Learning Objectives/Outcomes: After participating in this CME/CNE activity, the provider should be better able to:
1. Describe events in the history of opioid treatment that led to consideration of ketamine for treatment of acute and chronic pain.
2. Explain the pharmacodynamics of intravenously administered ketamine for treatment of acute and chronic pain.
3. Identify the types of pain for which intravenously administered ketamine is most effective in reducing pain intensity.
Ketamine is hardly a new drug, but in the past decade, it has been investigated and developed for expanded use in perioperative analgesia, chronic pain management, seizure control, and even depression and posttraumatic stress disorder. Although more research is needed-and is being performed-clinicians already are incorporating ketamine in ways to prevent and treat chronic pain, especially in the context of the drug's potential opioid-sparing effect.
Increased Attention to Pain in the United States in the 1980s
To understand the role ketamine plays in pain management, one first needs context about the shifts in opioid prescribing and the ripple effect of that over the last few decades.
The International Association for the Study of Pain's revised definition of pain, the first revision since 1979, provides further clarity in the separation between pain and tissue damage: "[P]ain is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage."1
Acute pain due to tissue damage is a fundamental aspect of human existence; it alerts us to actual or potential injury or disease and warns us of things that may be harmful. When the inciting source is removed or tissue healing takes place, acute pain is expected to resolve over time. However, for many individuals, there is no inciting source or tissue damage associated with acute or chronic pain-it is pain that serves no useful purpose and causes detrimental consequences on quality of life, physical and social functioning, and mental health. Currently, an estimated 50 million people in the United States live with chronic pain and approximately 20 million have high-impact chronic pain, which is characterized by causing limitations in life or work activities on most days during the past 6 months.2
Evolution of Opioid Prescribing
Opioids were first introduced in the 1860s to help wounded soldiers with management of their acute pain.3 Typically, pain was only treated in acute settings when related to injury or surgery, and those reporting constant pain were thought to be dramatic, malingering or drug addicts.4 During this period, opioid treatment was discouraged even for cancer pain until the patient was clearly at the end of life.
In the latter half of the 20th century, it became more common to prescribe opioid medication for chronic pain because of the effectiveness of these drugs in reducing pain and assumption of low addiction risk without any high-quality evidence to support the claim.3,4 Consequentially, pharmaceutical companies downplayed the adverse effects of opioid medications and heavily influenced the clinical community by encouraging the use of opioids for all types of pain-acute, chronic, cancer-related, and nonmalignant pain.4
Additionally, in 1995, the American Pain Society launched a campaign to make pain the fifth vital sign, which was adopted across health care settings.4 Not long after, opioids became the most common treatment of chronic pain in the United States.
In 2000, the Joint Commission created standards for pain assessment and management, and the Federation of State Medical Boards and the Drug Enforcement Agency loosened regulations on opioid prescriptions.5 Subsequently, opioids were being prescribed at higher rates and dosages than ever before, and the opioid epidemic was only beginning to be recognized.
From 1999 to 2017, mortality rates climbed from under 10,000 per year to over 64,000 per year, and clear evidence accumulated on the association between increased opioid use and mortality.6 It was not until 2017 that the United States government declared the opioid epidemic a public health emergency.
In response to the growing reports of abuse and side effects of opioids, clinicians and researchers were looking for a drug to reduce pain as effectively as opioids but without the negative consequences. Interest in the use of ketamine for acute and chronic pain conditions has been increasing for some time.7
Ketamine Emerges as Anesthetic, but Other Effects Discovered
Ketamine is a phencyclidine analog and dissociative anesthetic agent that has been used as a general anesthetic since the 1960s, but it was found to be effective for severe depression and pain at subanesthetic concentrations; and for treatment of seizure disorder, posttraumatic stress disorder, and status asthmaticus.8-13
In addition to its use as an anesthetic, analgesic, and sedative, ketamine has been abused as a recreational hallucinogen. The active enantiomer is S(+)-ketamine, and ketamine is metabolized mainly to norketamine.9
Ketamine can be administered by intravenous, intramuscular, intrarectal, oral, or intranasal routes. It is rapid-acting with an anesthetic state characterized by analgesia, normal pharyngeal-laryngeal reflexes, enhanced muscle tone, cardiovascular and respiratory stimulation, and minimal respiratory depression.10 Ketamine is classified as a dissociative anesthetic because it interrupts association pathways of the brain before producing somesthetic sensory blockade.11
Ketamine was designed as a derivative of phencyclidine, which was removed from the market because of its popularity as a substance of abuse.13 Ketamine was an attractive alternative to phencyclidine because of its unique ability to produce analgesia without a loss of consciousness. The dissociative qualities of ketamine are described as being aware but without response to painful stimuli, and some patients describe a feeling of floating or being outside of their body.9,10 During recovery from ketamine administration, some patients remain completely oriented, whereas others may display aggression, somnolence, withdrawal, or experience hallucinations and confusion; these effects are known as the emergence phenomenon, or ketamine dysphoria.13
Analgesic Properties of Ketamine
The analgesic properties of ketamine are primarily due to the antagonism of N-methyl-D-aspartate (NMDA) receptor. Ketamine also interacts with many other binding sites, including opioid, monoaminergic, cholinergic, nicotinic, and muscarinic receptors.8 However, unlike other anesthetics, ketamine does not interact with D-aminobutyric acid (GABA) receptors. The major endogenous agonist of the NMDA receptor is glutamate. By binding to NMDA receptors residing in the central nervous system, especially the prefrontal cortex and hippocampus, ketamine causes decreased neuronal activity, and therefore reduces neuronal firing and pain transmission.
The NMDA receptor is also involved in cognition, learning, opioid tolerance, and mood regulation, which is a reason that this target may be effective in chronic pain states; it possibly recalibrates the central nervous system's processing of pain, thereby reducing pain sensitization and amplification.
Ketamine also enhances descending inhibiting serotoninergic pathways, which can facilitate antidepressive effects, at concentrations 10 times lower than concentrations needed for anesthetic purposes.12 At plasma concentrations of 200 ng/mL, adequate to reduce pain intensity, ketamine decreases insular cortex and thalamus activities that are usually activated by nociceptive stimulation.13 Ketamine has a dose-dependent effect on pain processing, causing decreased activation of the secondary somatosensory cortex, insula, and anterior cingulate cortex, thereby producing a significant impact on affective pain processing. At subanesthetic doses, adverse psychomimetic effects are often reported, including hallucinations, visual disturbances, unpleasant dreams, and dysphoria. In the presence of chronic pain, ketamine is thought to reduce pain by binding to NMDA receptors and reversing central sensitization and windup.9
Society Recommendations and Guidelines on Ketamine for Chronic Pain
Current recommendations from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists on the use of IV ketamine for acute pain include consideration for use in patients undergoing painful surgery, especially those who are opioid-dependent or tolerant, because of its opioid-sparing effects.7 Additional considerations include use in opioid-dependent or opioid-tolerant patients with acute or chronic sickle cell pain or as an adjunct to limit opioids in patients with sleep apnea.
Another recent guideline statement was published in 2019, which concluded that there was adequate evidence to support the use of IV ketamine for chronic pain.9 However, the committee found only moderate evidence supporting ketamine infusion for complex regional pain syndrome (CRPS) at doses of 22 mg/hr for 4 days or 0.35 mg/kg per hour over 4 hours daily for 10 days to provide improvement in pain for up to 12 weeks.
The committee found weak evidence supporting ketamine infusion for spinal cord injury pain (0.42 mg/kg per hour to 0.4 mg/kg per 17 minutes - 5 hours for 7 consecutive days) for short-term improvement in pain.
Weak to no evidence was found for immediate improvement of mixed neuropathic pain conditions, or for phantom limb pain, postherpetic neuralgia, fibromyalgia, cancer, ischemic pain, low back pain, or migraine headaches.
Review Yields 17 Studies on Ketamine Infusion
In order to further assess the evidence on effectiveness of ketamine in patients with chronic pain conditions, a nonexhaustive literature review was performed. For the review, the search engines PubMed/Medline, CINAHL, and Scopus were used to identify research publication on the use of subanesthetic-dose IV ketamine for reducing chronic pain intensity.
Key words used for each search included "ketamine," "N-methyl-D-aspartate receptor" and "central sensitization." References of relevant articles were also reviewed for inclusion. Articles considered for inclusion were clinical trials, systematic reviews, and meta-analyses. Excluded were case reports, descriptive studies, and research studies without an appropriate control group. There were no time limitations.
After a review of all of the articles, 17 studies were found to meet the requirements and were used to perform the analysis (Table 1).
Most Studies Addressed Neuropathic Pain
A variety of chronic pain conditions were evaluated across the 17 studies. However, most had a neuropathic component. Ketamine is most commonly used in the presence of neuropathic pain conditions because of its effect on the NMDA receptor, which is thought to have a substantial impact on pain processing in this population.
Participants with mixed neuropathic pain conditions14,17,19,20 reported greater effect of ketamine compared with placebo or other comparison, but effects were short-lived. In participants with CRPS,26,27 ketamine infusion caused a significant reduction in pain to postinfusion week 11, but it did not improve function. Participants with other neuropathic pain conditions22,24 also reported superior effect of ketamine compared with placebo, results that were affirmed by a meta-analysis.30
In patients with fibromyalgia,15,16,29 ketamine seemed to cause a short-term (90-180 minutes after infusion) reduction in pain. However, longer-term follow-up evaluations did not show any difference on pain or function.
A small study in patients with chronic pain due to spinal cord injury demonstrated a significant effect of ketamine compared with placebo, but it did not change pain thresholds.21 A second study in patients with spinal cord injury demonstrated a significant reduction in pain to postinfusion week 3.28
Studies of Ischemic Pain, TMJ, and Other Types of Pain
Ischemic pain was evaluated in one study comparing ketamine to placebo, with ketamine demonstrating a reduction in pain up to day 5 post-infusion.18
Ketamine did not seem to have an effect in patients with temporomandibular joint (TMJ) disorder.23 In addition, it did not seem to reduce the likelihood of chronic pain in women undergoing elective hyserectomy.25
Ten studies assessed the effectiveness of ketamine versus a placebo,14,16,18,20,21,23,25-29 with 8 of those studies using saline as the placebo and 1 of the studies using midazolam as the placebo.
Comparative Studies
The other studies compared ketamine to other commonly used medications and sometimes combined ketamine with one of the drugs as a treatment option. One of the studies compared treatments of calcitonin to treatment with calcitonin with ketamine; to ketamine alone; and then to saline alone.24 In this case, calcitonin had no substantial effect on the pain; however, ketamine did reduce phantom limb pain.
Another study compared the results of patients receiving opioids versus opioids plus ketamine.18 The study demonstrated the combination of ketamine plus opioids to be superior in pain relief.
Two studies looked at the effectiveness of pain relief from morphine versus lidocaine versus ketamine versus placebo.20,21 These studies demonstrated a significant pain improvement when comparing ketamine to the placebo and found lidocaine to have little analgesic effect.
Another 2 studies looked at ketamine versus alfentanil.14,19 In these studies, ketamine was found to be the most effective out of the 4 treatments.
One of the most common comparisons was among alfentanil, ketamine, and a placebo.14,17,19 In all 3 of these studies, both alfentanil and ketamine were effective at relieving pain. The other common drug comparison study looked at ketamine, morphine, both, and placebo.18,22 In these 2 studies, although ketamine was found to be effective, the combination of ketamine and morphine yielded more significant results.
Limitations to Several Studies
There were several limitations to these studies. First, many of the studies had relatively small sample sizes. Only 6 of the 17 studies had a sample size of 30 or more15,18,25,26,28,30 and only 3 of those 6 had a sample size 60 or more.25,26 Furthermore, most of these studies have only been conducted over a period of days to weeks. Therefore, there is a lack of research performed on the long-term effectiveness and side effects of ketamine as used to treat chronic pain. In addition, dosing of ketamine varied greatly both in terms of bolus and infusion rates and duration.
It should be noted that no clinical trial was identified that studied ketamine in pediatric, pregnant, or geriatric populations. In the future, larger studies should be performed and more studies focused on higher risk populations.
Conclusion
Ketamine is an anesthetic dissociative agent that currently has limited evidence-outside of treatment for CRPS-of short- or long-term effectiveness in reducing chronic pain intensity and improving function, or for reducing the likelihood of chronic pain.
For CRPS, studies have demonstrated moderate evidence to support the use of ketamine infusion.31
Research on the effectiveness of ketamine in chronic pain populations has been hampered by small sample sizes, variation in dosage and duration of administration, and limited evaluation of intermediate or long-term outcomes. Greater efforts toward collaborative research or research registries to facilitate high-quality clinical trials are needed and could help bridge knowledge gaps on the indications, short- and long-term benefits, and adverse risks associated with IV ketamine treatment for chronic pain conditions.
Due to its unique properties as an NMDA receptor antagonist that does not interact with GABA receptors, more precise identification of painful conditions for which ketamine could help to relieve pain and functioning is needed. In particular, research on the use of ketamine for the comorbid conditions of chronic pain and treatment-resistant depression could be particularly insightful.
References