minus the respiratory depression or hemodynamic side effects. However, special attention should be paid to signs of local anesthetic toxicity in postsurgical patients. These patients may receive additional peripheral nerve blocks or neuraxial nerve blocks with local anesthetics. Thus, repeated doses of local anesthetics could have a cumulative effect, leading to deleterious toxic levels.

Analgesic Adjuncts
Analgesic adjuncts lower opioid consumption, facilitate opioid rotation, and may also reduce sedative requirements. They may also provide additional benefit in alcohol withdrawal scenarios.

Alpha-2 agonists
Dexmedetomidine is an alpha-2 agonist with some opioid-sparing effects, but it can cause hypotension and bradycardia. Dexmedetomidine has been utilized as an IV sedative to facilitate successful extubation in patients on prolonged mechanical ventilation. Because it has opioid-sparing effects, it may be helpful to attempt to decrease IV opioid use in critically ill patients.

Ketamine
Ketamine is an NMDA antagonist and is effective as both an analgesic and a sedative agent in the ICU. When combined with other analgesic agents, ketamine may exhibit synergy, with tolerable side effects. IV ketamine can be utilized as an effective adjunct in analgesic drug rotation and to facilitate weaning from prolonged sedation in the ICU. Ketamine provides an opioid-sparing effect in patients with burns and in nonopioid-naive patients. Side effects include delirium, visual hallucinations, nausea, and vomiting, which can make ketamine difficult for patients to tolerate

Gabapentinoids
Gabapentin and oral pregabalin have shown efficacy in patients with peripheral neuropathy.2 Neuropathic pain is usually poorly treated with opioids and may be better treated with analgesic adjuncts such as gabapentinoids. Established neuropathic pain is commonly refractory to opioid treatment; therefore, high-risk patients should be started on the adjuvant medications early. Studies involving gabapentinoids have demonstrated mixed results, with some research showing their benefit as analgesic adjuncts.

Magnesium sulfate
Magnesium causes blockade of NMDA receptors and may reduce analgesic requirements without significant hemodynamic complications. However, current evidence supporting the utility of magnesium sulfate in critical care is limited to management of atrial fibrillation or peripartum blood pressure control in preeclampsia/ eclampsia. More data are needed on the potential role of magnesium sulfate as an opioid-sparing agent in critically ill patients.

Conclusion
Opioid shortages are a common challenge in many critical care settings. Fortunately, several opioids alternatives are available. A multimodal analgesic approach incorporating noninjectable opioid analgesics, nonopioid analgesics, and analgesic adjuncts may be considered for pain management in both surgical and nonsurgical critically ill patients. This multidisciplinary strategy requires close collaboration between critical care pharmacists and clinicians and may ultimately reduce side effects by employing novel various pain pathways.

References

  1. Barr J, Fraser GL, Puntillo K, et al; American College of Critical Care Medicine. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013 Jan;41(1):263-306
  2. Narayanan M, Venkataraju A, Jennings J. Analgesia in intensive care: part 1. BJA Educ. 2016 Feb;16(2):72-78.