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.

The Pharmacological Treatment of Chronic Pain: From Guidelines to Daily Clinical Practice

“…Palmitoylethanolamide (PEA) and acetyl-L-carnitine (ALC) may be used in patients with nociplastic and neuropathic pain [149]. L-acetyl-carnitine is an endogenous substance that modulates pain via different mechanisms: stimulation of mitochondrial function and repair factors such as nerve growth factor, antioxidant activity, and activation of metabotropic glutamate receptor 2 (mGlu2).…”

Effectiveness of L-carnitine Supplementation to Sertraline for Treatment of Major Depressive Disorder: A Double-blind Randomized Placebo-controlled Trial

“…ALC, an acetyl ester of carnitine, is an endogenous molecule with biological and pharmacological activities in central and peripheral nervous systems and has a key role in neuronal metabolisms such as β-oxidation, glucose utilization, glycogen production, and ammonia cycle; furthermore, exogenous ALC may increase the process of neurogenesis in prefrontallimbic areas. [17] Although animal and cellular models suggest that ALCs on neurotransmitter regulation, improvement in dysfunctional neuroplastic changes, and membrane modulation may play important role in the treatment of depression, more controlled trial data with adequately-powered, well-designed, and advanced methodology should be performed to conclude whether ALC as a monotherapy or supplementation agent may be clinically beneficial for MDD. [9,18] Although pharmacologic approaches are the most important treatment strategies for MDD, response rates to the firstline antidepressants are moderate and remission is observed in about 30-45% of patients.…”

Novel Drug Targets and Emerging Pharmacotherapies in Neuropathic Pain

“…There are several non-traditional compounds that show potential for the management of neuropathic pain [ 110 , 111 , 191 ] ( Figure 2 ). Acetyl-L-carnitine was investigated for its potential role in managing neuropathic pain [ 192 , 193 ]. It exerts its effects through multiple mechanisms, including modulation of neurotransmitters such as glutamate and GABA; promotion of nerve regeneration, antioxidant activity, and anti-inflammatory effects; and modulation of synaptic plasticity [ 193 , 194 , 195 ].…”