Managing Chronic Pain: The Ketamine Option

Abstract

Ketamine, an anaesthetic and sedative drug, has emerged as a promising therapeutic option for the management of chronic refractory pain, but is used off-label in this indication and known for its psychomimetic side-effects. The primary objective of this manuscript is to synthesize the current evidence on ketamine efficacy and safety for chronic refractory pain. Furthermore, it aims to identify critical knowledge gaps and propose a framework for its rational and safe clinical application. This narrative review analyses key findings from randomised and non-randomised clinical trials investigating ketamine’s use in chronic pain conditions. It also examines existing clinical guidelines and expert consensus statements to reach a comprehensive clinical perspective. Current evidence demonstrates that ketamine can provide significant short-term analgesia, especially in neuropathic pain, and is fairly well-tolerated in patients with severe refractory pain. However, long-term data on efficacy, cognitive impact, addiction risk and optimal dosing are severely lacking. The intravenous route remains the most studied, while alternatives are still underexplored. Ketamine is not a first-line treatment for pain and must be prescribed and supervised by trained specialists within a structured standard of care. Its future role in pain management hinges on collaborative translational research to define optimal administration routes, establish phenotyping strategies (on the basis of pain type, comorbidities and comedication), and conduct long-term studies assessing mood, quality of life and cognitive function to ensure both efficacy and safety.

Key Points

Short-Term Efficacy and Tolerability: Ketamine is a promising treatment for refractory chronic pain, demonstrating significant short-term efficacy and an acceptable tolerability profile.

Significant Knowledge Gaps: Long-term data are urgently required to evaluate the risks of addiction and cognitive impairment, and to determine other than intravenous optimal administration routes and dosages.

Requirement for Supervised Use: Despite its potential for severe pain relief, ketamine’s off-label status, psychomimetic side effects and addiction potential necessitate strict administration under the supervision of trained specialists to ensure patient safety.

Not a First-Line Treatment: Ketamine should be reserved for refractory pain treatment and is not a first-line therapy for chronic pain.

Towards Precision Medicine: Future implementation must focus on patient phenotyping – based on pain type and comorbidities – and rigorous dose optimization, to clearly define ketamine’s role in pain management and prevent its inappropriate use.

Introduction

Chronic Pain

Chronic pain management remains one of the most complex challenges in healthcare, often requiring a multimodal approach that combines pharmacological, psychotherapeutic and physical rehabilitation interventions [1, 2]. Chronic pain, defined as pain that persists or recurs for longer than 3 months [3], affects 20% of the population worldwide. It is a multifaceted condition, generally categorized into primary and secondary types. Primary chronic pain is not attributable to another underlying condition, whereas secondary forms include neuropathic, musculoskeletal, cancer-related, postsurgical, posttraumatic and visceral pain [4]. Despite the high prevalence of chronic pain, its treatment remains a significant challenge, with many patients experiencing inadequate relief from current, on-label and recommended therapies. Outcomes for patients experiencing chronic pain frequently remain suboptimal, with many treatments offering limited effectiveness and notable side effects [5]. Traditional pharmaceutical options, including opioids, antidepressants, and anticonvulsants, are commonly used but are often hindered by adverse effects that can restrict their therapeutic potential. In response, the search for alternative treatments has gained momentum, with ketamine, a N-methyl d aspartate (NMDA) receptor antagonist emerging as a promising option. The objectives of this narrative review of the literature are to synthesize and analyse current evidence on ketamine efficacy and safety in chronic refractory pain, to identify gaps and propose a framework for optimal clinical use.

Ketamine

History

Ketamine was first synthesized in 1962 and its initial clinical trials were as a rapid-onset general anaesthetic [6, 7] at the time of the withdrawal of phencyclidine (PCP) by authorities [8]. It was approved by the US Food and Drug Administration (FDA) in 1972 as a general anaesthetic and its adverse effects including psychomotor disturbances, hallucinations, dysphoria and delirium, along with its growing use as a recreational substance, led to its classification as a Schedule III Controlled Substance in 1999 [9]. Today, it is widely used in anaesthesia and its offer is extended to many other conditions: major depressive disorder, postpartum and peripartum depression, anxiety, post-traumatic stress disorder, mood disorders, substance abuse and chronic pain, complex regional pain syndrome (CRPS), fibromyalgia and chronic daily headache. Esketamine ((S)-ketamine) (intranasal), suggested to be more potent than racemic ketamine, has been approved by the FDA and European Medicines Agency (EMA) for patients with treatment-resistant depression in 2019 [10, 11]. Emergency departments now frequently use ketamine to manage acute pain that is unresponsive to conventional analgesics, or in patients with opioid use disorders and opioid induced hyperalgesia [12]. Ketamine is increasingly used in chronic pain situations and in pain clinics to modulate central sensitization and hyperalgesia in patients with chronic refractory pain [13, 14], but it remains off-label for this indication.

Mechanism of Action

Ketamine is a chiral arylcyclohexylamine compound. Its core structure consists of a cyclohexanone ring with an ortho-chlorophenyl group and a methylamino substituent. The presence of a single chiral carbon gives rise to the (S)- and (R)-enantiomers, which differ significantly in their pharmacological potency and affinity for the NMDA receptor [15]. NMDA receptors are glutamate receptors, the predominant excitatory neurotransmitter in the central nervous system. They are distributed all along pain pathways and play a role in synaptic plasticity in chronic pain situations with increased pre- and post-synaptic NMDAR activity and molecular signalling. Ketamine has a non-competitive antagonism with NMDA receptors, a mechanism that plays a central role in both its analgesic and antidepressant effects [16]. While the exact interaction between ketamine and NMDA receptors remains only partially understood, it is known to bind deep into the pore of NMDA receptors where it blocks current influx, leading to increased intracellular calcium, followed by downregulation of NMDA receptor expression. This antagonism occurs via binding to the dizocilpine site, a region typically occupied by magnesium ions, thereby preventing calcium influx through the NMDA channel in an activity-dependent manner [16–18]. Ketamine’s unique property as an open-channel blocker means it exerts its effects only when the channel is active, sparing resting receptors [19]. NMDA receptors are critical for excitatory synaptic transmission, central sensitization and neuroplasticity within the central nervous system. Their upregulation in nociceptive pathways contributes significantly to chronic pain states, including visceral pain [17, 20]. By blocking NMDA receptors, ketamine disrupts this sensitization and reduces spinal wind-up phenomena, contributing to its efficacy in chronic and neuropathic pain management [20–22]. Furthermore, NMDA antagonism in inhibitory γ-aminobutyric acid (GABA)ergic interneurons leads to increased extracellular glutamate and subsequent activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This cascade, involving mechanistic Target Of Rapamycin Complex 1 (mTORC1) signalling in pyramidal neurons, underlies ketamine’s rapid antidepressant effects [15, 23]. In addition to NMDA antagonism, ketamine interacts with a range of other receptor systems, though generally with less potency. It modulates dopaminergic, adrenergic, serotoninergic, cholinergic and opioid pathways [16, 24–27]. Notably, its interaction with opioid receptors remains complex: ketamine may act as an antagonist at μ-receptors while exerting agonist effects at κ-receptors, with dose-dependent modulation of opioid analgesia [28]. It also inhibits catecholamine reuptake, increasing synaptic norepinephrine and dopamine levels, which may contribute to both analgesic and sympathomimetic effects [29]. Ketamine has demonstrated anti-inflammatory properties through reduction of proinflammatory cytokines such as interleukin (IL)-6 and tumour necrosis factor (TNF)-α [30] and may exert additional anti-inflammatory actions via inhibition of transcription factors like nuclear factor (NF)-κB and activator protein (AP)-1 [31]. Moreover, ketamine exhibits neuroprotective effects in certain contexts, such as acute stress or encephalopathic conditions, possibly through modulation of nitric oxide pathways and calcium homeostasis [32–37]. Despite its therapeutic potential, NMDA receptor inhibition by ketamine is associated with adverse central effects including ataxia and memory impairment, prompting ongoing efforts to refine its molecular targets [17, 18, 20, 31]. The psychomimetic symptoms often observed are partly attributed to elevated dopamine in cortical and subcortical regions, mimicking aspects of schizophrenia [38]. Ketamine’s complex pharmacodynamic profile—encompassing receptor-level interactions, neurotransmitter modulation and downstream signalling cascades—underscores its promise as a therapeutic agent in pain, while highlighting the necessity for further research into its multifaceted mechanisms of action

Pharmacokinetics

Ketamine is a lipophilic compound that rapidly crosses the blood–brain barrier and is swiftly distributed throughout the central nervous system. Its binding to plasma proteins is relatively low, typically ranging between 10 and 50%. It has a distribution half-life (alpha) of approximately 2 to 4 min, and an elimination half-life (beta) between 2 and 4 h [29, 39]. Owing to its high lipid solubility, ketamine has a large volume of distribution, estimated between 160 and 550 L [29]. Hepatic metabolism of ketamine occurs primarily via cytochrome P450 enzymes CYP2B6 and CYP3A4, resulting in the formation of (R,S)-norketamine, which is subsequently metabolized into 6-hydroxynorketamine and 5,6-dehydronorketamine [15]. These metabolites exhibit extended half-lives of up to 72 h and, according to several sources, contribute to prolonged analgesic and antidepressant effects [12, 15, 40, 41].

Bioavailability—defined as the fraction of an administered drug that reaches the systemic circulation unchanged—is a critical determinant of its efficacy. For ketamine, pharmacokinetic parameters such as bioavailability and time to onset vary depending on the route of administration. Intravenous delivery ensures 100% bioavailability and reaches peak effect within 1 to 2 min [15, 19, 42]. Intramuscular administration achieves approximately 93% bioavailability with maximal effects within 5–10 min [15, 19, 42]. Oral administration, in contrast, provides lower bioavailability (16–29%) owing to significant first-pass hepatic metabolism, with peak effects occurring between 20 and 120 min post-ingestion [15]. Intranasal ketamine has a bioavailability of approximately 35–50% [23, 43, 44], with analgesic effects beginning within 10 min, peak effects between 10 and 14 min [45] and total duration of action up to 60 min [46]. Because of its poor oral bioavailability and high potential for misuse, oral administration is generally discouraged [29, 47].

Ketamine and its metabolites are primarily excreted via the renal pathway [15], but because of its short half-life, dosage adjustments are not typically required in patients with renal impairment [48].

Ketamine, Chronic Pain and Depression

Ketamine (especially infusions) has been increasingly used as a treatment option for both acute pain and chronic pain conditions such as complex regional pain syndrome (CRPS), neuropathic pain (NP) and other refractory pain syndromes. Apart from the action on NMDA receptors, ketamine has been shown to reduce the binding affinity of receptors for substance P, a neuropeptide implicated in chronic pain sensitization and diminished spinal inhibitory control [49, 50]. Moreover, ketamine’s antagonism of muscarinic acetylcholine receptors, particularly M1 receptors which are themselves implicated in pain modulation and whose activation elevates pain thresholds is not responsible for its analgesic effect. Instead, this action is primarily associated with its psychomimetic and cognitive side effects. [27, 51]. Experimental studies further suggest that ketamine modulates astrocytic and glial cell responses involved in chronic neuropathic pain mechanisms [52, 53]. Although the analgesic role of ketamine’s metabolites remains under investigation, some studies propose they actively contribute to the total analgesic effect. Their accumulation during prolonged infusion protocols may also sustain analgesia over several days [54–56]. Ketamine has been shown to reduce the activity in pain-related brain regions such as the insular cortex and thalamus [57–59], indicating a central modulatory effect relevant to both pain and mood regulation. While the exact interaction between ketamine and NMDA receptors remains partially understood, it is evident that NMDA receptor antagonism leads to increased intracellular calcium, followed by downregulation of NMDA receptor expression. This process enhances brain-derived neurotrophic factor (BDNF) expression, a molecule known to be decreased in animal models of depression and restored by ketamine administration [60].

Comorbid depression and pain are highly prevalent conditions. Studies in treatment-resistant depression have reported that ketamine produces rapid antidepressant and anti-suicidal effects [13, 61–63]. A dopaminergic effect of ketamine with induced dopamine release has also been suggested in the rodent brain but inter-species variations need to be further studied in humans [64]. Similarly, the burden of chronic pain is substantial, with up to 85% of patients experiencing depressive symptoms depending on the clinical context [65], and pain prevalence among individuals with depression ranging between 43 and 80% [66, 67]. This significant overlap not only impairs overall function and quality of life [67, 68] but also complicates the treatment of depression when pain is present [67, 69]. The shared neurobiological substrates—cerebral, brainstem and spinal descending inhibitory pathways—likely underlie the concomitant reduction in both pain and depressive symptoms observed with ketamine treatment [70]. For instance, studies have shown that oral ketamine administered over 6 weeks alleviated depressive symptoms in patients with chronic pain [71], and additional research indicates that ketamine can improve both pain and depression simultaneously [72]. A recent investigation further demonstrated that individuals with depression who also suffer from varying degrees of pain, especially severe pain, exhibit rapid and significant improvement in depressive symptoms following repeated ketamine infusions [67]. This improvement likely reflects a dual mechanism: ketamine’s direct neuromodulatory effects on mood circuits, combined with the significant alleviation of pain—a key driver of depressive symptoms—creating a synergistic therapeutic response.

Although ketamine’s benefits for pain or depression treatment have been shown, ketamine has a number of important side effects. Psychotomimetic side effects—such as euphoria, dysphoria, psychomotor retardation, hallucinations, vivid dreams and nightmares—are commonly associated with its administration. Given the various formulations of ketamine available and its potential for managing chronic pain, it is crucial to assess both its therapeutic benefits and the risks involved.

Patient phenotyping prior to ketamine administration is emerging as a critical strategy to optimize its efficacy and safety in chronic refractory pain. This review underlines that a one-size-fits-all approach is inadequate, given the significant interindividual variability in treatment response observed in the literature [1, 22, 73]. Phenotyping extends beyond a mere pain diagnosis; it entails a fine-grained characterization based on pain type and intensity, comorbidities (particularly anxiety and depression), concomitant medication and potentially genetic biomarkers. The necessity of this approach is strongly supported by data from a pioneering observational study that identified three distinct pain trajectories over 1 year [13]. Crucially, all pain types were represented across every trajectory, suggesting the existence of subtypes, or phenotypical variations, within refractory pain. Therefore, phenotyping moves clinical practice away from a binary view of response versus non-response and towards a more personalized medicine model. Integrating this paradigm into future clinical guidelines and expert consensus is essential to establish a rational framework for use. It guides the selection of patients most likely to derive benefit while identifying those for whom the risks may outweigh the benefits, ultimately fulfilling ketamine’s therapeutic potential through targeted, collaborative translational research.

Considering the increasing use worldwide of ketamine as an alternative therapeutic option in chronic pain management [11], this review focuses on the literature, reviews and randomised clinical trials (RCTs) and non-RCTs to evaluate how ketamine may be a valuable alternative for an optimized chronic pain management and in multimodal analgesia.

Literature Search Methods

For this review of clinical data, studies were included if they met the following criteria:

1. Meta-analyses/systematic reviews, randomized controlled trials (RCTs) and open-label trials, retrospective and/or prospective observational studies. Case studies/reports, abstracts/posters, articles from non-English literature and grey literature were excluded. All included studies have their limitations, but the inclusion of randomized trials and non-randomized studies allows for a wider view of ketamine use in real life for pain management. Biases were not evaluated, and data were not statistically analysed.

2. Chronic pain (CP) indicated as such in the publication.

3. Efficacy or tolerability of ketamine taken as primary or secondary endpoint. Ketamine efficacy was defined as a significant change in pain using diverse measures : Numerical Rating Scale score (NRS), Numerical Rating Scale for Pain Intensity (NRS-PI), Numerical Verbal Scale (NVS), Numeric Pain Intensity Scale (NPIS), Visual Analog Scale score (VAS), Verbal Rating Scale (VRS), Verbal Numerical Rating Scale (VNRS), Brief Pain Inventory (BPI), Mechanical Visual Analog Scale (M-VAS), McGill pain questionnaire, Quantitative Sensory Testing (QST), Present Pain Intensity (PPI), Global Pain Relief (GPR), number of responders (30% or 50% diminution of pain)

This review was conducted through an exhaustive electronic search of Medline, PubMed, Google Scholar, and Cochrane databases up to May 2025. The following keywords were used in different combinations: ‘ketamine,’ ‘esketamine,’ ‘chronic pain,’ ‘neuropathic pain,’ ‘complex regional pain syndrome,’ ‘fibromyalgia,’ without limitation in language. This manuscript adheres to the applicable PRISMA guidelines.

After the initial title and abstract screening (M.V.), studies were independently extracted by two reviewers (M.V., V.M.). Any difference of opinion was resolved by consensus and discussion with an independent reviewer (G.P.), and reasons for exclusion of studies were noted. Data for the selected studies were extracted as follows: study design, aetiology/intervention, treatment and comparator, sample size, route and dose of ketamine, follow-up, outcome measurements and effectiveness, adverse events (Fig. 1).

Fig. 1.

Study flowchart

Ketamine and Chronic Pain: The Evidence

In total, the initial search identified 913 studies. After having discarded duplicates and removed excluded publications, 70 studies were included in this review. Six meta-analyses/systematic reviews (Table 1), 41 RCTs (Table 2) and 23 retrospective/prospective and observational studies (Table 3) met the predefined inclusion criteria.

Table 1.

Systematic reviews and meta-analysis with ketamine in chronic pain

Study	Indication	Design	Sample size	Route ketamine	Dose ketamine	Follow-up	Outcome [scale, questionnaire]
Umbacia et al. [148]	Chronic paina	Ketamine (vs. placebo, morphine, methdaone)	3 RCTs (316)	Oral	0.5 mg/kg to 10 mg/kg	1 day - 90 days	(primary outcome) Three trials in chronic pain comparing ketamine with other analgesics found no difference between groups [VAS, VNRS]
Shetty et al. [137]	Chronic postsurgical pain, chronic pain	Ketamine Placebo	5 RCTs (449)	Mixed	Mixed	Mixed	(primary outcome) Pain reduction on average, (− 1.26 [− 1.85, − 0.68]) [0–10 evaluation scale]
Liu et al. [127]	Chronic pain in posttraumatic stress disorder	Ketamineb	3 studiesc (48)	IV	Mixed	Not evaluated	(secondary outcome) Pooled effect of ketamine intervention on the pain outcome, positive moderate effect, (p=0.001) [VAS, BPI]
Bruna-Mejias et al. [130]	Multifactorial neuropathic pain	Ketamine Placebo	6 RCTs (315)	IV or Oral	0.5 mg/d	1–3 months	(primary outcome) Pain score lower at M1 versus placebo, (p<0.001); unchanged at M3, (p=NS) [NRS]
Guimarães Pereira et al. [129]	Neuropathic pain	Ketamine+ST ST	4 RCTs 122	Mixed	Mixed	30 days	(primary outcome) Reduction in pain score, (p<0.00001) [NRS; VAS]
Orhurhu et al. [128]	Chronic paind	Ketamine Placebo	7 RCTs 108 103	IV	High or low dose (≥400mg or <400mg)	≥48 hours	(primary outcome) Reduction in pain scores, (p<0.0001) Ketamine dose, (p=NS) [VAS]

^aCancer pain, chronic neuropathic pain, neuropathic cancer pain ; ^bComparator : no control (n=2), ketorolac (n=1), treatment added (dextrometorphan, n=1) ; ^cRetrospective study (n=1), RCT (n=1), prospective study (n=1) ; ^dchronic pain : moderate to severe pain [>4/10], phantom limb pain, post-spinal cord injury, pain, CRPS types I and II, cancer related paina, fibromyalgia and ischemic limb pain

Table 2.

Randomized controlled trials with ketamine in neuropathic pain, chronic pain, complex regional pain syndrome and fibromyalgia

Study	Design (number of patients)	Route ketamine	Dose ketamine (duration)	Follow-up	Outcome [scale/questionnaire]
Cross-over trials in neuropathic pain
Pickering et al. [98]	Ketamine (n=20) Ketamine/Magnesium (n=20) Placebo (n=20)	IV	0.5 mg/kg (2 hours)	35 days	(primary outcome) Daily pain intensity not different between 3 groups, (p=NS) [NRS]
Niesters et al. [131]	S(+)- Ketamine (n=10) Morphine (n=10) Placebo (n=10)	IV	0.57 mg/kg/h (1 hour)	1 day (100 min after)	(secondary outcome) Pain relief greatest after ketamine*; (baseline vs. after treatment: 6.2 (0.5) vs. 0.3 (0.3), p<0.01) [NRS]
Gottrup et al. [82]	Ketamine/Placebo (n=20) Lidocaine/Placebo (n=20)	IV	Bolus: 0.1 mg/kg Infusion: 0.007 mg/kg (30 min)	1 day (during and post-infusion)	(primary outcome) Reduction in VAS pain score compared to placebo during infusion period, (p<0.01) and after treamtent (p<0.05) [VAS]
Jørum et al. [84]	Ketamine (n=12) Alfentanil (n=12) Placebo (n=12)	IV	Bolus: 60 µg/kg Infusion: 6 µg/kg/min (20 min)	1 day (post-infusion)	(secondary outcome) Reduction in VAS pain score intra ketamine group after infusion period, (p=0.015) [VAS]
Lynch et al. [90]	Ketamine (n=20) Amitriptyline (n=20) Ketamine/Amitriptyline (n=20) Placebo (n=20)	Topical	5 mL q.i.d. (2 days)	2 days	(primary outcome) No difference in reduction of pain score from placebo for any treatment, (p = NS) [VAS]
Kvarnström et al. [86]	Ketamine (n=12) Lidocaine (n=12) Placebo (n=12)	IV	0.4 mg/kg (40 min)	1 day (post-infusion)	(primary outcome) Reduction in VAS pain score of 55%, 34% and 22% (ketamine, lidocaine, placebo) with difference between ketamine and placebo post-infusion period, (p=0.009) [VAS]
Leung et al. [88]	Ketamine (n=12) Alfentanil (n=12) Placebo (n=12)	IV	Targeted plasma level: 50, 100 and 150 ng/ml (20 min)	1 day (post-infusion)	(secondary outcome) No reduction in spontaneous pain intensity (p=NS), reduction in the von Frey evoked allodynic area, (p<0.01) [M-VAS]
Haines et al. [83]	Ketamine (n=9) Placebo (n=9)	Oral	20 mg to 100 mg/day (1 week, 3 cycles)	6 weeks	(primary outcome) No difference in VAS pain score compared to placebo; analgesic effect in 3/9 patients [VAS]
Nikolajsen et al. [94]	Ketamine (n=11) Placebo (n=11)	IV	Bolus: 0.1 mg/kg/5min Infusion: 7 µg/kg/min (45 min)	1 day (post-infusion and 30 min after)	(primary outcome) Decrease in the rating of stump and phantom limb pain intra ketamine group after infusion, (p<0.05) [VAS]
Felsby et al. [81]	Ketamine (n=10) Magnesium chloride (n=10) Placebo (n=10)	IV	Bolus: 0.2 mg/kg Infusion: 0.3 mg/kg/h (10 min – 1h max)	1 day (during infusion)	(primary outcome) Reduction in VAS pain score (57%) compared to placebo after bolus and continuous infusion, (p=0.006) [VAS]
Max et al. [92]	Ketamine (n=8) Alfentanil (n=8) Placebo (n=8)	IV	Starting infusion: 0.75mg/kg/h Doubled if no pain relief (2 hours)	1 day (during infusion)	(primary outcome) Pain relief scores compared to placebo, ketamine 65% (p<0.01), alfentanil 46% (p=NS) and placebo 21% [VAS]
Eide et al. [79]	Ketamine (n=8) Morphine (n=8) Placebo (n=8)	IV	0.15 mg/kg (10 min)	1 day (post-infusion)	(primary outcome) Degree of pain relief caused by ketamine vs. placebo, (p<0.03); ketamine vs. morphine, (p=NS) [VAS]
Backonja et al. [77]	Ketamine (n=6) Placebo (n=6)	IV	250 µg/kg (5 min, 2 cycles)	1 day (post-infusion)	(primary outcome) Pain relief in 5/6 patients (37.5 to 100%) [VAS]
Parallel trials in neuropathic pain
Fallon et al. [80]	Ketamine (n=107) Gabapentine (n=107)	Oral	40 to 400 mg/day max (16 days on stable dosage)	16 days	(primary outcome) No difference on duration of analgesic benefit between arms (improvement of 5 point or more), (p=NS) [McGill Pain Q.]
Rigo et al. [96]	Ketamine (n=14) Methadone (n=14) Ketamine/Methadone (n=14)	Oral	90 mg/day (1 month)	1 month	(primary outcome) Equal reduction of the level of neuropathic pain regardless of treatment (40, 60 and 70% after 7, 15 and 30 days of treatment), (p=NS) [VAS]
Kim et al. [85]	Ketamine (n=15) Magnesium (n=15)	IV	1 mg/kg (1 hour)	2 weeks	(primary outcome) 50% reduction in VAS n=10/15 in ketamine vs. n=7/15 in Mg, (p=NS) [VAS]
Mahoney et al. [91]	Ketamine (n=10) Placebo (n=7)	Topical	1 mL cream t.i.d. (1 month)	1 month	(primary outcome) Pain improved significantly over the time in both groups, no treatment main effect, (p=NS) [NRS]
Amr et al. [75]	Ketamine (n=20) Gabapentine (n=20)	IV	80 mg over 5h (1 week)	1 month	(primary outcome) Pain score improvment during infusion and 2 weeks after with ketamine over gabapentine, (p<0.0001); no difference at 3 and 4 weeks after infusion [VAS]
Vranken et al. [97]	S(+)-Ketamine 75mg (n=11) S(+)-Ketamine 50mg (n=11) Placebo (n=11)	Ionophoresis-assisted transdermal drug	50 or 75 mg (5 days)	1 week	(primary outcome) No difference on decrease in pain intensity compared to placebo or between treatment, (p=NS) [VAS]
Lynch et al. [90]	Ketamine (n=22) Amitriptyline (n=22) Ketamine+Amitriptyline (n=23) Placebo (n=25)	Topical	4 mL cream t.i.d. (3 weeks)	3 weeks	(primary outcome) Reduction in pain z scores of 1.1-1.5 units but no difference between groups, (p=NS) [NRS-PI]
Lauretti et al. [126]	Ketamine (n=15) Morphine (n=15) Dipyrone (n=15) Nitroglycerin (n=15)	Oral	0.5 mg/kg (every 12h)	30 days	(primary outcome) No significant differences in the VAS score between groups, (p=NS) [VAS]
Cross-over trials in chronic pain
Barros et al. [78]	Ketamine (n=12) Placebo (n=12)	Topical	Topical SKET 1%, q.i.d. (15 days)	2 weeks	(primary outcome) No improvement in NVS scores at any time, (p=NS) [NVS]
Eichenberger et al. [109]	Ketamine (n=10) Calcitonin (n=20) Ketamine+Calcitonin (n=20) Placebo (n=20)	IV	0.4 mg/kg (1 hour)	1 day (post-infusion)	(primary outcome) Ketamine infusion or combination reduced phantom limb pain compared with placebo, respectively, (6/10 patients, p=0.003; 12/20 patients, p<0.001); combination not superior to ketamine alone [VAS]
Kvarnström et al. [87]	Ketamine (n=10) Lidocaine (n=10) Placebo (n=10)	IV	0.4 mg/kg (40 min)	1 day (during infusion)	(primary outcome) 50% reduction in VAS pain score: 5/10 in ketamine, 1/10 in lidocaine, 0/10 in placebo with difference between ketamine and placebo during infusion period, (p=0.01) [VAS]
Carr et al. [46]	Ketamine (n=20) Placebo (n=20)	Intranasal	10 mg – 50 mg (1-5 sprays) (1 hour)	1 day (1 hour)	(primary outcome) Lower breakthrough pain intensity following ketamine than after placebo, (p<0.0001) [NPIS]
Furuhashi-Yonaha et al. [110]	Ketamine (n=8) Placebo (n=8)	Oral	0.5 mg/kg every 6 hours (7 days)	1 week	(primary outcome) Average pain intensity, (p<0.05) [VAS]
Mercadante et al. [93]	Ketamine 0.25 (n=10) Ketamine 0.50 (n=10) Placebo (n=10)	IV	0.25 mg/kg or 0.5 mg/kg (30 min)	1 day (3 hours)	(primary outcome) Decrease in pain intensity in both doses in comparison with placebo (p<0.05), with more relevant analgesic effect with 0.50 mg/kg of ketamine than 0.25 mg/kg of ketamine, (T180, p<0.05) [NRS]
Rabben et al. [95]	(1) Ketamine+midazolam (n=30) Pethidine (n=30) (2) Ketamine (n=26) Placebo (n=26)	IM, Oral	(1) IM administration K: 0.4 mg/kg (2) Oral administration K: 4 mg/kg/day (3 consecutive days)	(1) 3 days (2) 6 days	(1) (primary outcome) Three different response patterns: long-term analgesia (6-24h) (n=8), short-lasting analgesic effect (<2h)(n=9), no analgesia (n=9) [VAS] (2) (secondary outcome) Decreased pain in 5/8 patients who had long-term analgesic effect after the IM administration [VAS]
Persson et al. [118]	Ketamine (n=8) Morphine (n=8)	IV	K: 0.15 mg/kg for 5 min (d1) K: 0.30 mg/kg for 5 min (d2) K: 0.45 mg/kg for 5 min (d3) Morphine (d4)	1 day (60 min)	(primary outcome) Dose-dependent analgesic effect with transient but complete pain relief in all patients at the highest dose compared to morphine, (p<0.01) [VAS]
Yang et al. [122]	Ketamine+Morphine (n=20) Morphine (n=20)	Intrathecal	1.0 mg (twice daily)	Several days	(primary outcome) Lower dose of intrathecal morphine in phase ketamine+morphine, (p<0.05); reduction in pain intensity in same phase, (p<0.05) [NRS]
Parallel trials in chronic pain
Dadabayev et al. [108]	Ketamine (n=20) Ketorolac (n=20)	IV	0.5 mg/kg (40 min)	1 day (24h post-infusion)	(primary outcome) Lower pain scores compared to ketorolac in chronic pain group (without post-traumatic stress syndrome), (p<0.001) [VAS]
Lumanauw et al. [114]	Ketamine 0.5 (n=30) Ketamine 0.25 (n=35) Gabapentine (n=32)	IV	0.5 mg/kg or 0.25 mg/kg (20 min)	1 day (60 min)	(primary outcome) 20-mm decreased on 100-mm pain score in both ketamine groups compared with placebo, (p=0.001) ; ketamine doses, (p=NS) [VAS]
Maher et al. [124]	Ketamine (n=30) *Opioid therapy (n=12) *No opioid therapy (n=18) Placebo (n=31) *Opioid therapy (n=13) *No opioid therapy (n=18)	IV	0.05 mg/kg (30 min)	1 day (post-infusion)	(primary outcome) Decreased average change in temporal summation response between ketamine and placebo (with or without opioid therapy), (p<0.01) [QST changes]
Salas et al. [120]	Ketamine (n=11) Placebo (n=9)	IV	Starting infusion: 0.5 mg/kg/day Then 1mg/kg/day after 24h (48 hours)	2 days	(primary outcome) Self-reported pain not differ between groups, (p=NS) [NPIS]
Amr [76]	Ketamine+Gabapentine (n=20) Placebo+Gabapentine (n=20)	Epidural injection	Single bolus: 0.2 mg/kg (2ml)	2 months	(primary outcome) Lower pain scores in ketamine group than placebo group at 7, 15, 30 days after injection, (p<0.05, p<0.0001, p=0.0001, respectively); no difference between groups at 45, 60 days post-injection, (p=NS) [VAS]
Hardy et al. [111]	Ketamine (n=93) Placebo (n=92)	SC	3 dose levels (depending on degree of improvement): 100 mg/24h 200 mg/24h 500 mg/24 h (max) (5 days)	5 days	(primary outcome) No difference in response between arms (reduction in average pain score by ≥2), (p=NS) [BPI]
Parallel trials in complex regional pain syndrome
Sigtermans et al. [56]	Ketamine (n=30) Gabapentine (n=30)	IV	Mean rate: 22.2±2.0 mg/h/70 kg (4 days)	3 months	(primary outcome) Reduction of pain intensity during 12-week study period more favorable with ketamine than placebo, (p<0.001) [NRS]
Schwartzman et al. [100]	Ketamine (n=9) Placebo (n=10)	IV	0.35 mg/kg/h max in 4h (10 days)	3 months	(primary outcome) Reductions in many pain parameters at different times (pain in the most affected area, burning pain, pain when touched or brushed lightly and overall pain level) while placebo group showed no effect, (p<0.05) [NRS]
Cross-over trial in fibromyalgia
Graven-Nielsen et al. [134]	(1) Ketamine (n=29) Placebo (n=29) (2) Ketamine (n=15) Placebo (n=15)	IV	0.3 mg/kg (30 min, 2 cycles)	1 day (post-injection)	(1) Screening for ketamine-responders (50% decrease in pain intensity) in 17/29 patients (VAS scores reduced in contrast to placebo, p<0.0001) (2) Pain intensity after i.m. infusion of hypertonic saline reduced compared with placebo (p<0.05) [VAS]
Parallel trials in fibromyalgia
Noppers et al. [133]	Ketamine (n=12) Midazolam (n=12)	IV	0.5 mg/kg (30 min)	8 weeks	(primary outcome) Reduction of FM pain from baseline to 180 min (p<0.01) but no difference during 8 week follow-up, no difference between treatment (p=NS) [VAS]
Sörensen et al. [135]	Ketamine/Placebo (n=11) Morphine/Placebo (n=9) Lidocaine/Placebo (n=11)	IV	0.3 mg/kg (10 min, 2 cycles/2weeks)	1 day (post-infusion)	(primary outcome) Decrease in pain intensity at the end of injection compared to placebo (p<0.05) with 8 responders patients [VAS]

^*Without statistical analysis

Table 3.

Prospective, retrospective and observational studies with ketamine in neuropathic pain, chronic pain, complex regional pain syndrome and fibromyalgia

Study	Design (number of patients)	Route ketamine	Dose ketamine (duration)	Follow-up	Outcome [scale/questionnaire]
Neuropathic pain
Polomano et al. [149]	Retrospective case series Ketamine (n=19)	IV	Doses ≤120 µg/kg/h (3 days)	3 days	(primary outcome) Reduction in present pain intensity (p<0.001) and improvement in global pain relief, (p=0.031) [PPI, GRS]
Kang et al. [150]	Open label uncontrolled study Ketamine (n=103)	IV	Bolus: 0.5mg/kg (5 min) Infusion: 0.5 mg/kg/h (2 h)	2 weeks	(primary outcome) Reduction in pain intensity from baseline to 2 weeks after treatment, (p<0.001) [VAS]
Webster et al. [121]	Retrospective chart review Ketamine (n=13)	IV, SC	(mean) 0.12 mg/kg/h (13.2 days)	13 days	(primary outcome) Decreased pain severity, (p=0.003), 11/13 patients reported decrease in pain intensity [VAS]
Rabben and Øye [151]	Open label study (1) Ketamine+midazolam (n=17) (2) Ketamine (n=13)	IM, Oral	(1) IM administration K: 0.4 mg/kg (2) Oral administration K: 4 mg/kg (3 consecutive days)	(3) 3 days (2) 6 days	(1) (primary outcome) Three different response patterns: long-term analgesia (6-24h) (n=6), short-lasting analgesic effect (<2h)(n=7), no analgesia (n=4) [VAS] (2) (secondary outcome) Reduction in pain in all patients [VAS]
Eide et al. [99]	Open prospective study Ketamine different dosages (n=5) Placebo (n=5)	SC	0.05 mg/kg/h (1 week) 0.075 mg/kg/h (1 week) 0.10 mg/kg/h (1 week) 0.15 mg/kg/h (1 week)	1 week	(primary outcome) Relief of continuous pain observed at the infusion of 0.05 mg/kg/h but most marked during infusion of 0.15 mg/kg/h (4/5 patients) [VAS]
Chronic pain
Voute et al. [14]	Prospective multicenter observational study Ketamine (n=329)	IV	444 mg (median cumulative dose on the year of follow-up)	12 months	(primary outcome) Decreased pain intensity, (p<0.001) [NPRS]
Chebini et al. [107]	Retrospective observational study Ketamine (n=77)	IV	5 mg/h (max 30 mg/h) based on 0.5mg/kg (10 – 14 days)	2 weeks	(secondary outcome) Decreased pain score ≥ 30%, (56/77, 72.7%) [NRS]
Batievsky et al. [106]	Observational preliminary study Ketamine IM (n=5) Ketamine Oral (n=5)	IM, Oral	IM: 40-100 mg (2 injection/session, 6 sessions on 6 weeks) Oral: 25-75 mg (6 sessions on 6 weeks)	6 weeks	(primary outcome) Pain score between treatment at all time, (p=NS) [BPI]
Corriger et al. [13]	Prospective multicenter observational study Ketamine (n=256)	IV	222 mg (median cumulative dose on the year of follow-up)	12 months	(primary outcome) Decreased pain intensity, (p=0.001) [NRS]
Schwenk et al. [125]	Open-label prospective observational study Ketamine (n=6) Lidocaine (n=6)	IV	10 mg/h, increased of 5-10 mg/h up to 1mg/kg/h (max) (5 days)	5 days	(primary outcome) Change in pain from baseline to end of treatment is greater for ketamine than lidocaine, (p<0.05) [VNRS]
Moisset et al. [116]	Retrospective obervational study Ketamine/Magnesium (n=14)	IV	0.5 mg/kg (2 hours)	1 week	(primary outcome) Decreased number of daily attacks, (p<0.001) [NA]
Pomeroy et al. [119]	Retrospective study Ketamine (n=77)	IV	Start dose : 0.1 mg/kg/h (increased by 0.05 mg/kg/h until pain relief) Infusion rate: 0.25 mg/kg/h (6 hours for max of 5 days)	5 days	(primary outcome) Reduction in mean headache pain rating, (p<0.0001) [VRS]
Jackson et al. [112]	Open label prospective audit Ketamine (n=39)	SC	100 mg/24h to 300 mg/24h then 500 mg/24h (max dose) (3 – 5 days)	5 days	(primary outcome) Overall response rate (defined as 50%, or greater, reduction in mean VRS) is 29/43 (67%); 24/29 maintened good pain control after ketamine cessation [VRS]
Jackson et al. [113]	Open label prospective audit Ketamine (n=44)	SC	100 mg/24h to 300 mg/24h then 500 mg/24h (max dose) (3 – 5 days)	5 days	(primary outcome) 50% responder rate in 22/44 (50%) with 4 (9%) becoming painfree [VRS]
Zekry et al. [123]	Open-label prospective study Ketamine (n=70)	IV, SC (+sublingual)	Start dose: 0.1 mg/kg/h Increased by 4 to 32 mg/h max (3-7 days)	3-7 days	(primary outcome) Reduction in pain intensity, (p<0.005) [NRS]
Marchetti et al. [115]	Retrospective study Ketamine (n=55)	IV, Oral	Infusion: 0.5 mg/kg to of 1.5-3.0 mg/kg + orally 3 or 4 intakes/day (continuous 3 months)	3 months	(primary outcome) Mean reduction in pain was 40±33%, really effective in 24 patients (67±17%) [NRS]
Patil et al. [117]	Retrospective study Ketamine (n=49)	IV	0.5 mg/kg for 30-45 min (every 3-4 weeks)	1 day (post-infusion)	(primary outcome) 77% pain relief in total sample, with reduction in VAS score 7.2 CRPS vs. 5.1 no-CRPS (p=0.002) [VAS]
Kapural et al. [139]	Retrospective study Ketamine (n=18) No ketamine (n=18)	IV	10 mg/h to 100 mg/h for 3h (3 to 6 weekly infusion)	6 months	(primary outcome) Average pain intensity at 6 months between ketamine and control group, (p=NS) [VAS]
Complex regional pain syndrome
Goldberg et al. [103]	Observational study Ketamine (n=16)	IV	10 to 40 mg/hour (5 days)	5 days	(primary outcome) Pain relief by Day 3 compared to baseline (p<0.05) continued to improve over 5-day infusion period, [NRS]
Kiefer et al. [104]	Open label phase II study Ketamine (n=20)	IV	Bolus: 1-1.5 mg/kg Infusion: 3mg/kg/h up to 7 mg/kg/h (5 days)	6 months	(primary outcome) Pain relief observed at 1, 3 and 6 months following treatment, (p<0.001) [NRS]
Koffler et al. [105]	Open label uncontrolled study Ketamine (n=9)	IV	250 to 300 µg/dl (4.5 days)	6 weeks	(primary outcome) Reductions in acute (p=0.044) and overall pain (p=0.005) [McGill questionnaire]
Goldberg et al. [102]	Open label prospective study Ketamine (n=40)	IV	40 to 80 mg/day (10 days)	10 days	(primary outcome) Reduction in pain intensity from Day 1 to Day 10, (p=0.001) [VAS]
Correll et al. [101]	Retrospective study Ketamine 1 cycle (n=21) Ketamine 2 cycles (n=10) Ketamine 3 cycles (n=2)	IV	(1 cycle, mean±SD) 23.4±9.6 mg/hr in 4.7±3.9 days	6 months	(primary outcome) 100% pain relief in 76% patients, partial pain relief in 18% patients and no pain relief 6% following initial cycle, with 54% of 33 patients remaining pain free for >3 months and 31% for ≥ 6 months [%Pain Relief]

Chronic pain publications have been subgrouped as 1-chronic pain itself that usually includes different aetiologies, 2-neuropathic pain (NP), 3-fibromyalgia and 4-complex regional pain syndrome (CRPS) that are three chronic pain situations with specificities and a prevalence that enticed us to give them specific entries in this review. NP arises as a direct consequence of a lesion or diseases affecting the somatosensory system and has 8–10% prevalence with specific characteristics (burning, itching, allodynia). FMS is a common widespread primary pain condition, with a worldwide prevalence of 2–4%, characterised by diffuse nociplastic pain [74]. CRPS is a rare chronic pain disorder that develops 4–6 weeks after direct trauma, injury or surgery, and causes pain that is out of proportion to the inciting injury.

NP studies were carried out in 25 RCTs [55, 75–98] versus 4 non-RCTs, with different aetiologies including post-surgical/trauma pain (PS) [75, 76, 82, 87, 88, 90, 92, 94]; post-herpetic neuralgia (PHN) [78, 79, 84, 85, 89, 90, 99], post-diabete [89–91], post-cancer [80, 93]. Fibromyalgia was studied as a unique aetiology in three RCTs and CRPS in two RCTs versus five non-RCTs [56, 100–105]. Finally, patients suffering from ‘chronic pain’ were studied in 11 RCTs versus 14 non-RCTs where several pain aetiologies were mixed within the same trial such as low-back pain, chronic headache, migraine, fibromyalgia, CRPS, chronic ischemic pain, post-cancer pain, post-surgery pain, chronic abdominal pain, trigeminal neuralgia and PHN [13, 14, 25, 46, 106–126].

Six meta-analyses/systematic reviews have been published since 2019, four in chronic pain and two in NP. They included a small number of RCTs (three [127] to seven [128]) of ketamine versus placebo or other comparator (i.e. ketorolac, dextromethorphan, morphine, methadone or no control). All report a reduction of pain score, after 48 h [128] and 1 month [129, 130].

Ketamine is mainly administered intravenously (IV, 64%) [44 ref], often with a dosage of 0.5–1 mg/kg/day, and a few studies use other routes: 12% in oral ketamine [9 ref], 9% in subcutaneous [6 ref], 7% in topical [5 ref], 4% in intramuscular [3 ref] and only 1% in sublingual, intranasal, epidural and intrathecal [4 ref] (Fig. 2).

Fig. 2.

Distribution of routes of administration by study type

In order to evaluate the efficacy of ketamine in analgesia/anti-hyperalgesia, we relied on data from RCTs, cross-over or parallel trials (Table 2 and Figs. 2, 3).

Fig. 3.

Ketamine efficacy in chronic pain in randomised controlled trials (RCT) and non-RCT studies

For NP, nine cross-over trials of IV ketamine efficacy versus lidocaine, placebo, magnesium or alfentanil show a reduction of pain at day 1 [77, 79, 81, 82, 84, 86, 92, 94, 131], and some trials fulfil NEUPSIG guidelines of 50% or 30% responders [132]. Only two randomised clinical trials follow patients up to 5 [98] and 6 weeks of oral ketamine [83] and report no pain diminution. A parallel trial in NP with ketamine versus amitriptyline, placebo, methadone or gabapentin show an improvement at 2 weeks with the IV route [75] while other routes (topical, oral) give mixed results [80, 89, 91, 96, 97].

Likewise, nine cross-over trials and six parallel trials in chronic pain show predominantly an improvement but with a short time pain evaluation (1 to several days) [46, 76, 87, 93, 95, 108–110, 114, 118, 122, 124]. Both randomised parallel trials in CRPS of IV ketamine versus gabapentine or placebo show an improvement at 3 months [56, 100]. In fibromyalgia, a reduction of pain is observed in three trials [133–135].

Of the eight studies that evaluated the impact of ketamine on quality of life and/or sleep using the SF-12, SF-36, EuroQoL or Pittsburgh scales, only five described an improvement in scores after treatment with ketamine [13, 14, 56, 97, 122]. Across 23 non-RCT, open label, prospective and retrospective studies for CP, NP and CRPS, ketamine demonstrates significant pain relief with IV, subcutaneous or oral routes. Two prospective studies [13, 14] follow patients up to 1 year with decreased pain (Fig. 3).

Concerning tolerability, expected side effects and adverse events of ketamine (headache, dizziness, nausea, psychotomimetic effects such as dysphoria, euphoria, hallucinations, vivid dreams and nightmares, dissociative state, neuropsychiatric effects, somnolence, oscillations in electroencephalography (EEG), QT changes, elevations in heart rate and blood pressure) have been described at the time of infusion and in the week following but not in all trials (72% for ketamine and 36% for esketamine respectively [7]. These are mild and transient [14] at low doses. Bladder dysfunction, cystitis, dysuria, urgency, hepatic impairment and psychological sequelae, although listed as potential adverse events [7] have not been reported in the long term [14]. It is suggested that high doses ketamine could lead to long-term cognitive impairment but this has not been studied with neuropsychological tests even with repeated doses at a month interval [14].

Discussion

This review aims at providing a comprehensive understanding of the existing literature on the efficacy and tolerability of ketamine and on its usefulness in chronic pain conditions. The limited number of publications on chronic pain (70), for a drug that has been synthesized more than 50 years ago is explained by the fact that ketamine has been used primarily for intraoperative anaesthetic management of patients undergoing surgical intervention, in a second time as a preventive measure of post-surgical chronic pain and progressively and over the past three decades for chronic pain. The dramatic increase of use of ketamine for chronic pain with wide variations in settings, dosing and monitoring called for the development of consensus guidelines [22, 136]. The studies included in this review carry a risk of bias. On the one hand, the RCTs are rigorous tools via randomization, but carry the difficulty in generalizing findings to a large population, and on the other hand, observational (prospective or retrospective), often open label not controlled studies are at risk of selection bias but are real-life studies. A comprehensive approach allows, however, to be closer to real life clinical challenges and needs.

All selected systematic reviews and meta-analyses showed positive results, low/moderate efficacy of ketamine in reducing pain scores. Indeed, Orhurhu et al. demonstrated a significant reduction in pain scores in favour of ketamine compared with standard or control treatments (mean difference, −1.83 points ; 95%CI, −2.35 to −1.31 points; P < 0.0001) [128]. A recent meta-analysis on chronic non-cancer pain also showed optimal efficacy of ketamine with an average pain reduction of 1.26 points [137]. Similar results have been described up to 30 days after treatment with ketamine [129], although this effect appears to be more transient and limited to the first month of treatment [130] (Table 1).

Since 2019, only two RCTs looked at the anti-hyperalgesic property of ketamine in patients already suffering from chronic pain of various aetiologies (musculoskeletal pain, radicular pain, fibromyalgia, chronic headache, chronic abdominal pain, cancer) [98, 114]. Sub-dissociative-dose ketamine was used by Lumanauw et al. to treat acute exacerbations of chronic pain. Pain scores decreased significantly between ketamine and placebo, but there appeared to be no difference between the doses administered (0.5 mg/kg versus 0.25 mg/kg). Another randomised controlled trial in 20 patients with neuropathic pain refuted the hypothesis that ketamine, with or without magnesium or any additional analgesic effect, provided pain relief compared with placebo [98] (Table 2).

There are several limitations associated with the RCTs, including a small number of patients enrolled (6 to 22 per group) with a heterogeneity of chronic pain aetiology and a wide variation in patient selection (research centre, pain clinic), dosing (bolus or not, dosage), monitoring and collection of adverse events (usually with no validated tool). Blinding is difficult with ketamine, and midazolam has been used to mimic some of the side-effects of ketamine; many studies do not report if patients are ketamine naive or not as this information is crucial for the placebo/nocebo effect. Most of the trials have a short follow-up period (1 day to 3 months), with a sub-anaesthetic dosage (0.5 mg/kg/day).

While real-life studies (prospective/retrospective) have demonstrated the efficacy of ketamine in refractory chronic pain, the long-term effects of repeated ketamine administration remain poorly characterized. This knowledge gap is underscored by limited evidence; a systematic review on CRPS identified only three RCTs alongside a limited number of observational studies, yet still concluded ketamine is a promising treatment [138]. This pattern is consistent in chronic pain: only five prospective publications, three in chronic pain [13, 14, 139], two in CRPS [101, 104] have followed a cohort for 6 months and one for 1 year. These studies have no control group and do not compare face to face with other recommended drugs in refractory pain management. Repetition of ketamine administration [14] did not, however, provide more analgesia than the immediate relief of one sub-anaesthetic dose at 1 week, suggesting a threshold beyond which ketamine cannot diminish pain any further. A prospective multicentre observational study included 586 patients who received one [13] or repeated ketamine administration [14], described a reduction of pain intensity over 1 year with distinct pain trajectories and predictive variables of ketamine efficacy. Patients with neuropathic pain had an alleviation of pain while fibromyalgia patients did not, suggesting a different response according to pain types, and probably underlying chronic pain hyperalgesia aetiology (nerve-lesion related versus diffuse pain).

Robust evidence on the long-term safety and addiction risk of repeated doses is still missing, and addiction has not been measured in the literature. Data from depression studies do not bring more factual information on the addictive potential. Quality of life improvement, sleep or societal impact are also missing in the literature.

Concerning ketamine dosage, there is no real optimal dosage although sub-anaesthetic dosages are recommended to minimize the risks of adverse events. Information from this review, our Delphi study [136] and American guidelines [22] point towards an IV dosage of 0.1–0.9 mg/kg /day intravenously and 20–400 mg orally. Our Delphi survey in chronic pain clinicians working in pain clinics reached agreement on four main observations: (1) NP treatment with evaluation of effectiveness at 1 month; (2) No deleterious effects with the absence or < 3% of suggested adverse events; (3) 0.5–0.9 mg/kg/d IV infusion; and (4) combination with non-pharmacological treatment [136]. Regarding the optimal duration and protocol of ketamine administration, our review underscores a significant lack of consensus in the literature, precluding a definitive, universal recommendation. The heterogeneity in infusion protocols, with durations ranging from brief boluses to prolonged infusions over several hours, is a major barrier to standardization. In light of this ambiguity and of the paramount importance of safety, clinicians may pragmatically adhere to the expert consensus guidelines proposed by Cohen et al. [22], which commonly advise a slow, monitored infusion over a period of 2 h. Ultimately, the establishment of an evidence-based standard of care for ketamine administration awaits future rigorous, comparative studies designed to systematically evaluate different durations, frequencies and long-term treatment strategies.

The tolerability profile of ketamine is mainly characterized by a number of expected cardiovascular, psychiatric or cardiac side-effects but the review does not stress an unexpected burden of adverse events as these were mild and limited and attributed to ketamine only. In 256 patients [13], adverse events occurred at 1 week in 50% patients, and this rate gradually decreased throughout the 1 year follow-up period. Likewise with repeated doses over 1 year, ketamine was overall well-tolerated and associated with significantly improved quality of life [14].

The effect of drug interactions with ketamine is usually not reported. While ketamine is known for opioid sparing in the immediate post-surgery period [140], such a diminution of opioid consumption is not reported in chronic pain situations. In studies where patients were maintained on their chronic pain treatment, comorbidity and comedication were often missing. An important comorbidity is the depressive/anxiety status of patients but information on the simultaneous consumption of antidepressants and/or the reason of this consumption (primary depression or depression caused par pain) is often absent. Comorbid pain and depression are common, as patients with chronic pain often experience depressive symptoms (up to 85%) and pain among patients with depression is frequent (43–80% patients) [141]. They share common neurobiological processes but the direction of comorbidity (i.e., pain with depression versus depression with secondary pain) may matter and a prospective study with 329 patients showed that depression (and not ketamine dose or anxiety) is the mediator (64.6% of the mediation) of the association of ketamine with pain diminution. While our review cannot definitively disentangle these mechanisms, we speculate that both are likely involved in a synergistic manner. Ketamine’s established rapid direct action on mood via NMDA receptor antagonism and subsequent AMPA receptor activation, leading to enhanced synaptic plasticity, is well-documented [142, 143]. This primary antidepressant effect may be potentiated by the profound relief of the aversive and debilitating experience of chronic pain. This relief may break the cycle of the pain-depression dyad [144], a link supported by meta-analytic evidence showing ketamine’s efficacy for both conditions [145], leading to a more robust and rapid overall clinical improvement.

A number of open questions have emerged from the studies included in this review.

Patients with refractory chronic pain will often necessitate repeated treatment with ketamine. How these ketamine repetitions will improve the negative symptoms of pain and the impact on sleep and mood disorders and cognition is poorly known. It has been shown that ketamine reduces pain by dampening depression [14]. A more global approach is to assess all these symptoms in addition to the standard assessment of pain. Likewise, cognition is known to be impaired in pain and in depression and the effect of ketamine on cognitive processes with belief updating becoming more optimistically biased rapidly after the first ketamine infusion needs to be further assessed on the long term [146].

Phenotyping of patients before ketamine administration may help to better treat chronic pain. Subgroups of ketamine responders [98] suffering from neuropathic pain have been shown, fibromyalgia patients appear as poor responders [13] and patients with CRPS [56, 100] tend to respond well to ketamine but publications are still limited. Anxiety and depression presence before treatment may be predictive of less improvement [13].

Information on the duration of efficacy is also limited: for example, immediate analgesia [133] obtained versus midazolam wears off at 8 weeks. A specific point concerns adverse events such as bladder dysfunction or addiction that should be followed with appropriate validated tools.

Most of the studies have been performed in Western countries and the impact of ethnicity has not been studied; this missing point prevents extrapolation of results to different populations as ketamine mechanism of action via CYP450 may change the analgesic effect of the molecule and of its metabolites.

Finally, the literature does not include much information on age and gender. Pharmacokinetic differences have been observed across populations and women tend to metabolize ketamine up to 20% faster than men, while older individuals often exhibit slower metabolism [15]. However, concerning the gender-related pharmacodynamics of ketamine, we recently showed that gender and age do not influence the analgesic effect of ketamine [147].

In clinical practice, management of chronic pain with ketamine must follow recommended guidelines and expert consensus [22] as regards proper monitoring before, during and after the treatment with cardiovascular, hepatic and psychological assessment. Oral administration needs to be studied; other routes of administration than IV (intranasal, sublingual, topical) of ketamine and of its enantiomers are under study for psychiatric disorders and may also feed new opportunities for chronic pain treatment.

Conclusions

Ketamine has emerged as a promising therapeutic option for chronic pain management. RCTs and non-RCTs indicate that it provides low-to-moderate short-term efficacy with a fairly favourable tolerability profile. However, there is a critical need for more long-term studies that would concomitantly screen for mood disorders, chronic pain characteristics, quality of life and cognitive performance to thoroughly evaluate the risk of addiction and assess long-term efficacy. Furthermore, alternative routes of administration to intravenous delivery must be developed, and optimal dosing regimens need to be established. Phenotyping patients on the basis of pain type, intensity, comorbidities and concomitant medication could complement existing guidelines and expert consensus. This approach would help to establish a framework for safety and efficacy, supported by collaborative translational research on ketamine in both depression and pain. It is crucial to emphasize that ketamine is not a first-line treatment for chronic pain; its use for pain is off-label, and it possesses psychomimetic and addictive properties that preclude its trivialization. Consequently, its administration for refractory chronic pain must adhere to a strict standard of care, involving prescription and supervision exclusively by trained healthcare practitioners.

Funding

The authors have no relevant financial or non-financial interests to disclose. This work was conducted without any external financial support. The open access publication of this work was supported by the Clermont-Ferrand University Hospital.

Declarations

Conflicts of Interest

Gisèle Pickering, Véronique Morel and Marion Voute declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Ethics Approval

Not applicable. This manuscript is a review article and does not report on any original studies involving human participants or animals.

Consent (Participation & Publication)

Not applicable.

Author Contributions

After the initial title and abstract screening (M.V.), studies were independently extracted by two reviewers (M.V., V.M.). Any difference of opinion was resolved by consensus and discussion with an independent reviewer (G.P.), and reasons for exclusion of studies were noted. M.V. wrote the first draft and all authors agreed on the final version.

Data Availability Statement

All data generated or analysed during this study are included in this published article.

Code Availability

Not applicable.