Topical review Ketamine for chronic non-cancer pain

PAIN, 2011

Inhibitory and facilitatory descending pathways, originating at higher central nervous system sites, modulate activity of dorsal horn nociceptive neurons, and thereby influence pain perception. Dysfunction of inhibitory pain pathways or a shift in the balance between pain facilitation and pain inhibition has been associated with the development of chronic pain. The N-methyl-D-aspartate receptor antagonist ketamine has a prolonged analgesic effect in chronic pain patients. This effect is due to desensitization of sensitized N-methyl-D-aspartate receptors. Additionally, ketamine may modulate or enhance endogenous inhibitory control of pain perception. Diffuse noxious inhibitory control (DNIC) and offset analgesia (OA) are 2 mechanisms involved in descending inhibition. The present study investigates the effect of a ketamine infusion on subsequent DNIC and OA responses to determine whether ketamine has an influence on descending pain control. Ten healthy subjects (4 men/6 women) received a 1-hour placebo or S(+)-ketamine (40 mg per 70 kg) infusion on 2 separate occasions in random order. Upon the termination of the infusion, DNIC and OA responses were obtained. After placebo treatment, significant descending inhibition of pain responses was present for DNIC and OA. In contrast, after ketamine infusion, no DNIC was observed, but rather a significant facilitatory pain response (P < 0.01); the OA response remained unchanged. These findings suggest that the balance between pain inhibition and pain facilitation was shifted by ketamine towards pain facilitation. The absence of an effect of ketamine on OA indicates differences in the mechanisms and neurotransmitter influences between OA and DNIC.

Canadian Journal of Anesthesia/Journal canadien d'anesthésie, 2015

Ideggyogyaszati Szemle-clinical Neuroscience, 2004

Psychiatry and Clinical Psychopharmacology

OBJECTIVE: In pain management, alternative medications are necessary due to the development of tolerance to traditional opioid analgesics. Literature data suggest that Nmethyl-D-aspartate (NMDA) receptor antagonizing drugs can induce antinociception, and can reduce the opioid requirement. Ketamine is a non-competitive NMDA receptor antagonist drug and has well-known antinociceptive properties. The drug acts not only on NMDA receptors but also has effects on the monoaminergic system and non-NMDA glutamatergic receptors which have vital roles in the regulation of pain. This study was conducted to investigate the serotonergic and glutamatergic involvement in low-dose ketamine (20 mg/ kg) analgesia in mice. METHOD: The effects of serotonin were suppressed with two different ways; either the serotonin was depleted with p-chlorophenylalanine (pCPA, 150 mg/kg/d; 4 days) or the serotonin receptors were blocked with methiothepin (0.1 mg/kg), and α-amino-3-hydroxy-5methyl-4-isoxazole propionic acid (AMPA) receptors were antagonized with GYKI-52466 (20 mg/kg). Fluoxetine (20 mg/kg; 7 days) was used to increase the serotoninergic activity. We used a hotplate (HP) test to measure pain reaction latencies. Furthermore, we tested sustained analgesic effects of ketamine for six consecutive times (1-hour break between each test). RESULTS: In our experiment, ketamine treatment increased pain reaction latencies, yet it failed to increase the latencies when combined with antiserotonergic drugs, e.g. pCPA and methiothepin. The latencies were increased with AMPA receptor blockade, yet ketamine did not increase the analgesic effect of the AMPA receptor antagonist, i.e. GYKI-52466. In consecutive tests, ketamine was effective for 5 h, and the peak effect was seen at the 3rd-hour test. CONCLUSION: Our data suggest that the activity of the serotonergic system and AMPA receptors are necessary for ketamine to produce antinociceptive effects. In pain management, ketamine can offer an alternative option to traditional analgesics and may be useful to reduce opioid tolerance.

Current Physical Medicine and Rehabilitation Reports, 2014

Hyperactivity of N-methyl-D-aspartate (NMDA) receptors may be one of the factors in the genesis of neuropathic pain (NP). Ketamine is a dissociative anesthetic and analgesic that is the most potent NMDA receptor antagonist currently available for human use. There is a growing body of literature for three decades suggesting efficacy of subanaesthetic doses of ketamine in the treatment of NP, particularly the pain in complex regional pain syndromes. The primary limitations of ketamine use are secondary to psychotomimetic and, to a lesser extent, sympathetic activation. The purpose of this article is to review the history, pharmacology, pharmacodynamics, clinical benefits, and limitations of ketamine for treatment of NP. Methods of administration and management of adverse effects are highlighted based on the clinical experience of the authors.

Health Psychology Research, 2021

Background Chronic pain significantly worsens the quality of life. Unlike neuropathic, musculoskeletal, postoperative pain, and cancer pain, chronic primary pain cannot be explained by an underlying disease or condition, making its treatment arduous. Objectives This manuscript intends to provide a comprehensive review of the use of ketamine as a treatment option for specific chronic pain conditions. Study Design A review article. Setting A review of the literature. Methods A search was done on PubMed for relevant articles. Results A comprehensive review of the current understanding of chronic pain and the treatment of specific chronic pain conditions with ketamine. Limitations Literature is scarce regarding the use of ketamine for the treatment of chronic pain. Conclusion First-line treatment for many chronic pain conditions includes NSAIDs, antidepressants, anticonvulsants, and opioids. However, these treatment methods are unsuccessful in a subset of patients. Ketamine has been exp...

BMC Pharmacology and Toxicology

Background Ketamine, a widely used anaesthetic and analgesic agent, is known to improve the analgesic efficacy of opioids and to attenuate central sensitisation and opioid-induced hyperalgesia. Clinical use is, however, curtailed by unwanted psychomimetic effects thought to be mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. KEA-1010, a ketamine ester-analogue designed for rapid offset of hypnosis through hydrolysis mediated break-down, has been shown to result in short duration sedation yet prolonged attenuation of nociceptive responses in animal models. Here we report on behavioural effects following KEA-1010 administration to rodents. Methods KEA-1010 was compared with racemic ketamine in its ability to produce loss of righting reflex following intravenous injection in rats. Analgesic activity was assessed in thermal tail flick latency (TFL) and paw incision models when injected acutely and when co-administered with fentanyl. Tail flick analgesic assessment was furthe...

Journal of Clinical Medicine

Pain is the leading cause of medical consultations and occurs in 50–70% of emergency department visits. To date, several drugs have been used to manage pain. The clinical use of ketamine began in the 1960s and it immediately emerged as a manageable and safe drug for sedation and anesthesia. The analgesic properties of this drug were first reported shortly after its use; however, its psychomimetic effects have limited its use in emergency departments. Owing to the misuse and abuse of opioids in some countries worldwide, ketamine has become a versatile tool for sedation and analgesia. In this narrative review, ketamine’s role as an analgesic is discussed, with both known and new applications in various contexts (acute, chronic, and neuropathic pain), along with its strengths and weaknesses, especially in terms of psychomimetic, cardiovascular, and hepatic effects. Moreover, new scientific evidence has been reviewed on the use of additional drugs with ketamine, such as magnesium infusi...

Pain, 1999 Aug;82(2):111-25., 1999

Ketamine hydrochloride is a well known general anesthetic and short acting analgesic in use for almost 3 decades. The role of the NMDA receptor in the processing of nociceptive input has led naturally to renewed clinical interest in N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine. This paper reviews the use and efficacy of low-dose ketamine in the management of acute postoperative pain. The literature was obtained from a computer search of the MEDLINE database from 1966 through December 1998. Studies were included for review if they were randomized, prospective, controlled, double-blind and reported pain scores. We evaluate the clinical literature and discuss the efficacy of low-dose ketamine in the management of acute postoperative pain when administered alone or in conjunction with other agents via the oral, intramuscular, subcutaneous, intravenous and intraspinal routes. Low-dose ketamine is defined as a bolus dose of less than 2 mg/g when given intramuscularly or less than 1 mg/kg when administered via the intravenous or epidural route. For continuous i.v. administration low-dose ketamine is defined as a rate of &amp;lt; or =20 microg/kg per min. We conclude that ketamine may provide clinicians with a tool to improve postoperative pain management and to reduce opioid related adverse effects. The evidence suggests that low-dose ketamine may play an important role in postoperative pain management when used as an adjunct to local anesthetics, opioids, or other analgesic agents. Further research is required in the following areas: (a) dose-finding studies for ketamine as an adjunct to opioids and local anesthetics (b) efficacy and optimal route of administration (c) the role of S(+)-ketamine; (d) the influence of ketamine on long-term outcome such as chronic pain (e) long-term physical and chemical stability of mixtures containing ketamine (f) spinal toxicity of ketamine and (g) effects of low-dose ketamine on cognitive and memory functioning after surgery.

Pharmacy Today, 2018

PubMed, 1996

Ketamine has been shown to have potent analgesic properties at low dosages. Bioavailability is high when it is given parenterally, but low after oral or rectal administration. Active metabolites should account for part of the analgesic effect of ketamine during long-term oral administration. NMDA receptor inhibition by ketamine may reflect a wind-down phenomenon, and should alleviate NMDA-related neuropathic pain, reversing the rightward shift of the opioid-response curve. A synergistic effect between ketamine and opioids has been observed in cancer pain patients who have lost an analgesic response to high doses of morphine. Further studies need to be carried out to confirm the benefits of ketamine in cancer pain, and to determine the best route of administration, dosages and the incidence of side effects.

Medicine and Pharmacy Reports, 2015

Background and aim. Ketamine is a drug used for the induction and maintenance of general anesthesia, for the treatment of postoperative and posttraumatic acute pain, and more recently, for the reduction of postoperative opioid requirements. The main mechanism of action of ketamine is the antagonization of N-methyl-D-aspartate (NMDA) receptors that are associated with central sensitization. In the pathogenesis of chronic pain and particularly in neuropathic pain, an important role is played by the activation of NMDA receptors. Although ketamine is indicated and used for the treatment of chronic cancer pain as an adjuvant to opioids, there are few clinical studies that clearly demonstrate the effectiveness of ketamine in this type of pain.The aim of this study is to analyze evidence-based clinical data on the effectiveness and safety of ketamine administration in the treatment of chronic neoplastic pain, and to summarize the evidence-based recommendations for the use of ketam...

Revista Médica del Hospital General de México, 2016

The pharmacological effects of ketamine are being discovered constantly, and new mechanisms involving epi-genetics could account for some of its clinical responses. Nowadays, it is regarded as a pharmacological tool in translational research and has the potential to revolutionise the therapy of complex patient conditions such as pain and depression. Medical interest in exploring the drug's properties has grown, as is demonstrated by the increased investigation over the last five years, according to research sites such as Pubmed. These publications draw attention to the multifaceted roles of ketamine as an anaesthetic, analgesic (in multiple contexts, chronic, acute, refractory and breakthrough pain), antihyperalgesic, neuromodulator, bronchodilator and/or antidepressant. It is therefore important to review the pharmacological characteristics and their implications in current treatments.

Anesthesia & Analgesia, 2014

Ketamine, in subanesthetic doses, produces systemic analgesia in chronic pain settings, an action largely attributed to block of N-methyl-d-aspartate receptors in the spinal cord and inhibition of central sensitization processes. N-methyl-d-aspartate receptors also are located peripherally on sensory afferent nerve endings, and this provided the initial impetus for exploring peripheral applications of ketamine. Ketamine also produces several other pharmacological actions (block of ion channels and receptors, modulation of transporters, anti-inflammatory effects), and while these may require higher concentrations, after topical (e.g., as gels, creams) and peripheral application (e.g., localized injections), local tissue concentrations are higher than those after systemic administration and can engage lower affinity mechanisms. Peripheral administration of ketamine by localized injection produced some alterations in sensory thresholds in experimental trials in volunteers and in complex regional pain syndrome subjects in experimental settings, but many variables were unaltered. There are several case reports of analgesia after topical application of ketamine given alone in neuropathic pain, but controlled trials have not confirmed such effects. A combination of topical ketamine with several other agents produced pain relief in case, and case series, reports with response rates of 40% to 75% in retrospective analyses. In controlled trials of neuropathic pain with topical ketamine combinations, there were improvements in some outcomes, but optimal dosing and drug combinations were not clear. Given orally (as a gargle, throat swab, localized peritonsillar injections), ketamine produced significant oral/throat analgesia in controlled trials in postoperative settings. Topical analgesics are likely more effective in particular conditions (patient factors, disease factors), and future trials of topical ketamine should include a consideration of factors that could predispose to favorable outcomes.

Advances in Clinical and Experimental Medicine

Background. Glutamate N-methyl-D-aspartate (NMDA) receptors are known for their importance in the perseverance of chronic neuropathic pain. Ketamine, an intravenous anesthetic agent, is a non-competitive blocker of NMDA receptors. Applied in anesthetic doses, ketamine has anti-nociceptive effects in various animal pain models. Objectives. The objective of this study was to investigate the anti-nociceptive effect of ketamine in acute and neuropathic pain models in rats. Material and methods. To study the anti-nociceptive effect of ketamine on acute pain, 40 Wistar rats were divided into 5 groups (n = 8): control, positive control group and 3 experimental groups treated intraperitoneally (ip.) with 30 mg/kg bw, 40 mg/kg bw and 50 mg/kg bw ketamine, respectively. The anti-nociceptive effect was evaluated in hot plate, analgesy-meter and formalin tests. The model of neuropathic pain was induced by left sciatic nerve ligation. Twenty-four Wistar rats were divided into 3 groups (n = 8): sham-control group, model group and ketamine-treated group subsequently tested in hot plate and analgesy-meter tests. Results. In the hot plate test, the rats treated with ketamine presented increased reaction latency at the 120 th min and 180 th min compared to the controls. In the analgesy-meter test, ketamine produced an antinociceptive effect at the 60 th min compared to the controls. In the formalin test, the paw licking time across the early phase of testing was reduced in the rats treated with the 2 higher doses of ketamine. In a neuropathic pain model, ketamine increased the reaction latency at the 120 th min and 180 th min compared with the model group in the hot plate test. In the analgesy-meter test, in the ketamine-treated animals the paw withdrawal threshold increased at the 60 th min compared with the model group. Conclusions. Our results suggest that ketamine produces peripheral anti-nociceptive effect in an acute pain model. Also, it relieves thermal and mechanical allodynia after 14 days of treatment in a neuropathic pain model.