Description:
Intravenous (IV) infusion of lidocaine or ketamine has been investigated for the treatment of migraine and chronic daily headache, fibromyalgia, and chronic neuropathic pain. Chronic neuropathic pain disorders include phantom limb pain, post-herpetic neuralgia, complex regional pain syndrome, diabetic neuropathy, and pain related to stroke or spinal cord injuries. An IV infusion of ketamine has also been investigated for the treatment of depression and obsessive-compulsive disorder. For these applications, one or more courses of IV infusion would be administered over several hours or several days.

For individuals who have chronic pain syndromes (e.g., complex regional pain syndrome, fibromyalgia, headache, neuropathic pain, spinal cord injury) who receive a course of IV anesthetics (e.g., lidocaine, ketamine), the evidence includes several randomized controlled trials. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, quality of life, medication use, and treatment-related morbidity. Evidence, primarily from outside of the United States, has suggested that courses of IV lidocaine and ketamine may provide — at least temporary — relief to some chronic pain patients. However, the intense treatment protocols, the severity of adverse events, and the limited treatment durability raises questions about the overall health benefit of this procedure. Additional clinical trials are needed to evaluate the long-term safety of repeat courses of IV anesthetics. The evidence is insufficient to determine the effects of the technology on health outcomes. 

For individuals who have psychiatric disorders (e.g., depression, obsessive-compulsive disorder) who receive a course of IV anesthetics (e.g., lidocaine, ketamine), the evidence is limited. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, quality of life, medication use, and treatment-related morbidity. Several trials on the IV infusion of ketamine for the treatment of suicidal ideation in patients with depression are ongoing. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background 
INTRAVENOUS ANESTHETIC AGENTS
Courses of intravenous (IV) anesthetic agents may be given in the inpatient or outpatient setting as part of a pain management program, with the infusion of a subanesthetic dose preceded by a bolus infusion to achieve desired blood levels sooner.

Lidocaine
Lidocaine, which prevents neural depolarization through effects on voltage-dependent sodium channels, is also used systemically for the treatment of arrhythmias. Adverse events for lidocaine are common, can be mild to moderate, and include general fatigue, somnolence, dizziness, headache, periorbital and extremity numbness and tingling, nausea, vomiting, tremors, and changes in blood pressure and pulse. Severe adverse effects may include arrhythmias, seizures, loss of consciousness, confusion, or even death. Lidocaine should only be given intravenously to patients with normal conduction on electrocardiography and normal serum electrolyte concentrations to minimize the risk of cardiac arrhythmias.

Ketamine
Ketamine is an antagonist of the N-methyl-D-aspartate (NMDA) receptor and a dissociative anesthetic. It is the sole anesthetic agent approved for diagnostic and surgical procedures that do not require skeletal muscle relaxation. Respiratory depression may occur with overdosage or too rapid a rate of administration of ketamine; it should be used by or under the direction of physicians experienced in administering general anesthetics. Ketamine is a schedule III controlled substance. Psychological manifestations vary in severity from pleasant, dream-like states to hallucinations and delirium; futher, these manifestations can be accompanied by confusion, excitement, aggression, or irrational behavior. The occurrence of adverse events with IV anesthetics may be reduced by the careful titration of subanesthetic doses. However, the potential benefits of pain control must be carefully weighed against the potential for serious, harmful adverse events.  

Indications
IV administration of anesthetic has been reported for various conditions, including chronic pain of neuropathic origin, chronic headache, fibromyalgia, depression, and obsessive-compulsive disorders. Chronic daily headache is defined as a headache disorder that occurs more than 15 days a month for at least 3 months. Chronic daily headache includes chronic migraine, new daily persistent headache, hemicranias continua, and chronic tension-type headache.

Neuropathic pain is often disproportionate to the extent of the primary triggering injury and may consist of thermal or mechanical allodynia, dysesthesia, and/or hyperalgesia. Allodynia is pain that occurs from a stimulus that normally does not elicit a painful response (e.g., light touch, warmth). Dysesthesia is a constant or ongoing unpleasant or electrical sensation of pain. Hyperalgesia is an exaggerated response to normally painful stimuli. In the latter, symptoms may continue for a period of time that is longer (e.g., ≥ 6 months) than clinically expected after an illness or injury. It is proposed that chronic neuropathic pain results from peripheral afferent sensitization, neurogenic inflammation, and sympathetic afferent coupling, along with sensitization and functional reorganization of the somatosensory, motor, and autonomic circuits in the central nervous system. Therefore, treatments focus on reducing activity and desensitizing pain pathways, thought to be mediated through NMDA receptors in the peripheral and central nervous system. Sympathetic ganglion blocks with lidocaine have been used for a number of years to treat sympathetically maintained chronic pain conditions, such as complex regional pain syndrome (previously known as reflex sympathetic dystrophy). Test infusion of an anesthetic has also been used in treatment planning to assess patient responsiveness to determine whether medications, such as oral mexiletine or oral ketamine, may be effective. A course of IV lidocaine or ketamine, usually at subanesthetic doses, has also been examined. This approach for treating chronic neuropathic pain differs from continuous subcutaneous or IV infusion of anesthetics for the management of chronic pain conditions, such as terminal cancer pain, which are not discussed herein.

Fibromyalgia is a chronic state of widespread pain and tenderness. Although fibromyalgia is generally considered to be a disorder of central pain processing or central sensitization, others have proposed that the nerve stimuli causing pain originates mainly in the muscle, causing both widespread pain and pain on movement. There are focal areas of hyperalgesia, or tender points, which tend to occur at muscle tendon junctions. Biochemical changes that have been associated with fibromyalgia include alterations in NMDA receptors, low levels of serotonin, suppression of dopamine-releasing neurons in the limbic system, dysfunction of the hypothalamic-pituitary-adrenal axis, and elevated substance P levels. Fibromyalgia is typically treated with neuropathic pain medications such as pregabalin, non-narcotic pain relievers, or low doses of antidepressants.

The use of IV ketamine has also been reported for treatment-resistant depression, defined as depression that does not respond adequately to appropriate courses of antidepressant medications. Particularly challenging are patients with treatment-resistant depression with suicidal ideation. Several studies are ongoing to test the efficacy of IV ketamine in patients with suicidal ideation who present to the emergency department.

Regulatory Status
IV lidocaine is approved by the U.S. Food and Drug Administration (FDA) for systemic use in the acute treatment of arrhythmias and locally as an anesthetic. IV lidocaine for the treatment of chronic pain is an off-label use.

Ketamine hydrochloride injection is FDA-indicated for diagnostic and surgical procedures that do not require skeletal muscle relaxation, for the induction of anesthesia before the administration of other general anesthetic agents, and to supplement low-potency agents, such as nitrous oxide. IV ketamine for the treatment of chronic pain is an off-label use.

Related Policies
70141 Implantable Infusion Pump

Policy:
Intravenous infusion of anesthetics (e.g., ketamine or lidocaine) for the treatment of chronic pain, including, but not limited to chronic neuropathic pain, chronic daily headache, fibromyalgia, is investigational and/or unproven and therefore NOT MEDICALLY NECESSARY.

Intravenous infusion of anesthetics (e.g., ketamine or lidocaine) for the treatment of psychiatric disorders, including but not limited to depression and obsessive-compulsive disorder, is investigational and/or unproven and therefore NOT MEDICALLY NECESSARY. 

Benefit Application
BlueCard/National Account Issues
Intravenous (IV) lidocaine or ketamine may be best addressed contractually as a component of a pain management program.

Some facilities may negotiate global fees for pain management. However, charges for pain management may be subject to individual contractual limitations.

Rationale
This evidence review was created in April 2004 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through Oct. 5, 2021.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Intravenous Anesthetics for Individuals with Chronic Pain
Clinical Context and Therapy Purpose
The purpose of a course of IV anesthetics (e.g., lidocaine, ketamine) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with chronic pain syndromes (e.g., complex regional pain syndrome [CRPS], fibromyalgia, headache, neuropathic pain, spinal cord injury).

The question addressed in this evidence review is: Does a course of IV anesthetics improve the net health outcome in individuals with chronic pain syndromes?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest are individuals with chronic pain syndromes (e.g., CRPS, fibromyalgia, headache, neuropathic pain, spinal cord injury).

Interventions
The therapy being considered is a course of IV anesthetics (e.g., lidocaine, ketamine).

Comparators
The following therapy is currently being used to treat chronic pain syndromes: oral pain medication.

Outcomes
The general outcomes of interest are symptoms, change in disease status, morbid events, functional outcomes, QOL, medication use, and treatment-related morbidity.

Follow-up of at least 4 weeks is of interest to monitor for outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.
• Studies with short-term outcomes (< 24 h) were excluded.

Review of Evidence
Neuropathic Pain
Systematic Reviews
A network meta-analysis by Wertli et al. (2014) evaluated the efficacy of all medication classes investigated in RCTs and provided a rank order of various substances.¹ Sixteen studies on bisphosphonates, calcitonin, N-methyl-d-aspartate analogues, analgesics, vasodilators, steroids, anticonvulsive agents, and radical scavengers were analyzed. Of these, only bisphosphonates, N-methyl-d-aspartate analogues (ketamine), and vasodilators showed better long-term pain reduction than placebo. The 2 RCTs with ketamine were reported by Schwartzman et al. (2009) (n = 19) and Sigtermans et al. (2009) (n = 60), the latter of which is described below.^2,3

The same 16 studies were selected by O'Connell et al. (2013) in a Cochrane overview of interventions for CRPS, which found low-quality evidence that a course of IV ketamine may be effective for CRPS-related pain; the effects of such a course were not sustained beyond 4 to 11 weeks posttreatment.⁴

Randomized Controlled Trials
Tables 1 and 2 summarize the characteristics and results of selected RCTs.

Lidocaine
Several RCTs have been performed using IV lidocaine for postherpetic neuralgia (PHN), CRPS, and diabetic neuropathy. These trials have failed to show a durable effect of lidocaine infusion on chronic pain.

Kim et al. (2018) published a prospective, randomized, double-blind, placebo-controlled trial evaluating 43 patients with PHN or CRPS who were randomized to lidocaine or placebo (saline) in 4 weekly infusions.⁵ The groups did not differ significantly at weeks 1 and 2 in a reduction in pain; however, there were between-group differences after weeks 3 and 4 (p = .001 and p = .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 = .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.

Liu et al. (2018) randomized 189 patients with PHN to a single 1.5 hour infusion of lidocaine with an injection of midazolam and granisetron.⁶ Patients were also taking pregabalin and oxycodone as needed. The control group received saline with midazolam and granisetron. The study was double-blind with allocation concealment and an independent assessor. Pain scores decreased from baseline in both groups, but there was no significant difference in scores between the lidocaine and placebo groups. However, patients treated with a lidocaine infusion had a greater change in the 36-item Short Form Health Survey score (maximal at 1 week), and had a greater reduction in analgesic use (relative risk, 6.2; 95% confidence interval, 2.24 to 17.16), with 26.6% of patients in the lidocaine group either decreasing or stopping use of analgesics compared to 2.2% of controls. Side effects were generally mild and did not differ between the groups. The main limitation of this study is the short infusion of lidocaine.

A randomized 4-week crossover trial by Moulin et al. (2019) found no significant differences between a single infusion of lidocaine (5 mg/kg over 45 minutes) and diphenydramine (active control) in patients (n = 34) with primarily diabetic neuropathy.⁷ This study is limited by the short infusion of lidocaine.

Ketamine
Three double-blind RCTs on ketamine for neuropathic pain were identified. One examined a 4-day infusion in patients with CRPS³, the second examined infusions on 7 days in patients with spinal cord injury⁸, and the third examined a single ketamine infusion in patients with mixed refractory neuropathic pain.⁹

A double-blind RCT of ketamine for CRPS was reported by Sigtermanset al. (2009).³ Sixty patients were randomized to ketamine or saline, infused over 4 days. The mean ketamine infusion rate was 22 mg/h (normalized to a 70-kg patient) at the end of the treatment phase. Blood samples were collected to assess the plasma concentration of ketamine, and patients were monitored for adverse events. Two patients terminated ketamine infusion early due to psychomimetic effects (e.g., delusions, hallucinations). At baseline, numeric rating scale (NRS) scores for pain were 7.2 (maximum, 10) for ketamine and 6.9 for the placebo group. The lowest pain scores (ketamine, 2.7; placebo, 5.5) were observed at the end of the first week (no patients were lost to follow-up for the primary outcome measure). Although pain scores remained statistically lower through week 11, the clinically significant difference of 2 points was maintained until week 4. None of the secondary (functional) outcome measures were improved by treatment. Moreover, 60% of patients in the placebo group correctly deduced treatment assignment (slightly better than chance); 93% of patients in the ketamine group correctly deduced treatment assignment due primarily to psychomimetic effects.

Amr (2010) published results from a double-blind, randomized, placebo-controlled study of 40 patients with neuropathic pain secondary to spinal cord injury.⁸ Ketamine or saline were infused for 5 hours over 7 days. All patients received gabapentin (300 mg) 3 times daily. Visual analog scale (VAS) scores for pain were similar in the ketamine and saline groups at baseline (VAS of 84 of 100). During the week of infusion, VAS scores decreased more in the ketamine-infused group than in 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 the infusion. By the third week after the ketamine infusion, VAS scores had increased to 43 in the ketamine group and were the same as the placebo group. Three patients were reported to have had short-lasting delusions with ketamine infusion.

A third, small, crossover RCT conducted by Pickering et al. (2020) compared a single infusion each of ketamine, ketamine/magnesium, and placebo.⁹ The study enrolled 20 patients with refractory neuropathic pain of mixed etiology and assessed patients 5 weeks after each crossover period. The study found no difference between groups in average daily pain intensity based on mean area under the curve (p = .296), nor was there a difference in maximal pain (p = .291) or nightly pain (p = .261). The study also found no difference between interventions in any measure of function or QOL, including Brief Pain Inventory score (p = .527), Hospital Anxiety and Depression Scale (HADS)-Depression (p = .484) or HADS-Anxiety (p = .155) scores. There were no serious adverse events or withdrawals due to adverse events.

Table 1. Summary of Key Randomized Controlled Trial Characteristics

Study	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Lidocaine
Kim et al. (2018)5	South Korea	1	2015 – 2016	Patients had PHN or CRPS type II with an 11-point NRS score of 4 or ≥ 3 mo without pain relief from conservative treatment	IV lidocaine 3 mg/kg for 4 weekly treatments of 1 h each (n = 21)	IV saline for 4 weekly treatments of 1 h each (n = 21)
Liu et al. (2018)6	China	1	2015 – 2017	189 patients with post-herpetic neuralgiaPHN and pain > 1 mo with VAS > 4	A single 1.5 h infusion of 5 mg/kg lidocaine, injection of 1.5 mg midazolam and 3 mg granisetron, also taking pregabalin and oxycodone	1.5 h infusion of saline, plus midazolam and granisetron, also taking pregabalin and oxycodone
Ketamine
Sigtermans et al. (2009)3	NL	1	2006 –2008	Patients were diagnosed with CRPS type I	30 patients randomized to ketamine infused over 4 d (titrated up to 30 mg/h for a 70-kg patient)	30 patients randomized to saline infused over 4 d
Amr (2010)8	Egypt	1	Not reported	40 patients with neuropathic pain secondary to spinal cord injury Baseline mean VAS of 84	Ketamine infusion (80 mg) over a 5-hour period daily for 7 days, with gabapentin during and after infusion (n = 20)	Saline infusion over the same time period, with gabapentin during and after infusion (n = 20)
Pickering et al. (2020)9	France	1	2015 –2018	20 ketamine-naive patients with refractory neuropathic pain	Ketamine infusion 0.5 mg/kg over a 2-hour period	Magnesium 3 g over 30 mins Saline infusion over a 2-hour period

CRPS: complex regional pain syndrome; IV: intravenous; NL: Netherlands; NRS: numeric rating scale; PHN: postherpetic neuralgia; VAS: visual analog score.

Table 2. Summary of Key Randomized Controlled Trial Results

Study	Pain Scores (SD), %	Other Clinical Outcomes	AEs
Lidocaine
Kim et al. (2018)5	VAS (100 mm)
N	42		42
Lidocaine	48.71 (40.59)		3 mild
Saline	19.51 (27.27)		4 mild
p-Value	.011		.698
Liu et al. (2018)6	VAS (10 cm) at 2 weeks	SF-36 at 1 week
N	183
Lidocaine	2.74	80.09 (7.64)
Placebo	2.94	30.28 (7.07)
p-Value	NS
Ketamine
Sigtermans et al. (2009)3	11 point NRS at 1 week	Reduction in NRS Pain Score (SD), %a
N	60		60
Ketamine	2.68 (0.51)		Nausea: 63; Vomiting: 47; Psychomimetic effects: 93; Headache: 37
Placebo	5.45 (0.48)		Nausea: 17; Vomiting: 10; Psychomimetic effects: 17; Headache: 33
p-Value		Clinically significant difference (2 points) maintained until week 4. Statistical difference maintained until week 11; at week 12, ketamine’s treatment effect no longer significant (p = .07)	Nausea: p < .001; Vomiting: p = .004; Psychomimetic effects: p < .001; Headache: p = .78
Amr et al. (2010)8,	VAS (100 mm) at 2 weeks	Reduction in NRS Pain Score (SD), %a
N	40
Ketamine	22.4 (7.54)
Placebo	44.0 (6.41)
p-Value	p < .01	Maintained for 2 weeks after infusion. Ketamine not significantly different from placebo at 3 and 4 weeks after infusion.
Pickering et al. (2020)9	Average daily pain AUC	Brief Pain Inventory pain severity score	Any adverse event
N	20	20	20
Ketamine	196 (SD 92)	6 (SD 3)	20% (4/20)
Ketamine/magnesium	185 (SD 100)	6 (SD 2)	35% (7/20)
Placebo	187 (SD 90)	6 (SD 2)	10% (2/20)
p-Value	.296	.527	Not reported

AE: adverse event; AUC: area under the curve; NRS: numeric rating scale; NS: not significant; SD: standard deviation; SF-36: 36-item Short-Form health survey; VAS: visual analog score.
^a Measured from baseline to after the final infusion.

The purpose of the limitations tables (see Tables 3 and 4) is to display notable limitations identified in each study. The primary limitations of the RCTs are the lack of active control for the psychomimetic effects of ketamine.

Table 3. Study Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Kim et al. (2018)5			2. Did not use active placebo (diphenhydramine)
Liu et al. (2018)6		4. The dose was higher and duration of treatment lower compared to other studies
Sigtermans et al. (2009)3			2. Did not use an active placebo (saline)
Amir et al. (2010)8			2. Did not use an active placebo (saline)
Pickering et al. (2020)9				5. Pain reported as area under the curve, mean pain scores not reported

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 4. Study Design and Conduct Limitations

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Kim et al. (2018)5
Liu et al. (2018)6
Sigtermans et al. (2009)3
Amir et al. (2010)8					1. Power calculations were not reported, but significance was obtained	2. Used a Mann-Whitney-U test rather than repeated measures analysis
Pickering et al. (2020)9	3. Allocation concealment unclear				1. Power calculations were not reported

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Observational Studies
Patil and Anitescu (2012) retrospectively analyzed data from 49 patients with severe refractory pain who had undergone 369 outpatient ketamine infusions during a 5-year period at a U.S. academic medical center.¹⁰ Eighteen patients were diagnosed with CRPS, and 31 had other diagnoses including refractory headache (n = 8) and severe back pain (n = 7). All patients exhibited signs of central sensitization. Following pretreatment with midazolam and ondansetron, ketamine infusions were administered at the highest tolerated dose for a duration ranging from 30 minutes to 8 hours. The interval between infusions ranged from 12 to 680 days (median, 233.7 days). The immediate reduction in the VAS score was 7.2 for patients with CRPS and 5.1 for non-CRPS pain. Query of available patients (59%) indicated that, for 38%, pain relief lasted more than 3 weeks. Adverse events, which included confusion and hallucination, were considered minimal.

A retrospective analysis by Przeklasa-Muszynska et al. (2016) examined the use of 3 to 25 IV infusions of lidocaine (5 mg/kg over 30 min) in 85 patients (57% women; mean age, 63 years) with neuropathic pain.¹¹ These disorders included: trigeminal neuralgia (n = 18), chemo-induced peripheral neuropathy (n = 6), PHN (n = 16), diabetic neuropathy (n = 7), persistent postoperative pain (n = 21), and other pain syndromes, including phantom pains, mononeuropathies, compression neuropathies, central pain syndrome, CRPS, and facial neuropathy (n = 17). A total of 814 infusions were delivered to 85 patients; however, treatment was discontinued in 4 patients after the first infusion due to the lack of efficacy. Assessment of pain using a NRS ranged from 0 to 10. The mean change from baseline in NRS score was 4.2. Efficacy increased significantly with age (71 to 90 years, p < .05). There was a correlation between treatment efficacy and the number of infusions (6 to10 infusions, p < .01) and the severity of pain (NRS range, 9 to 10; p < .001). There was no correlation between treatment efficacy and the number of years patients had experienced pain symptoms (range, 19 to 30 years; p < .05). Reviewers reported that infusions were not interrupted due to adverse events; however, they did not report whether adverse events occurred.

Mangnus et al. (2021) performed a retrospective analysis of data from 48 adult patients with CRPS treated with ketamine infusions at a single center in the Netherlands.¹² The median duration of diagnosis was 5 years. Ketamine infusions were started at 3 mg/hour during a 7-day inpatient stay, and were increased twice daily in increments of 1 to 2 mg/hour until patients reached an effective dose. At the end of infusion and at 4 weeks post-infusion, pain score was significantly reduced from baseline (8 vs. 6; p < .001 and 8 vs. 7; p = .015, respectively). Response (decrease in pain score of ≥ 2 from baseline) occurred in 62% of patients at the end of infusion, but decreased to 48% at 4 weeks.

Tables 5 and 6 summarize the characteristics and results of selected observational studies.

Table 5. Summary of Key Observational Study Characteristics

Study	Study Type	Country	Dates	Participants	Treatment	Follow-Up
Patil & Anitescu (2012)10	Retrospective chart review	U.S.	2004 – 2009	Patients with CRPS, refractory headaches, or severe back pain (n = 49)	Ketamine 0.5 mg/kg over 30 to 45 min for a total of 369 infusions	NR
Przeklasa-Muszynska et al. (2016)11	Retrospective chart review	Poland	Jan – Nov 2015	Adults with refractory neuropathic pain (n = 85)	Lidocaine 5 mg/kg over 30 min once a week; range, 3 to 25 infusions	4 weeks
Mangnus et al. (2021)12	Retrospective chart review	Netherlands	2010 – 2019	Adult patients with CRPS (n = 48)	Ketamine 3 mg/hour increased twice daily in increments of 1 to 2 mg over a 7-day inpatient stay	4 weeks

CRPS: complex regional pain syndrome; NR: not reported.

Table 6. Summary of Key Observational Study Results

Study	Change in Pain Score From Start of Infusion to Discontinuation	Change in Pain Score From Start of Infusion to 4 weeks	Durability	Adverse Events Patient-reported, n (%)
Patil & Anitescu (2012)10
N	49		29	49
	VAS: 5.9 (0.35)		Pain relief lasted at least 3 weeks in 38% of patients queried	23 (46.9) reported; 35 nonserious
Przeklasa-Muszynska et al. (2016)11
N	81		-	-
	NRS: 4.2 (SE not reported)		Not reported	Not reported
Mangnus et al. (2021)12
N	36	18
	NRS: 2	NRS: 1

NRS: numeric rating scale; SE: standard error; VAS: visual analog scale.

Fibromyalgia
Randomized Controlled Trials
Noppers et al. (2011) reported on a randomized, double-blind, active placebo-controlled trial conducted in Europe using a 30-minute infusion of ketamine (n = 12) or midazolam (n = 12).¹³ Baseline VAS pain scores were 5.4 in the ketamine group and 5.8 in the midazolam group. At 15 minutes after termination of the infusion, significantly more patients in the ketamine group showed a reduction in VAS score for pain exceeding 50% than in the placebo group (8 vs. 3). There were no significant differences between the groups at 180 minutes after infusion (6 vs. 3), at the end of week 1 (2 vs. 0), or at the end of week 8 (2 vs. 2), all respectively. There was no difference between groups on the Fibromyalgia Impact Questionnaire scores measured weekly over 8 weeks. In this well-conducted study, a short infusion of ketamine (30 minutes) did not have a long-term analgesic effect on fibromyalgia pain.

Vlainich et al. (2011) reported on a randomized, double-blind trial of IV lidocaine plus amitriptyline versus amitriptyline monotherapy in 30 patients with fibromyalgia.¹⁴ Infusion of lidocaine or saline was given once a week for 4 weeks. Pain intensity decreased in both groups during treatment; however, there was no significant difference between the treatment groups (VAS, 4.1 for combined treatment vs. 4.0 for monotherapy).

Section Summary: Intravenous Anesthetics for Individuals With Chronic Pain
Several RCTs have been performed using IV lidocaine or ketamine for PHN, CRPS, and diabetic neuropathy. Trials have failed to show a durable effect of lidocaine infusion on chronic pain. Two trials with a total of 100 patients provide limited evidence that courses of IV ketamine may provide temporary relief (2 to 4 weeks) to some chronic pain patients. Neither of the RCTs with ketamine infusion used an active control, raising the possibility of placebo effects and unblinding of patients and investigators. Overall, the intense treatment protocols, the severity of adverse events, and the limited treatment durability raise questions about the net health benefit of this therapy. Additional clinical trials are needed to evaluate the long-term efficacy and safety of repeat courses of IV anesthetics for chronic pain.

Psychiatric Disorders
Clinical Context and Therapy Purpose
The purpose of a course of IV anesthetics (e.g., lidocaine, ketamine) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with psychiatric disorders (e.g., depression, obsessive-compulsive disorder [OCD]).

The question addressed in this evidence review is: Does a course of IV anesthetics improve the net health outcome in individuals with psychiatric disorders?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest are individuals with psychiatric disorders (e.g., depression, OCD).

Interventions
The therapy being considered is ketamine . Ketamine is approved by the U.S. Food and Drug Administration as an anesthetic and use for psychiatric conditions is off-label. The mechanism for its effects in psychiatric disorders is uncertain. Ketamine is administered as an IV infusion in a medically-supervised setting.

Comparators
The following therapies are currently being used to treat psychiatric disorders: psychotropic medications and psychotherapy. Long-standing refractory depression in patients who do not benefit from treatment modification or augmentation strategies is referred to as treatment-resistant depression (TRD). The strategy for managing TRD generally involves modifying current antidepressant therapy or augmenting existing therapies with non-antidepressant medications (such as atypical antipsychotics). For these patients, other strategies such as electroconvulsive therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation techniques have also been used. Depression-focused psychotherapy may be added to pharmacotherapy, but is generally not considered stand-alone therapy for refractory depression.

Outcomes
The general outcomes of interest are symptoms, change in disease status, morbid events, functional outcomes, QOL, medication use, and treatment-related morbidity. Commonly used scales are the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Rating Scale for Depression (HAM-D), the Clinically Administered Post-Traumatic Stress Disorder (PTSD) Scale (CAPS-5), and the Yale-Brown Obsessive-Compulsive Scale (YBOCS).

MADRS is commonly used to evaluate the efficacy of antidepressants by assessing the severity of depression. It contains 10 items and the total score ranges from 0 to 60. The following cut-offs were proposed to classify the level of depression severity:

• 0 – 6: No depression (absence of symptoms)
• 7 – 19: Mild depression
• 20 – 34: Moderate depression
• 35 – 60: Severe depression

HAM-D is a 17-item rating scale to determine the severity level of depression in a patient before, during, and after treatment. The total score ranges from 0 to 52, with the score corresponding to the following classifications:

• 0 – 7: No depression (normal)
• 8 – 16: Mild depression
• 17 – 23: Moderate depression
• ≥ 24: Severe depression

Inventory of Depressive Symptomatology — Clinician Rated 30 items

Though not completely standardized, follow-up for psychiatric disorders symptoms would typically occur in the months to years after starting treatment.

The CAPS-5 is the gold standard in assessment of PTSD symptoms. The CAPS-5 is a structured interview performed by clinicians or researchers that is used to diagnose PTSD and assess PTSD symptoms. Scores for each item range from 0 (absent) to 4 (extreme/incapacitating); total scores range from 0 to 120.

The YBOCS is a 10-item clinician-administered scale that is the most widely used rating scale for OCD. The YBOCS rates 5 dimensions related to obsessions and compulsions: time spent or occupied; interference with functioning or relationships; degree of distress; resistance; and control (i.e., success in resistance). Each item is scored on a 4-point scale with 0 representing no symptoms and 4 representing extreme symptoms. Total scores of the YBOCS correspond to the following indicated classifications:

• 0 – 7: Subclinical
• 8 – 15: Mild
• 16 – 23: Moderate
• 24 – 31: Severe
• 32 – 40: Extreme

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for double-blind RCTs.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.
• Studies with short-term outcomes (< 24 h) were excluded.
• Studies examining a single infusion in an inpatient setting (e.g., in conjunction with electroconvulsive therapy or emergency services for suicidal ideation) were excluded.

Review of Evidence
Randomized Controlled Trials
Tables 7 through 11 summarize the characteristics and results of identified RCTs. Rodriguez et al. (2013) performed a double-blind, placebo-controlled trial in patients with serotonin reuptake inhibitor (SRI)-resistant OCD to compare the effects of ketamine (0.5 mg/kg given over 40 minutes on 2 occasions at least 1 week apart) with saline placebo.¹⁵ Patients had failed or refused treatment with at least 1 trial of SRI therapy and/or cognitive behavioral therapy. The mean age of patients was 34.2 years and the mean YBOCS score was 28.2. A significant carryover effect was detected with ketamine, and these patients did not return to their baseline disease severity; therefore, data from each phase of the crossover trial were not combined and results were presented only for the first-phase data (ketamine first [n = 8] and saline first [n = 7]). A higher proportion of patients treated with ketamine achieved treatment response (≥ 35% reduction in YBOCS score; 50% vs. 0%; p < .05). The authors noted the small sample size and unblinding due to adverse effects of ketamine.

Singh et al. (2016) reported an industry-sponsored phase 2 multi-center double-blind trial of ketamine (0.5 mg/kg) either 2 or 3 times per week for 4 weeks, followed by 2 weeks of open-label treatment, and then a 3-week ketamine-free phase.¹⁶ Two control groups received saline infusions over the same intervals. Ketamine infusion resulted in significantly greater improvement in the MADRS compared to saline during the weeks of infusion. Thirty of the 33 patients in the placebo group withdrew from the study for lack of efficacy, compared to 3 of 35 who withdrew due to lack of efficacy in the ketamine groups. Although the analysis was intent-to-treat with the imputation of missing values, the lack of active control and high drop-out rate are limitations of the study. The most common adverse events (> 20%) were headache, anxiety, dissociation, nausea, and dizziness. By the third withdrawal week, only 9 of 33 ketamine patients remained in the study with diminishing benefits shown on the MADRS. Thus, the benefit observed during the infusion phase does not appear to have been maintained after the end of infusions.

Feder et al. (2021) performed a double-blind trial comparing IV ketamine with IV midazolam, each administered 3 times weekly over 2 weeks, in adult patients with PTSD.¹⁷ The primary outcome measure was change in PTSD symptom severity, assessed using the CAPS-5, from baseline to 2 weeks. The mean duration of PTSD was 14.9 years. Thirteen (43.3%) patients were receiving concomitant psychotropic medications, and 17 (56.7%) were receiving concomitant psychotherapy. At week 2, the mean CAPS-5 total score was lower in the ketamine group compared to the midazolam group (difference, 11.88 points; p = .004). The most common adverse events that occurred more frequently with ketamine included nausea or vomiting (33% vs. 20%), headache (33% vs. 20%), and fatigue (20% vs. 7%). The authors noted the potential for unblinding in the ketamine group due to the higher rate of dissociative symptoms.

Table 7. Summary of Key Randomized Controlled Trial Characteristics

Study; Trial	Design	Countries	Sites	Dates	Participants	Interventions
						Active	Comparator
Rodriguez et al. (2013)15	Double-blind, crossover RCT	U.S.	1	2010 – 2012	15 adult patients with SRI-resistant OCD and near-constant obsessions	IV ketamine (0.5 mg/kg) given over 40 min on 2 occasions at least 1 week apart	Saline infusion given over 40 min on 2 occasions at least 1 week apart
Singh et al. (2016)16	Double-blind, phase 2	U.S.	14	2012 – 2013	68 patients with TRD and a score > 34 on the IDS-CR	IV ketamine (0.5 mg/kg for 40 min), either 2 (n = 18) or 3 (n = 17) times a week for 4 weeks, followed by 2 weeks of open-label and then a 3-week ketamine-free phase	Saline infusion either 2 (n = 17) or 3 (n = 16) times per week over the same interval
Feder et al. (2021)17	Double-blind RCT	U.S.	1	2015 – 2020	30 adult patients with chronic PTSD	IV ketamine 0.5 mg/kg 3 times per week over 2 consecutive weeks	IV midazolam 0.045 mg/kg 3 times per week over 2 consecutive weeks

IDS-CR: Inventory of Depressive Symptomatology — Clinician Rated; IV: intravenous; OCD: obsessive-compulsive disorder; PTSD: post-traumatic stress disorder; RCT: randomized controlled trial; SRI: serotonin reuptake inhibitor; TRD: treatment-resistant depression

Table 8. Summary of Key Randomized Controlled Trial Results

Study	YBOCS Response to Day 71, n (%)	Change in MADRS to Day 15, Mean (SD)	Change in MADRS to Day 29, Mean (SD)	Remitters (MADRS < 10) at Day 15, n (%)	Drug-related Adverse Events, n (%)	Change in CAPS-5 at Day 15, Mean (SD)
Rodriguez et al. (2013)15
N	15
Ketamine	7 (50)
Placebo	0
Singh et al. (2016)16
N		67 ITT	67 ITT	58	68
Ketamine 2		-18.4 (12)	-21.2 (12.9)	6 (37.5)	13 (72.2)
Ketamine 3		-17.7 (7.3)	-21.1 (11.2)	3 (23.1)	10 (58.8)
Saline 2		-5.7 (10.2)	-4.0 (9.1)	1 (7.7)	6 (37.5)
Saline 3		-3.1 (5.7)	-3.6 (6.6)	0 (0)	5 (31.3)
p-Value		< .001	NR	NS
Feder et al. (2021)17
Ketamine						NR
Midazolam						NR
Difference (p value)						-11.88 (.004)

CAPS-5: Clinician-Administered PTSD Scale for DSM-5; CI: confidence interval; ITT: intent to treat; MADRS: Montgomery-Asberg Depression Rating Scale; NR: not reported; NS: not significant; SD: standard deviation; YBOCS: Yale-Brown Obsessive-Compulsive Scale.
¹ YBOCS reduction ≥ 35%.

Trials that have found no benefit of ketamine infusion are described in Table 9. Ionescu et al. (2019) reported a double-blind trial in 26 patients with chronic and current suicidal ideation.¹⁸ The study found no significant difference in HAM-D between the saline and ketamine groups at the end of infusion (6 infusions over 3 weeks) or after 3 months of follow-up. Limitations of the study included possible insufficient power due to difficulties in recruitment and a high drop-out rate. Review of clinicaltrials.gov shows a large number of small studies that have not been published or followed with larger trials.

Table 9. Randomized Controlled Trials with Negative Results

Study; Trial	Countries	Sites	Dates	Design	Participants	Interventions		Outcome Measure	Follow-up	Comment
						Active	Comparator
Ionescu et al. (2019)18	U.S.	1	2013 – 2015	Double-Blind	26 medicated patients with chronic and current suicidal ideation	6 ketamine infusions (0.5 mg/kg for 45 min) over 3 weeks	Saline at the same schedule	HAM-D	End of infusion and at 3 mo after infusion	No significant difference in HAM-D between groups at the end of infusion. 2 patients in each group were in remission at 3 mo follow-up.

HAM-D: Hamilton Rating Scale for Depression.

Table 10. Study Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Rodriguez et al. (2013)15					1. Follow-up only performed up to 1 week
Singh et al. (2016)16			2. Did not use an active placebo (saline)
Ionescu (2019)18			2. Did not use an active placebo (saline)		1. Follow-up was performed at 3 mo, but not earlier time points
Feder et al. (2021)17					1. Follow-up only performed up to 2 weeks

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 11. Study Design and Conduct Limitations

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Rodriguez et al. (2013)15		1. Potential unblinding due to dissociative effects of ketamine				4. Data from second phase of crossover not included due to carryover effect of ketamine
Singh et al. (2016)16				1. 91% of patients in the control group withdrew due to lack of efficacy. Only 27% of ketamine patients remained in the study at the end of the withdrawal phase.
Ionescu (2019)18				1. Only 14 of 26 patients completed the study	1. Power calculations were not reported
Feder et al. (2021)17		1. Potential unblinding due to dissociative effects of ketamine

 

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Case Series
Sharma et al. (2020) reported results from a series of 14 adult inpatients with SRI-resistant OCD who received multiple infusions of ketamine (Tables 12 and 13).¹⁹ Twelve patients had not responded to at least 2 adequate trials and 1 patient had failed a single trial of SRI therapy. Ketamine was administered as an IV infusion of 0.5 mg/kg over 40 minutes either twice weekly or 3 times weekly; the number of infusions ranged from 2 to 10 (mean, 5.4). The mean age of patients was 36.2 years, and mean YBOCS total score was 31.4. There was a significant reduction in YBOCS score from baseline (mean, 31.4 vs. 26.9; p = .01). However, only 1 patient demonstrated a response (defined as ≥ 35% reduction in YBOCS) and 2 patients demonstrated partial response (defined as 25% to 35% reduction in YBOCS). The authors concluded ketamine may have some benefit in a subset of patients with SRI-resistant OCD, but that larger controlled studies are required.

Table 12. Summary of Key Case Series Characteristics

Study	Country	Participants	Treatment Delivery	Follow-Up
Sharma et al. (2020)19	India	14 patients with SRI-resistant OCD	Ketamine 0.5 mg/kg over 40 min either twice weekly or 3 times weekly	2 to 3 weeks

OCD: obsessive-compulsive disorder; SRI: serotonin reuptake inhibitor.

Table 13. Summary of Key Case Series Results

Study	Treatment	Change From Baseline in YBOCS	YBOCS Response1, n (%)	YBOCS Partial Response2, n (%)
Sharma et al. (2020)19	Ketamine	31.4 vs. 26.9 p = .01	1 (7.1)	2 (14.3)

YBOCS:Yale-Brown Obsessive-Compulsive Scale.
¹ YBOCS reduction ≥ 35%.
¹ YBOCS reduction 25% to 35%.

Section Summary: Intravenous Anesthetics for Patients With Psychiatric Disorders
Two double-blind trials have been published that compared multiple ketamine infusions with saline for TRD, one double-blind placebo-controlled trial and case series were identified in OCD, and one double-blind trial was identified that compared multiple ketamine infusions with midazolam in chronic PTSD. There is a possibility of publication bias due to the lack of publication of many other small trials. One study with 26 patients found no significant difference in a depression scale at the end of infusion. A larger RCT (n = 68) found a significantly greater improvement in a depression scale during the 4-week infusion period, but the effect diminished over 3 weeks post-infusion. The trial did not use an active control, raising the possibility of placebo effects and unblinding of patients and investigators. One small double-blind, crossover RCT in patients with SRI-resistant OCD found that ketamine infusion provided higher frequency of YBOCS response at day 7 compared to placebo; however, unblinding was suspected and only data from the first phase were analyzed because of a carryover effect of ketamine. A small case series also found significant improvements in YBOCS at 2 to 3 weeks, but only 1 patient demonstrated YBOCS response. A single small RCT in patients with chronic PTSD (n = 30) found that ketamine infusion produced significantly greater improvements in a PTSD symptom scale at 2 weeks compared to midazolam. Common side effects of ketamine infusion include headache, anxiety, dissociation, nausea, and dizziness. The intense treatment protocols, the severity of adverse events, and the limited treatment durability raise questions about the net health benefit of this therapy. High-quality clinical trials, several of which are in progress, are needed to evaluate the long-term safety and efficacy of IV ketamine for psychiatric disorders.

Summary of Evidence
For individuals who have chronic pain syndromes (e.g., neuropathic pain or fibromyalgia) who receive a course of IV anesthetics (e.g., lidocaine, ketamine), the evidence includes a systematic review, several RCTs , and observational studies. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, medication use, and treatment-related morbidity. Several RCTs have been performed using IV lidocaine for PHN, CRPS, and diabetic neuropathy. These trials have failed to show a durable effect of lidocaine infusion on chronic pain. Two trials with a total of 100 patients provide limited evidence that courses of IV ketamine may provide temporary relief (2 to 4 weeks) to some chronic pain patients in some settings. Neither of the RCTs used an active control, raising concerns about placebo effects. A third trial found no benefit of a single infusion of ketamine or ketamine/magnesium. Overall, the intense treatment protocols, the severity of adverse events, and the limited treatment durability raise questions about the net health benefit of this therapy. Additional clinical trials are needed to evaluate the long-term efficacy and safety of repeat courses of IV anesthetics for chronic pain. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have psychiatric disorders (e.g., TRD, OCD) who receive a course of IV ketamine, the evidence consists of RCTs and case series. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, medication use, and treatment-related morbidity. Two publications of double-blind trials were identified that compared repeated ketamine infusion with an infusion of saline for TRD, one double-blind placebo-controlled trial and case series were identified in OCD, and one double-blind trial has been published that compared multiple ketamine infusions with midazolam in chronic PTSD. There is a possibility of publication bias due to the lack of publication of many other small trials. One study with 26 patients found no significant difference in a depression scale at the end of infusion. A larger RCT (n = 68) found a significantly greater improvement in a depression scale during the 4-week infusion period, but the effect diminished over 3 weeks post-infusion. The trial did not use an active control, raising the possibility of placebo effects and unblinding of patients and investigators. One small double-blind, crossover RCT in patients with SRI-resistant OCD (n = 15) found that ketamine infusion provided higher frequency of YBOCS response at day 7 compared with placebo; however, unblinding was suspected and only data from the first phase were analyzed because of a carryover effect of ketamine. A small case series also found significant improvements in YBOCS at 2 to 3 weeks, but only 1 patient demonstrated YBOCS response. A single small RCT in patients with chronic PTSD (n = 30) found that ketamine infusion produced significantly greater improvements in a PTSD symptom scale at 2 weeks compared to midazolam. Common side effects of ketamine infusion include headache, anxiety, dissociation, nausea, and dizziness. The intense treatment protocols, the severity of adverse events, and the limited treatment durability raise questions about the net health benefit of this therapy. High-quality clinical trials, several of which are in progress, are needed to evaluate the long-term safety and efficacy of IV ketamine for psychiatric disorders. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in "Supplemental Information" if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Society of Regional Anesthesia and Pain Medicine et al.
In 2018, the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine and the American Society of Anesthesiologists issued a joint consensus guideline on the use of intravenous (IV) ketamine for treatment of chronic pain.²⁰ The guideline found:

• Weak evidence supporting use of IV ketamine for short-term improvement in patients with spinal cord injury pain.
• Moderate evidence supporting use of IV ketamine for improvement in patients with chronic regional pain syndrome up to 12 weeks.
• Weak or no evidence for immediate improvement with IV ketamine use for other pain conditions, including mixed neuropathic pain, fibromyalgia, cancer pain, ischemic pain, headache and spinal pain.

American Psychiatric Association
In 2017, the American Psychiatric Association (APA) published an evidence review and consensus opinion of the use of ketamine in treatment-resistant depression.²¹ The APA noted 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."

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Over 100 trials evaluating IV infusion of ketamine for depression are listed on clinicaltrials.gov.²² The majority are completed but not published. Some currently ongoing and unpublished trials that include over 40 participants are listed in Table 14.

Table 14. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02556606	Ketamine for Treatment-Resistant Late-Life Depression	72	Mar 2021
NCT02461927	Ketamine for The Rapid Treatment of Major Depression and Alcohol Use Disorder	65	Dec 2021
NCT03666390	A Double-blind, Randomized-controlled Trial Using a Low Dose of Ketamine vs Active Placebo in Treating Severe Depression and Suicide	48	Dec 2021
NCT03674671	Investigations on the Efficacy of Ketamine in Depression in Comparison to Electroconvulsive Therapy	240	Mar 2023
NCT03113968	ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment-Resistant Depression (TRD)	400	Apr 2022
NCT03237286	Testing a Synergistic, Neuroplasticity-Based Intervention for Depressive Neurocognition	150	Oct 2023
Unpublished
NCT01920555	Double-Blind, Placebo-Controlled Trial of Ketamine Therapy in Treatment-Resistant Depression (TRD)	99	Feb 2017 (completed)
NCT02659085	A Randomized Controlled Non-inferiority Trial Comparing Ketamine With ECT in Patients With Major Depressive Disorder	200	Dec 2018
NCT02299440	Evaluation of the Effects of Ketamine in the Acute Phase of Suicidal Ideation: a Multicenter Randomized Double-blind Trial	156	Mar 2019 (completed)
NCT02360280	Intravenous Sub-anesthetic Ketamine Treatment in Treatment-Resistant Depression	62	Mar 2019 (completed)

NCT: national clinical trial.

References:  

1. Wertli MM, Kessels AG, Perez RS, et al. Rational pain management in complex regional pain syndrome 1 (CRPS 1)--a network meta-analysis. Pain Med. Sep 2014; 15(9): 1575-89. PMID 25234478
2. Schwartzman RJ, Alexander GM, Grothusen JR, et al. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain. Dec 15 2009; 147(1-3): 107-15. PMID 19783371
3. Sigtermans MJ, van Hilten JJ, Bauer MCR, et al. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain. Oct 2009; 145(3): 304-311. PMID 19604642
4. O'Connell NE, Wand BM, McAuley J, et al. Interventions for treating pain and disability in adults with complex regional pain syndrome. Cochrane Database Syst Rev. Apr 30 2013; (4): CD009416. PMID 23633371
5. Kim YC, Castaneda AM, Lee CS, et al. Efficacy and Safety of Lidocaine Infusion Treatment for Neuropathic Pain: A Randomized, Double-Blind, and Placebo-Controlled Study. Reg Anesth Pain Med. May 2018; 43(4): 415-424. PMID 29381569
6. Liu H, Lu F, Zhou D, et al. The Analgesic and Emotional Response to Intravenous Lidocaine Infusion in the Treatment of Postherpetic Neuralgia: A Randomized, Double-Blinded, Placebo-controlled Study. Clin J Pain. Nov 2018; 34(11): 1025-1031. PMID 29698250
7. Moulin DE, Morley-Forster PK, Pirani Z, et al. Intravenous lidocaine in the management of chronic peripheral neuropathic pain: a randomized-controlled trial. Can J Anaesth. Jul 2019; 66(7): 820-827. PMID 31098961
8. Amr YM. Multi-day low dose ketamine infusion as adjuvant to oral gabapentin in spinal cord injury related chronic pain: a prospective, randomized, double blind trial. Pain Physician. May-Jun 2010; 13(3): 245-9. PMID 20495588
9. Pickering G, Pereira B, Morel V, et al. Ketamine and Magnesium for Refractory Neuropathic Pain: A Randomized, Double-blind, Crossover Trial. Anesthesiology. Jul 2020; 133(1): 154-164. PMID 32384291
10. Patil S, Anitescu M. Efficacy of outpatient ketamine infusions in refractory chronic pain syndromes: a 5-year retrospective analysis. Pain Med. Feb 2012; 13(2): 263-9. PMID 21939497
11. Przeklasa-Muszynska A, Kocot-Kepska M, Dobrogowski J, et al. Intravenous lidocaine infusions in a multidirectional model of treatment of neuropathic pain patients. Pharmacol Rep. Oct 2016; 68(5): 1069-75. PMID 27552062
12. Mangnus TJP, Dirckx M, Bharwani KD, et al. Effect of intravenous low-dose S-ketamine on pain in patients with Complex Regional Pain Syndrome: A retrospective cohort study. Pain Pract. Nov 2021; 21(8): 890-897. PMID 34233070
13. Noppers I, Niesters M, Swartjes M, et al. Absence of long-term analgesic effect from a short-term S-ketamine infusion on fibromyalgia pain: a randomized, prospective, double blind, active placebo-controlled trial. Eur J Pain. Oct 2011; 15(9): 942-9. PMID 21482474
14. Vlainich R, Issy AM, Sakata RK. Effect of intravenous lidocaine associated with amitriptyline on pain relief and plasma serotonin, norepinephrine, and dopamine concentrations in fibromyalgia. Clin J Pain. May 2011; 27(4): 285-8. PMID 21178598
15. Rodriguez CI, Kegeles LS, Levinson A, et al. Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology. Nov 2013; 38(12): 2475-83. PMID 23783065
16. Singh JB, Fedgchin M, Daly EJ, et al. A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression. Am J Psychiatry. Aug 01 2016; 173(8): 816-26. PMID 27056608
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Coding Section

Codes	Number	Description
CPT	96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
	96366	Each additional hour (list separately in addition to code for primary procedure)
	96374	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); intravenous push, single or initial substance/drug
ICD-9 Diagnosis		Investigational for all diagnoses
HCPCS	J2001	Injection, lidocaine hydrochloride for intravenous infusion, 10 mg
ICD-10-CM (effective 10/01/15)		Investigational for all diagnoses
ICD-10-PCS (effective 10/01/15)		ICD-10-PCS codes are only used for inpatient services.
	3E0T3CZ	Introduction, peripheral nerves, percutaneous, regional anesthetic
Type of Service
Place of Service

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2014 Forward     

05/25/2023	Annual review, no changes to policy intent.
04/01/2022	Annual review, no change to policy intent. Updating rationale and references.
04/01/2021	Annual review, no change to policy intent. Updating rationale and references.
04/08/2020	Annual review, updating title and policy to address psychiatric disorders in addition to chronic pain. Also updating rationale and references.
04/02/2019	Annual review, adding "psychiatric disorders" to the policy statement. No change to policy intent, also expanded list of other investigational issues. Also updating rationale and references.
04/16/2018	Annual review, no change to policy intent. Updating background and description, rationale and references.
02/12/2018	Interim review to update policy verbiage for clarity and specificity. No other changes made.
04/04/2017	Annual review, no change to policy intent.
04/07/2016	Annual review, no change to policy intent. Updating background, description, rationale and references.
04/16/2015	Annual review, minor revision to policy language to include chronic daily headache in the verbiage as being investigational. Updated background, description, rationale and references. Added coding.
04/02/2014	Annual review. Added related policy and benefit application. Updated rationale, references, description and background. No change to policy intent.