Pharmacists Participating in Advanced Pain Management Modalities for Refractory Pain


Patient selection is a key factor in the safe and effective administration of advanced pain management modalities.

As the field of palliative care evolves, clinicians have expressed increased interest in advanced methods to manage refractory pain. Toward that end, the American Academy of Hospice and Palliative Medicine sponsored a day-long “Advanced Pain Management Course” in August.

Nearly 120 individuals attended, mostly physicians as well as a modest number of advance practice nurses and pharmacists. Separate sessions were held on opioid infusions, lidocaine infusions, ketamine, and buprenorphine.

One’s clinical setting will determine which modalities are most relevant to their practice. For the most part, opioid infusions are utilized in the inpatient setting, although many hospices will arrange subcutaneous or intravenous (IV) home infusions or infusions in skilled nursing settings as well.

Lidocaine infusions are almost exclusively restricted to the inpatient setting, whereas ketamine and buprenorphine can be administered in both inpatient and outpatient settings. As with all holistic approaches to care, these agents should be considered within a matrix of non-pharmacologic aspects of pain management, including biofeedback, guided imagery, distraction, and virtual reality.

Patient selection is a key factor in the safe and effective administration of these advanced pain management modalities. Although opioid infusions are most commonly used for patients who are near the end of life, on occasion a “respite” infusion can get a patient through a pain crisis (e.g., a patient with an acute pain crisis from metastatic cancer who wishes to continue active cancer treatments, including radiation therapy, to decrease baseline pain from bony metastases).

Lidocaine infusions are not first- or even second-line, but for patients who failed other modalities and are in the appropriate setting for close monitoring, they can dramatically improve a patient’s quality of life. Ketamine may be delivered as an infusion in a monitored setting for refractory pain or depression, but it is increasingly being administered orally—most commonly by mixing the IV solution into juice. However, some practitioners prefer to work with a compounding pharmacy to create an acceptable formulation for use at home.

Intranasal formulations of ketamine are also available, including the commercially available Spravato. Although buprenorphine was initially approved to manage opioid use disorder (OUD), it is increasingly used in lieu of more traditional opioids to manage chronic pain.

There are multiple caveats to the use of these drugs. Although it may seem self-evident, it is worth calling out that clinicians utilizing agents with a higher risk for adverse effects (AEs) should have the requisite training and expertise to do so. Familiarity with legal and regulatory issues is essential, at both the federal and state level.

Similarly, clinicians need to be cognizant of the policies and protocols of their employer, their practice, and/or the facility in which they are utilizing these agents. For physicians and pharmacists, having a clinical support system is also essential for safe and effective practice—who will provide backup during the off hours or time away?

Interprofessional collaboration should be transparent and iterative, as it is much better to over-communicate than under-communicate. Prescribers, pharmacists, and nursing staff each have unique expertise on practical considerations ranging from equipment such as infusion pumps, concentrations and bag volumes based on anticipated infusion rates, integrating order sets within the electronic health record, staffing considerations for pain assessments and medication administration, and delivering the medications in the patient’s care setting.

Reviewing the 4 agents addressed in the course described above in their order of likely relevance, buprenorphine appears to be the proverbial low-hanging fruit. Many proponents argue buprenorphine should be considered as a first-line agent for chronic pain.

Of its various formulations, sublingual and buccal administration have the greatest bioavailability. It can be safely used in renal failure and mild or moderate liver failure. Due to its strong affinity for the mu-receptor, it can precipitate iatrogenic withdrawal in patients already on opioid analgesics.

Determining equianalgesic doses of buprenorphine based on baseline opioid dosage is complex. The buprenorphine patch and low-dose buccal formulations are FDA-approved for pain and do not require the “X-waiver” required to prescribe buprenorphine for OUD.

They are also DEA schedule III, allowing for refills to be included on prescriptions in many states. Unfortunately, insurance coverage is quite variable and many patients will be unable to afford the out-of-pocket expense of buprenorphine without coverage.

Opioid infusions have come a long way from the days of “morphine drip, titrate to comfort.” However, many opioid infusion order sets do not reflect current best practice.

In particular, infusion rates are frequently titrated at an interval that does not allow steady state to be achieved, which increases the risk for opioid toxicity, including opioid-induced hyperalgesia. Typically, steady state is achieved after 4-5 half-lives, which for morphine would be 8-20 hours.

Instead of increasing the infusion rate at shorter intervals, bolus doses should be used for a minimum of 8 hours to determine the optimal infusion rate following titration. If a PRN bolus dose is ineffective, another can be given after the first reaches peak effect, typically around 15 minutes.

Many standard order sets do not include nurse-driven titration of infusion rates, instead utilizing nurse-driven administration of bolus doses with infusion rates titrated only upon a provider’s order. Bender, et al, published a model “comfort care” order set that reflects current best practice.1 They include distinct recommendations for low-, moderate-, and high-dose opioid infusions based on the patient’s baseline opioid use prior to initiating an infusion.

Situations in which subanesthetic dosing of ketamine as an analgesic may be indicated include cancer pain refractory to opioids, neuropathic pain inadequately controlled with oral adjuvant medications, patients who are experiencing opioid-induced hyperalgesia, and acute or chronic pain for which minimizing opioid dosage is desired. For patients with higher risk of cardiovascular disease, a baseline ECG should be performed to exclude those with uncontrolled ischemic heart disease.

For those with concerns about liver dysfunction or who are expected to receive higher and/or frequent dosing, consider baseline and post-infusion live function tests. Monitoring for ketamine infusions include vital signs, pain ratings, sedation assessment via a standardized system, such as the Pasero Opioid-induce Sedation Scale or the Richmond Agitation-Sedation Scale, and nursing assessments for neuro-psychiatric AEs.

For patients managed with ketamine in the ambulatory setting, a controlled substance agreement should be completed, similar to those used with chronic opioid administration. Studies suggest patients with the greatest response to ketamine were those with chemotherapy-induced peripheral neuropathy and patients who were concurrently taking a serotonin and norepinephrine reuptake inhibitor (SNRI).2

Challenges include limited clinician training on the use of ketamine, product shortages, insufficient staff training in all settings, lack of call coverage by physicians trained in ketamine management, and regulatory and policy restrictions. For patients with refractory pain, especially neuropathic pain, for which a lidocaine infusion is under consideration, contraindications include recent cardiac event, bradycardia, inability to communicate about symptoms of toxicity, liver failure, severe heart failure, second- or third-degree heart block, uncontrolled seizures, systolic blood pressure greater than 160, hypokalemia, and allergy to amide anesthetics.

Monitoring includes close assessment of vital signs, consideration of cardiac telemetry, and routine assessment of signs or symptoms of toxicity. Potential AEs that should raise concerns about toxicity include drowsiness, perioral numbness, nausea, and blood pressure fluctuations. Once satisfactory pain relief is achieved for patients who are not imminently terminal, transitioning to an alternative treatment regimen appropriate to their care setting will be necessary.

Training programs and certifications in pain management enable providers, including pharmacists, to develop the knowledge and skills to safely and effectively use these modalities. Several examples include the Pain Management Certificate from the American Society of Health-System Pharmacists, and the Pain Management Specialty Pharmacist Certificate: Managing Opioids from FreeCE. PainWeek also offers several pain-related certificate programs.

For those who are interested in pain management and palliative care, the University of Maryland, Baltimore offers several graduate certificates, a Master of Science, and a Doctor of Philosophy degree. The University of Colorado Denver Graduate School offers a palliative care certificate program and a Master of Science degree.

There are several additional graduate certificates available in palliative care as well, such as at the University of Washington and Coleman Palliative Medicine Training Program. The range of educational opportunities allows pharmacists to advance their knowledge and career in pain management and palliative care to a modest degree or a greater degree. Pharmacists may also benefit from membership in the American Academy of Hospice and Palliative Medicine, the Hospice and Palliative Nurses Association, or the National Hospice and Palliative Care Organization.

With compassion, clinical interest, training, collaboration, and interdisciplinary support, physicians, pharmacists, nurses, and other members of the care team can expand the range of options for patients experiencing refractory pain through innovative advanced pain management strategies. We encourage interested individuals to explore the above resources and to communicate with colleagues to better understand what is most relevant and practical in each practice setting.

About the Authors

Gregg VandeKieft, MD, MA

Palliative Care Physician, Clinical Ethicist; Providence St. Peter Hospital

VandeKieft practices palliative medicine in Olympia, Washington. He has held multiple leadership positions within Providence St. Joseph Health and the American Academy of Hospice and Palliative Medicine. VandeKieft attended the University of Iowa’s College of Medicine and the Phoenix Baptist Hospital’s Family Medicine Residency Program. He completed Michigan State University’s master’s program in Health and Humanities and Harvard Medical School’s program in Palliative Care Education and Practice. He is the recipient of the Stuart J. Farber Award for Excellence in Palliative Care and Hospice, and the Hastings Center Cunniff-Dixon Physician Award.

Mary Lynn McPherson, PharmD, MA, MDE, FAAHPM

Professor, University of Maryland, Baltimore

McPherson is a professor at the University of Maryland School of Pharmacy. She serves as a consultant pharmacist for local and national hospice and palliative care programs and has designed a critical thinking process for appropriate drug use in end-of-life patients. McPherson teaches the PharmD curriculum on pain management and end-of-life care extensively, including didactic and experiential content, and is the Executive Program Director of Online Graduate Studies in Palliative Care (graduate certificates, master of science, and doctor of philosophy) at University of Maryland, Baltimore. She serves on the Board of the American Academy of Hospice and Palliative Medicine.


1. Bender MA, Hurd C, Solvang N, Colagrossi K, Matsuwaka D, Curtis JR. A new generation of comfort care order sets: aligning protocols with current principles. J Palliat Med. 2017 Sep;20(9):922-929.

2. Oh D, Haffey P, Patel A, and Gulati A. Intravenous ketamine for cancer pain management, including flares during the COVID-19 pandemic: A retrospective study. Pain Med. 22(7)2021: 1642-1650.

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