Analgesic and Antidepressant Effects of the Clinical Glutamate Modulators Acetyl-L-Carnitine and Ketamine

Abstract

Pain and depression are leading causes of disability and of profound social and economic burden. Their impact is aggravated by their chronicity and comorbidity and the insufficient efficacy of current treatments. Morphological and functional metabolism studies link chronic pain and depressive disorders to dysfunctional neuroplastic changes in fronto-limbic brain regions that control emotional responses to painful injuries and stressful events. Glutamate modulators are emerging new therapies targeting dysfunctional brain areas implicated in the generation and maintenance of chronic pain and depression. Here, we report the effects of two clinically approved glutamate modulators: acetyl-L-carnitine (ALCAR) and S, R(±)ketamine (KET). ALCAR is a natural neurotrophic compound currently marketed for the treatment of neuropathies. KET is the prototypical non-competitive antagonist at N-methyl-D-aspartate glutamate receptors and a clinically approved anesthetic. Although they differ in pharmacological profiles, ALCAR and KET both modulate aminergic and glutamatergic neurotransmissions and pain and mood. We assessed in rats the effects of ALCAR and KET on cerebral metabolic rates for glucose (rCMRglc) and assessed clinically the effects of ALCAR in chronic pain and of KET in post-operative pain. ALCAR and KET increased rCMRglc at similar degrees in prefrontal, somatosensory, and cingulate cortices, and KET increased rCMRglc at a different, much larger, degree in limbic and dopaminergic areas. While rCMRglc increases in prefrontal cortical areas have been associated with analgesic and antidepressant effects of ALCAR and KET, the marked metabolic increases KET induces in limbic and dopaminergic areas have been related to its psychotomimetic and abuse properties. In patients with chronic neuropathic pain, ALCAR (1,000 mg/day) yielded to a fast (2 weeks) improvement of mood and then of pain and quality of life. In day-surgery patients, KET improved dischargeability and satisfaction. In obese patients undergoing bariatric surgery, a single, low dose of KET (0.5 mg/kg) at induction of anesthesia determined a very fast (hours) amelioration of post-operative depression and pain and an opioid-sparing effect. These findings indicate that ALCAR and KET, two non-selective glutamate modulators, still offer viable therapeutic options in comorbid pain and depression.

Keywords: acetyl-L-carnitine; depression; ketamine; pain; regional cerebral metabolic rates for glucose.

FIGURE 1

Effect of ALCAR and KET on rCMRglc. Bars are mean rCMRglc differences (percent) from saline controls in groups of 5–7 Fischer-344, male rats at 30 min after IV administration of ALCAR 500 mg (hatched) and 20 min after IV KET 20 mg (solid). ALCAR difference from saline control: ^∗P < 0.05; ALCAR difference from KET: ^#P < 0.05.

FIGURE 2

Effects of ALCAR on chronic pain and depression. Points are means ± standard deviation of 24-h average pain NRS scores (above) and depression HADS scores (below) from pre-treatment baseline to month 4 treatment in 28 patients receiving ALCAR 500 mg BID IM/PO for chronic neuropathy or radiculopathy pain. Significantly different from baseline: *P < 0.05; **P < 0.01.

FIGURE 3

Effects of KET on post-operative pain in obese bariatric patients. Points are means ± standard deviations of NRS scores of pain in the first 36 h after bariatric surgery in 41 obese patients who had received either saline (broken line) or KET 0.5 mg/kg (continuous line) at induction of anesthesia. Significantly different from saline controls: **P < 0.01.

FIGURE 4

Effects of KET on depression in obese bariatric patients. Columns are means ± standard deviations of HAMD scores from baseline to post-operative day 7 in 41 bariatric patients who had received either saline (hatched columns) or KET 0.5 mg/kg (solid columns) at induction of anesthesia. Significantly different from saline controls: ^∗P < 0.05; ^∗∗P < 0.01.