Synergistic antinociceptive effects of ketamine and morphine in the orofacial capsaicin test in the rat

BACKGROUND: The clinical efficacy of the noncompetitive N-methyl-d-aspartate receptor antagonist ketamine for treating orofacial pain has already been reported. Side effects related to psychotomimetic disturbances, however, limit ketamine use as an analgesic. Theoretically, this limitation could be minimized by using low doses of ketamine in combination with other analgesics. In the present study, the potential synergistic antinociceptive interaction between ketamine and morphine in the orofacial capsaicin test in rats was investigated. METHODS: Male Sprague-Dawley rats were subcutaneously injected with solvent, ketamine, morphine, or combination of both drugs. Thirty minutes later, the orofacial capsaicin test was performed by injecting of 1.5 microg/25 microl of a capsaicin solution into the vibrissa pad. Animal behavior was recorded on videotape and analyzed off-line. The total time spent on rubbing-scratching nociceptive behavior during a period of 42 min was measured. RESULTS: Subcutaneously administered ketamine (0.4, 1.25, 4, 12.5 mg/kg), morphine (0.5, 1, 2, 4 mg/kg) and ketamine + morphine (0.20 + 0.12, 0.40 + 0.24, 0.80 + 0.49, 1.61 + 0.97, 3.21 + 1.94 mg/kg) reduced the rat facial rubbing-scratching behavior in a dose-dependent manner. Isobolographic analysis showed that the ketamine + morphine association inhibited the studied behavior in a superadditive manner. CONCLUSIONS: These results indicate that ketamine and morphine have antinociceptive effects on the orofacial capsaicin test. Furthermore, their combination produces synergistic antinociception. It is therefore suggested that, used together, ketamine and morphine might be clinically efficient at lower doses than those currently used when administered separately. This could provide a useful strategy for the clinical management of orofacial pain.     

Synergistic Antinociceptive Effects of Ketamine and Morphine in the Orofacial Capsaicin Test in the Rat

Background: The clinical efficacy of the noncompetitive N-methyl-d-aspartate receptor antagonist ketamine for treating orofacial pain has already been reported. Side effects related to psychotomimetic disturbances, however, limit ketamine use as an analgesic. Theoretically, this limitation could be minimized by using low doses of ketamine in combination with other analgesics. In the present study, the potential synergistic antinociceptive interaction between ketamine and morphine in the orofacial capsaicin test in rats was investigated.

Methods: Male Sprague-Dawley rats were subcutaneously injected with solvent, ketamine, morphine, or combination of both drugs. Thirty minutes later, the orofacial capsaicin test was performed by injecting of 1.5 [mu]g/25 [mu]l of a capsaicin solution into the vibrissa pad. Animal behavior was recorded on videotape and analyzed off-line. The total time spent on rubbing-scratching nociceptive behavior during a period of 42 min was measured.

Results: Subcutaneously administered ketamine (0.4, 1.25, 4, 12.5 mg/kg), morphine (0.5, 1, 2, 4 mg/kg) and ketamine + morphine (0.20 + 0.12, 0.40 + 0.24, 0.80 + 0.49, 1.61 + 0.97, 3.21 + 1.94 mg/kg) reduced the rat facial rubbing-scratching behavior in a dose-dependent manner. Isobolographic analysis showed that the ketamine + morphine association inhibited the studied behavior in a superadditive manner.     

Adding ketamine to morphine for patient-controlled analgesia after major abdominal surgery: a double-blinded, randomized controlled trial.

In this double-blinded, randomized controlled trial we tested if the addition of ketamine to morphine for patient-controlled analgesia (PCA) resulted in improved analgesic efficacy and lower pain scores compared with morphine PCA alone after major abdominal surgery. Seventy-one patients were randomly allocated to receive either morphine 1 mg/mL (Group M) or morphine 1 mg/mL plus ketamine 1 mg/mL (Group MK) delivered via PCA after surgery. No other analgesics or regional blocks were permitted during the 48-h study period. Postoperatively there were no differences between the groups for subjective assessment of analgesic efficacy, pain scores at rest, and on movement, opioid consumption, or adverse events. Group MK patients performed worse in cognitive testing (P = 0.037). There was an increased risk of vivid dreaming in patients who received ketamine (relative risk = 1.8, 95% confidence interval 0.78-4.3). We conclude that small-dose ketamine combined with PCA morphine provides no benefit to patients undergoing major abdominal surgery. Implications: We performed a randomized, controlled trial comparing the use of ketamine and morphine with morphine alone to relieve pain after major abdominal surgery.Ketamine did not improve pain relief and merely increased side effects.     

Improvement of pain treatment after major abdominal surgery by intravenous S+-ketamine

The use of intraoperative racemic ketamine for pain prevention after abdominal surgery is controversial. We compared one preincisional i.v. injection of S(+)-ketamine with its preincisional and repeated intraoperative use in 45 patients undergoing surgery with epidural and general anesthesia. S(+)-ketamine is a new drug formulation that contains the more potent S(+)-stereoisomer of ketamine. Patients were randomized to receive placebo, 0.5 mg/kg preincisional S(+)ketamine, or 0.5 mg/kg preincisional and 0.2 mg/kg intraoperative S(+)-ketamine repeated at 20-min intervals. In the postoperative period, epidural ropivacaine (2 mg/mL; 0.12 mL.kg(-1).h(-1)) was infused for pain therapy. Patients who received repeated S(+)-ketamine reported smaller pain scores than those who received placebo after awakening and 3 and 6 h later (P < or = 0.05). Fewer patients with repeated S(+)-ketamine required additional analgesics than those with placebo (P < or = 0.05). Cumulative consumption of additional diclofenac and dextropropoxyphene at 24 h was less after single (P < 0.05) and repeated (P < 0.05) S(+)-ketamine versus placebo. After awakening, patients who received repeated S(+)-ketamine reported being in a better mood than those in the other groups (P < 0.05). No psychotomimetic side effects were noted. In conclusion, preincisional and repeated intraoperative small-dose S(+)-ketamine added to general and epidural anesthesia causes better postoperative pain relief than general and epidural anesthesia alone. IMPLICATIONS: After major visceral surgery, preincisional and repeated intraoperative small-dose S(+)-ketamine added to general and epidural anesthesia causes better postoperative pain relief than general and epidural anesthesia alone.     

The preventative analgesic effect of preincisional peritonsillar infiltration of two low doses of ketamine for postoperative pain relief in children following adenotonsillectomy. A randomized, double-blind, placebo-controlled study

Background:  In literature, the use of ketamine for the preventative analgesia in the management of postoperative pain is controversial. The purpose of the present study was the clinical assessment of the efficacy of preincisional peritonsillar infiltration of two doses of ketamine on postoperative pain relief compared with peritonsillar saline in children undergoing adenotonsillectomy.
Methods/materials:  Seventy-five ASA physical status I and II patients, aged 3–12 years, scheduled for adenotonsillectomy were enrolled in this randomized, double-blind, placebo-controlled study. Patients were divided into three groups of 25 each and received a local peritonsillar infiltration of 0.9% saline (group S), ketamine 0.5 mg·kg⁻¹ (group K1), or ketamine 1 mg·kg⁻¹ (group K2). All medications were 2 ml in volume which was applied 1 ml per tonsil 3 min prior to tonsillectomy. The Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and Wilson sedation scale were used to evaluate pain levels and sedative conditions, respectively.
Results:  Group S had significantly higher CHEOPS scores than group K1 and K2. Both K1 and K2 groups had comparable scores, which were not statistically significant ( P  > 0.05). During 24 h after surgery, 16 patients in group S and no patients in groups K1 or K2 needed analgesics ( P  <   0.001).
Conclusions:  A 0.5 or 1 mg·kg⁻¹ dose of ketamine given at approximately 3 min before surgery by peritonsillar infiltration provides efficient pain relief during 24 h after surgery without side-effects in children undergoing adenotonsillectomy.     

Intramuscular ketamine analgesia in emergency patients. I. Clinico--pharmacokinetic study

Effective analgesia under conditions of emergency and disaster is still a problem which can be considered as unsolved. The i.m. administration of ketamine in subanaesthetic doses could be one step forward, particularly in regard to a possible application by paramedical personnel. In order to evaluate this hypothesis, we compared 2 groups of 6 patients each, who received either 0.5 mg/kg or 1 mg/kg ketamine respectively i.m. for p.o. pain relief after tonsillectomies. The analgesic efficacy, the levels of consciousness, the blood pressure values and the ketamine plasma levels demonstrated, that effective analgesia can be obtained within 10 min following either dose. The dosage of 1 mg/kg however was followed by a transient impairment of the levels of consciousness. The pharmacokinetic data may lead to the conclusion that analgesia starts above plasma levels of 100 ng/ml. Important side effects were not be observed in these few cases. A further study, which has almost been completed, will demonstrate whether the same results apply to emergency out-patients suffering from fractures, burns etc.     

Preemptive ketamine during general anesthesia for postoperative analgesia in patients undergoing laparoscopic cholecystectomy

AIM: Preemptive analgesia is currently in use in the management of postoperative pain and no more under search. The administration of ketamine as intraoperative analgesic agent is well-known since a long time; the analgesic properties of this drug are related to its actions as a non-competitive N-methyl-D-aspartate receptors antagonist; these receptors present an excitatory function on pain transmission and this binding seems to prevent or reverse the central sensitisation of every kind of pain, including postoperative pain. In literature, the use of this anesthetic for the preemptive analgesia in the management of postoperative pain is controversial; for this reason the aim of our study was the clinical evaluation of preemptive perioperative analgesia with low-doses ketamine. METHODS: This trial involved 40 patients undergoing laparoscopic cholecystectomy, with the same surgical operator; postoperative analgesia was performed with the intraoperative administration of ketamine (0.7 mg/kg) or tramadol (15 mg/kg). A randomized, double-blind study was performed; after an inhalatory/analgesic general anesthesia (sevofluorane + remifentanyl) the postoperative-pain control was clinically evaluated through algometric measurements (Visual Analog Scale, Verbal Rating Scale, Pain Intensity Difference); supplemental doses of tramadol were administered if required, also to quantify the adequacy of analgesia, and adverse effects were evaluated. RESULTS: The results show that preemptive intraoperative analgesia with ketamine produces a good analgesia at the awakening, despite low duration (approximately 1 hour), and upgrades the analgesic effect of tramadol in the postoperative period. Among the adverse effects, some (for example nausea) were related to the administration of both analgesics and to the kind of surgery, others (hallucinosis, nystagmus, photophobia, psychomotor excitation, psychotic symptoms) were due to ketamine, and others (respiratory depression and hypotension) could be related to tramadol. Although the adverse effects due to ketamine are more numerous than those related to tramadol, the second could potentially be more dangerous. CONCLUSION: Our study suggests that preemptive low-doses ketamine is able to produce an adequate postoperative analgesia and increases the analgesic effect of tramadol; furthermore, ketamine adverse effects could be reduced by intraoperative administration of benzodiazepines and/or antiemetic drugs, or by the association of ketamine and a peripheral analgesic (ketorolac).     

Ventilatory and analgesic effects of dezocine in humans

The respiratory depressant and analgesic effects of intravenous dezocine were evaluated in six healthy volunteers. Single 0.15 mg/kg doses were compared with identical amounts of morphine, and the two drugs were given in combination. Five successive 0.15 mg/kg doses of dezocine also were given to identify dose-effect relationships. Respiratory center sensitivity was monitored by carbon dioxide (CO2) rebreathing and mouth occlusion pressure (P0.1) measurement, while analgesia to experimental pain was tested with submaximal tourniquet ischemia. Single 0.15 mg/kg doses of dezocine produced significantly more tolerance to experimental pain and greater respiratory depression than a comparable dose of morphine in the first hour, but effects of both drugs were similar thereafter. Multiple doses of dezocine progressively increased pain tolerance from 46 +/- 14% above control with the first dose to 70 +/- 18% above control with the second dose (cumulative total 0.30 mg/kg). Additional dezocine doses did not result in significantly more analgesia. Depression of CO2 sensitivity followed a similar pattern. Morphine 0.15 mg/kg, when given to subjects who had received a prior dose of dezocine, produced no additional effect beyond that observed with dezocine. With the reverse sequence, dezocine increased the respiratory depression of morphine but also produced a dramatic increment in analgesia, which suggested an additive action. Dezocine is therefore an effective analgesic with morphine-like effects. In human subjects it appears to be a slightly more potent analgesic than morphine in identical clinical doses (0.15 mg/kg). Dezocine is similar to other agonist-antagonist analgesics in that it exhibits a ceiling effect for respiratory depression that parallels its analgesic activity.     

Untoward Effects of Ketamine Combined with Diazepam for Supplementing Conduction Anaesthesia in Young and Middle-Aged Adults

Fifty-six young and 29 middle-aged adults who were scheduled for lower abdominal, anorectal or extremity surgery under epidural, sacral or brachial plexus blockades received intravenous analgesic or anaesthetic doses of ketamine, combined with diazepam, immediately before the start of the operation. Forty-one patients received no supplementary drugs for the conduction anaesthesia and were divided into two groups of controls. On the day following the operation, all the patients were asked about their postanaesthetic reactions and their acceptance of the anaesthetic technique, and the nursing staff expressed their opinion on the amount of work and supervision needed during the post-operative care of the patients. Administration of ketamine 0.5 mg/kg with diazepam 0.15 mg/kg to young or middle-aged patients was not associated with more side-effects or a greater need for post-operative care and supervision than in the control groups. Administration of anaesthetic doses of ketamine 1.5 mg/kg and 3.0 mg/kg with 0.15 mg/kg and 0.3 mg/kg of diazepam, respectively, caused significantly ( P <0.05) more post-operative anxiety and confusion, as well as a significantly greater need for post-operative care and supervision than in the control patients. It is concluded that, in young or middle-aged patients, supplementing conduction anaesthesia with ketamine 0.5 mg/kg plus diazepam 0.15 mg/kg is not associated with the untoward effects which can be expected after anaesthetic doses of 1.5 mg/kg (or more) of ketamine.     

Ketamine for co-induction of anaesthesia in oral surgery

Ketamine has additive interaction with propofol and analgesic properties. The aim was to determine if ketamine co-induction reduced propofol induction doses, improved pain relief and produced any adverse effects. Forty ASA I and II patients scheduled for extraction of third molars were enrolled in a randomised, double blind study. Group ketamine patients (n=20) received ketamine 0.3 mg/kg prior to induction with propofol running at 300 ml/h. Group control patients (n=20) received a corresponding volume of normal saline. All patients were intubated and maintained on N₂O:O₂ admixture and isoflurane. Post-operatively, patients were given i.v. fentanyl boluses, oral Panadeine Forte or Oxycodone as rescue medication for pain. Data collected consisted of propofol induction doses, blood pressure and heart rate readings at 1 min intervals, visual analogue score (VAS) pain scores at various intervals and fentanyl requirements in recovery. Duration of surgery and time to discharge were also recorded. Possible side effects of nausea, dreams and hallucinations were noted. There was no significant difference in propofol induction doses, pain requirements and pain scores between the two groups. However, there was significant increase in the blood pressure (P<0.006) and heart rate (P<0.009) at induction. The discharge time in the ketamine group was not prolonged and no adverse side-effects like bad dreams or emergence delirium were noted. We conclude that low-dose ketamine at 0.3 mg/kg does not reduce the induction dose of propofol or improve the post-operative pain of oral surgery. However, this dose does not affect recovery or produce unpleasant side-effects, making it a possibility for use in day surgery.     

Bupivacaine/ketamine is superior to intra-articu-lar ketamine analgesia following arthroscopic knee surgery

PURPOSE: Centroneuraxial and parenteral administration of ketamine has been shown to produce analgesia. However, this analgesia is limited by adverse effects. The purpose of this study was to determine whether ketamine alone or in combination with bupivacaine provides superior pain relief after surgery in patients undergoing knee arthroscopy. METHODS: Sixty patients (classified as ASA status I or II) under-going arthroscopic meniscus repair during general anesthesia were randomized to receive 1.0 mg x kg(-1) ketamine (Group K), 0.25% bupivacaine (Group B) or a combination of 1.0 mg x kg(-1) ketamine and 0.25% bupivacaine (Group BK) to a total volume of 20 mL by intra-articular route following surgery. Visual analogue score in the postanesthesia care unit at 0.5, 1, 2, 4, 6, 8, 12 and 24 hr after surgery, duration of analgesia and subsequent 24 hr consumption of rescue analgesic (dextroproxyphene/acetaminophen) were evaluated. RESULTS: The results showed significantly higher pain scores in Group K as compared to Group B and Group BK. The duration of analgesia was significantly shorter in Group K as compared to the other two groups (Group B = 5.7 +/- 0.8; Group BK = 5.1 +/- 1.1 vs Group K = 1.7 +/- 0.9 hr; P < 0.05). However, 24 hr consumption of analgesic was similar in the three groups. CONCLUSION: We conclude that intra-articular bupivacaine-ketamine combination provides better pain relief than intra-articular ketamine after day care arthroscopic knee surgery.     

P‐I‐04 Treatment for Limb Ulcer with Severe Ischemia: Therapeutic Angiogenesis by Autologous Transplantation of Bone‐Marrow

Aim: Limb ulcer due to severe ischemia often needs revascularization. In our hospital, the result of lower extremity bypass surgery for these patients is satisfactory, however, indication of this procedure is limited pathologically and technically. We recently have demonstrated a possibility of efficacy of therapeutic angiogenesis by autologous bone marrow cell transplantation for severe ischemic ulcer of extremity. Methods: Eight patients (9limbs; 3limbs with arteriosclerosis obliterans, 6limbs with Buerger's disease) with ischemic ulcer of lower and/or upper extremity were treated with implantation of autologous bone marrow mononuclear cell into ischemic skeletal muscles. Four weeks after transplantation, efficacy of this procedure were evaluated by Visual Ana log Scale, angiography and Laser Doppler Flow Analysis (LDFA). Results: In 4 out of 9 limbs, the ulcers healed dramatically. Seven limbs revealed angiographically improvement and icrease of blood flow by LDFA. Conclusions: Our findings suggest that therapeutic angiogenesis by autologous bone marrow cell transplantation is an effective and safty strategy for patient with peripheral arterial disease. We considered that it is more effective to Buerger's disease than arteriosclerosis obliterans.     

Racemic, S(+)- and R(-)-ketamine do not increase elevated intracranial pressure

Background: There is controversy regarding the influence of ketamine and its enantiomers on cerebral haemodynamics at increased intracranial pressure (ICP). This study was designed to compare cerebrovascular responses, with particular respect to ICP, to bolus injections of racemic, S(+)- and R(−)-ketamine in an experimental model of intracranial hypertension.
Methods: Nine pigs were anaesthetised with fentanyl and vecuronium during mechanical normoventilation. The ICP was raised with extradural balloon catheters to 23 mmHg. The intra-arterial xenon clearance technique was used to determine cerebral blood flow (CBF). Three 60-s bolus injections of racemic ketamine (10 mg/kg), S-ketamine (5 mg/kg) and R-ketamine (20 mg/kg) were given in a randomised sequence. Cerebral and systemic haemodynamic responses were evaluated before and at 1, 5, 10, 15, 30 and 45 min after each injection.
Results: Racemic ketamine decreased ICP ( P =0.026) by maximally 10.8%, whereas there was no effect on ICP of S- ( P =0.178) or R-ketamine ( P =0.15). All study drugs had similar biphasic effects on CBF, with maximal initial decreases by 25–29%, followed by transient increases by 7–15%, and a reduction of mean arterial pressure by maximally 22–37%.
Conclusions: A decrease or a lack of an increase in ICP in response to intravenous bolus injections of racemic, S- or R-ketamine suggests that the administration of racemic or S-ketamine might be safe in patients with intracranial hypertension due to a space-occupying lesion. The ICP-lowering effect indicates that racemic ketamine might offer a therapeutic advantage over S-ketamine.     

The analgesic effect of intravenous ketamine and lidocaine on pain after spinal cord injury

BACKGROUND: Pain following spinal cord injury (SCI) is a therapeutic challenge. Only a few treatments have been assessed in randomized, controlled trials. The primary objective of the present study was to examine the analgesic effect of ketamine and lidocaine in a group of patients with neuropathic pain below the level of spinal cord injury. We also wanted to assess sensory abnormalities to see if this could help us to identify responders and if treatments resulted in changes of sensibility. METHODS: Ten patients with spinal cord injury and neuropathic pain below the level of injury were included. The analgesic effect of ketamine 0.4 mg kg(-1) and lidocaine 2.5 mg kg(-1) was investigated. Saline was used as placebo. The drugs were infused over 40 min. A randomized, double-blind, three-period, three-treatment, cross-over design was used. Systemic plasma concentrations of ketamine and lidocaine were assessed. Pain rating was performed using a visual analogue scale (VAS). Sensory function was assessed with a combination of traditional sensory tests and quantitative measurement of temperature thresholds. RESULTS: Response to treatment, defined as 50% reduction in VAS-score during infusion, was recorded in 5/10 in the ketamine, 1/10 in the lidocaine and 0/10 in the placebo groups. Neither ketamine nor lidocaine changed temperature thresholds or assessments of mechanical; dynamic and static sensibility. Nor could these sensory assessments predict response to treatment in this setting. Lidocaine and particularly ketamine were associated with frequent side-effects. CONCLUSION: Ketamine but not lidocaine showed a significant analgesic effect in patients with neuropathic pain after spinal cord injury. The pain relief was not associated with altered temperature thresholds or other changes of sensory function.     

The comparison of caudal ketamine,alfentanil and ketamine plus alfentanil administration for postoperative analgesia in children

BACKGROUND: Our aim was to compare the effect of single dose caudal ketamine, alfentanil or a mixture of both drugs in the treatment of pain after hypospadias repair surgery in children. METHODS: The group comprised 109 boys, ASA I-II, aged 1-9 years, who were undergoing hypospadias repair surgery as day cases. The children were randomly divided into three groups for postoperative analgesia: group 1, only alfentanil (20 microg x kg(-10) was given caudally; group 2, ketamine (0.5 mg x kg(-1)) alone; and group 3, alfentanil (20 microg x kg(-1))-ketamine (0.5 mg x kg(-1)) was given caudally. The analgesic effect of caudal block was evaluated using the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and sedation was assessed using a five-point sedation score. The first analgesic requirement time and the number of supplementary analgesics required by each child in a 24-h period were also recorded. RESULTS: No statistical differences were found in demographic characteristics, haemodynamic and respiratory parameters, objective pain scores, postoperative sedation scores and duration of surgery among the groups. The median time to first analgesia was significantly shorter in group 1 than in groups 2 and 3 (P=0.009, P=0.001). Significantly more patients in group 1 required additional postoperative analgesia (paracetamol 15 mg x kg(-1)) compared with groups 2 and 3 (P < 0.001). CONCLUSIONS: Caudal administration of ketamine 0.5 mg.kg-1 with or without alfentanil in children produced satisfactory postoperative analgesia without respiratory depression or other side-effects.     

Intravenous ketoprofen for pain relief after total hip or knee replacement

Background: There are few studies in which ketoprofen, a propionic acid derivate NSAID, has been tested as an intravenous postoperative analgesic. The aim of this double-blind, randomized, placebo-controlled work was to study the tolerability and efficacy of intravenous ketoprofen in seventy-six patients undergoing hip or knee total endoprothesis surgery using three different doses.
Methods: The patients received either ketoprofen 50 mg, 100 mg or 150 mg, or placebo as an initial intravenous loading, followed by an infusion containing 50 mg, 100 mg or 150 mg or placebo, respectively, over the following eleven and a half hours. The consumption of fentanyl was recorded and the patients assessed their pain intensity on a 10-cm visual analogue scale (VAS) at 0, 2, 4 and 12 hours. Possible side-effects were recorded at the same intervals.
Results: Patients receiving ketoprofen showed significantly lower total fentanyl consumption and significantly better pain relief at 12 hours was achieved by a 300 mg dose of ketoprofen than by placebo. Side-effects were minimal, with no differences between the groups.
Conclusion : A bolus of ketoprofen following continuous infusion of ketoprofen, coupled with a PCA-system, was an effective and safe approach for the relief of postoperative pain.     

Buprenorphine hydrochloride: determination of analgesic potency.

An open evaluation of relief from severe pain following major abdominal operations was carried out on at least ten patients, who had given written consent, with 0.1 to 0.4 mg doses of buprenorphine hydrochloride administered intramuscularly. Statistical analysis of the data showed that 0.3 mg of this compound provided quite satisfactory relief from pain for up to six hours. Seven more consenting patients were given buprenorphine hydrochloride 0.5 to 0.6 mg, but they did not receive much greater or longer pain relief than those receiving 0.3 to 0.4 mg. However, the latter patients were younger and heavier. It was concluded that buprenorphine hydrochloride 0.2 to 0.4 mg provided relief of severe pain probably as well as is observed with morphine 10 mg for the average-size patient, but the duration of pain relief with the new compound is substantially longer than with other strong analgesics previously tested. The only common side effect noted was drowsiness, which was observed during the analgesic action of the compound. No appreciable alterations were seen in the respiration, pulse rate and blood pressure. On the basis of these tests, buprenorphine hydrochloride appears to be a satisfactory analgesic for severe postoperative pain, and it deserves extensive study.     

The use of ketamine as rescue analgesia in the recovery room following morphine administration--a double-blind randomised controlled trial in postoperative patients

In some patients, control of postoperative pain can be difficult with morphine alone. This double-blind randomised controlled trial was designed to evaluate whether a small bolus dose of ketamine could improve pain scores in those patients who had inadequate relief of their postoperative pain after two standard doses of morphine. Forty-one patients with uncontrolled postoperative pain were randomly assigned to receive either morphine (M) alone, or morphine plus 0.25 mg/kg ketamine (K) in the recovery room. No other analgesics were to be given. The study had adequate power to detect a 25% difference in pain scores. There was no statistically significant difference in verbal rating scale pain scores between the two groups either in the recovery room (K = 5.16, M = 6.28, P = 0.065), or at a later time on the ward. There was no apparent difference between groups in sedation, morphine consumption, postoperative nausea and vomiting, quality of recovery or need for rescue analgesia. We could not demonstrate an effective role for ketamine in the management of problematic postoperative pain at the dose studied.     

Preoperative epidural ketamine in combination with morphine does not have a clinically relevant intra- and postoperative opioid-sparing effect

In this prospective, randomized, and double-blinded clinical trial, we evaluated the efficacy of preincisional administration of epidural ketamine with morphine compared with epidural morphine alone for postoperative pain relief after major upper-abdominal surgery. We studied 50 ASA I and II patients undergoing major upper-abdominal procedures. These patients were randomly allocated to one of the two treatment groups: patients in Group 1 received epidural morphine 50 microg/kg, whereas those in Group 2 received epidural ketamine 1 mg/kg combined with 50 microg/kg of morphine 30 min before incision. Intraoperative analgesia was provided in addition, with IV morphine, and the requirement was noted. A blinded observer using a visual analog scale for pain assessment observed patients for 48 h after surgery. Additional doses of epidural morphine were provided when the visual analog scale score was more than 4. Analgesic requirements and side effects were compared between the two groups. There were no differences between the two groups with respect to age, sex, weight, or duration or type of the surgical procedures. The intraoperative morphine requirement was significantly (P = 0.018) less in Group 2 patients (median, 6.8 mg; range, 3-15 mg) compared with patients in Group 1 (median, 8.3 mg; range, 4.5-15 mg). The time for the first requirement of analgesia was significantly (P = 0.021) longer (median, 17 h; range, 10-48 h) in Group 2 patients than in Group 1 (median, 12 h; range, 4-36 h). The total number of supplemental doses of epidural morphine required in the first 48 h after surgery was comparable (P = 0.1977) in both groups. Sedation scores were similar in both groups. One patient in Group 2 developed hallucinations after study drug administration. None of the patients in either group developed respiratory depression. Other side effects, such as pruritus, nausea, and vomiting, were also similar in both groups. Although the addition of ketamine had synergistic analgesic effects with morphine (reduced intraoperative morphine consumption and prolonged time for first requirement of analgesia), there was no long- lasting preemptive benefit seen with this combination (in terms of reduction in supplemental analgesia) for patients undergoing major upper-abdominal procedures. IMPLICATIONS: Ketamine added to epidural morphine given before surgery can decrease postoperative pain by its preemptive effect, opioid potentiation, and prevention of acute opioid tolerance. A single epidural bolus of 1 mg/kg of ketamine with morphine given before major upper-abdominal surgery did not result in a clinically relevant reduction in postoperative pain relief.     

The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance

Perioperative opioids increase postoperative pain and morphine requirement, suggesting acute opioid tolerance. Furthermore, opioids elicit N-methyl-D-aspartate (NMDA)-dependent pain hypersensitivity. We investigated postfentanyl morphine analgesic effects and the consequences of NMDA-receptor antagonist (ketamine) pretreatment. The rat nociceptive threshold was measured by the paw-pressure vocalization test. Four fentanyl boluses (every 15 min) elicited a dose-dependent (a) increase followed by an immediate decrease of the nociceptive threshold and (b) reduction of the analgesic effect of a subsequent morphine administration (5 mg/kg): -15.8%, -46.6%, -85.1% (4 x 20, 4 x 60, 4 x 100 microg/kg of fentanyl, respectively). Ketamine pretreatment (10 mg/kg) increased the fentanyl analgesic effect (4 x 60 microg/kg), suppressed the immediate hyperalgesic phase, and restored the full effect of a subsequent morphine injection. Fentanyl also elicited a delayed dose-dependent long-lasting decrease of the nociceptive threshold (days) that was prevented by a single ketamine pretreatment before fentanyl. However, a morphine administration at the end of the fentanyl effects restored the long-lasting hyperalgesia. Repeated ketamine administrations were required to obtain a complete preventive effect. Although ketamine had no analgesic effect per se at the dose used herein, our results indicate that sustained NMDA-receptor blocking could be a fruitful therapy for improving postoperative morphine effectiveness. IMPLICATIONS: Fentanyl-induced analgesia is followed by early hyperalgesia (hours), acute tolerance to the analgesic effects of morphine, and long-lasting hyperalgesia (days). All these phenomena are totally prevented by repeated administrations of the NMDA-receptor antagonist, ketamine, simultaneously with fentanyl and morphine administration.