Subanesthetic Ketamine for Chronic Non-Cancer Pain: A Systematic Review of Evidence from Randomized Trials over the Past Two Decades

Abstract

Introduction: Chronic non-cancer pain represents a major global health challenge because of its high prevalence, functional impact, and limited response to conventional therapies, highlighting the need for alternative approaches. In this context, subanesthetic-dose ketamine has emerged as a promising therapeutic option because of its ability to modulate central sensitization and enhance analgesia through NMDA receptor antagonism. However, current evidence regarding its long-term efficacy and safety remains limited and heterogeneous. Objective: To evaluate the efficacy and safety of subanesthetic ketamine for the management of chronic non-cancer pain in adults, based on randomized controlled trials published between 2005 and 2025. Methods: A systematic review was conducted in accordance with the PRISMA 2020 guidelines. Randomized controlled trials involving adults with chronic non-cancer pain were included, comparing ketamine with placebo or other active agents. The databases searched were PubMed, ScienceDirect, and the Cochrane Library. Risk of bias was assessed using the Cochrane RoB-2 tool, and the certainty of evidence was evaluated using GRADE. Results: Five trials met the inclusion criteria. All included studies evaluated intravenous ketamine at doses ranging from 0.3 to 0.5 mg/kg. Overall, ketamine demonstrated significant short-term pain relief (p < 0.05), particularly in neuropathic conditions; however, the magnitude of this effect decreased progressively after the infusion ended. Reported adverse effects were mild and transient, with no evidence of severe toxicity. Heterogeneity in dosing protocols, pain phenotypes, comparator strategies, and follow-up duration limited cross-study comparability. Conclusions: Current evidence supports the short-term efficacy and safety of subanesthetic-dose ketamine as an analgesic option for chronic non-cancer pain, especially in neuropathic syndromes. However, the transient nature of its effects and the heterogeneity among studies underscore the need for standardized protocols and longer follow-up periods. Despite its generally favorable short-term safety profile, subanesthetic ketamine should be used with caution under strict clinical supervision, as the potential for long-term neurocognitive, urological, and hepatic adverse effects remains insufficiently defined.

1. Introduction

Chronic non-cancer pain represents a major global health problem, affecting approximately 20% of the worldwide population [1]. This condition is associated with a significant reduction in quality of life, functional capacity, and psychological well-being, and continues to pose a persistent clinical challenge. Despite the availability of multiple therapeutic options, a considerable proportion of patients experience persistent or refractory pain that does not respond adequately to conventional treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and antidepressants. This unmet need has driven the exploration of alternative therapeutic strategies with different mechanisms of action, including the use of subanesthetic-dose ketamine, defined in this review as ketamine administered at doses below those used to induce general anesthesia, with the aim of achieving analgesic or neuromodulatory effects without loss of consciousness, a drug originally developed as an anesthetic agent [2].

Epidemiological studies have consistently shown a higher prevalence of chronic pain among adult women, with reported rates of 47.3% compared with 33.6% in men [3]. Beyond its clinical implications, chronic pain imposes a substantial social and economic burden. In Canada, approximately one in five individuals is estimated to live with chronic non-cancer pain, with direct and indirect costs ranging between USD 38.2 and 40.3 billion in 2019 [2].

The therapeutic management of chronic non-cancer pain includes non-opioid analgesics, non-pharmacological interventions such as therapeutic exercise and cognitive behavioral therapy, and the treatment of psychiatric comorbidities using tricyclic antidepressants or selective serotonin reuptake inhibitors. Opioid therapy is generally reserved as a last-line option, only when the expected clinical benefit outweighs the associated risks [4].

In this context, ketamine has been proposed as a treatment of clinical interest. At subanesthetic doses, ketamine has demonstrated the ability to modulate central sensitization, primarily through noncompetitive antagonism of the N-methyl-D-aspartate (NMDA) receptor, a mechanism closely linked to the pathophysiology of neuropathic pain [5]. In addition to its NMDA receptor activity, ketamine interacts with other systems, including cholinergic, monoaminergic, and opioid receptors, as well as sodium and calcium channels. These interactions may contribute to its analgesic efficacy and to a reduction in opioid tolerance development [6].

At subanesthetic doses, such as 0.5 mg/kg administered intravenously, ketamine has shown significant analgesic effects in patients with neuropathic, refractory, or centrally mediated pain [6]. However, this route of administration has been associated with a higher incidence of neuropsychiatric adverse effects, including hallucinations, delirium, and dissociative experiences, particularly at higher doses [7,8].

Although ketamine is primarily classified as a general anesthetic, its use has expanded off-label to the management of acute and chronic pain, procedural sedation in emergency settings, and perioperative sedation, where it may also contribute to a reduction in postoperative pain. Additionally, ketamine has been used in the treatment of asthma due to its bronchodilatory properties [9]. Given its pharmacological profile, off-label use of ketamine should be carefully evaluated within a risk–benefit framework and, preferably, restricted to controlled clinical trials [10].

Multiple routes of administration have been investigated for non-anesthetic indications in an effort to optimize analgesic efficacy while minimizing adverse effects. The present review focuses on the systemic administration of ketamine and analyzes its therapeutic potential from a pharmacological perspective. This evaluation is conducted in a context characterized by persistent heterogeneity among available clinical trial results [11].

Although there is no clear consensus regarding the risk of dependence associated with long-term use, cases of tolerance without clear withdrawal symptoms have been reported. These findings position ketamine as a potential alternative to drugs with higher addictive potential. Nevertheless, not all patients achieve a clinically meaningful response [11].

Against this background, the aim of this systematic review is to integrate and critically analyze evidence from randomized controlled trials conducted over the past two decades evaluating the efficacy and safety of subanesthetic-dose ketamine for the management of chronic non-cancer pain in adults. Particular emphasis is placed on dosing, route of administration, and pharmacological implications. The objective is to provide an updated perspective to inform clinical practice and guide future research in this field.

2. Materials and Methods

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [12]. The methodological design was established to ensure transparency, reproducibility, and consistency in the identification, selection, evaluation, and synthesis of the included studies. he completed PRISMA 2020 checklist is provided in the Supplementary Materials.

2.1. Protocol Registration

The protocol for this systematic review was prospectively registered in the PROSPERO database (International Prospective Register of Systematic Reviews) under registration number CRD420261289158. The full registration record is publicly available at: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261289158 (accessed on 23 February 2026).

2.2. Search Strategy and Information Sources

Systematic searches were performed in three major electronic databases: PubMed, ScienceDirect, and the Cochrane Library, covering publications from 1 June 2005 to 30 August 2025, with the aim of identifying randomized controlled trials published over the past two decades. The complete search strategies are detailed in Appendix A and included the use of Boolean operators, Medical Subject Headings (MeSH) terms, and applied filters such as English language, adult population, and randomized controlled trial design.

To narrow the clinical focus of the review, search terms related to psychiatric disorders, such as depression or post-traumatic stress disorder, as well as studies associated with surgical procedures, were excluded. This approach was intended to restrict the scope exclusively to the management of chronic non-cancer pain.

2.3. Eligibility Criteria

Study selection was conducted in accordance with the PRISMA framework and structured using the PICO model (Population, Intervention, Comparator, and Outcomes). The target population comprised adults aged ≥18 years diagnosed with chronic non-cancer pain with a duration of more than three months (P). The intervention of interest was the administration of subanesthetic-dose ketamine (I), compared with placebo or other active pharmacological treatments, such as morphine (C). The outcomes assessed included pain relief, occurrence of adverse events, functional outcomes, and duration of the analgesic effect (O). Only randomized controlled trials were considered eligible for inclusion.

Accordingly, the research question was formulated as follows: Does the administration of subanesthetic-dose ketamine improve pain control and demonstrate an acceptable safety profile compared with placebo or other pharmacological interventions in adult patients with chronic non-cancer pain?

2.3.1. Inclusion Criteria

Randomized controlled trials published between 2005 and 2025, in English or with an available English translation, were included if they evaluated the efficacy and safety of subanesthetic-dose ketamine in adults aged ≥18 years with chronic non-cancer pain. All routes of administration and dosing regimens were considered eligible at the screening stage, provided that a comparator group receiving placebo or an active pharmacological treatment was included. However, after the selection process, all randomized controlled trials that met the final inclusion criteria evaluated intravenous administration; therefore, other routes were not represented in the final evidence base.

2.3.2. Exclusion Criteria

Studies focusing on acute pain, cancer-related pain, surgical procedures, or the anesthetic use of ketamine were excluded. In addition, non-randomized study designs, case series, individual case reports, narrative reviews, and publications with incomplete or insufficient data for analysis were excluded.

2.4. Study Selection Process

The titles and abstracts of all identified records were independently screened by two investigators to determine study eligibility based on the predefined criteria. Full-text articles of potentially relevant studies were subsequently reviewed. The search was complemented by a manual screening of reference lists from relevant studies and reviews. Any discrepancies between reviewers were resolved by consensus or, when necessary, through consultation with a third investigator.

2.5. Risk of Bias Assessment

The risk of bias of the included randomized controlled trials was assessed using the Cochrane Risk of Bias tool, version 2 (RoB 2), which evaluates five key domains: the randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of the reported results.

2.6. Data Synthesis

A quantitative meta-analysis was planned only if sufficient clinical and methodological homogeneity was observed across the included studies. However, meta-analysis was not performed because the eligible trials showed substantial heterogeneity in several key aspects, including pain phenotypes, ketamine dosing and infusion regimens, treatment duration, comparator interventions, concomitant therapies, outcome measures, and follow-up periods. Given this degree of variability, pooled quantitative synthesis was considered methodologically inappropriate and potentially misleading. Therefore, the findings were synthesized narratively.

3. Results

3.1. Study Selection

The study selection process is summarized in Figure 1, which presents the PRISMA 2020 flow diagram. Following the initial search conducted in the PubMed, ScienceDirect, and Cochrane Library databases, a total of 209 records were identified.

Subsequently, duplicate records were removed, and an initial screening of titles and abstracts was performed. Studies that were not relevant or did not meet the predefined PICO criteria were excluded. The main reasons for exclusion included a focus on acute or cancer-related pain, the anesthetic use of ketamine, and non-randomized study designs. Ultimately, five randomized controlled trials met all inclusion criteria and were included in the qualitative synthesis of the present review. Because of the substantial clinical and methodological heterogeneity across pain conditions, infusion protocols, comparator interventions, outcome measures, and follow-up periods, a quantitative meta-analysis was not considered appropriate; therefore, the findings were synthesized narratively.

3.2. Study Characteristics

The five randomized controlled trials included in this review evaluated the efficacy and safety of subanesthetic-dose ketamine in adult populations with chronic non-cancer pain, predominantly of neuropathic, musculoskeletal, or mixed origin. In all studies, ketamine was administered intravenously, using infusion regimens with doses ranging between 0.3 and 0.5 mg/kg, which are considered within the subanesthetic range.

Sample sizes across the studies ranged from 19 to 61 participants, reflecting relatively small populations typical of exploratory trials in this clinical context. The duration of follow-up was heterogeneous, varying from assessments of immediate analgesic effects, measured within minutes or hours after administration, to longer follow-up periods of up to 12 weeks, aimed at evaluating the persistence of analgesic effects and the occurrence of adverse events.

This variability in study designs, population characteristics, comparator strategies, and follow-up periods highlights substantial clinical and methodological heterogeneity, which should be taken into account when interpreting the findings. Accordingly, the efficacy results were synthesized narratively using a thematic approach rather than through study-by-study quantitative comparison. The main characteristics of the included studies are summarized in

Table 1. Main characteristics and summary findings of the included randomized controlled trials.

Study	Study Design	Study Population	Protocol	Study Focus	Summary of Findings
Pickering et al., 2020 [13]	Randomized, double-blind, placebo-controlled, crossover trial	20 participants aged ≥18 years with chronic pain lasting at least 3 months	0.5 mg/kg intravenous infusion, single dose every 35 days (2 h infusion), with or without magnesium	Pain relief and cognitive–emotional outcomes	Ketamine did not demonstrate a significant difference compared with placebo or ketamine plus magnesium in pain reduction over five weeks. No differences were observed in emotional measures or quality of life.
Schwartzman et al., 2009 [14]	Randomized, double-blind, controlled trial	19 participants with Complex Regional Pain Syndrome (CRPS)	0.35 mg/kg intravenous infusion (maximum 25 mg/h), administered daily for 10 days (4 h infusion)	Efficacy of intravenous ketamine at different doses for the treatment of CRPS	Subanesthetic-dose ketamine provided significant pain relief during treatment and early follow-up in patients with CRPS; however, sustained long-term analgesic benefit was not consistently demonstrated.
Maher et al., 2017 [15]	Randomized, double-blind, placebo-controlled trial	61 patients with chronic whiplash-associated pain	0.05 mg/kg intravenous infusion, single dose (30 min infusion)	Pain intensity and exploratory assessment of temporal summation	No clinically significant improvement in pain intensity was observed after infusion; however, ketamine reduced temporal summation and showed a more favorable response pattern in patients receiving concomitant opioid therapy.
Lemming et al., 2005 [16]	Randomized, double-blind, placebo-controlled, crossover trial	30 patients diagnosed with grade II whiplash-associated disorder	0.3 mg/kg intravenous infusion, single dose (30 min infusion)	Pain reduction in whiplash-associated disorder and assessment of response according to pain duration	Heterogeneous results were observed: response patterns showed no significant association with pain duration, and a large proportion of patients were identified as non-responders to therapy.
Amr, 2010 [17]	Randomized, double-blind, controlled trial	Adults diagnosed with pain secondary to spinal cord injury	80 mg intravenous infusion daily for 7 days (5 h infusion), administered concomitantly with gabapentin	Adjunctive use with oral gabapentin for refractory neuropathic pain	Ketamine demonstrated greater pain reduction than placebo during infusion and up to two weeks afterward; however, the analgesic effect dissipated by weeks 3–4, without statistical significance.

.

3.3. Synthesis of Primary Outcomes

The primary outcomes assessed across the included studies focused mainly on pain relief, measured using visual analogue scales (VAS), numerical rating scales, or comparable pain instruments, as summarized in

Table 2. Efficacy of ketamine in chronic non-cancer pain.

Study	Pain Condition	Primary Efficacy Outcome	Statistical Result
Pickering et al., 2020 [13]	Refractory neuropathic pain	Area under the curve (AUC) of pain over 35 days	No statistically significant differences were observed in pain AUC among groups during the follow-up period (p = 0.296), indicating no sustained analgesic benefit.
Schwartzman et al., 2009 [14]	Complex regional pain syndrome (CRPS)	Pain reduction (McGill Pain Questionnaire)	A reduction in pain measured by the McGill Pain Questionnaire was reported; however, no statistically significant relationship was found between plasma ketamine levels and the magnitude of clinical improvement (p = 0.93).
Maher et al., 2017 [15]	Chronic whiplash-associated pain	Primary: Pain intensity (NRS-11). Exploratory: Temporal summation assessed by quantitative sensory testing (QST)	No significant change in NRS-11 scores was observed after infusion. A significant reduction in temporal summation was detected in opioid users treated with ketamine compared with placebo (p = 0.004), as well as in non-opioid users compared with opioid users receiving placebo (p = 0.007).
Lemming et al., 2005 [16]	Chronic whiplash-associated pain	Pain reduction (VAS, AUC) during and after infusion	Statistically significant differences favoring ketamine were observed in pain AUC and visual analogue scale (VAS) scores compared with placebo (p = 0.001–0.044).
Amr, 2010 [17]	Neuropathic pain secondary to spinal cord injury	Pain reduction (VAS) during and after infusion	A significant reduction in pain scores was observed during infusion and up to two weeks thereafter compared with the control group (p < 0.0001). No significant differences were detected at 3–4 weeks (p = 0.54 and 0.25).

. Across the included randomized controlled trials, the analgesic signal appeared to be more consistent in neuropathic and centrally sensitized pain conditions, particularly complex regional pain syndrome and spinal cord injury-related neuropathic pain, than in more heterogeneous musculoskeletal pain states [14,17]. By contrast, findings in chronic whiplash-associated pain and other mixed pain populations were more variable [15,16], while one trial in refractory neuropathic pain did not demonstrate sustained benefit during follow-up [13].

A second consistent pattern across studies was the difference between short-term and longer-term efficacy. In general, ketamine was associated with a reduction in pain intensity during infusion or in the early post-infusion period, supporting a predominantly short-term analgesic effect [14,16,17]. However, this benefit tended to diminish after treatment discontinuation, and sustained analgesia beyond the first weeks of follow-up was inconsistently demonstrated. Notably, one study in CRPS suggested persistence of analgesic benefit during extended follow-up, although sustained long-term superiority was not consistently demonstrated [14], whereas another showed significant benefit only during infusion and up to 2 weeks, with no significant differences at 3–4 weeks [17]. In addition, no sustained analgesic benefit was observed at 35 days in the refractory neuropathic pain trial [13].

Taken together, these findings suggest that subanesthetic intravenous ketamine may provide transient analgesic benefit in selected patients with chronic non-cancer pain, particularly in neuropathic pain states, but that the magnitude and duration of benefit remain uncertain because of heterogeneity in pain phenotype, infusion protocol, concomitant therapy, and follow-up design [13,14,15,16,17].

Additional exploratory findings also suggest that ketamine may modulate central sensitization, as reflected by reductions in temporal summation in one study [15]. However, this neurophysiological effect did not consistently translate into clinically meaningful improvement in pain intensity across all patient groups [15].

3.4. Synthesis of Secondary Results

Ketamine exhibited a generally acceptable short-term tolerability profile, with a predominance of mild and transient adverse events, as summarized in

Table 3. Safety and duration of ketamine in chronic non-cancer pain.

Study	Adverse Events	Other Outcomes
Pickering et al., 2020 [13]	Higher frequency of adverse events in the ketamine plus magnesium group compared with the other groups; events were mainly mild to moderate	No sustained analgesic benefit was observed at 35 days
Schwartzman et al., 2009 [14]	No clinically relevant safety issues were reported	Prolonged analgesic benefit was suggested during follow-up; however, sustained long-term benefit was not consistently demonstrated.
Maher et al., 2017 [15]	No clinically significant adverse events were reported; subtle changes were observed in quantitative sensory testing (QST)	Analgesic response was modulated by concomitant opioid use; opioid users showed a better response than non-users
Lemming et al., 2005 [16]	Mild adverse events; a heterogeneous group of responders and non-responders was observed	Analgesic effect was limited to the infusion period and the hours thereafter
Amr, 2010 [17]	Mild and transient adverse events; no serious adverse events were reported	The analgesic effect disappeared between 3 and 4 weeks after administration

. Across the included trials, no severe safety signals were consistently reported under the subanesthetic intravenous regimens evaluated, although the frequency and type of adverse events varied among studies [13,14,15,16,17]. Overall, the most commonly reported adverse effects were neuropsychiatric or nonspecific and were generally manageable within the monitored clinical setting [13,14,15,16,17].

With regard to the duration of benefit, the evidence again suggested a predominantly transient effect. Although one study in CRPS suggested a longer persistence of analgesic benefit during follow-up [14], most trials showed that the analgesic effect diminished over time and was no longer clearly distinguishable after treatment discontinuation or within a few weeks of follow-up [13,15,17]. In one study involving spinal cord injury-related neuropathic pain, the analgesic effect persisted for up to 2 weeks but was no longer significant at 3–4 weeks [17]. These findings reinforce the interpretation that ketamine may provide short-term benefit in selected patients, while its long-term clinical role remains uncertain.

3.5. Methodological Quality

3.5.1. Assessment Using the RoB-2 Tool

Figure 2 presents the results of the risk of bias assessment of the included randomized controlled trials, conducted using the Cochrane Risk of Bias tool, version 2 (RoB-2). Maher et al. [15] and Lemming et al. [16] showed some concerns in Domain 1 (D1), corresponding to the randomization process, because the published reports provided insufficient detail regarding sequence generation and allocation concealment. Although no clear baseline imbalances suggesting failed randomization were identified, the available information was not sufficient to support a confident judgment of low risk in this domain.

In Domain 3 (D3), which assesses bias due to missing outcome data, Schwartzman et al. [14] showed concerns related to incomplete outcome data. Similar concerns were also identified for Maher et al. [15] and Lemming et al. [16], mainly because the extent, handling, and potential impact of missing data were not fully clarified in the published reports.

Finally, all included trials showed some concerns in Domain 5 (D5), related to selection of the reported results. This judgment reflected the limited availability of protocols or prespecified statistical analysis plans, which prevented confirmation that the reported outcomes and analyses fully corresponded to those originally intended. Overall, the majority of studies were classified as having a moderate overall risk of bias, while two trials were considered to be at low risk of bias.

3.5.2. Evaluation Using the Grade for Certainty of Evidence (GRADE) Tool

Figure 3 summarizes the certainty of evidence for the main outcomes using the GRADE framework. The certainty of evidence for short-term pain relief was judged as moderate, as several trials showed a favorable analgesic effect during infusion or in the early post-infusion period; however, confidence was lowered because of imprecision related to small sample sizes across the included studies.

By contrast, the certainty of evidence for long-term pain relief was judged as low. This downgrade reflected both imprecision and inconsistency. Imprecision was mainly related to the small size of the included randomized controlled trials, whereas inconsistency reflected important heterogeneity in pain phenotypes, ketamine infusion regimens, comparator interventions, and duration of follow-up. In addition, sustained analgesic benefit was not consistently demonstrated across studies: one trial in CRPS suggested benefit during extended follow-up without consistent demonstration of sustained long-term superiority, another showed benefit up to 2 weeks but not at 3–4 weeks, and another did not demonstrate sustained benefit at 35 days [13,14,17].

The certainty of evidence for safety outcomes was also limited by the small number of studies and by variation in the reporting and duration of adverse event assessment, which restricted confidence in conclusions regarding long-term tolerability.

4. Discussion

Overall, the findings suggest that ketamine provides significant short-term analgesic relief; however, the magnitude and duration of this effect vary considerably across the analyzed clinical trials. This heterogeneity is consistent with reports by Kamp et al. [18] and Carvalho et al. [19], who emphasize that differences in dosage, routes of administration, infusion duration, and pain phenotypes hinder direct comparison between studies and limit the robustness of the available evidence.

4.1. Effectiveness of Ketamine

The results of the included trials indicate that intravenous administration of subanesthetic doses of ketamine, generally ranging from 0.3 to 0.5 mg/kg, produces a statistically significant reduction in pain intensity during the infusion period (p < 0.05), with clinical benefits that tend to diminish after treatment discontinuation. This pattern was evident in the studies by Schwartzman et al. [14] and Amr [17] in which analgesia was pronounced during administration but was not consistently maintained during follow-up. Similarly, Lemming et al. [16] and Maher et al. [15] reported significant but transient analgesic improvements.

These findings support the efficacy of ketamine as an analgesic alternative in patients with refractory chronic pain, although sustained effects appear to depend on the duration, frequency, and structure of infusion regimens.

In the study by Maher et al. [15], the results suggest that ketamine may exert an early effect on central sensitization, assessed through quantitative sensory testing, even in the absence of clinically perceptible changes in pain intensity. This observation may be explained by the fact that both pain intensity and experimental measurements were recorded only before and immediately after administration, without extended follow-up to assess the persistence of the effect.

From a pharmacokinetic perspective, Peltoniemi et al. [20] highlight that ketamine has a relatively short plasma half-life, approximately 2 to 4 h, along with rapid tissue redistribution, which may explain the transient nature of its analgesic effects. The intravenous route avoids first-pass metabolism and allows for higher bioavailability and more predictable plasma concentrations compared with oral or intranasal routes, justifying its preferential use in controlled clinical settings.

Pain phenotype appears to directly influence ketamine’s analgesic efficacy. The most favorable outcomes have been observed in neuropathic or centrally mediated pain, in which NMDA receptor–mediated sensitization plays a predominant pathophysiological role. In contrast, in diffuse or mixed chronic pain conditions, such as fibromyalgia or musculoskeletal pain, the response is typically more limited, as NMDA receptor activation does not represent the primary pain mechanism. In the study by Graven-Nielsen et al. [21], intravenous ketamine administration in patients with fibromyalgia resulted in significant reductions in pain and hyperalgesia only in a subgroup of patients, suggesting that central sensitization is not uniformly present in this population.

4.2. Long-Term Use

Although most included trials assessed short-term outcomes, the study by Corriger et al. [22], provides relevant evidence regarding the potential for sustained ketamine effects. In a one-year follow-up, patients with refractory chronic pain maintained a significant reduction in pain intensity (p < 0.001) and improvements in quality of life using a more prolonged subanesthetic infusion regimen. These findings suggest that duration and periodicity of administration may directly influence the persistence of analgesic effects.

Moreover, patients with neuropathic pain exhibited a more stable response compared with those with fibromyalgia, reinforcing the hypothesis that ketamine’s mechanism of action is closely linked to pathophysiological differences among chronic pain subtypes.

4.3. Clinical Implications

The findings of Maher et al. [15] support the use of ketamine as an adjunctive therapy in patients receiving opioid treatment, as greater pain reduction was observed in this subgroup. This effect may be explained by a synergistic interaction between NMDA receptor antagonism and opioid system modulation, suggesting that ketamine may enhance opioid analgesia and attenuate tolerance. Consistent with this observation, experimental studies have demonstrated that opioid antagonists such as naloxone and naltrexone can attenuate ketamine’s analgesic and antidepressant effects, reinforcing the hypothesis of joint involvement of both systems in its therapeutic action [23].

Nevertheless, the duration of clinical benefit observed in the randomized controlled trials included in this review was generally limited, with analgesic effects predominantly occurring during infusion or in the hours and days following discontinuation. In this context, the duration and structure of infusion regimens emerge as critical determinants of sustained analgesic effects.

4.4. Emerging Evidence Beyond the Included RCTs

The following publications were not part of the randomized controlled trial evidence base included in this systematic review and are discussed only as emerging contextual evidence relevant to future clinical and research developments.

In a prospective randomized comparative study, Elsafa et al. evaluated three subanesthetic ketamine infusion regimens in patients with complex regional pain syndrome, comparing 3-, 5-, and 7-day protocols using continuous doses of 0.1–0.35 mg/kg/h during prolonged daily sessions. The authors demonstrated that the 5-day regimen was associated with a significant and sustained reduction in pain, with maintenance of analgesic effects for up to 3 months, whereas extending treatment to 7 days did not confer additional efficacy benefits and was associated with a higher incidence of adverse events. Conversely, the 3-day regimen showed a favorable safety profile but a less durable analgesic effect [24].

Based on this and other prior evidence, Tankha et al. proposed the KIT protocol, a standardized clinical administration model consisting of five consecutive ketamine infusions at a dose of 0.5 mg/kg, administered once daily over five consecutive days. For intravenous administration, ketamine should be reconstituted and diluted in compatible solutions such as 0.9% sodium chloride or 5% dextrose, ensuring adequate physicochemical stability and controlled infusion in a monitored clinical environment. Unlike traditional clinical trials, the KIT protocol allows assessment of medium-term persistence of clinical benefit, reporting sustained improvements in pain outcomes and functional interference over several months, with the option to repeat cycles in selected patients [25].

Collectively, these findings suggest that beyond isolated dosing, daily treatment continuity over an intermediate five-day period may represent a balance between efficacy and tolerability, differentiating it from brief regimens with transient effects and more prolonged infusions associated with a higher adverse event burden. However, these publications were not part of the five randomized controlled trials formally included in the present review and should therefore be interpreted as external emerging evidence rather than as part of the systematic review’s core evidence base.

4.5. Safety and Tolerability

Overall, ketamine was well tolerated in the included trials, with a predominance of mild and manageable adverse events, likely attributable to the use of doses substantially lower than those associated with severe toxicity. Nevertheless, NMDA receptor blockade has been linked to clinically relevant adverse effects, sustaining ongoing debate regarding ketamine’s safety profile [26]. Webster notes that ketamine’s side effects are dose dependent and rarely constitute a reason for treatment discontinuation [27].

However, recent studies have warned of potential hepatic, urological, and neurocognitive toxicities associated with prolonged ketamine use [28]. Although evidence remains limited, these findings underscore the need for close clinical monitoring and for restricting chronic use.

From a mechanistic perspective, ketamine toxicity is primarily related to its action as a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor widely distributed in the central nervous system. This inhibition alters glutamatergic neurotransmission and may contribute to acute neuropsychiatric effects such as delirium, hallucinations, and altered consciousness, while repeated or prolonged exposure has been associated with cognitive impairment and broader neurotoxic effects. At the molecular level, ketamine-induced neuronal injury has been linked to several forms of programmed cell death, including apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis. These processes appear to be mediated by disruption of intracellular homeostasis, increased production of reactive oxygen species, mitochondrial dysfunction, and endoplasmic reticulum stress, ultimately leading to neuronal damage and loss of cognitive function [29].

Experimental evidence further suggests that ketamine may induce neuronal apoptosis through inhibition of the PKC/ERK signaling pathway and disruption of cell-cycle regulation in developing neurons, effects that may be reversed by NMDA receptor activation. In addition, ketamine has been reported to affect glymphatic system function by altering aquaporin-4 (AQP4) expression in astrocytes, potentially contributing to impaired metabolic waste clearance and cognitive dysfunction [30]. Beyond the central nervous system, chronic ketamine exposure has been associated with cystitis and cholangiopathy, likely mediated by inflammatory mechanisms and direct epithelial injury affecting the urothelium and biliary tract. Cardiovascular effects such as hypertension and tachycardia may also occur, probably due to inhibition of catecholamine reuptake and indirect sympathetic stimulation. Although many of these complications have been described primarily in the setting of repeated or prolonged exposure rather than short controlled analgesic protocols, they remain clinically relevant when considering subanesthetic ketamine as a repeated strategy for chronic pain management [29].

Additionally, ketamine may induce psychological dependence and pharmacological tolerance, particularly with long-term exposure. Cosci et al. [31] describe withdrawal symptoms following discontinuation, including dysphoria, craving, anxiety, insomnia, and tremors, typically occurring within the first 24 h and resolving within a few days. Progressive loss of therapeutic effect and limited long-term safety data pose a potential risk of misuse, reinforcing the need for caution in clinical application.

4.6. Current Therapeutic Limitations and the Need for Innovation in Analgesia

Although ketamine has emerged as a relevant non-opioid alternative for refractory chronic pain management due to its NMDA receptor antagonism, its clinical utility is limited by rapid development of pharmacological tolerance and a relatively narrow therapeutic window. In a substantial proportion of patients, initial analgesic effects diminish over time, necessitating repeated or prolonged exposure to maintain efficacy, thereby increasing the risk of neuropsychiatric and systemic adverse effects. These limitations highlight that, despite its pharmacological value, ketamine does not fully address the inherent challenges of chronic pain pharmacotherapy [32].

More broadly, the limited availability of analgesic therapies that combine sustained efficacy with an acceptable safety profile remains a clinical and public health concern. Despite significant advances in pharmaceutical innovation across other therapeutic areas, pain management continues to rely largely on traditional drug classes such as nonsteroidal anti-inflammatory drugs and opioids, with minimal incorporation of novel alternatives offering improved efficacy or reduced risks of adverse events and dependence [32].

This lack of progress is related to the complexity of pain pathophysiology, heterogeneity of underlying mechanisms, limited translation of preclinical models into clinical practice, absence of reliable biomarkers, and difficulty in identifying new therapeutic targets. Consequently, many patients continue to experience inadequate pain control and prolonged exposure to treatments with suboptimal safety profiles. In this context, the development of safer and more effective non-opioid therapies, along with more representative clinical models and biomarker-based strategies, will be essential to advance toward more rational and sustainable chronic pain management [32].

4.7. Future Directions

Future research should prioritize adequately powered multicenter randomized controlled trials with standardized ketamine dosing and infusion protocols, more consistent comparator strategies, and harmonized outcome measures. Longer follow-up periods are also needed to determine whether the analgesic effects observed in the short term can be sustained over time and to better characterize the long-term safety profile of repeated or prolonged exposure. In addition, stratification by pain phenotype, particularly neuropathic versus non-neuropathic conditions, may help identify the subgroups of patients most likely to benefit from subanesthetic-dose ketamine. Further investigation should also explore optimal treatment schedules, the role of concomitant therapies, and the balance between transient efficacy and potential cumulative toxicity.

From a broader scientific perspective, progress in analgesic innovation remains hindered by the complexity and heterogeneity of the pathophysiological mechanisms underlying chronic pain. One of the major barriers is the limited availability of preclinical animal models that adequately reproduce the biological mechanisms and clinical experience of human chronic pain, which has contributed to the poor translation of preclinical findings into meaningful clinical efficacy [33]. As a result, many compounds with initially promising mechanisms have failed in later clinical stages because of insufficient efficacy or unexpected adverse effects. In addition, inadequate patient stratification and the lack of robust biomarkers continue to limit the identification of patient subgroups most likely to benefit from mechanism-based therapies [34]. Addressing these challenges will be essential not only for optimizing the future clinical development of ketamine-based strategies, but also for advancing the broader field of non-opioid analgesic research.

4.8. Study Limitations

The main limitations of this review include the small number of included randomized controlled trials (n = 5), small sample sizes, and methodological heterogeneity, which precluded meta-analysis. In addition, short follow-up periods limited the assessment of sustained efficacy and long-term safety of ketamine in chronic pain management. Restricting inclusion to English-language publications may have introduced language bias, reducing the geographic representativeness of the available evidence.

5. Conclusions

The analyzed evidence supports the use of subanesthetic doses of ketamine as an effective therapeutic option with an acceptable short-term safety profile for the management of chronic non-cancer pain, particularly in neuropathic and refractory conditions in which NMDA receptor-mediated sensitization plays a relevant pathophysiological role. However, the observed analgesic benefits are predominantly transient, and their maintenance appears to depend not only on the administered dose but also on the duration, continuity, and frequency of infusion regimens, as well as on the type of pain treated.

Despite its generally favorable short-term safety profile, subanesthetic ketamine should be used with caution under strict clinical supervision, as the potential for long-term neurocognitive, urological, and hepatic adverse effects remains insufficiently defined. In summary, ketamine represents a valuable analgesic tool within a multimodal approach to refractory chronic pain, provided that its indication is based on individualized assessment, doses and regimens are carefully controlled, and multidisciplinary supervision is maintained to maximize clinical efficacy while minimizing long-term risks.