Ketamine was first synthesized in the 1960s as a safer dissociative analgesic and amnestic alternative to phencyclidine.1 Initial evidence for the treatment of neuropathic pain with ketamine was derived from clinical case reports on the management of nerve injury in the setting of oncologic disease.2 Moving forward, ketamine infusions have been studied in the treatment of complex regional pain syndrome (CRPS),3–7 spinal cord injury,8–10 phantom limb pain,11 postherpetic neuralgia,12,13 fibromyalgia,14–16 and oncologically mediated neuropathic pain.17–19 Additional prospective studies also suggest a role for ketamine infusion therapy in the treatment of trigeminal neuropathic pain, acute and chronic migraines, and temporomandibular pain.20–23 Moreover, several retrospective studies further contribute meaningful data regarding the clinical use of ketamine infusions.24–27
As a noncompetitive antagonist of the N-methyl-d-aspartic acid receptor, ketamine produces profound modulatory effects on ascending nociceptive transmission.28,29 As is the case with many neuropathic pain agents, transient antagonism at the receptor level may not fully explain the mechanism of neuropathic pain alleviation observed with ketamine therapy as the relief seems to significantly outlast the plasma half-life in many reports. Ketamine also modulates descending inhibitory pathways through activation of areas involved in regulation of pain, including the anterior cingulate cortex, orbital frontal cortex, insula, and brainstem in healthy volunteers receiving low-dose ketamine infusions.30
Ketamine binds noncompetitively to or otherwise influences multiple receptors and ion channels, mainly N-methyl-d-aspartic acid receptor antagonism, but also pharmacologic effects on α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors, kainite receptors, and γ-aminobutyric acid receptors, l-type calcium channels, μ-opioid receptors, and muscarinic and monoaminergic receptors.31,32 The analgesic effects of ketamine may also be derived from inhibition of inducible nitric oxide synthase.32 Ketamine has documented efficacy at subanesthetic doses (<1 mg/kg or alternately defined as doses that will cause minimal acceptable levels of sedation) for the amelioration of postoperative pain, decreasing postoperative opioid analgesic requirements and decreasing nausea and vomiting while adding only a mild side effect profile.33 After single bolus administration, its redistribution half-life is 7 to 15 minutes and elimination is 2 to 3 hours.34 Ketamine also has rapid passage through the blood-brain barrier with blood-effect site equilibration in 1 to 10 minutes.35,36 After a 100-hour duration administration of S-ketamine at 20 to 30 mg/h in CRPS-1 patients, the analgesic half-life was 11 days.3,34 Ketamine is metabolized by CYP3A4, CYP2B6, and CPY2C9 to norketamine via N-demethylation.34 The plasma concentration of norketamine may exceed ketamine after prolonged infusions, possibly contributing to the analgesic profile.1,3,35
Despite the extensive utilization in various clinical arenas, there is no consensus on an optimal intravenous (IV) ketamine infusion protocol for the treatment of neuropathic pain conditions.37 At this point, the numerous described ketamine infusion protocols and their indications prohibit a meta-analysis. Therefore, the objectives of this topical review are to (1) examine which common components of ketamine infusion protocols are associated with prolonged duration of relief, minimal side effects, and increased pain relief for the treatment of neuropathic pain and (2) call for clinical studies to identify optimal ketamine infusion protocols tailored for individual neuropathic pain conditions. Many studies failed to report changes in functional status, and this metric could not be appropriately incorporated in our analysis. The purpose of this study is not to either make or stratify the strength of recommendations for the use of ketamine infusions, because the existing literature does not allow for such analysis.
METHODS
An electronic literature search was conducted using the National Library of Medicine’s MEDLINE database, PubMed, and Google Scholar to identify relevant peer-reviewed articles discussing the use of IV ketamine infusions for the treatment of neurologic pain. The detailed search strategy included the following subject headings: “ketamine infusion” and “neuropathic pain.” Our search included doses of ketamine infusions in both the subanesthetic and the sedative range, but excluded studies for the use of ketamine in the perioperative phase of care. Search was limited to human subjects, English language, and articles with available full text. The references of articles found in the initial search were then iteratively searched for additional relevant citations. Both prospective and large retrospective studies were included in final analysis. This review excluded case reports and small retrospective studies (<5 subjects). The search yielded a total of 26 articles, including 16 prospective randomized placebo-controlled trials,3,4,8–11,13–17,19–23 4 prospective, observational nonrandomized studies providing,5–7,18,38 4 retrospective studies,24–27 and 1 prospective randomized non–placebo-controlled study.12
The majority of the evidence for the treatment of neuropathic pain with ketamine infusions comes from case reports or case series. Although case reports and small cohort analyses are scientifically intriguing and medically encouraging, we excluded case reports and smaller retrospective cohort analyses of fewer than 5 patients from this review to focus on higher-quality evidence, with an emphasis on the reported infusion protocol, duration, and degree of measured benefits and side effects. In addition, we excluded studies addressing the utilization of ketamine for perioperative pain because of the lack of clarity with regard to the nature of postoperative pain. A PRISMA flow diagram (Figure) details the search strategy for this review.
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Figure.: PRISMA flow diagram.
Table 1.: Oxford University Center for Evidence-Based Medicine (CEBM) Levels of Evidence
The level of evidence for the treatment of neuropathic pain conditions with ketamine infusions was stratified based on the Oxford University Center for Evidence-Based Medicine (CEBM) criteria, which are presented in Table 1.39
RESULTS
Ketamine Infusion Protocols
Table 2.: Summary of Reported Ketamine Infusion Protocols
As summarized in Table 2, the majority of ketamine infusion protocols included in this review demonstrated a decrease in self-reported pain. Direct comparisons of protocols with regard to the degree of pain relief may be inaccurate because of the various outcome metrics and pain scales reported. In addition, the different time points at which pain was measured further confound interpretation. Studies used heterogeneous inclusion and exclusion criteria. As numerous protocols with significant variation have been described, no definitive recommendations or even gradation of the strengths of recommendations are provided in this review.40 However, certain infusion parameters are suggested to have a more profound effect particularly on the duration of clinical effects. If a purified isomer of ketamine, such as S(+)-ketamine, was used in a study, it was indicated in Table 2. Two studies used S(+)-ketamine.3,16 All other studies apparently used a racemic mixture.
Duration of Infusion
- Studies utilizing infusions lasting 1 hour or less reported a decrease in visual analog scale (VAS) or 11-point numerical rating scale only for 3 hours or less.15–17 An exception is a retrospective study indicating that, after an infusion of less than 1 hour, most patients, including a large percentage diagnosed with CRPS, reported an average of 1 to 2 days of relief in the total study cohort and over one-third of subjects reported relief lasting more than 3 weeks.27 Although several studies utilizing infusions of 1 hour or less did not report the exact times at which pain and symptom outcomes were measured, it was presumably measured near the completion of the infusion.9,13,14,22,23
- A study of 3 consecutive infusions lasting 1 hour administered in sequence every other day demonstrated a decrease in VAS compared with placebo that persisted for 2 weeks.12 A protocol utilizing ketamine infused over 1 hour only demonstrated a sustained decrease in VAS at 48 hours if the ketamine infusion was combined with a calcitonin infusion.11
- One study only gave a single 2-hour infusion and reported an equivalent decrease in VAS compared with alfentanil administered over the same time period.21 An infusion protocol of 5 hours’ duration reported decreased pain scores at 2 weeks but not at 3 and 4 weeks.10 Another protocol utilizing ketamine infusions over 4 hours given for 10 days resulted in reduced burning pain at 4 weeks, decreased hyperesthesia at 8 weeks, and decreased responses to components of the McGill Pain Questionnaire (MPQ) at 12 weeks.4 This study’s outcomes seem to suggest that the duration of pain relief of individual protocols could be dependent on the measured outcome variable with some, such as the MPQ, more susceptible to pronounced improvements with ketamine therapy.
- Finally, studies involving the use of 4- to 5-day infusion protocols in subanesthetic inpatient or intentionally sedating patients in intensive care unit (ICU) settings demonstrate pain relief lasting from 6 weeks to 6 months.3,5–7,18 Two retrospective studies did not report the duration of pain relief after a multiday infusion.24,25 In general, however, patients experienced side effects at the same rate regardless of the duration of the ketamine infusion.
Total Infusion Dose
Differences in reported measurements of pain make it challenging to compare pain relief achieved by different doses of ketamine over a similar period. Furthermore, it is not possible to attribute the duration of pain relief mostly to either the duration of infusion or the dose based on weight of infused ketamine.
- In several studies, a total infused dose of ketamine ranging from 324 to 6800 mg administered over several days normalized to a 70-kg patient resulted in reductions in reported pain lasting between 4 weeks and 6 months, depending on the measurement tool used to evaluate pain reduction.3–7 The range of ketamine doses was administered in both the inpatient and the outpatient setting. In contrast, 2 studies with infusions at this dose did not report the duration with regard to pain relief.24,25 It should be noted that to achieve some of the noted anesthetic doses of ketamine, patients were often placed in inpatient and ICU settings. However, one of these studies was able to achieve a cumulative dose of 1000 mg normalized to a 70-kg patient of ketamine infused at a subanesthetic rate over 10 days in the outpatient setting resulting in decreased burning pain for 4 weeks and decreased MPQ for 12 weeks.4 Presumably, this would also result in a decrease in the cost of the infusion protocol by sparing use of ICU or inpatient resources. It should be noted that high-dose infusions have only been studied in CRPS patients.
- One study comparing an infused ketamine dose of either 17.5 or 35 mg normalized to a 70-kg patient given over 30 minutes in patients with oncologically induced pain resulted in a decrease in pain lasting 3 hours.17 A larger total dose of ketamine was reported to decrease pain to a greater extent. This is one of the few studies directly comparing different amounts of ketamine and demonstrates that increased doses will result in more profound, but not more lasting, pain relief when administered over the same period. In another study, 80 mg IV ketamine for the treatment of traumatic spinal cord injury resulted in 2 weeks of relief, which was not detectable at 3 or 4 weeks.10 Smaller total doses of infused ketamine did not result in continued pain relief beyond the immediate postinfusion period.15,21,22
- Of significance to note is that, in the previously discussed studies, unpleasant psychomimetic side effects occurred at approximately the same rate regardless of the infused dose. This observation might be confounded by the use of coadministered medications, such as midazolam, in the cases with higher-dose ketamine infusions. Nonetheless, unpleasant psychomimetic side effects were described even at low total doses of ketamine in the above studies.17,21,22
Infusion Rate
The majority of described protocols use an infusion rate between 0.1 and 0.5 mg/kg/h.3,4,7,9–17,19,38 Three protocols describe the use of infusion rates of greater than 0.1 mg/kg/h, 2 of which required admission to an ICU setting for supportive care and monitoring, and 1 that was conducted as an outpatient also with appropriate monitoring.5,6,27 When described, the reason for choosing a certain rate is attributed to the authors’ clinical experiences or a desire to avoid unpleasant side effects. The high infusion rates in ICU settings did result in increased duration of pain relief. However, similar durations of pain relief were reported with comparably lower infusion rates given for a prolonged period of time in an inpatient and outpatient setting.3,4 The percentage of patients experiencing unpleasant side effects is reported to be comparable between different infusion rates.
Combination Drug Protocols
Several studies have examined the use of coadministered medications for either reduction of side effects or improvement of analgesia. Several of the reviewed studies gave adjuvant medications as a standing component of a ketamine infusion protocol.4,6,10–12,18,19,24,38
- One protocol gave midazolam on “pro re nata” (PRN) basis.7 Other studies describe ICU or inpatient supportive care without significant elaboration with regard to the use of adjunct medications.5,6 Several protocols used coadministration of midazolam as preinfusion IV boluses of 2 to 7.5 mg, 2 to 4 mg IV PRN doses, or simultaneous infusions at rates of 0.1 to 0.4 mg/kg/h.4,6,7,10,12 Combination protocols resulted in decreases in reported pain ranging from 2 weeks to 6 months of duration. Larger cumulative doses of midazolam were used to provide sedation in an effort to keep patients comfortable during an infusion, and the dose did not seem to correlate with the duration of pain relief. One study used 5 mg IV midazolam as an active placebo and demonstrated decreased pain at 1½ and 3 hours but no decreases in pain at 8 weeks, which was equivalent in both groups.16 The authors suggest that midazolam’s muscle relaxation properties may have contributed to the equivalence between the 2 groups. The muscle-relaxing effects of midazolam may have also contributed to the observed duration of pain reduction in the previously referenced protocols. The use of midazolam is associated with a decrease in hallucinations and dysphoria. However, ketamine-infused patients who additionally received midazolam did not have a reduction in the incidence of headaches, nausea, somnolence, and dizziness. It is not possible to clearly attribute the observed effects to ketamine, midazolam, or a combination.
- Three protocols utilized 0.1 mg oral clonidine, 0.1 mg/d clonidine patch, or 0.2 to 0.85 μg/kg/h infused clonidine to decrease side effects when coadministered with ketamine and midazolam.4,6,7 One of these studies reported nausea, headaches, and tiredness in 4 of 9 ketamine-infused patients in the outpatient setting.4 Another protocol coadministered ketamine with 200 IU calcitonin, and only the combination protocol resulted in decreased pain at 48 hours.11 Several studies coadministered opioids as study treatment group or as part of standard continued patient therapy.18–21 Comparisons of short infusions of ketamine with short-acting opioids, such as alfentanil, resulted in equivalent and relatively short-lived duration of pain relief.20,21 Finally, in one study 300 mg oral gabapentin was combined with 2 to 5 mg of midazolam and 80 mg ketamine, which resulted in decreased pain both immediately after and 2 weeks after the infusion.10
Results for Specific Pain Conditions
Complex Regional Pain Syndrome
Six studies focused exclusively on the use of ketamine infusions for the treatment of CRPS.3–7,26 In addition, a majority of patients analyzed in a retrospective study were diagnosed with CRPS.27 The majority of these articles report pain relief of several weeks after an infusion in an inpatient setting over 4 to 5 days. However, outpatient infusion protocols requiring multiple serial infusions also reported pain relief lasting several months in some cases.26,27 Although the general trend when all studies are considered is that longer durations provide increased duration of pain relief, there may be an optimal infusion duration of several hours beyond which no benefit is derived but the potential for side effects increases. The effective treatment of management of CRPS pain did not seem to be related to the actual dose of ketamine or the rate of infusion, with subanesthetic doses in the outpatient setting providing comparable duration of pain relief compared with higher-dose infusion protocols designed to be performed in ICU settings. The cost and required resource allocation for inpatient and ICU care are presumably greater than for outpatient management.
Fibromyalgia
Three studies focused on the use of ketamine infusions for the treatment of fibromyalgia.14–16 All 3 studies utilized a relatively low dose of ketamine between 0.3 and 0.5 mg/kg administered over 10 to 30 minutes. No study reported benefits beyond the first few hours after the infusion. It is not certain whether this is because of a lack of responsiveness of fibromyalgia pain to ketamine infusions or whether a higher dose is required to produce longer lasting analgesia. The changes in pain scores after the infusion in 2 studies are encouraging and suggest that further optimization of dose and duration may provide some degree of relief.
Traumatic Spinal Cord Injury
The studies focused on the utilization of ketamine infusions to treat pain after traumatic spinal cord injury.8–10 Two of the studies utilized a relatively low dose of ketamine between 6 μg/kg and 0.4 mg/kg over 17 to 40 minutes.8,9 One protocol utilized approximately 0.2 mg/kg (based on 70 kg) over 5 hours for a total dose of 80 mg a ketamine.10 In keeping with the general trend, shorter infusion times and lower total doses of ketamine provided relief only in the immediate postinfusion phase, whereas higher doses provided relief that lasted 2 weeks.
Several other pain pathologies have been studied in well-conducted studies. However, the small number of available studies for discreet pain diagnoses does not allow for meaningful comparison.
DISCUSSION
Because of the diversity of infusion protocols and the lack of direct protocol comparisons, conducting a formal meta-analysis is not possible at this time. Definite recommendations cannot be made based on available literature. However, several relationships do emerge from inspection of the available data. These trends may provide guidance for clinicians initiating ketamine infusion therapy in their practice and to guide future optimization research.
- CEBM level 2 evidence for treatment suggests that longer-duration infusions of ketamine provide longer lasting pain relief for patients with chronic neuropathic pain. Although admitting patients to ICUs may be prohibitively expensive, multihour outpatient treatments over the course of several days may provide more longer-lasting benefit than single- or short-duration infusions. This may also be a more logistically and financially feasible situation.
- Although the rate of infusion does not appear to be related to either the duration or the degree of pain relief offered by different ketamine infusion protocols, increases in the total dose of ketamine administered result in a higher degree of pain relief and possibly greater duration of pain relief. The later observation could possibly be attributed to either the extended duration of infusions or the higher delivered doses of ketamine. This is also CEBM level 2 evidence for treatment with ketamine infusions. However, a lack of comparative effectiveness studies and different primary end points does not allow for direct comparison and optimization of protocols.
- There is level 2 evidence for treatment that patients subject to almost all infusion protocols experience side effects regardless of infusion rate, infusion duration, or total ketamine infused. The use of coadministered medications, such as midazolam, reduces the incidences of side effects and may also provide additional analgesic benefit. Other serious side effects may still occur and should be monitored.
On the basis of the available evidence, a successful ketamine infusion protocol for the treatment of chronic neuropathic pain would include several components: (1) applying the longest possible infusion duration that is logistically feasible using multiple outpatient clinic visits if necessary; (2) using a dose of ketamine between 0.1 and 0.5 mg/kg/h to avoid excessive sedation in the majority of patients; and (3) utilizing adjunct medications such as midazolam to decrease the incidence of psychomimetic side effects and possibly improve the degree of pain relief. All infusions should be done in a monitored setting with standard American Society of Anesthesiology monitors under physician supervision. Although a dose of ketamine between 0.1 and 0.5 mg/kg/h does not eliminate the need for monitoring of the risk of sedation, safe and effective use of this range has been reported in the monitored outpatient, non-ICU setting. Potential adverse outcomes, such as excessive sedation, dysphoria, and cardiovascular complications, should be monitored during and after the infusion.
Caveats of Current Ketamine Infusion Protocols
There are several important caveats regarding the protocols used in prospective studies for discrete chronic neuropathic pain conditions.
- Although many of the published protocols for ketamine infusions are prospective, placebo-controlled, observational studies, or retrospective studies, there is a lack of comparative effectiveness trials analyzing different infusion protocols. In addition, there is overlap between inpatient and outpatient ketamine infusion protocols with regard to overall dosing and duration of treatment. Although several of the protocols compared a single ketamine infusion protocol with another therapy,9,11–13,15,16,20,21 only 1 study directly compared 2 different doses of ketamine.17 To our knowledge, no studies have compared the impact of different infusion durations, infusion frequency, and use of different adjunct medications on pain relief. There have also been sparse studies that compared ketamine infusions with other forms of neuropathic pain treatment modalities, such as spinal cord stimulators or transcranial electrical stimulation.
- Although empirical experience is an important aspect of clinical practice, the lack of clarification of ketamine infusion protocols in the literature calls for comparative effectiveness trials to optimize the degree and duration of pain relief by using a practical and cost-effective protocol. Without such comparative trials, it is difficult to assess the failure or success of a particular protocol with regard to a particular infusion variable, such as ketamine dose or infusion duration.
- It is yet to be established whether different protocols are best suited for different neuropathic pain diagnoses or different levels of severity. For example, will a patient with traumatic spinal cord injury for 25 years find therapeutic benefit with the same ketamine infusion protocol as a patient with fibromyalgia for 3 years?
- Currently, the mitigation of unpleasant psychomimetic side effects is potentially achieved by coadministration of medications, such as midazolam or clonidine. Other nonpsychomimetic side effects may be intrinsic to the use of ketamine infusions and require further investigation, particularly in cases that utilize high doses and long duration of ketamine infusions. In this regard, hepatotoxicity has been reported after ketamine infusions.41
SUMMARY AND FUTURE DIRECTIONS
Given a relative paucity of evidence in the current literature to guide ketamine infusion therapy for the treatment of various neuropathic pain conditions, such as CRPS, postherpetic neuralgia, traumatic spinal cord injury, and phantom limb pain, further well-conducted prospective comparative effectiveness studies are needed to analyze different ketamine infusion protocols in discreet neuropathic pain states. The goal of this study is to identify factors associated with better outcomes for the treatment of neuropathic pain with ketamine infusion therapy and to underscore the need for optimization through further clinical trials.
DISCLOSURES
Name: Dermot P Maher, MD, MS.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Conflicts of Interest: Dermot P Maher reported no conflicts of interest.
Name: Lucy Chen, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Conflicts of Interest: Lucy Chen reported no conflicts of interest.
Name: Jianren Mao, MD, PhD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Conflicts of Interest: Jianren Mao reported no conflicts of interest. His work is funded by NIH R01 grant DA036564.
This manuscript was handled by: Honorio T. Benzon, MD.
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