Ketamine and Magnesium for Refractory Neuropathic Pain: A Randomized, Double-blind, Crossover Trial

Anesthesiology. 2020 Jul;133(1):154-164. doi: 10.1097/ALN.0000000000003345.


Background: Ketamine is often used for the management of refractory chronic pain. There is, however, a paucity of trials exploring its analgesic effect several weeks after intravenous administration or in association with magnesium. The authors hypothesized that ketamine in neuropathic pain may provide pain relief and cognitive-emotional benefit versus placebo and that a combination with magnesium may have an additive effect for 5 weeks.

Methods: A randomized, double-blind, crossover, placebo-controlled study (NCT02467517) included 20 patients with neuropathic pain. Each ketamine-naïve patient received one infusion every 35 days in a random order: ketamine (0.5 mg/kg)/placebo or ketamine (0.5 mg/kg)/magnesium sulfate (3g) or placebo/placebo.The primary endpoint was the area under the curve of daily pain intensity for a period of 35 days after infusion. Secondary endpoints included pain (at 7, 15, 21 and 28 days) and health-related, emotional, sleep, and quality of life questionnaires.

Results: Daily pain intensity was not significantly different between the three groups (n = 20) over 35 days (mean area under the curve = 185 ± 100, 196 ± 92, and 187 ± 90 pain score-days for ketamine, ketamine/magnesium, and placebo, respectively, P = 0.296). The effect size of the main endpoint was -0.2 (95% CI [-0.6 to 0.3]; P = 0.425) for ketamine versus placebo, 0.2 (95% CI [-0.3 to 0.6]; P = 0.445) for placebo versus ketamine/magnesium and -0.4 (95% CI [-0.8 to 0.1]; P = 0.119) for ketamine versus ketamine/magnesium. There were no significant differences in emotional, sleep, and quality of life measures. During placebo, ketamine, and ketamine/magnesium infusions, 10%, 20%, and 35% of patients respectively reported at least one adverse event.

Conclusions: The results of this trial in neuropathic pain refuted the hypothesis that ketamine provided pain relief at 5 weeks and cognitive-emotional benefit versus placebo and that a combination with magnesium had any additional analgesic effect.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cognition / drug effects
  • Cross-Over Studies
  • Double-Blind Method
  • Drug Therapy, Combination
  • Emotions
  • Excitatory Amino Acid Antagonists / adverse effects
  • Excitatory Amino Acid Antagonists / therapeutic use*
  • Female
  • Humans
  • Infusions, Intravenous
  • Ketamine / adverse effects
  • Ketamine / therapeutic use*
  • Magnesium Sulfate / adverse effects
  • Magnesium Sulfate / therapeutic use*
  • Male
  • Middle Aged
  • Neuralgia / drug therapy*
  • Neuralgia / psychology
  • Pain Measurement / drug effects
  • Treatment Outcome


  • Excitatory Amino Acid Antagonists
  • Ketamine
  • Magnesium Sulfate