ASRA, AAPM, and ASA Release First IV Ketamine Infusion Guidelines For Chronic Pain

Ketamine infusions have seen a recent surge in usage as a chronic pain treatment, and thus, a need for consensus guidelines for patient selection, treatment parameters, and monitoring was needed. Guidelines have recently been approved¹ by the Boards of Directors at both the American Society of Regional Anesthesia and Pain Medicine (ASRA) and the American Academy of Pain Medicine (AAPM), who approved the document along with the American Society of Anesthesiologists' (ASA) Committees on Pain Medicine and Standards and Practice Parameters.

Guidelines were prepared for the following areas: indications; contraindications; whether there was evidence for a dose-response relationship, or a minimum or therapeutic dose range; whether oral ketamine or another N-methyl-D-aspartate receptor antagonist was a reasonable treatment option as a follow-up to infusions; preinfusion testing requirements; settings and personnel necessary to administer and monitor treatment; the use of preemptive and rescue medications to address adverse effects; and what constitutes a positive treatment response.¹

The guideline questions and committee conclusions¹ are as follows:

1. Which patients and chronic pain conditions should be considered for ketamine infusions?

For spinal cord injury pain, there is weak evidence supporting ketamine infusions (0.42 mg/kg per hour to 0.4 mg/kg ranging from 17 minutes to 5 hours for 7 consecutive days) for short-term improvements in pain. For CRPS, there is moderate evidence supporting ketamine infusions (22 mg/h for 4 days or 0.35 mg/kg per hour over 4 hours daily for 10 days) to provide improvements in pain for up to 12 weeks. For mixed neuropathic pain, phantom limb pain, postherpetic neuralgia, fibromyalgia, cancer pain, ischemic pain, migraine headache, and low-back pain, there was weak or no evidence supporting ketamine infusions for immediate improvements in pain. Excluding CRPS, there was no evidence supporting ketamine infusions for intermediate or long-term improvements in pain.

2. What are the contraindications for ketamine infusions?

Ketamine should not be used in patients with poorly controlled cardiovascular disease and should be avoided in individuals with certain poorly controlled psychoses.

3. Is there any evidence for a therapeutic dose cutoff threshold, a dose-response relationship, longer (ie, continuous versus boluses), more frequent (repeat) infusions, or higher dosages to be more effective for chronic pain?

We conclude that there is moderate evidence to support higher dosages of ketamine over longer time periods, and more frequent administration, for chronic pain.

4. Is there any role for oral ketamine or another NMDA-receptor antagonist as a follow-up treatment in lieu of repeat infusions?

We conclude that there is low-level evidence to support the use of oral ketamine (150 mg/d or 0.5 mg/kg every 6 hours) and other NMDA-receptor antagonists such as dextromethorphan (0.5–1 mg/kg every 8 hours) as follow-up therapy following IV infusions, and moderate evidence to support intranasal ketamine (1–5 sprays of ketamine 10 mg, 0.2–0.4 mg/kg (S)-ketamine, and single dose ketamine 25 mg every 6 hours as needed) as a treatment for breakthrough pain.

5. What tests should be ordered prior to an infusion of ketamine?

There is insufficient evidence supporting preinfusion testing prior to the administration of IV ketamine for chronic neuropathic pain conditions in healthy individuals.

6. What training is prudent for personnel who administer boluses and infusions and oversee dose titration? Does this recommendation change with dosage (that is, subanesthetic versus anesthetic range) or route of administration?

We conclude that there is limited direct evidence supporting the preemptive use of benzodiazepines and α2 agonists and no evidence to support antidepressant, antihistamine, or anticholinergic premedicants prior to the initiation of subanesthetic ketamine for chronic pain treatment.

7. What constitutes a positive treatment response for chronic pain?

Given the refractory nature of patients who receive ketamine infusions, we recommend that a positive outcome be considered as 30% pain relief or greater in conjunction with patient satisfaction and/or more objective indicators of meaningful benefit, such as a 12.8% improvement in Oswestry Disability Index (ODI) score in a patient with back pain or a 20% or greater reduction in opioid use.

The committee said that “most studies evaluating the efficacy of ketamine were small and uncontrolled and were either unblinded or ineffectively blinded” and that while there were few adverse effects, “the rate of serious adverse effects was similar to placebo in most studies, with higher dosages and more frequent infusions associated with greater risks.”

“Larger studies evaluating a wider variety of conditions are needed to better quantify efficacy, improve patient selection, refine the therapeutic dose range, determine the effectiveness of nonintravenous ketamine alternatives, and develop a greater understanding of the long-term risks of repeated treatments,” the committee concluded.