Anesth Analg 1997 Mar;84(3):560-563
Department of Anesthesiology, Chonbuk National University Medical School, Chonju, Republic of Korea.
Increased postoperative pain may be caused by central nervous system plasticity, which may be related to actions of N-methyl-D-aspartic acid (NMDA) receptors on neurons in the dorsal horn of the spinal cord. Opioids act mainly on presynaptic receptors and reduce neurotransmitter release, while ketamine antagonizes NMDA receptors and prevents wind-up and long-term potentiation. Thus, we postulated that central nervous system sensitization would be prevented more effectively by the preoperative use of these two drugs simultaneously, and the effect of preemptive analgesia would be demonstrated. Ketamine, 60 mg, and morphine, 2 mg, were injected epidurally through an indwelling catheter that was inserted at the T7-8 interspace in 60 ASA physical status class 1-2 patients. The drugs were injected before induction of anesthesia (Group 1; n = 30) or immediately after removal of a surgical specimen (Group 2; n = 30). An additional 2 mg of morphine was injected when the patients complained of resting pain. The analgesic effect was assessed by the time from first analgesic injection to second dose and the number of patients who needed supplemental injections. Complications were also noted. The duration of analgesia was longer (P < 0.01) in Group 1 (31.1 +/- 16.0 h) than in Group 2 (21.1 +/- 12.0 h), and the proportion of patients who needed supplemental injections was decreased (P < 0.05) in Group 1 (56.7%) compared with Group 2 (90.0%). The incidence of adverse effects was not different between the two groups. In conclusion, preoperative administration of morphine and ketamine is more effective in reducing postoperative pain than it is when given during the operation.
Can J Anaesth 1997 Jan;44(1):31-37
Department of Anesthesiology, National Defense Medical Center, Taipei, Taiwan, Republic of China.
PURPOSE: Pre-emptive analgesia can improve postoperative pain management. The purpose of this study was to examine the effectiveness of ketamine as a pre-emptive analgesic as previous studies have shown the involvement of N-methyl-D-Aspartate (NMDA) receptor in neuroplasticity. METHODS: Forty-five ASA 1-2 patients, undergoing unilateral total knee replacement were studied. In the study groups, epidural lidocaine was used as the primary anaesthestic. Patients received ketamine + morphine epidurally 30 min either before (group EB) or after skin incision (group EA). Group G patients received general anaesthesia and ketamine + morphine were given 30 min after skin incision via an epidural catheter used for postoperative pain control. Epidural morphine and ketamine in lidocaine was given to all patients at the end of surgery and every 12 hr for three days for analgesia supplemented with PCA morphine. The time until first PCA trigger, morphine consumption, pain scores, satisfaction scores, and morphine related side effects were recorded at 6, 12, 24, 48 and 72 hr after surgery. RESULTS: Epidural ketamine plus morphine with lidocaine before surgical incision produced better pain relief and patient satisfaction than when given after incision. A longer time to PCA and decreased morphine consumption were observed in group EB than in group G. In group EA, epidural anaesthesia also produced some pre-emptive analgesic effect compared with general anaesthesia shown by decreased morphine consumption. CONCLUSIONS: Administration of ketamine plus morphine with epidural lidocaine anesthesia before surgery provided improved postoperative analgesia compared with general anaesthesia alone or when analgesics were given after skin incision.
Anesth Analg 1987 Aug;66(8):735-738
This double-blind study evaluates whether ketamine given epidurally is effective for postoperative pain relief, and compares the effects of epidural ketamine with those of epidural morphine. Sixty-eight patients undergoing abdominal gynecologic surgery were randomly assigned into six groups (control; ketamine 4, 6, and 8 mg in saline; 6 mg in 10% glucose; morphine 3 mg). All patients were anesthetized with thiopental, nitrous oxide, and enflurane, and drugs were administered epidurally at the end of the operation. The duration of analgesia in the ketamine groups did not differ from that in control patients and the difference in diluent had no observable effects. Significantly, none of the patients in the morphine group needed additional analgesics within 24 hr, whereas 85% in the other five groups did. We conclude that ketamine administered epidurally is inadequate for postoperative pain relief after gynecologic operations.
Can J Anaesth 1996 Apr;43(4):379-383
Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
PURPOSE: Ketamine has been administered epidurally and intrathecally for operative and post-operative pain control. Animal studies showed potentiation of analgesia induced by ketamine and morphine. We hypothesized that intrathecal ketamine would potentiate the effects of intrathecal morphine in the treatment of cancer pain. METHODS: A double blind, cross over study was designed to evaluate the effect of ketamine on spinal morphine analgesia in terminal cancer pain patients. A two-phase protocol was used; phase M, intrathecal morphine alone twice daily; phase M + K, co-administration of ketamine (1.0 mg) with morphine intrathecally twice daily. The dose of morphine was titrated upwards until acceptable pain relief was achieved, defined by numeric rating scales (0-10) < or = 3, and the rescue dose of morphine was less than 5 mg after each intrathecal administration for two days. The dose of intrathecal morphine was defined as the effective dose. RESULTS: The effective dose of intrathecal morphine in phase M of 0.38 +/- 0.04 mg.day-1 was higher than that in phase M + K (0.17 +/- 0.02 mg.day-1) (P < 0.05). The average pain scales were 7.95 +/- 0.25 before intrathecal drug administration. Pain scales were decreased to 2.2 +/- 0.17 (P < 0.05) in phase M and 1.95 +/- 0.20 (P < 0.05) in phase M + K after the effective dose of morphine had been reached. No serious side effects were observed in this study. CONCLUSION: The present study demonstrates that ketamine enhances the analgesic effect of morphine, thus reducing the dose of intrathecal morphine.
Can Anaesth Soc J 1986 Jan;33(1):16-21
Thirty-four patients of ASA physical status I or II scheduled for gall bladder surgery were studied in a comparative prospective trial to evaluate the efficacy of epidural and intramuscular ketamine for postoperative pain relief. They were divided randomly into three groups. Group I (11 patients) received 30 mg intramuscular ketamine. Group II (10 patients) and Group III (13 patients) received 10 and 30 mg ketamine in 10 ml saline respectively, through epidural catheters. Pain was evaluated every two hours for the first 24 hours post-operatively by using a linear analogue pain scale from 0-10. Ketamine was given on the patient's request and whenever the pain score exceeded three. Ketamine produced analgesia in all patients studied. The reduction of pain score after two and four hours in Group I and III was significant when compared to Group II. Seven patients (54 per cent) in Group III did not require further analgesia after the initial injection. However, following 10 mg epidural ketamine or 30 mg IM ketamine, post-operative pain was more frequent. Four patients who received epidural ketamine complained of transient burning pain in the back during injection. No patient developed respiratory depression, psychic disturbance, cardiovascular instability, bladder dysfunction or neurologic deficit. It is concluded that 30 mg epidural ketamine is a safe and effective method for postoperative analgesia.
Masui 1995 Apr;44(4):583-587
Department of Anesthesiology, Ohta Central Nishinouchi Hospital, Koriyama.
Postoperative pain relief and sedation with epidural ketamine were studied. Twenty-four patients for elective upper abdominal surgery were divided into 4 groups. Epidural catheter was inserted into thoracic epidural space before induction of general anesthesia. In each group, either 0.25% bupivacaine 5 ml only, ketamine 0.1 mg.kg-1 + bupivacaine 5 ml, or ketamine 0.3 mg.kg-1 + bupivacaine 5 ml, or ketamine 0.5 mg.kg-1 + bupivacaine 5 ml was injected into epidural catheter for complaint of pain in recovery room. In ketamine injected groups, blood pressure and heart were unchanged, but respiration rate increased significantly. Patients in ketamine 0.3 or 0.5 mg.kg-1 injected groups, pain relief and sedation score were significantly intensified, but patients in ketamine 0.5 mg.kg-1 injected group, incidence of pain in the back during injection and headache was high. We conclude that epidural ketamine is useful for postoperative pain relief, and the superior dose of epidural ketamine is 0.3 mg.kg-1.
Anaesthesia 1989 Jul;44(7):555-558
Department of Anaesthesia, Kings College Hospital, Denmark Hill, London.
Twenty patients who had abdominal hysterectomy under general anaesthesia were randomly assigned to receive either epidural ketamine (30 mg), or epidural diamorphine (5 mg) peri-operatively and on first request for analgesia. Failure to obtain satisfactory analgesia with one of the agents was treated by epidural administration of the other. Pain was assessed by an independent observer, and by the patient using a visual analogue scale. The mean (SD) pain score on recovery from general anaesthesia, on a scale of 0-4, was 2.9 (1.2) for the ketamine group and 1.0 (1.0) for the diamorphine group (p less than 0.01). The mean (SD) time to first request for analgesia was 272 (206) and 72 (41) minutes in the diamorphine and ketamine groups respectively (p less than 0.01). All patients in the diamorphine group obtained adequate analgesia, but all patients in the ketamine group were changed to epidural diamorphine. Epidural ketamine does not appear to be a sufficiently effective alternative to epidural diamorphine for routine use in postoperative pain.
Acta Anaesthesiol Sin 1996 Sep;34(3):151-155
Department of Anesthesiology, National Defense Medical Center, Taipei, Taiwan, R.O.C.
The N-methyl-D-aspartate (NMDA) receptor system plays an important role in nociceptive signal modulation in the central nerve system. There is considerable evidence that NMDA receptor antagonists can abolish hypersensitivity of nociceptors in animal models. In this case report, we described a patient who suffered post-herpetic neuralgia with severe pain, allodynia, and hyperesthesia over right side T2 to T8 dermatomes. Treatment with conventional doses of non-steroid anti-inflammatory drug (NSAID), antidepressant, anticonvulsant and benzodiazepine failed to provide satisfactory pain relief. With the patient's consent, we administered subanalgesic doses of ketamine (10 mg), morphine (1 mg), and 6 ml bupivacaine (0.1%) through the thoracic epidural route. After the treatment, hyperalgesia and allodynia improved dramatically, and the receptive field also reduced. After four weeks' treatment, satisfactory pain relief was achieved with conventional analgesics treatment. The combination of relatively low doses of morphine, ketamine and bupivacaine epidurally provides effective pain relief in this case. The result strongly suggests a synergy from this combination that warrants a formal study of the dose-response relationship involved in this treatment and the mechanism by which this effect is achieved. This regimen provides a promising treatment for the neuropathic pain with limited side effects.
Anaesthesist 1994 Nov;43 Suppl 2:S34-S40
[Article in German]
Parke-Davis GmbH, Freiburg.
The epidural and intrathecal administration of opioids has gained wide acceptance among anaesthesiologists during recent years. Ketamine, an anaesthetic agent with an unusual pharmacological profile, has also attracted some interest in this context, as in subanaesthetic doses it provides marked analgesia without inducing respiratory depression. Since the first publication on the epidural administration of ketamine in humans in 1982, various studies on the pharmacology, toxicology and clinical use of ketamine by the epidural and intrathecal routes have been published. PHARMACOLOGY. There is a large body of evidence to show that systemically administered ketamine interacts with different neurotransmitter systems and may even produce local anaesthetic effects when used for intravenous regional anaesthesia. The results of animal studies suggest that ketamine may cause complete sensory and motor blockade after intrathecal administration, which leads to high concentrations in the cerebrospinal fluid. One study investigating the effects after epidural administration showed motor blockade only after high doses of ketamine. Binding to local opiate receptors seems to play only a minor role, whereas significant analgesia after even low doses of ketamine is the result of antagonism to NMDA receptors. In vitro and animal data also suggest an involvement of the descending inhibitory pathways, mainly through inhibition of re-uptake of neurotransmitters. NEUROTOXICITY. Data relating to the neurotoxicity of ketamine after intrathecal administration are confusing. While no neurotoxic effects have been observed in studies in primates and rabbits, experimental rats and monkeys have sustained lesions: they may have been caused by a faulty puncture technique or by inherent neurotoxicity of the drug. CLINICAL RESULTS. The only study of intrathecal administration of ketamine in humans revealed local anaesthetic effects after doses of 50 mg. For epidural use, doses up to 30 mg did not give adequate pain relief after surgery in controlled studies, but had some analgesic effect in patients with chronic pain syndromes. When doses of 30 mg and over were used, postoperative analgesia was generally assessed as good. CONCLUSIONS. When administered intrathecally, ketamine shows local anaesthetic effects in both animals and humans. Unfortunately, all commercially available ketamine preparations contain disinfectant agents whose intrathecal administration is prohibited. Epidurally administered ketamine doses of 30 mg and more seem to provide adequate postoperative analgesia, while smaller doses might be effective in chronic pain syndromes. More studies investigating the neurotoxicity and clinical effects of ketamine on the spinal cord are needed before wider use of the substance by this route of administration can be recommended.