From the initial 696 records identified through searching databases and other sources, we removed duplicate records and then screened the remaining 467 relevant publications. Among these, 437 were excluded because the publications focused on the perioperative period or failed to report our primary outcome. Thirty full-text articles were assessed for eligibility, with 23 of these excluded because they did not meet inclusion criteria (Figure 1). Seven randomized control trials23–29 consisting of 211 patients (108 in the IV ketamine groups and 103 in comparator groups; 1 trial had a crossover design with the subjects receiving each of the trial infusions sequentially after the washout period) were included for the systematic review (Table 1), and data from all of these were subjected to meta-analysis.
Participants and Interventions
The median (range) sample size of the 7 randomized control trials was 24 participants (range, 19–60). The median (range) age of participants in the 7 randomized control trials was 48 years (range, 41.9–71 years). All trials evaluated chronic pain syndromes, but there was wide variation in type of pain, distribution, and etiology. Two studies (on phantom limb pain26 and post–spinal cord injury pain27) enrolled patients with predominantly neuropathic pain according to the International Association for the Study of Pain definition.11 Two studies enrolled patients with pain syndromes considered to have a mix of neuropathic and nociceptive characteristics30,31 (ie, complex regional pain syndrome types I and II24 and cancer-related pain25), and 3 studies23,28,29 enrolled patients with nociplastic23,28 or nociceptive29 (ie, nonneuropathic) pain. In 2 of these, the conditions treated are believed to derive from disorders involving central pain processing rather than discrete nerve injury (complex regional pain syndrome type I23 and fibromyalgia28), while in the other (limb ischemia29), pain is predominantly nociceptive. The exclusion criteria based on participants’ age and comorbidities were fairly similar in all studies, although the study on fibromyalgia28 did not state reasons for exclusion of eligible participants. IV ketamine was used as a primary analgesic in all studies. Two studies included the use of opioids in the intervention and control arms throughout the trial,25,29 subjects in both arms of another study received gabapentin,27 and 1 study used midazolam and clonidine in both arms.24
Ketamine Infusion Regimens
A wide range of infusion protocols was investigated in the studies included in this review.23–29 The median (range) duration of ketamine infusion for all 7 studies was 5 hours (range, 0.5–100 hours), and the median number of days over which ketamine was administered, continuously or intermittently, was 1 day (range, 1–10 days). The median (range) dose of ketamine during the infusion using a 70-kg patient as the reference was 0.35 mg·kg−1 (0.23–0.6 mg·kg−1). For data available on analgesic effects at the end of the second week after infusion, 3 of 7 studies were included.23,24,27 One study used the S(+)-isomer of ketamine at an infusion dose range of 0.07–0.43 mg·kg−1·hour−1.23
Risk of Bias Assessment
Overall, the risk of bias was considered high in 4 trials23,27–29 (Figure 2). These trials did not adequately describe the procedures for blinding participants and personnel. The majority of participants in the only 2 studies to assess blinding were able to correctly guess their treatment allocation.23,28 This suggests that blinding was ineffective in the other trials.23,24,27–29 Detection bias was high in 2 of the studies.27,29 Quality of reporting was fair in 6 trials23–28 and good in 1 trial.29 There was no difference between the 2 reviewers (V.O. and M.S.O.) for assessment of risk of bias in any study.
Six23,24,26–29 of the 7 studies reported the lowest pain score between 48 hours and 2 weeks after treatments on a 10-point numerical rating scale, and data from these studies were included in the meta-analysis. The study by Salas et al,25 which reported no benefit from ketamine in patients with refractory cancer pain, could not be included because it did not provide the variance (SDs) for the mean pain scores. Meta-analysis of the data from these trials revealed a significant reduction in pain scores favoring ketamine over standard or control comparative treatments (mean difference, −1.83 points; 95% CI, −2.35 to −1.31 points; P < .0001; I2 = 48.5%; Figure 3).23,24,26–29
We conducted a subgroup analysis to determine whether the effect on our primary outcome differed depending on the dose of ketamine (high versus low), with the high-dose threshold designated as a cumulative dose exceeding 400 mg. Three studies that reported our primary outcome treated patients with high-dose ketamine,23,24,27 with 2 of these23,27 reporting lower pain scores in the ketamine as compared to the control groups. A meta-analysis of data from these high-dose ketamine trials demonstrated a significant reduction in pain scores with ketamine compared to placebo (mean difference, −2.11 points; 95% CI, −2.87 to −1.35 points; P < .0001; I2 = 69.2%). Three of the studies that reported our primary outcome of interest treated patients with low-dose ketamine,26,28,29 with 1 study reporting benefit.29 Meta-analysis of data from the low-dose ketamine trials revealed an analgesic benefit for IV ketamine compared to the placebo group (mean difference, −1.30 points; 95% CI, −2.01 to −0.59 points; P = .0001; I2 = 0.0%). When the primary outcome for both categories was compared using meta-regression, the use of high-dose ketamine was not significantly different from the use of low-dose ketamine (P = .213) (Supplemental Digital Content, Figure 1, http://links.lww.com/AA/C794).
Efficacy in Different Types of Pain.
We performed a subgroup analysis comparing analgesic efficacy of ketamine infusions in participants with neuropathic and mixed neuropathic–nociceptive pain syndromes (spinal cord injury, phantom limb pain, and complex regional pain syndrome types I and II)24,26,27 to primarily nociceptive (ischemic limb pain)29 or nociplastic pain syndromes (complex regional pain syndrome type I and fibromyalgia).23,28 Three studies investigated patient populations that had either neuropathic26,27 or mixed neuropathic–nociceptive pain,24 with 1 study27 reporting a significant reduction in pain scores with ketamine infusion. Meta-analyses of these data demonstrated a significant reduction in pain scores with ketamine compared to placebo control groups (mean difference, −1.75 points; 95% CI, −2.08 to −1.43 points; P < .00001; I2 = 0.0%). For the nonneuropathic (nociceptive or nociplastic) pain category, 123 of the 3 trials23,28,29 reported lower pain scores favoring IV ketamine. This trial enrolled patients with a nociplastic pain syndrome (complex regional pain syndrome type I).23 Meta-analysis of these data revealed a significant reduction in pain scores with IV ketamine (mean difference, −1.97 points; 95% CI, −3.04 to −0.90 points; P < .00001; I2 = 69.5%). However, there was no significant difference when the primary outcomes for both groups were compared using meta-regression (P = .720) (Supplemental Digital Content, Figure 2, http://links.lww.com/AA/C794).
We also performed a subgroup analysis comparing studies that enrolled participants with complex regional pain syndrome compared to those whose participants did not have complex regional pain syndrome. Two trials investigated patients with complex regional pain syndrome23,24 with 123 revealing lower pain scores with ketamine as compared to placebo control groups. Meta-analysis of these data demonstrated a significant reduction in pain with IV ketamine compared to control (mean difference, −2.38 points; 95% CI, −3.53 to −1.23 points; P < .0001; I2 = 34.9%). Four trials investigated patients without complex regional pain syndrome.26–29 Two27,29 of these studies, which enrolled patients with neuropathic pain after spinal cord injury27 and ischemic limb,29 reported lower pain scores favoring IV ketamine compared to placebo control group, with the studies performed for phantom limb26 and fibromyalgia28 pain reporting a lack of efficacy. Meta-analysis of these data demonstrated a significant reduction in pain scores with ketamine (mean difference, −1.71 points; 95% CI, −2.01 to −1.41 points; P = .001; I2 = 0.0%). When the primary outcomes for both categories were compared using meta-regression, there was no significant difference between groups (P = .079) (Supplemental Digital Content, Figure 3, http://links.lww.com/AA/C794).
Efficacy With Adjunct Medications Versus Stand-Alone Therapy.
We performed a subgroup analysis comparing studies using only ketamine23,24,28 to studies that used analgesic adjuncts (opioids, gabapentin, and calcitonin) in the group receiving ketamine infusion.26,27,29 Medications administered with the expressed purpose to prevent adverse effects (eg, midazolam and low-dose clonidine) were not considered analgesics.24 When the primary outcome for both categories were compared using meta-regression, there were no significant differences (P = .127) (Supplemental Digital Content, Figure 4, http://links.lww.com/AA/C794).
Efficacy of Ketamine at Different Time Points.
Three trials reported pain scores at 2 weeks posttreatment.23,24,27 Two of these found lower pain scores in the ketamine group compared to placebo.23,27 Meta-analysis of these data revealed a significant reduction in pain scores favoring IV ketamine (mean difference, −2.23 points; 95% CI, −2.59 to −1.87 points; P < .001; I2 = 0.0%) (Supplemental Digital Content, Figure 5, http://links.lww.com/AA/C794). Three trials23,24,27 reported pain scores 4 weeks after treatment, with 123 finding lower pain scores in the ketamine group. Meta-analysis of these data revealed a nonsignificant reduction in pain scores with IV ketamine compared to placebo (mean difference, −0.74 points; 95% CI, −1.88 to 0.41 points; P = .208; I2 = 58.6%) (Supplemental Digital Content, Figure 6, http://links.lww.com/AA/C794). Three trials23,24,28 reported pain scores at 8 weeks (2 months) posttreatment, with 123 reporting lower pain scores in the IV ketamine group. Meta-analysis of these data yielded a nonsignificant reduction in pain scores with ketamine compared to placebo (mean difference, −0.68 points; 95% CI, −1.75 to −0.40 points; P = .174; I2 = 48.2%) (Supplemental Digital Content, Figure 7, http://links.lww.com/AA/C794). Two trials23,24 reported pain scores 12 weeks (3 months) after treatment, with neither reporting lower pain scores in the IV ketamine group. Meta-analysis of these data revealed a nonsignificant reduction in pain scores with IV ketamine compared to placebo (mean difference, −0.55 points; 95% CI, −1.50 to 0.39 points; P = .251; I2 = 0.0%) (Supplemental Digital Content, Figure 8, http://links.lww.com/AA/C794). In summary, administration of ketamine resulted in a significant reduction of pain scores when compared to placebo at 2 and 8 weeks (but not 4 weeks) after treatment.
Three of the 7 studies in this review reported the proportion of patients achieving a positive analgesic response (as designated by the authors) with ketamine compared to placebo.25,26,28 One study used a ≥30% reduction in pain as the criterion for a positive outcome,25 whereas the other 2 used a ≥50% reduction as the threshold.26,28 A meta-analysis of these studies demonstrated analgesic superiority for IV ketamine compared to placebo control based on the study-designated definition of success25,26,28 (19.4% vs 51.3%; relative risk, 2.43; 95% CI, 1.10–5.40; P = .029; I2 = 0.0%) (Supplemental Digital Content, Figure 9, http://links.lww.com/AA/C794).
Common ketamine-related adverse outcomes reported in the trials included nausea, vomiting, psychotomimetic effects, headache, fatigue, and sedation. Compared to placebo, the ketamine group had significantly higher relative risk of nausea (relative risk, 3.52; 95% CI, 1.74–7.14; P < .00001; Figure 4A) and psychotomimetic effects (relative risk, 5.92; 95% CI, 2.95–11.89; P < .00001; Figure 4B). The relative risk of headache (relative risk, 1.26; 95% CI, 0.67–2.34; P = .475; Figure 4C) and tiredness (relative risk, 2.16; 95% CI, 0.64–7.33; P = .218; Figure 4D) was higher among the ketamine group, but the differences were not statistically significant. Nausea and vomiting were also higher in the ketamine group, but this was reported by one study. The incidence of these side effect measures is reported in Supplemental Digital Content, Table 2, http://links.lww.com/AA/C794.
For the primary outcome, the I2 statistic was 45.9% for the meta-analysis of IV ketamine use from 6 randomized control trials. These results indicate the presence of a moderate degree of heterogeneity. Several characteristics of these studies may have contributed to heterogeneity including differences in the types of pain conditions and patient populations, time periods for assessing the primary outcome, and variations in the ketamine infusion regimen and comparators explored. To explore the sources of heterogeneity, we conducted subgroup analyses using meta-regression and a sensitivity analysis. We found no significant differences between the following groups: mixed or neuropathic versus nociceptive or nociplastic pain, complex regional pain syndrome versus non–complex regional pain syndrome, inpatient setting (n = 5 studies)23,25–27,29 versus outpatient setting (n = 2 studies),23,24 studies with >60% females versus those with less, and studies with a median age >46 years versus those under 46 years. A sensitivity analysis was performed by sequentially removing each individual trial and evaluating how it affected the pooled estimate of the primary outcome, but this process failed to find a significant difference (Supplemental Digital Content, Figure 10, http://links.lww.com/AA/C794).
To elucidate this possibility, we performed Begg and Egger tests, with the nonsignificant P values (P = .380 and .423, respectively) suggesting an absence of publication bias. We did not display a funnel plot because the studies in our analysis did not meet the minimum recommended number of studies required for interpreting a funnel plot (usually 10).18,32
We provided evidence as per GRADE recommendations22 for the primary outcome, secondary outcomes, and complication profile based on risk of bias, inconsistencies, indirectness, imprecision, magnitude of effect size, evidence of dose–response, and other methodological shortcomings. Based on these considerations, the grade of evidence for the analgesic efficacy of IV ketamine in chronic pain was determined to be low (Table 2). For similar reasons, the grade of evidence for categorical response (≥30% or ≥50% pain relief) and efficacy at 2 weeks after the infusion was also deemed to be low. Our analysis suggests that we have limited confidence in the analgesic effect of IV ketamine in chronic pain patients. However, the true effect with IV ketamine use may be significantly different from the proposed estimates in our study.
This systematic review and meta-analysis of 7 randomized control trials evaluated persistent analgesic efficacy from IV ketamine infusions versus placebo for chronic pain. It reveals that IV ketamine is effective for a wide array of chronic pain conditions, although the benefits dissipate with time. Use of IV ketamine resulted in a reduction in pain scores between 48 hours and 2 and 8 weeks after the infusion, but the pooled difference in pain reduction at 4 weeks fell shy of significance. The incidence of nausea and vomiting with IV ketamine was higher than with placebo.
A recently published systematic review and meta-analysis that investigated ketamine for chronic pain included non-IV routes of administration,4 while another limited the study cohort to participants with complex regional pain syndrome.33 The review by Michelet et al4 found no analgesic efficacy with ketamine at 4 weeks, but paradoxically some benefit at 12 weeks, which is a function of methodology that failed to account for differences in follow-up (ie, negative studies at 4 weeks were not considered negative evidence at 12 weeks).4 It is hypothesized that reversing wind-up and central sensitization require high-concentration bombardment and blockade of NMDA receptors, which are intimately involved in neuroplasticity.34 Consequently, extremely low-dose transdermal administration or intermittent blockade with “as needed” oral ketamine, which has a very low bioavailability of 8%–24%,35 is unlikely to accomplish this goal. This fact, along with the widespread interest in IV administration among patients and caregivers, led us to include only studies that examined outcomes after IV administration.
The randomized control trials included in our analysis used diverse pain scales that were often presented in ways that made accurate extraction of raw data difficult. Hence, the results in some studies were standardized during quantitative analysis. The challenges imposed by heterogeneity of outcomes in the pain literature36 have compelled authors of systematic reviews to adopt a “best available evidence approach.”37–39 The conclusions from our meta-analysis examining maximum pain relief should be interpreted with caution because they are based only on 6 small studies. Furthermore, the heterogeneity in time points used for analgesic assessment poses a challenge in evaluating duration of benefit of ketamine infusions.
Analgesic Effect of Ketamine in Different Pain Syndromes
The randomized control trials evaluated in this review included neuropathic, mixed nociceptive and neuropathic pain (eg, spinal cord injury, phantom limb pain, cancer, complex regional pain syndrome types I and II),24–27 and nociceptive (eg, ischemic limb pain)29 or nociplastic pain syndromes (eg, complex regional pain syndrome type I and fibromyalgia).23,28 In subgroup analysis, we found no evidence for superior analgesic benefit from ketamine in neuropathic compared to nociceptive or nociplastic pain syndromes. The same held true for a comparison between non–complex regional pain syndrome and complex regional pain syndrome populations. Some may consider this surprising considering that ketamine has been better studied in neuropathic pain models. It is worth noting that, although not significant, the magnitude of reduction in pain scores was greater among complex regional pain syndrome subgroups, indicating a need for larger and more methodologically robust trials. The International Association for the Study of Pain defines neuropathic pain as “pain caused by a lesion or disease of the somatosensory nervous system.”40 This definition excludes conditions characterized by central sensitization in the absence of a discrete nerve injury, such as complex regional pain syndrome type I and fibromyalgia.40 More recently, a third pain descriptor, nociplastic, has been introduced to classify conditions associated with altered processing of pain that do not conform to the nociceptive category. Examples of nociplastic pain include fibromyalgia, complex regional pain syndrome, nonspecific chronic low-back pain, irritable bowel syndrome, and other “functional” visceral pain disorders.41 However, ketamine’s primary analgesic effect remains ambiguous because it is purported to work by either dampening of CNS pain amplification via numerous pathways and/or reversal of central sensitization by NMDA receptor blockade.34 Whereas the preclinical evidence supporting ketamine is strongest for neuropathic pain, there is a growing body of evidence demonstrating antinociceptive and analgesic effects in inflammatory and other nociceptive as well as nociplastic pain conditions, including headaches.42,43 Whether differences in analgesic effects are due to actual differences in efficacy or a byproduct of methodological differences are areas ripe for further research.
We included studies that evaluated ketamine as add-on therapy for neuropathic and nociceptive or nociplastic pain, which reflects clinical practice. For cancer, the World Health Organization analgesic stepladder recommends adding adjuvants to existing therapy, not as a replacement,44 and ketamine is not considered a first-line agent for neuropathic pain, but it is typically used as a rescue agent.45 Reviews have also found that combination therapy is superior to single-agent therapy for chronic pain syndromes.46 In the recently published guidelines on IV ketamine for acute pain, one of the questions addressed is whether there is any benefit to adding ketamine to opioid therapy, which was answered affirmatively.47
Dose–Response Effect of Ketamine
We found evidence for higher dosages to be associated with greater and longer pain relief, which is not surprising because nearly all analgesic medications are associated with a dose–response effect. However, our analysis may not have shown statistical significance because of the small number of studies in our subgroup analysis. We found that IV ketamine is associated with a significantly higher incidence of nausea and vomiting compared to placebo. However, the data were insufficient to determine the cause–effect relationship between adverse effects and discontinuation of IV ketamine. A previous retrospective study found that discontinuation of IV ketamine secondary to side effects was unrelated to maximum infusion rate.48 This may be a function of the relatively low incidence of certain adverse effects and flaws in surveillance methods. In 1 review,49as well as in the consensus guidelines on the use of ketamine in chronic pain,3 the authors concluded that higher dosages are associated with better analgesia, although studies correlating blood levels with pain relief have yielded mixed results.24,50–52 Variables that may affect the therapeutic dose range include underlying pathology, previous exposure to ketamine and comedications.
Challenges With Blinding Participants in Studies Evaluating Ketamine
Although all studies included in our review were ostensibly double-blinded, 83% of participants allocated to ketamine correctly guessed treatment in the 2 studies in which blinding was assessed.24,26 Studies have found that ineffective blinding may augment the treatment effect by between 15% and 25%.53–55 Although it is challenging to ensure effective blinding when the medication of interest is associated with unique psychotropic effects, the expectations associated with receiving therapy play an integral role in treatment response,56 and steps can be taken to reduce bias when blinding is not feasible.57
Limitations of Current Evidence
There are several limitations to this review including the small number of patients enrolled in trials (median sample size of 24 participants), which may be attributed to the lack of industry funding for a generic medication, and the lack of standardization for infusion regimens, patient selection, and follow-up periods. In general, studies for medications that receive Food and Drug Administration approval go through a well-defined process that includes determining the optimal dose via phase I and II clinical trials, followed by large-scale randomized trials with stringent selection criteria that typically assess participants for 12 weeks. In contrast, the studies in this review treated small number of patients with refractory pain using myriad dose regimens, and often failed to include secondary outcomes or evaluate intermediate-term effects. Clinical heterogeneity in the studies included in this review was a significant challenge we attempted to explore but were unable to identify causes. In addition, the difference in effect size required to detect a statistically significant improvement in pain score may not fully reflect the true clinical effect. For example, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) guidelines note, “… in evaluating a new analgesic, if a 2-point decrease on a 0 to 10 numerical rating scale of pain intensity is considered a clinically important improvement for an individual, it should not be inferred that a 2-point difference in pain reduction between the analgesic and placebo must occur before the treatment benefit can be considered clinically important.”58 Due to the subjectivity of reported pain scores among patients, wide variations in response, and high placebo response rates, the clinical relevance of the differences in effect size is hard to determine. Finally, chronic pain management includes not only the reduction of pain but also improved quality of life, which should be measured via validated instruments.59 Unfortunately, our analysis could not account for these outcomes due to limited availability of outcome data.
Recommendations and Conclusions
Based on the quality of the evidence from studies in this review and the strength of effect, it is recommended that IV ketamine be used, on a case-by-case basis, as a primary analgesic in patients with chronic pain refractory to more conventional treatments (GRADE: weak recommendation; low evidence)22 (Table 2). However, our confidence in this analgesic effect is limited and the actual effect of IV ketamine among chronic pain patients may vary widely. IV ketamine may be associated with improvement in pain scores observed during the infusion, quantified as early as 48 hours after the infusion, and lasting for ≥2 weeks when high-dose regimens are used. Whereas reductions in pain scores were observed with a range of dosages, more robust analgesic effects were observed with higher dosages. Further research should seek to determine the ideal patients and conditions for this treatment, the optimal dosing regimen, whether combination therapy with ketamine provides superior benefit than stand-alone treatment, the impact of infusions on physical and psychological functioning, and long-term adverse effects.
Name: Vwaire Orhurhu, MD, MPH.
Contribution: This author helped perform the literature search, data extraction, and statistical analysis, draft and critically revise the manuscript, interpret the results, and perform a critical review of the manuscript for intellectual content.
Name: Mariam Salisu Orhurhu, MD, MPH.
Contribution: This author helped perform the literature search and data extraction, draft the manuscript, critically revise the manuscript, interpret the results, and perform a critical review of the manuscript for intellectual content.
Name: Anuj Bhatia, MD, FRCPC.
Contribution: This author helped draft the manuscript, critically revise the manuscript, interpret the results, and perform a critical review of the manuscript for intellectual content.
Name: Steven P. Cohen, MD.
Contribution: This author helped design the study, draft and critically revise the manuscript, interpret the results, and perform a critical review of the manuscript for intellectual content.
This manuscript was handled by: Honorio T. Benzon, MD.
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