Topical and Peripheral Ketamine as an Analgesic

Expert Opinion on Pharmacotherapy, 2010

Importance of the field: Worldwide the number of patients affected by chronic pain is growing and conventional treatment is often insufficient. Recently the importance of the N-methyl-D-aspartate receptor (NMDAR) in the mechanisms and maintenance of chronic pain was established. Ketamine (introduced in the 1960s as an anesthetic) is the most studied NMDAR antagonist in the treatment of various chronic pain syndromes. Areas covered in this review: The pharmacology, safety and toxicology of ketamine are discussed. Further, electronic databases were scanned for prospective, randomized controlled trials that assessed ketamine's analgesic effect in patients with chronic pain. The focus of this review is on trials published after 2008 that applied long-term intravenous infusions. What the reader will gain: While most studies on intravenous ketamine show acute analgesic effects, three recent trials on long-term ketamine treatment (days to weeks) demonstrate the effectiveness of ketamine in causing longterm (months) relief of chronic pain. Despite these positive results, further studies are needed on safety/toxicity issues. Other administration modes are less effective in causing long-term pain relief. Take home message: There is now evidence form a limited number of studies that pain relief lasting for months is observed after long-term intravenous ketamine infusion, suggesting a modulatory effect of ketamine in the process of chronic pain, possibly via blockade of upregulated NMDAR.

Anesthesiology, 2000

Background The studies on the mechanisms of ketamine antinociception have led to conflicting results. In this study, the authors investigated the contribution of supraspinal monoaminergic descending inhibitory system to ketamine analgesia for acute nociception and inflammation-induced hyperalgesia. Methods Male Sprague-Dawley rats were used. The paw withdrawal latencies to radiant heat stimuli were measured to assess the thermal nociceptive threshold. The analgesic effects of intrathecal or intraperitoneal ketamine were examined in the rats that received unilateral intraplantar carrageenan and in those that were untreated. In addition, it was examined whether pretreatment with intrathecal yohimbine or methysergide inhibited the analgesic effects of ketamine. Using an intrathecal microdialysis method, noradrenaline and 5-hydroxytryptamine concentrations in lumbar cerebrospinal fluid were measured after intraperitoneal ketamine in both saline- and carrageenan-treated rats. Results In ...

Anesthesiology, 2005

Anesthesiology and Pain Medicine, 2019

Peri-operative pain management is one of the important tasks of medical staff. The problems arising afterwards not only have a pathophysiological adverse effect on patients, but also detrimentally affect the health system, treatment costs, and delay in discharge, for which pain management should be planned prior to surgery, and the resulting stress (1-3). Recent studies indicate a high incidence of persistent postoperative pain, and anesthesiologists should thus take proactive measures to control postoperative pain, particularly as some surgeries have more severe acute pain. Not only have a variety of drugs (such as opioids, NSAIDs, and adjuvants) been studied, but also several methods of administration (including oral, intravenous, epidural, inhalation, etc.) have been evaluated (4-6).

The Clinical Journal of Pain, 2006

Background: The n-methyl-d-aspartate receptor antagonists such as ketamine relieve chronic pain but their oral and parenteral use is limited by the adverse effects. Experimental studies indicate that the peripheral n-methyl-d-aspartate receptors are involved in nociception. Recent clinical findings suggest that ketamine gel alleviates neuropathic pain, but no placebo-controlled randomized studies are available on the neurosensory effects of ketamine gel in experimental neurogenic pain. Objectives: The aim of this study was to assess the effects of topically applied ketamine using the intradermal capsaicin model in healthy volunteers. Methods: Nine healthy subjects received ketamine and placebo gel on 3 occasions in a randomized, double-blind, and crossover manner. The concentration of ketamine was 50 mg/mL. One milliliter of gel was rubbed into the skin of both forearms 10 minutes before the intradermal injection of capsaicin (250 mg). Thereafter, the intensity and unpleasantness of spontaneous and evoked pain and dysesthesia was assessed up to 60 minutes using a 10-cm visual analog scale. Pain and dysesthesia were evoked using cotton gauze, a von Frey microfilament, and 38°C, 42°C, and 47°C heat. Side effects were recorded, and individuals' subjective experiences were assessed with a standard questionnaire. Results: Ketamine gel had no effect on immediate burning pain followed by the capsaicin injection. Both the intensity and unpleasantness of mechanical hyperalgesia was statistically significantly reduced by ketamine gel applied both on the left and right side. Neither tactile allodynia evoked by a brush nor thermal hyperalgesia were observed in any volunteer. No local or systemic side effects were observed. No patient reported any drug effects. Discussion: A significant reduction of mechanical hyperalgesia was produced by topically and pre-emptively applied ketamine in healthy patients. We propose that the mechanism of action would be the reduction of central sensitization caused by the absorption of ketamine in circulation.

Journal of oral & facial pain and headache

To assess the analgesic effect of intranasal administration of S-ketamine in different rat models of facial pain. Nociceptive responses induced by formalin injected into the upper lip and facial hyperalgesia induced by capsaicin or carrageenan injected into the upper lip were used to evaluate the analgesic effect of intranasal ketamine in acute facial pain models in rats (n = 173). The effect of intranasal ketamine on heat and mechanical hyperalgesia induced by constriction of the infraorbital nerve (CION) was also evaluated. In addition, locomotor activity in the open field test was assessed after intranasal ketamine administration. Two-way repeated measures analysis of variance followed by Bonferroni post hoc correction were used to analyze all data. Intranasal ketamine (0.5 mg/kg) failed to modify the first phase of the orofacial formalin test, but reduced the second phase by about 40%. Intranasal ketamine also reduced the facial heat hyperalgesia induced by capsaicin and carrage...

Pharmacy Today, 2018

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 < 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.

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

Canadian Journal of Anesthesia/Journal canadien d'anesthésie, 2011

Purpose Perioperative intravenous ketamine may be a useful addition in pain management regimens. Previous systematic reviews have included all methods of ketamine administration, and heterogeneity between studies has been substantial. This study addresses this issue by narrowing the inclusion criteria, using a random effects model, and performing subgroup analysis to determine the specific types of patients, surgery, and clinical indications which may benefit from perioperative ketamine administration. Source We included published studies from 1966 to 2010 which were randomized, double-blinded, and placebocontrolled using intravenous ketamine (bolus or infusion) to decrease postoperative pain. Studies using any form of regional anesthesia were excluded. No limitation was placed on the ketamine dose, patient age, or language of publication. Principal findings Ninety-one comparisons in seventy studies involving 4,701 patients met the inclusion criteria (2,652 in ketamine groups and 2,049 in placebo groups). Forty-seven of these studies were appropriate for evaluation in the core meta-analysis, and the remaining 23 studies were used to corroborate the results. A reduction in total opioid consumption and an increase in the time to first analgesic were observed across all studies (P \ 0.001). The greatest efficacy was found for thoracic, upper abdominal, and major orthopedic surgical subgroups. Despite using less opioid, 25 out of 32 treatment groups (78%) experienced less pain than the placebo groups at some point postoperatively when ketamine was efficacious. This finding implies an improved quality of pain control in addition to decreased opioid consumption. Hallucinations and nightmares were more common with ketamine but sedation was not. When ketamine was efficacious for pain, postoperative nausea and vomiting was less frequent in the ketamine group. The dose-dependent role of ketamine analgesia could not be determined. Conclusion Intravenous ketamine is an effective adjunct for postoperative analgesia. Particular benefit was observed in painful procedures, including upper abdominal, thoracic, and major orthopedic surgeries. The analgesic effect of ketamine was independent of the type of intraoperative opioid administered, timing of ketamine administration, and ketamine dose.

Journal of Pain Research

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.

Pain, 2004

Few placebo-controlled trials have investigated the treatment of breakthrough pain (BTP) in patients with chronic pain. We evaluated the efficacy and safety of intranasal ketamine for BTP in a randomized, double-blind, placebo-controlled, crossover trial. Twenty patients with chronic pain and at least two spontaneous BTP episodes daily self-administered up to five doses of intranasal ketamine or placebo at the onset of a spontaneous BTP episode (pain intensity $ 5 on a 0-10 scale). Two BTP episodes at least 48 h apart were treated with either ketamine or placebo. Patients reported significantly lower BTP intensity following intranasal ketamine than after placebo ðP , 0:0001Þ; with pain relief within 10 min of dosing and lasting for up to 60 min. No patient in the ketamine group required his/her usual rescue medication to treat the BTP episode, while seven out of 20 (35%) patients in placebo group did ðP ¼ 0:0135Þ: Intranasal ketamine was well tolerated with no serious adverse events. After ketamine administration, four patients reported a transient change in taste, one patient reported rhinorrhea, one patient reported nasal passage irritation, and two patients experienced transient elevation in blood pressure. A side effect questionnaire administered 60 min and 24 h after drug or placebo administration elicited no reports of auditory or visual hallucinations. These data suggest that intranasal administration of ketamine provides rapid, safe and effective relief for BTP.

Pain, 2004

Few placebo-controlled trials have investigated the treatment of breakthrough pain (BTP) in patients with chronic pain. We evaluated the efficacy and safety of intranasal ketamine for BTP in a randomized, double-blind, placebo-controlled, crossover trial. Twenty patients with chronic pain and at least two spontaneous BTP episodes daily self-administered up to five doses of intranasal ketamine or placebo at the onset of a spontaneous BTP episode (pain intensity $ 5 on a 0-10 scale). Two BTP episodes at least 48 h apart were treated with either ketamine or placebo. Patients reported significantly lower BTP intensity following intranasal ketamine than after placebo ðP , 0:0001Þ; with pain relief within 10 min of dosing and lasting for up to 60 min. No patient in the ketamine group required his/her usual rescue medication to treat the BTP episode, while seven out of 20 (35%) patients in placebo group did ðP ¼ 0:0135Þ: Intranasal ketamine was well tolerated with no serious adverse events. After ketamine administration, four patients reported a transient change in taste, one patient reported rhinorrhea, one patient reported nasal passage irritation, and two patients experienced transient elevation in blood pressure. A side effect questionnaire administered 60 min and 24 h after drug or placebo administration elicited no reports of auditory or visual hallucinations. These data suggest that intranasal administration of ketamine provides rapid, safe and effective relief for BTP.