Summary of Evidence

For individuals with chronic pain or psychiatric disorders who receive a course of IV anesthetics (e.g., ketamine, lidocaine), the evidence is limited. The studies found in literature have significant limitations and the durability of treatment effects has not been proven. Furthermore, the use of ketamine or lidocaine for the treatment of chronic pain or psychiatric disorders has not been approved by the FDA, nor is it supported in the drug compendia or by professional society guidelines. Further research, including large randomized controlled trials, on the efficacy of IV anesthetics for the treatment of chronic pain or psychiatric disorders is needed to determine optimal treatment protocols and long-term safety and effects of these drugs on health outcomes.

Rationale

The Visual Analogue Scale (VAS) and Numerical Rating Scale (NRS) are common pain assessments used for measuring pain intensity. The scales range from 0-10 and the patient selects the number that fits best to their pain intensity, where a higher score indicates greater pain intensity:

• Score of 0: no pain,
• Score of 1-3: mild pain,
• Score of 4-6: moderate pain,
• Score of 7-9: severe pain,
• Score of 10: worst pain imaginable.

The FDA has approved IV ketamine for use in general anesthesia and lidocaine for use as a local anesthetic and acute treatment of arrhythmias. The FDA has not approved ketamine or lidocaine for the treatment of chronic pain or psychiatric disorders.

In 2011, Vlainich et al reported a randomized double-blind trial of intravenous lidocaine plus amitriptyline versus amitriptyline monotherapy in 30 patients with fibromyalgia (FM). Infusion of lidocaine or saline was given once per week for 4 weeks. Pain intensity decreased in both groups over the course of treatment. However, there were no significant differences between the monotherapy and combined therapy groups at any point during the four weeks. At the end of the 4-week trial, p-values were reported as follows: pain intensity (p=0.64), plasma serotonin (p=0.229), norepinephrine (p=0.5069), and dopamine concentrations (p=0.0311).

In 2011, Noppers et al reported results of a double blind, active, placebo-controlled trial of 24 fibromyalgia (FM) patients who were randomized to receive a 30-minute infusion with 0.5 mg/kg ketamine (n=12) or 5 mg midazolam (n=12). The study consisted of a single treatment at the beginning of week one followed by an 8-week follow-up. Eight patients in the ketamine group experienced a 50% or greater reduction in Visual Analog Pain Scores (VAS) 45 minutes after infusion compared with 3 patients in the midazolam group (p<0.05). However, no significant treatment effects were observed either in the 2.5 hours following infusion (6 responders in the ketamine group; 2 in the midazolam group) or during long-term follow-up (2 vs 2 at the end of week 8).

In 2010, Amr published results from a double-blind, randomized, placebo-controlled study of 40 patients with neuropathic pain secondary to spinal cord injury. All patients received gabapentin (300 mg) 3 times daily. The experimental group also received ketamine infusions (80 mg) over a 5-hour period daily for 7 days. The control group received infusion of isotonic saline over the same period. Visual analog scores (VAS) for pain were similar in the two groups at baseline (VAS of 84 out of 100 for both groups). During the week of infusion, VAS scores decreased more in the ketamine-infused group than the gabapentin-only group (VAS score of 14 in the ketamine group vs. 43 in the control group at day 7). In the control group, VAS pain scores remained about the same during the 4-week follow-up. Pain scores in the ketamine-infused group increased from 14 to 22 at 1-week follow-up and remained at that level for 2 weeks after infusion. By the third week after the ketamine infusion, VAS scores had increased to 43 and were the same as the placebo group. Three patients were reported to have had short-lasting delusions with ketamine infusion.

In 2020, Pickering et al published results of a small randomized, double-blind, crossover, placebo-controlled study in adults with refractory neuropathic pain. This study compared a single infusion each of ketamine (0.5mg/kg), ketamine (0.5mg/kg)/magnesium sulfate (3g), and placebo. 20 patients were enrolled and assessed 5 weeks after each crossover period. The primary endpoint was the area under the curve of daily pain intensity for a period of 35 days after infusion. The study found no difference between groups in average daily pain intensity based on mean area under the curve (p=0.296) at day 35, nor was there a difference in maximal pain (p=0.291) or nightly pain (p=0.261). The study also found no difference between interventions in any measure of function or quality of life, including Brief Pain Inventory score (p=0.527), Hospital Anxiety and Depression Scale (HADS)-Depression (p=0.484) or HADS-Anxiety (p=0.155) scores. There were no serious adverse events or withdrawals due to adverse events.

In 2018, Kim et al published results of a prospective, randomized, double-blind, placebo-controlled study in adults with neuropathic pain. This study evaluated 42 patients with postherpetic neuralgia (PHN) or complex regional pain syndrome (CRPS). Patients were randomized to receive infusions of lidocaine (3 mg/kg) or placebo (saline) once a week for 4 consecutive weeks. The primary outcome was the difference in the percentage change in the 11-point numerical rating scale (NRS) pain score from baseline to after the final infusion. The groups did not differ significantly at weeks 1 and 2 in a reduction in pain; however, there were differences between groups after weeks 3 and 4 (p=0.001 and p=0.009, respectively). In the lidocaine-treated group, there was a significantly greater reduction in pain following the final infusion compared with the placebo group (p=0.011). However, this difference in the percentage of pain reduction was not reported at follow-up assessments in 1 and 4 weeks after the final infusion, suggesting only a temporary analgesic effect. No patients experienced serious complications from the treatment.

In 2016, Singh et al conducted a double-blind, randomized, placebo- controlled study evaluating the efficacy of two and three times a week intravenous administration of ketamine in sustaining initial antidepressant effects in patients with treatment-resistant depression. Patients were randomized to receive either intravenous ketamine (0.5 mg/kg of body weight) or intravenous placebo, administered over 40 minutes, either two or three times weekly for up to 4 weeks. The primary outcome was change from baseline to day 15 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS). In total, 67 of 68 randomized patients received treatment. In the twice-weekly dosing groups, the mean change in MADRS score at day 15 was -18.4 for ketamine and -5.7 for placebo; in the thrice-weekly groups, it was -17.7 for ketamine and -3.1 for placebo. Similar observations were noted for ketamine during the open-label phase (twice-weekly, -12.2 on day 4; thrice-weekly, -14.0 on day 5). Headache, anxiety, dissociation, nausea, and dizziness were the most common (≥20%) treatment-emergent adverse events. The authors concluded that ketamine, administered intravenously at 0.5 mg/kg of body weight either two or three times weekly, appeared comparably effective in both achieving rapid onset and maintaining antidepressant efficacy in patients with treatment-resistant depression across the 15-day period of assessment for the primary efficacy endpoint. The authors note significant limitations: the study had a short duration and assessed the maintenance of response for only 4-6 weeks. Treatment-resistant depression is a chronic condition, and studies with a longer duration are needed to determine whether the clinical benefits of ketamine can be maintained. Additionally, no active control was used in the study. Adverse events associated with ketamine may unblind the active drug administration to patients and/or clinicians.

In 2015, Newport et al conducted a systematic review and meta-analysis of ketamine and other NMDA receptor antagonists in the treatment of major depression. The authors searched databases for placebo-controlled, double-blind, randomized clinical trials of NMDA antagonists in the treatment of depression. Primary outcomes included rates of treatment response and transient remission of symptoms. The authors found that ketamine (seven trials with 147 ketamine-treated patients) produced rapid, yet transient, antidepressant effects, with odds ratios for response and transient remission of symptoms at 24 hours. Other NMDA antagonists did not consistently demonstrate efficacy, although two other NMDA antagonists (D-cycloserine and rapastinel) appeared to reduce depressive symptoms without psychotomimetic or dissociative effects. The researchers concluded that the antidepressant efficacy of ketamine, and perhaps those two other NMDA antagonists, may be a promising treatment option for future glutamate-modulating strategies. However, the authors note the importance of improving our understanding of ketamine’s mechanism of action. The fleeting nature of ketamine’s therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.

In 2021, Bahji et al conducted a systematic review of studies using ketamine for the treatment of bipolar depression. Six studies were identified with 135 participants. All studies used 0.5 mg/kg of add-on intravenous ketamine, with the number of doses ranging from 1 to 6; all participants continued a mood-stabilizing agent. The overall proportion achieving a response (defined as those having a reduction in their baseline depression severity of at least 50%) was 61% for those receiving ketamine and 5% for those receiving a placebo. The overall response rates varied from 52% to 80% across studies. Ketamine was reasonably well tolerated; however, 2 participants (1 receiving ketamine and 1 receiving placebo) developed manic symptoms. Some participants developed significant dissociative symptoms at the 40-minute mark following ketamine infusion in 2 trials. The authors concluded that there is some preliminary evidence supporting use of intravenous ketamine to treat adults with bipolar depression, however the level of proof of efficacy remains low. More randomized controlled trials are needed to explore efficacy and safety issues, as well as longer-term outcomes, for administering ketamine in the treatment of bipolar depression.

In 2021, Feder et al published results of a randomized, double-blind, parallel-arm controlled Phase 2 study in adults with chronic PTSD. Patients were randomly assigned to receive six infusions of ketamine 0.5 mg/kg or midazolam 0.045 mg/kg (psychoactive placebo control) over two consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). In this study, 30 adults were assigned to either ketamine (n=15) or midazolam (n=15) and the primary analysis population comprised all 30 participants. The ketamine group showed a significantly greater improvement in CAPS-5 and Montgomery- Åsberg Depression Rating Scale (MADRS) total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI 0.36-1.91; p=0.004). In the ketamine group, 67% of participants were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. There were no serious adverse events. The researchers concluded that findings from this study suggest the overall safety and tolerability of ketamine infusions for individuals with chronic PTSD, however further research is needed to evaluate safety, tolerability, and efficacy of periodic IV ketamine administration as maintenance over several months.

In 2022, Abdallah et al published results of a randomized, double-blind, placebo-controlled Phase 2 study in military adult veterans and active service members with PTSD who failed previous antidepressant treatment. Patients were randomly assigned to receive 8 infusions of intravenous low dose ketamine 0.2 mg/kg, standard dose ketamine 0.5 mg/kg, or placebo administered twice weekly. Participants were assessed at baseline, during treatment, and for 4 weeks after their last infusion. Primary analyses used mixed effects models. The primary outcome measure was the self-report PTSD Checklist for DSM-5 (PCL-5). In this study, 158 adults were assigned to low dose ketamine (n=53), standard dose ketamine (n=51), or placebo (n=54). The primary analysis on the PCL-5 scores found no significant effect of treatment (p=0.17) and there were no significant group-by-time interactions for PTSD symptoms measured by the PCL-5 or CAPS-5. Ketamine produced dose-related dissociative and psychotomimetic effects, which returned to baseline within 2 hours and were less pronounced with repeated administration. There was no evidence of differential treatment discontinuation by ketamine dose, consistent with good tolerability. There were no serious adverse events. The researchers concluded that this clinical trial failed to demonstrate significant efficacy on PTSD symptoms or find a significant dose-related effect of ketamine on PTSD symptoms and further studies are needed to determine the role of ketamine in PTSD treatment.

Technology Assessments

Hayes evaluates a wide range of medical technologies and provides evidence-based assessments to determine impacts on patient safety and health outcomes. The Hayes Rating has become the industry’s benchmark and reflects the strength and direction of the evidence regarding a medical technology. The Hayes Rating is C for ketamine as a treatment for treatment-resistant depression, indicating unproven benefit and low quality of evidence. The Hayes Rating is D2 for ketamine as a treatment for treatment-resistant bipolar depression, indicating insufficient published evidence to assess the safety and/or impact on health outcomes or patient management. The Hayes Rating is also D2 for ketamine as a treatment for PTSD. The Hayes Rating is C for ketamine for the treatment of chronic nonmalignant pain in adults with inadequate responses to standard therapy. The Hayes Rating is C for lidocaine infusions for treatment of neuropathic pain.

Practice Guidelines & Position Statements 

In 2017, the American Psychiatric Association (APA) Council of Research Task Force published a consensus statement on the use of ketamine in the treatment of mood disorders. In this statement, the APA council members note that several studies provide some evidence of ketamine’s ability to produce rapid antidepressant effects in patients with mood and anxiety disorders. They note the limitations of this body of evidence, including relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety provided by these studies. The authors note that while ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option. Furthermore, they note that the suggestions provided in the document are intended to facilitate clinical decision making and encourage an evidence-based approach to using ketamine in the treatment of psychiatric disorders considering the limited information that is currently available. There are no clearly established indications for the use of ketamine in the treatment of psychiatric disorders and future research is needed to address unanswered questions and concerns regarding risks, benefits, safety, long-term effectiveness, and treatment protocols.

In 2022, the Department of Veterans Affairs and Department of Defense published a clinical practice guideline for the management of major depressive disorder (MDD). In this guideline, the Work Group states that given the limited information on ketamine’s safety and long-term efficacy, they recommend against the use of ketamine as an initial pharmacotherapy to treat MDD. Ketamine lacks long-term efficacy and safety trials in MDD, and the bulk of the short-term efficacy has been studied in patients who have previously not responded to adequate trials of antidepressants. Therefore, the use of ketamine is not recommended as initial treatment. For patients with MDD who have not responded to several adequate pharmacologic trials, the guideline suggests ketamine as an option for augmentation; the Work Group decided upon a Weak recommendation as confidence in the quality of the evidence for this recommendation was low. The body of evidence had some limitations, including high risk of bias. However, the potential benefits of reduced depressive symptoms and remission slightly outweighed the potential harms and adverse events, which are largely transient and self-resolving.

In 2017, the Department of Veterans Affairs and Department of Defense published a clinical practice guideline for the management of post-traumatic stress disorder (PTSD) and acute stress disorder. In this guideline, the authors recommend against treating PTSD with ketamine due to the lack of strong evidence for its efficacy and/or known adverse effect profiles and associated risks. Well-designed studies could help shed light on the efficacy of ketamine on clinician-rated PTSD and depressive symptoms.

In 2023, the Florida Medicaid Mental Health Organization published a best practice guideline for psychotherapeutic medication. This guideline gives a level 4 recommendation for intravenous ketamine as treatment of acute bipolar disorder. Level 4 indicates treatments are not well supported. In addition, this guideline gives a level 2 recommendation for combining existing monotherapy with intranasal esketamine or intravenous ketamine as a treatment for major depressive disorder if multiple trials with initial treatment options are ineffective and/or not well tolerated. Level 2 indicates data on efficacy and/or safety are less robust and based on smaller randomized controlled trials, cohort studies, or systematic reviews.

Drug Compendia

The use of intravenous ketamine for the treatment of chronic pain or psychiatric disorders is not supported in any of the five CMS recognized drug compendia: NCCN, Micromedex, Clinical Pharmacology, AHFS-DI, and Lexi-Drugs. The majority of these compendia give the use of ketamine and lidocaine a weak recommendation characterized by a very low level of evidence. AHFS-DI does not address off-label uses of ketamine, and the NCCN does not address ketamine altogether.

Reference List

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