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19 Articles in Volume 20, Issue #4
20/20 with Dr. Nathaniel Katz: Pain Research and Future Therapeutics
A 20-Year Timeline: Pain Therapeutics and Regulations
A Comparison of the Alpha-2-Adrenergic Receptor Agonists for Managing Opioid Withdrawal
A Pain Assessment Primer
After the Task Force: A Conversation with Vanila A. Singh, MD
Ask the PharmD: Can opioids and benzodiazepines ever be used together?
Cognitive Strategies and Mindful Awareness for Integrative Pain Care
COVID: Clinical Considerations for Acute and Post-Infection Symptoms
Editorial: Fudin and Gudin Tackle Pain Care History – Asking, Have We Done a 180?
From Hands-On to Home-Based Care: Physical Therapy Undergoes a Paradigm Shift Due to Pandemic
MS-Related Pain and Spasticity: Are Cannabinoids an Option?
New Biological Agents for Psoriatic Arthritis: A Monoclonal Antibody Primer
Pandemic Presents Unexpected Opportunity to Embrace Multimodal Analgesia and the Integrative Care Team
Provider Perspective on Knee OA: Injections and RFA Options
Redefining the “Pain Specialist” of Today
Resident’s Corner: Climbing the Learning Curve in Pain Management
The Evolution of Pain Management: Experts Weigh In
Tips from the Field: How to Enhance Practice Efficiency
Tumor Necrosis Factor (TNF) Inhibitors: A Clinical Primer

Ask the PharmD: Can opioids and benzodiazepines ever be used together?

For brief periods and with proper dosing, monitoring, and tapering, the combination may be used for anxiety and panic disorders, terminal cancer pain, and palliative care.

Most practitioners are aware that opioids and benzodiazepines are not recommended to be prescribed concurrently. FDA issued a black box warning for concomitant use in August 2016, and both are listed on the American Geriatrics Society Beers Criteria, separately and in combination, to avoid prescribing for older patients.1,2 Despite this, concurrent prescribing occurs frequently.3

In certain practice settings or clinical situations, it may be appropriate to prescribe opioids and benzodiazepines together, as long as the patient is appropriately monitored and prescribed the lowest therapeutic dose for the shortest duration necessary. This combination is most often seen when treating anxiety and panic disorders, cancer pain in terminal patients, and when managing complications in palliative care.


Anxiety and Panic Disorders in Pain Patients

Anxiety disorders, the most commonly diagnosed psychiatric disorders, frequently coexist with chronic pain. First-line treatment for anxiety disorders is selective serotonin reuptake inhibitors (SSRIs), which often take 4 to 12 weeks to see a patient response. Benzodiazepines may be appropriate bridging therapy until the SSRI treatment takes effect. Failure to provide a bridge, however, may result in worsening anxiety, depression, or increased perception of pain despite concurrent opioid use.4

Panic disorders, which can be triggered by uncontrolled pain for which an opioid may be used, may require bridging benzodiazepines; first-line therapy is high dose SSRIs and psychotherapy. Often these patients require benzodiazepines as rescue medication for breakthrough attacks well after the bridging therapy period.4


Cancer Pain & Palliative Care

In patients with cancer, commonly used agents for end-of-life and refractory pain include opioids, benzodiazepines, and other options, such as neuroleptics, barbiturates, and propofol. Patients usually require more than one agent with dose titration to achieve adequate pain relief.5

Complications in palliative care may include dyspnea, anxiety, pain, and insomnia. For pain, opioids are considered second-line therapy when non-opioid analgesics fail. Drug classes routinely used for dyspnea include opioids, benzodiazepines, and antidepressants.

Despite limited evidence, opioids have been studied the most, specifically with refractory breathlessness at end of life, with benzodiazepines considered second- or third-line if opioids and nonpharmacologic therapies fail. Benzodiazepines also relieve anxiety and dyspnea exacerbated by anxiety, and may improve sleep latency and duration with insomnia.6,7

Other instances in which opioids and benzodiazepines may be co-prescribed, but not necessarily recommended, are in critical care patients on mechanical ventilation and in patients with low back pain. (Image: iStock: Robert Kirk)

Ventilation and Back Pain

Other instances in which opioids and benzodiazepines may be co-prescribed, but not necessarily recommended, are in critical care patients on mechanical ventilation and in patients with low back pain.

In critical care patients on mechanical ventilation, guidelines suggest targeting light levels of sedation for the duration of mechanical ventilation in an intensive care unit (ICU) and minimizing benzodiazepine use. Opioids remain a mainstay of therapy for critical care pain, however, a multimodal analgesia approach that also incorporates NSAIDS or other non-opioid analgesics, regional anesthetics, and nonpharmacologic interventions may be the best strategy. For critically ill patients requiring physical restraint, using higher doses of benzodiazepines, opioids, and antipsychotic medications present a higher risk for delirium and disorientation. No trials have been conducted to support this combination in critically ill adults and should therefore be avoided.8  

For low back pain, with or without radiculopathy, benzodiazepines are not FDA-approved for treatment. Opioids may be an option for severe, debilitating chronic low back pain that is refractory to acetaminophen or NSAIDS. If a patient fails to respond to short-course opioid therapy, alternative therapy or referral for re-evaluation should be considered instead. If benzodiazepines are used for acute back pain, a short duration of therapy is recommended, as evidence is insufficient to support efficacy because of the risk of added sedation. Benzodiazepines have shown no difference in function for patients with radiculopathy and may increase pain in this population. Therefore, the combination of benzodiazepines and opioids in patients with low back pain should be avoided due to risks.9


Opioids and Benzodiazepines: How to Monitor Concurrent Therapy

The following should be monitored with concurrent opioid and benzodiazepine therapy:10,11

  • signs and symptoms of ataxia
  • cognitive disorders: confusion, dysarthria, memory impairment, sedation, and somnolence
  • respiratory suppression
  • bradycardia
  • hypotension
  • xerostomia
  • constipation

It is wise to perform a toxicology screening/urinalysis on patients taking this combination, or to at least be aware of recreational substance use, in order to make educated decisions to help keep patients from an accidental overdose. (Details on co-prescribing naloxone below.)

Checking each patient in a national and/or state prescription drug monitoring program (PMDP) and/or controlled substance prescription registry, where one is available, is another way to keep patients safe. These registries show the medication and quantity the patient received and prescriber and pharmacy information. Patients may not remember what medications they take, fail to report information, or may get medication from multiple prescribers.


Tapering Opioids and Benzodiazepines  

Any patients taking opioids and benzodiazepines together for 2 weeks or longer should be tapered upon discontinuation. When discontinuing benzodiazepines or high-dose/long-term use opioids, it is recommended to titrate the dose down appropriately to avoid increased risk of neurologic adverse events or seizures.10,11 Doses may be reduced by 10% to 25% weekly, while monitoring for rebound insomnia, withdrawal symptoms, and anxiety. Tapers should be adjusted and individualized based on the patient response, and half-life of the drug. Some patients may need to be tapered more slowly.

For patients with a long history of medication use, consider titrating to 50% of the dose and stabilizing the patient at the 50% dose for several months before proceeding with the taper to decrease adverse events.12  More on opioid tapering and real-world drug monitoring scenarios.


Extra Cautions to Take

It is good practice to prescribe naloxone nasal spray to any patient taking concurrent opioid and benzodiazepine therapy for outpatient use, and to counsel both the patient and a family member/friend/caregiver on appropriate use and signs and symptoms of an accidental opioid overdose.

Other medication classes that prescribers should be cautious of prescribing with opioids are:

  • CNS depressants: sedatives, anxiolytics, hypnotics, muscle relaxants, general anesthetics
  • Gabapentinoids

These drugs have the potential to cause serious adverse effects when prescribed concurrently with opioids including respiratory depression and/or risk of opioid overdose.13  

It is still the best practice to avoid any concurrent prescribing of opioids and benzodiazepines (or other CNS depressants), and the above uses are not guideline-supported. If opioids and benzodiazepines must be prescribed together, it should be done in the safest way possible for patients: for the shortest duration, at the lowest effective dose, and tapered appropriately.

Last updated on: September 23, 2020
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