Chronic administration of ketamine for analgesia

Use of the dissociative anesthetic ketamine in subanesthetic doses has demonstrated efficacy in neuropathic pain. This article reviews the scientific and clinical literature on ketamine. Mechanisms of both central and peripheral neuropathic pain are described. Studies of ketamine analgesia in postherpetic neuralgia, phantom pain, complex regional pain syndrome and cancer pain are reviewed. A range of administration methods for ketamine including neuroaxial administration are described.     

Continuous intravenous infusion of ketamine and lidocaine as adjuvant analgesics in a 5-year-old patient with neuropathic cancer pain

For difficult to treat neuropathic pain from cancer, adjuvant analgesics are often used with opioids. We present the case of a 5-year-old girl who was diagnosed with meningitis caused by malignant T-cell lymphoma. She had severe neuropathic pain not relieved by increasing doses of a fentanyl infusion. Intravenous administration of ketamine and lidocaine in combination with fentanyl provided excellent analgesia without significant side effects. Ketamine and lidocaine can be safely infused together with concomitant opioids for the treatment of refractory neuropathic pain caused by cancer.     

An unusual case of chronic neuropathic pain responds to an optimum frequency of intravenous ketamine infusions

The effective treatment of patients suffering from a variety of difficult pain syndromes, including phantom pain and other neuropathic pains, remains a clinical challenge. Neuropathic pain has been shown to respond to drugs that block the N-methyl-D-aspartate (NMDA) receptor, such as ketamine and amantidine. A 44-year-old woman with a previous right-sided forequarter amputation presented to the Palliative Medicine Team complaining of neuropathic pain in her left arm, which was neurologically intact. The pain was treated with repeated infusions of intravenous ketamine. Twenty-one infusions were given over a period of four months. The pain intensity experienced by the patient lessened as the frequency of the ketamine infusions increased. This finding has not been described previously and supports the theory that there may be an optimum frequency of ketamine infusions to achieve adequate pain control.     

Analgesic effect of oral ketamine in chronic neuropathic pain of spinal origin: a case report.

Ketamine is an injectable anesthetic induction agent that has been reported to have analgesic activity in pain from a variety of mechanisms, but predominantly in neuralgic and dysesthetic neuropathic pain. In this case report we illustrate the effectiveness of ketamine in a patient with neuropathic pain resulting from cauda equina trauma. Among the issues addressed are the role of pretreatment with haloperidol to prevent ketamine-induced psychomimetic effects, the potential for fewer side effects and a need for lower doses when ketamine is administered orally, and the need for further study regarding appropriate monitoring parameters during the titration phase. Oral ketamine can be effective in treatment refractory chronic neuropathic pain of spinal origin.     

Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study

Pain not responsive to morphine is often problematic. Animal and clinical studies have suggested that N-methyl-D-aspartate (NMDA) antagonists, such as ketamine, may be effective in improving opioid analgesia in difficult pain syndromes, such as neuropathic pain. A slow bolus of subhypnotic doses of ketamine (0.25 mg/kg or 0.50 mg/kg) was given to 10 cancer patients whose pain was unrelieved by morphine in a randomized, double-blind, crossover, double-dose study. Pain intensity on a 0 to 10 numerical scale; nausea and vomiting, drowsiness, confusion, and dry mouth, using a scale from 0 to 3 (not at all, slight, a lot, awful); Mini-Mental State Examination (MMSE) (0-30); and arterial pressure were recorded before administration of drugs (T0) and after 30 minutes (T30), 60 minutes (T60), 120 minutes (T120), and 180 minutes (T180). Ketamine, but not saline solution, significantly reduced the pain intensity in almost all the patients at both doses. This effect was more relevant in patients treated with higher doses. Hallucinations occurred in 4 patients, and an unpleasant sensation ("empty head") was also reported by 2 patients. These episodes reversed after the administration of diazepam 1 mg intravenously. Significant increases in drowsiness were reported in patients treated with ketamine in both groups and were more marked with ketamine 0.50 mg/kg. A significant difference in MMSE was observed at T30 in patients who received 0.50 mg/kg of ketamine. Ketamine can improve morphine analgesia in difficult pain syndromes, such as neuropathic pain. However, the occurrence of central adverse effects should be taken into account, especially when using higher doses. This observation should be tested in studies of prolonged ketamine administration.     

Ketamine as an analgesic: parenteral, oral, rectal, subcutaneous, transdermal and intranasal administration

Ketamine is a parenteral anesthetic agent that provides analgesic activity at sub-anesthetic doses. It is an N-methyl-D-aspartate (NMDA) receptor antagonist with opioid receptor activity. Controlled studies and case reports on ketamine demonstrate efficacy in neuropathic and nociceptive pain. Because ketamine is a phencyclidine analogue, it has some of the psychological adverse effects found with that hallucinogen, especially in adults. Therefore, ketamine is not routinely used as an anesthetic in adult patients. It is a frequently used veterinary anesthetic, and is used more frequently in children than in adults. The psychotomimetic effects have prompted the DEA to classify ketamine as a Schedule III Controlled Substance. A review of the literature documents the analgesic use of ketamine by anesthesiologists and pain specialists in patients who have been refractory to standard analgesic medication regimens. Most reports demonstrate no or mild psychotomimetic effects when ketamine is dosed at sub-anesthetic doses. Patients who respond to ketamine tend to demonstrate dramatic pain relief that obviates the desire to stop treatment due to psychotomimetic effects (including hallucinations and extracorporeal experiences). Ketamine is approved by the FDA for intravenous and intramuscular administration. Use of this drug by the oral, intranasal, transdermal, rectal, and subcutaneous routes has been reported with analgesic efficacy in treating nociceptive and neuropathic pain. Ketamine also has been reported to produce opioid dose sparing and good patient acceptance. A transdermal formulation is currently under patent review in Brazil and an intranasal formulation is currently undergoing phase I/II clinical trials.     

Effects of low-dose intranasal (S)-ketamine in patients with neuropathic pain

Background: NMDA receptors are involved in the development and maintenance of neuropathic pain. We evaluated the efficacy and safety of intranasal (S)‐ketamine, one of the most potent clinically available NMDA receptor antagonists. Methods: Sixteen patients with neuropathic pain of various origins were randomized into two treatment groups: (S)‐ketamine 0.2mg/kg (group 1); (S)‐ketamine 0.4mg/kg (group 2). Plasma concentrations of (S)‐ketamine and (S)‐norketamine were measured over 6h by High Performance Liquid Chromatography combined with mass spectrometry. Quantitative sensory testing (QST) was conducted before, during and after treatment. Side effects and amount of pain reduction were recorded. Results: Intranasal (S)‐ketamine administration lead to peak plasma concentrations of 27.7±5.9ng/ml at 10±6.3min (group 1) and 34.3±22.2ng/ml at 13.8±4.8min after application (group 2). Maximal plasma concentrations of (S)‐norketamine were 18.3±14.9ng/ml at 81±59min (group 1) and 34.3±5.5ng/ml at 75±40min (group 2). Pain scores decreased significantly in both groups with minimal pain at 60min after drug administration (70±10% and 61±13% of initial pain in groups 1 and 2). The time course of pain decrease was significantly correlated with plasma concentrations of (S)‐ketamine and (S)‐norketamine (partial correlations: (S)‐norketamine: ⁻0.90 and ⁻0.86; (S)‐ketamine: ⁻0.72 and ⁻0.71 for group 1 and group 2, respectively). Higher dosing elicited significantly more side effects. Intranasal (S)‐ketamine had no significant impact on thermal or mechanical detection and pain thresholds in normal or symptomatic skin areas. Conclusions: Intranasal administration of low dose (S)‐ketamine rapidly induces adequate plasma concentrations of (S)‐ketamine and subsequently of its metabolite (S)‐norketamine. The time course of analgesia correlated with plasma concentrations.     

Successful pain relief in non-responders to spinal cord stimulation: The combined use of ketamine and spinal cord stimulation

Although spinal cord stimulation (SCS) is an established therapy for chronic neuropathic pain, still 30% of patients do not respond adequately to trial stimulation. These so called “non-responders” do not receive a permanent implantation for pain relief.The induction and maintenance of central sensitization plays a pivotal role in (chronic) neuropathic pain and is thought to be the resultant of the activation of the N-methyl-d-aspartate (NMDA) receptor in the dorsal horn. Blocking the NMDA receptor through the use of the non-competitive blocker ketamine has shown to attenuate neuropathic pain, although the undesirable side effects limit its use. The present study was performed to examine whether the combination of SCS with an individually determined sub-effective dose of intrathecal (i.t.) ketamine could convert non-responders into responders in rats with chronic neuropathic pain. Rats received a partial ligation of the sciatic nerve for the induction of neuropathic pain. Animals with tactile hypersensitivity to von Frey monofilaments (n = 15) received 30 min of SCS. Non-responders to SCS (n = 8) received their individually determined sub-effective i.t. dose of ketamine followed by 30 min of SCS. No side effects of the sub-effective dose of ketamine could be noted. The combined treatment of SCS and sub-effective dose of i.t. ketamine in non-responders resulted in a significant reduction of the withdrawal threshold in all previous non-responders to SCS, thereby converting them into responders to SCS.     

Low dose ketamine as an analgesic adjuvant in difficult pain syndromes: a strategy for conversion from parenteral to oral ketamine

Ketamine is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist with analgesic and dissociative anesthetic properties. Low dose or sub-anesthetic doses of ketamine have been used effectively as either a primary analgesic or analgesic adjuvant in a variety of pain syndromes. In this paper, three patients with difficult to treat, predominantly neuropathic pain syndromes will be described. Their pain syndromes were initially managed successfully with the addition of low dose parenteral ketamine as an analgesic adjuvant. The strategy of concurrently starting ketamine at a low dose, i.e., 40-60 mg over 24 hours, with a benzodiazepine proved effective in preventing psychotomimetic side effects. An unavoidable shortage of ketamine prompted a literature search, which suggested that the equianalgesic dose of oral ketamine could be lower than the parenteral dose. Subsequently the patients were converted to oral ketamine at doses 30 to 40% of the previous parenteral dose. Their pain syndromes remained controlled on the lower dose of oral ketamine with remarkably few side effects. The implications of this warrant further discussion and study.     

Safety and efficacy of prolonged outpatient ketamine infusions for neuropathic pain

Ketamine has demonstrated usefulness as an analgesic to treat nonresponsive neuropathic pain; however, it is not widely administered to outpatients due to fear of such side effects as hallucinations and other cognitive disturbances. This retrospective chart review is the first research to study the safety and efficacy of prolonged low-dose, continuous intravenous (IV) or subcutaneous ketamine infusions in noncancer outpatients. Thirteen outpatients with neuropathic pain were administered low-dose IV or subcutaneous ketamine infusions for up to 8 weeks under close supervision by home health care personnel. Using the 10-point verbal analog score (VAS), 11 of 13 patients (85%) reported a decrease in pain from the start of infusion treatment to the end. Side effects were minimal and not severe enough to deter treatment. Prolonged analgesic doses of ketamine infusions were safe for the small sample studied. The results demonstrate that ketamine may provide a reasonable alternative treatment for nonresponsive neuropathic pain in ambulatory outpatients.     

Neuropathological findings after continuous intrathecal administration of S(+)-ketamine for the management of neuropathic cancer pain

Questions have been raised about the potential neurotoxicity of the neuraxial use of ketamine although ketamine and its active enantiomer S(+)-ketamine have been used intrathecally and epidurally (caudally) for the management of perioperative pain and in a variety of chronic pain syndromes. Clinical experience following neuraxial administration of S(+)-ketamine has been documented without reference to local central nervous system toxicity following this approach. In addition, there are no preclinical safety data regarding stability, compatibility, and neurotoxicity on intrathecal use of single S(+)-ketamine or combinations of S(+)-ketamine, morphine, bupivacaine, and clonidine. In the present case, the continuous intrathecal administration of S(+)-ketamine, in combination with morphine, bupivacaine, and clonidine resulted in adequate pain relief in a patient suffering from intractable neuropathic cancer pain. However, postmortem observation of the spinal cord and nerve roots revealed severe histological abnormalities including central chromatolysis, nerve cell shrinkage, neuronophagia, microglial upregulation, and gliosis. Based on our results, neuraxial administration of S (+)-ketamine cannot be recommended for clinical practise before a systematic study of toxicology of neuraxial S(+)-ketamine in animals or humans has been performed.     

Perioperative ketamine does not prevent chronic pain after thoracotomy

Thoracotomy is often responsible for chronic pain, possibly of neuropathic origin. To confirm preclinical studies, the preventive effects of perioperative ketamine were tested in a randomized, double‐blind, placebo‐controlled clinical trial on persistent neuropathic pain after thoracotomy. Eighty‐six patients scheduled for thoracotomy under standardised general anaesthesia were randomised to receive either ketamine (1mgkg⁻¹ at the induction, 1mgkg⁻¹h⁻¹ during surgery, then 1mgkg⁻¹ during 24h; n=42) or normal saline (n=44). Postoperative analgesia included a single dose of intrapleural ropivacaine, intravenous paracetamol and nefopam, and patient‐controlled intravenous morphine. Vital parameters and analgesia were recorded during the 48 first postoperative hours. Seventy‐three patients were followed up. The patient's chest was examined 1–2 weeks, 6 weeks and 4 months after surgery. At the last two observations, spontaneous pain score over a one‐week period (visual analogue scale), neuropathic pain score (NPSI), and intake of analgesics, were assessed. No drug affecting neuropathic pain (except opiates) was given during the follow‐up. Two patients in each group were lost to follow‐up after the 6 week visit. Ketamine improved immediate postoperative pain, but the groups were similar in terms of neuropathic pain and intake of analgesics, 6 weeks (NPSI score: ketamine: 1.25 [0–4.125]; placebo: 1 [0–4]) and 4 months after surgery. Thus, ketamine given in 24‐h infusion failed to prevent chronic neuropathic pain after thoracotomy. Other perioperative preventive long‐lasting treatments or techniques could be tested in this context.     

Continuous brachial plexus block as treatment for the Pancoast syndrome

BACKGROUND: Six patients with severe neuropathic pain caused by a Pancoast tumor were treated with the continuous administration of local anesthetics. These patients had not responded to any other treatment, including nonsteroidal anti-inflammatory drugs, opioids, dexamethasone, tricyclic antidepressants, anticonvulsants, ketamine, and transcutaneous electric nerve stimulation. INTERVENTIONS: An axillary catheter was placed in the brachial plexus using a posterior approach that has not been described previously. A continuous infusion system of local anesthetics was delivered via a catheter. In two patients, the main purpose was to evaluate the technical possibilities and implications of this new approach. In all patients, the visual analogue scale score was evaluated until the patient died. In four additional patients, the quality of life and performance skills were recorded. RESULTS: In all patients, there was a significant reduction in the visual analog scale score, and there was an increase in performance skills and quality of life in four patients. No side effects occurred from this technique or from the continuous administration of local anesthetics. CONCLUSIONS: We conclude that neuropathic pain may be treated by local anesthetics administered through an axillary catheter placed in the brachial plexus. This technique is reversible and is preferable to destructive procedures such as cordotomy.     

N of 1 randomised controlled trials of oral ketamine in patients with chronic pain.

Anecdotal reports suggest that the general anaesthetic drug ketamine, taken orally in low doses, can give rise to some extra analgesia in patients with refractory neuropathic pain. This study was designed to determine the proportion of patients with chronic neuropathic pain responding to oral ketamine, and then to separate the true treatment effect from non-specific effects by means of an n of 1 randomised controlled trial. Twenty-one patients gave informed consent and completed daily pain diaries and continued on their usual treatments (drug and non-drug) for the duration of the study. After a 'baseline' week, oral ketamine was taken once a day for 1 week. The dose of 20 mg was increased each day until an analgesic effect was noticed or adverse effects occurred, or until a maximum of 100 mg was reached. Those patients responding to oral ketamine were then entered into the n of 1 randomised trial which consisted of three treatment/placebo week pairs. Twelve patients did not progress to the n of 1 trial because of no benefit and/or intolerable adverse effects (dizziness, drowsiness etc.). Nine patients completed the n of 1 trial; there was no difference between the ketamine and placebo weeks in six patients; one patient demonstrated effective analgesia with ketamine, but it was of short duration and marred by unpleasant adverse effects; two patients showed some evidence of a beneficial response to ketamine, and continued with the oral ketamine after the trial. We conclude that oral ketamine only gave rise to an extra analgesic response in three out of 21 patients with chronic neuropathic pain (14%). Adverse effects limited the use of the drug in almost half of the patients. The n of 1 trial was useful in demonstrating no true therapeutic effect for the ketamine in two thirds of the patients progressing to that part of the trial.     

Low doses of dextromethorphan have a beneficial effect in the treatment of neuropathic pain

N‐methyl‐D‐aspartate receptor (NMDAR) antagonists may be given in persistent neuropathic pain, but adverse events especially with ketamine may limit their clinical use. Less central and cognitive adverse events are described with dextromethorphan and memantine. These molecules have been explored in many preclinical and clinical studies, but data are conflicting as regards neuropathic pain alleviation. Dextromethorphan and memantine have been administered to animals after spinal nerve ligation (SNL) to evaluate their antinociceptive/cognitive effects and associated molecular events, including the phosphorylation of several tyrosine (pTyr¹³³⁶, pTyr¹⁴⁷²) residues in the NR2B NMDAR subunit. Spinal nerve ligation and sham animals received dextromethorphan (10 mg/kg, i.p.), memantine (20 mg/kg, i.p.) or saline (1 mL/kg, i.p.). These drugs were administered once symptoms of allodynia and hyperalgesia had developed. Tests were carried out before and after surgery. Tactile allodynia, mechanical hyperalgesia and spatial memory were, respectively, evaluated by von Frey, Randall & Selitto and Y‐maze tests and molecular events by Western blot analysis. Spinal nerve‐ligated animals displayed nociception and impaired spatial memory. Dextromethorphan, but not memantine, reversed neuropathic pain (NP) symptoms, restored spatial memory integrity and decreased the expression of pTyr¹³³⁶NR2B. Following postoperative administration of dextromethorphan, this study has demonstrated for the first time a concordance between behaviour, cognitive function and molecular events via pTyr¹³³⁶NR2B for neuropathic pain alleviation. Confirmation of these findings in patients would constitute a major step forward in the treatment of neuropathic pain and in the improvement of cognitive function and quality of life.     

Treatment of central post-stroke pain with oral ketamine

Case report of 68 year old female with central post-stroke pain successfully treated with oral ketamine. The patient's pain was refractory to conventional pain treatments and she had persistent right hemi-body neuropathic pain with allodynia and hyperalgesia. An intravenous ketamine trial, followed by oral ketamine with titration to 50mg three times a day was beneficial in decreasing allodynia and hyperalgesia, as well as improving functional capabilities. Known side effects including dysphoria, hallucinations, and paranoid feelings were attenuated with benzodiazepines.     

Glutamate antagonists for treatment of neuropathic pain

An altered glutamatergic transmission within the central nervous system is supposed to be involved in the generation and propagation of neuropathic pain. Results from experimental studies with animal models of neuropathic pain demonstrate that glutamate antagonists have a positive effect on various parameters. Clinical studies with the NMDA-receptor antagonists ketamine, amantadine, memantine and dextromethorphan and with the antiepileptics gabapentin and lamotrigine, which reduce presynaptic release of glutamate,have been performed. They have shown that most of these substances can reduce neuropathic pain. Important side effects of the NMDA receptor antagonists are hallucination and agitation, whereas tiredness and dizziness are the ones of the antiepileptics. Till now, glutamate antagonists are not drugs of first choice for the treatment of neuropathic pain. However, they are an effective alternative in case the established drugs are not helpful or are not tolerated well.     

Role of oxidative stress in pathophysiology of peripheral neuropathy and modulation by N-acetyl-L-cysteine in rats.

OBJECTIVES: The objectives of this study were to examine the role of reactive oxygen species and oxidative stress in peripheral neuropathy and behavioural pain responses in experimentally induced chronic constriction injury (CCI) of sciatic nerve of rat. Effect of N-acetyl-L-cysteine (NAC) administered intraperitoneally, was also investigated on CCI-induced neuropathic pain in rats. METHODS: Neuropathy was induced by CCI of the right sciatic nerve in ketamine anaesthetized rats. Effect of intraperitoneally administered NAC in rats was also investigated using nociceptive behavioural tests. Malondialdehyde, an index of oxidative stress and antioxidant enzymes was also estimated in ligated sciatic nerve. RESULTS: Behavioural tests, mechanical, thermal and cold stimuli confirmed the development of neuropathic pain after the CCI. The malondialdehyde levels of ligated sciatic nerves were significantly increased compared to non-ligated sciatic nerves (sham operated). The antioxidant enzyme reduced, glutathione was inhibited, while superoxide dismutase increased. However, catalase remained unaffected in the injured sciatic nerves. Intraperitoneal administration of NAC resulted in significant reduction of hyperalgesia in CCI-induced neuropathic rats. CONCLUSIONS: This study identifies antioxidants superoxide dismutase and reduced glutathione, and oxidative stress as important determinants of neuropathological and behavioural consequences of CCI-induced neuropathy, and NAC may be a potential candidate for alleviation of neuropathic pain.     

An intravenous ketamine test as a predictive response tool in opioid-exposed patients with persistent pain

Chronic pain patients who are treated with opioid therapy represent a significant challenge to medical professionals. When pain recurs in the face of a previously effective opioid regimen, treatment options include dose escalation, opioid rotation, drug holidays, and the addition of adjuvants. Some experts advocate the use of N-methyl-D-aspartate receptor (NMDA-R) antagonists to combat tolerance. Recently, the use of an intravenous (i.v.) ketamine infusion to predict the response to a dextromethorphan (DX) treatment trial has been described. In this study, 56 opioid-exposed patients with recurrent pain were treated with a low-dose (0.1mg/kg) i.v. ketamine test followed by a DX treatment course. Using previously designated cutoff values for a positive response to ketamine (67% or more pain relief) and DX (50% or more pain relief), the sensitivity, specificity, positive predictive value, and negative predictive value for an i.v. ketamine infusion to predict subsequent response to DX treatment were 72%, 68%, 52%, and 85%, respectively. The observed agreement between analgesic responses was 78%, indicating a highly significant correlation (r=0.54, P=0.0001). Subgroup classification revealed no significant differences in the response to either ketamine or DX treatment based on pain classification (i.e., nociceptive, neuropathic, or mixed) or placebo response. In contrast, a weaker correlation between ketamine and DX response was found in subjects requiring high-dose rather than low-dose opioid therapy. A significant correlation also was noted between the development of side effects for the two NMDA-R antagonists. Based on these results, we conclude that an i.v. ketamine test may be a valuable tool in predicting subsequent response to DX treatment in opioid-exposed patients. with persistent pain.