This article systematically reviewed for the first time the therapeutical effects of ketamine in FM patients.

The strengths of this study included the inclusion of studies with patients that fulfilled the international criteria for FM; and, second, the exclusion of case reports, case series, and observational studies. In this line, prospective studies are those with higher evidence degrees.

Ketamine was introduced as a dissociative anesthetic in 1965 and displayed analgesic, anesthetic, psychosensory, anti-inflammatory, and antidepressant properties [16]. Its primary action mechanism includes the noncompetitive blockade of N-Methyl-D-Aspartate (NMDA) receptors in the anterior cingulate, insula, prefrontal cortex, and dorsal horn neurons of the spinal cord. This blockage reduces calcium influx with a consequent decrease in glutamate receptor activity [16]. Furthermore, ketamine also acts on an opioid system via opioid receptors; in the noradrenergic, serotoninergic, and dopaminergic systems and the muscarinic and nicotinic acetylcholine receptors [16].

A recent meta-analysis explored the effectiveness of randomized controlled trials of intravenous ketamine compared to a placebo for pain relief in chronic diseases. The authors aimed to examine the lowest recorded pain score ≥ 48 h after treatment interruption, and secondary outcomes comprised response rates and tolerability. Seven studies with 211 patients investigating neuropathic (n = 2), non-neuropathic (nociplastic or nociceptive) (n = 3), and mixed pain (n = 2) were included. Small sample sizes (median sample size of 24 were a study limitation. After the infusion and up to 14 days of ketamine, minor effects were significantly seen. However, for the three studies reporting response rates, a positive outcome was more significant in the ketamine than in the placebo group [17].

A study in the Netherlands [8] examined the analgesic effect of esketamine in a randomized, double-blind trial controlled by midazolam in 24 FM patients. Research volunteers were randomized to receive an intravenous infusion with either esketamine or midazolam. Visual analog scale (VAS) scores and pain scores derived from the fibromyalgia impact questionnaire (FIQ) were obtained minutes after the end of the infusion and weekly during an 8-week follow-up. After 15 min, a significant reduction in pain scores > 50%, compared to midazolam, was observed. Although, for the VAS and FIQ scores, no significant differences were observed in the treatment effects within 2.5 h after infusion or during the 8-week follow-up. Side effects assessed by the Bowdle questionnaire were mild to moderate in both study groups and decreased rapidly. The effectiveness of esketamine was limited by its pharmacokinetics. The authors concluded that a short-term infusion of esketamine is unsatisfactory at inducing long-term analgesia in FM patients.

A French study [11] evaluated the recovery of pain from hyperalgesic fibromyalgia with single-photon tomography of ethyl perfusion ethyl cysteine (SPECT) after administration of ketamine in a group of 17 women, 11 of whom were considered “good responders,” with decreased pain intensity, assessed by the VAS. In contrast, six volunteers were considered “bad responders.” The authors found distinct brain functional SPECT patterns between those who responded and those who did not. Additionally, the difference in cerebral blood flow in the midbrain after ketamine injection was positively associated with reduced VAS pain scores.

A study in the United States of America [13] evaluated whether a ketamine test could predict the response to a therapeutic trial with oral dextromethorphan (DX) in 34 patients with fibromyalgia. The cut-off value for a positive response to the ketamine test was 67% pain relief, and a positive reaction to DX treatment was a 50% reduction in pain at 4-to-6-week follow-up visits. In addition, the correlation between pain relief with ketamine and DX was highly significant (P < 0.001). In the end, 10 patients responded positively to ketamine and DX, 19 responded to no drugs, 3 responded positively to ketamine but not DX, and 2 achieved adequate pain relief with DX but not ketamine.

Another article from France investigated the effects of ketamine infusions for three days on fibromyalgia pain [9]. This double-blind crossover study was intended to evaluate pain relief on the VAS. Patients were hospitalized for three-day ketamine vs. placebo infusions. As a crossover design, patients allocated to ketamine were then submitted to placebo (and vice-versa) in another 3-day hospitalization after 3 months. The ketamine infusion at a rate of 1 mg/kg/day for three days showed no significant effect on spontaneous pain if we consider all the patients. However, a subgroup of patients insensitive to placebo had 30% pain relief for at least two months.

A study in Sweden assessed the effects of a placebo or ketamine given over 30 min on two separate occasions in FM patients [14]. Pain intensity was evaluated employing the VAS. At first, 29 FMS patients received ketamine or isotonic saline to determine which subjects were ketamine responders (50% decrease in pain intensity at rest by the active drug on two consecutive VAS assessments). The authors found a pain intensity reduction in the ketamine group, and local and referred pain areas were also reduced in this group [14].

Another Swedish study [12] examined pain intensity and tolerance, pain pressure threshold, muscle strength, and static muscle endurance in 31 FM subjects before and after intravenous ketamine (11 patients), morphine (9 patients), and lidocaine (11 patients) injections. The ketamine group showed decreased pain intensity and tenderness at tender points [12].

In contrast to the lack of randomized controlled trials, systematic reviews, and meta-analyses of ketamine in fibromyalgia, there are many publications on mood disorders, particularly about its effectiveness in resistant depression and the management of suicidal ideation [17,18,19,20]. The first studies already pointed to a potent reduction in depressive symptoms in single doses [18]. Despite the encouraging results, strategies for maintaining improvement are the target of intense research. Repeated infusions of ketamine in subanesthetic doses (<0.5–2 mg/kg) are helpful to prolong the administration effect in the short term [21]. Several studies have been carried out in recent years, including investigations of biomarkers [22], which have multiplied in the literature, and various routes of administration in addition to intravenous (e.g., oral, subcutaneous, intramuscular, and intranasal). A study with the esketamine enantiomer has shown that it is possible, with lower doses, to mitigate dissociative effects [23]. Nasal esketamine has recently been approved in the US and Europe for resistant depression [17].

Finally, a few limitations were seen in the included studies, including no comparison between ketamine with the classical antidepressants used for FM, the number of participants being still low, and the relatively small follow-up. Therefore, future studies should involve large patient samples with more long-term follow-ups, enabling a better understanding of the course of this therapeutic modality in FM.