Chronic phantom limb pain: the effects of calcitonin, ketamine, and their combination on pain and sensory thresholds.

BACKGROUND: Calcitonin was effective in a study of acute phantom limb pain, but it was not studied in the chronic phase. The overall literature on N-methyl-D-aspartate antagonists is equivocal. We tested the hypothesis that calcitonin, ketamine, and their combination are effective in treating chronic phantom limb pain. Our secondary aim was to improve our understanding of the mechanisms of action of the investigated drugs using quantitative sensory testing. METHODS: Twenty patients received, in a randomized, double-blind, crossover manner, 4 i.v. infusions of: 200 IE calcitonin; ketamine 0.4 mg/kg (only 10 patients); 200 IE of calcitonin combined with ketamine 0.4 mg/kg; placebo, 0.9% saline. Intensity of phantom pain (visual analog scale) was recorded before, during, at the end, and the 48 h after each infusion. Pain thresholds after electrical, thermal, and pressure stimulation were recorded before and during each infusion. RESULTS: Ketamine, but not calcitonin, reduced phantom limb pain. The combination was not superior to ketamine alone. There was no difference in basal pain thresholds between the amputated and contralateral side except for pressure pain. Pain thresholds were unaffected by calcitonin. The analgesic effect of the combination of calcitonin and ketamine was associated with a significant increase in electrical thresholds, but with no change in pressure and heat thresholds. CONCLUSIONS: Our results question the usefulness of calcitonin in chronic phantom limb pain and stress the potential interest of N-methyl-D-aspartate antagonists. Sensory assessments indicated that peripheral mechanisms are unlikely important determinants of phantom limb pain. Ketamine, but not calcitonin, affects central sensitization processes that are probably involved in the pathophysiology of phantom limb pain.

Is the combination of morphine with ketamine better than morphine alone for postoperative intravenous patient-controlled analgesia?

BACKGROUND: The addition of ketamine to morphine for patient-controlled analgesia (PCA) is supported by previous basic and clinical research, but has been challenged by subsequent negative studies. Important limitations of previous studies are the low number of patients analyzed, the use of morphine-ketamine combinations that may not the optimal, and that not all the relevant outcomes have been analyzed. In this study, we compared the combination of morphine and ketamine with morphine alone for postoperative PCA in large patient groups. We used a morphine-ketamine combination identified by an optimization procedure in our previous study. METHODS: After major elective orthopedic surgery, 352 patients received either PCA with morphine bolus 1.5 mg (Group M, n = 176) or a bolus of morphine plus ketamine 1.5 mg each (Group MK, n = 176) in a randomized, double-blind fashion. Unsatisfactory treatment was defined as the occurrence of either inadequate analgesia or unacceptable side effects. In addition, total consumption of PCA drugs, duration of PCA use, direct medical costs, and number of patients with chronic postoperative pain 3 and 6 mo after operation were recorded. RESULTS: The incidence of unsatisfactory treatment was 33.0% in Group M and 36.9% in Group MK (P = 0.50). No significant differences were found between the groups with respect to secondary end points. CONCLUSIONS: Small-dose ketamine combined with morphine for PCA provides no benefit to patients undergoing major orthopedic surgery and cannot be recommended for routine use.

The well-being model: a new drug interaction model for positive and negative effects.

BACKGROUND: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account. METHODS: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs. RESULTS: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed. CONCLUSIONS: The model is consistent with clinical knowledge and supports previously published experimental results on optimal drug combinations. This new framework improves understanding of the characteristics of drug combinations used in clinical practice and can be used in clinical research to identify optimal drug dosing.

A new model for drug interactions and optimal drug dosing.

Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account. We propose a new method to study drug interactions considering also their side effects and to identify optimal drug dosing. The model is consistent with clinical knowledge and can explain previously published experimental results, improving our understanding of the characteristics of drug combinations used in clinical practice.

Combinations of bupivacaine, fentanyl, and clonidine for lumbar epidural postoperative analgesia: a novel optimization procedure.

BACKGROUND: The authors developed and applied a method to optimize the combination of bupivacaine, fentanyl, and clonidine for continuous postoperative lumbar epidural analgesia. METHODS: One hundred eighteen patients undergoing knee or hip surgery participated in the study. Postoperative epidural analgesia during 48 h after surgery was optimized under restrictions dictated by side effects. Initially, eight combinations of bupivacaine, fentanyl, and clonidine (expressed as drug concentration in the solution administered) were empirically chosen and investigated. To determine subsequent combinations, an optimization model was applied until three consecutive steps showed no decrease in pain score. For the first time in a clinical investigation, a regression model was applied when the optimization procedure led to combinations associated with unacceptable side effects. RESULTS: The authors analyzed 12 combinations with an allowed bupivacaine concentration range of 0-2.5 mg/ml, a fentanyl concentration range of 0-5 microg/ml, and a clonidine concentration range of 0-5 microg/ml. The best combinations of bupivacaine, fentanyl, and clonidine concentrations were 1.0 mg/ml-1.4 microg/ml-0.5 microg/ml, 0.9 mg/ml-3.0 microg/ml-0.3 microg/ml, 0.6 mg/ml-2.5 microg/ml-0.8 microg/ml, and 1.0 mg/ml-2.4 microg/ml-1.0 microg/ml, respectively, all producing a similarly low pain score. The incidence of side effects was low. The application of the regression model to combinations associated with high incidence of motor block successfully directed the optimization procedure to combinations within the therapeutic range. CONCLUSIONS: The results support further study of the combinations of bupivacaine, fentanyl, and clonidine mentioned above for postoperative analgesia after knee and hip surgery. This novel optimization method may be useful in clinical research.

Combinations of morphine with ketamine for patient-controlled analgesia: a new optimization method.

BACKGROUND: According to previous studies, the addition of ketamine to morphine for intravenous patient-controlled analgesia (PCA) may be beneficial. The authors developed and applied a new model to optimize the combination of morphine, ketamine, and a lockout interval for PCA after lumbar spine and hip surgery. METHODS: One-hundred two patients undergoing lumbar spine or hip surgery participated in the study. The analgesic effect of PCA during 48 h after surgery was optimized under restrictions dictated by side effects. Initially, eight combinations of morphine, ketamine (expressed as drug concentration in the solution administered), and a lockout interval (i.e., minimal allowed time between two consecutive PCA boluses) were empirically chosen and investigated. To determine subsequent combinations, an optimization model was applied until three consecutive steps showed no decrease in pain score. RESULTS: The authors analyzed 12 combinations with an allowed morphine and ketamine range in a PCA solution of 0-2 mg/ml and a lockout interval range of 5-12 min. During the optimization procedure, a reduction in mean pain scores with a low incidence of side effects was observed. The procedure converged to a morphine-to-ketamine ratio of 1:1 and a lockout interval of 8 min. CONCLUSIONS: Using a novel method to analyze drug combinations, the study supports combinations of morphine with ketamine in a ratio of 1:1 and a lockout interval of 8 min for postoperative PCA following spine and hip surgery.

Drug combinations in pain treatment: a review of the published evidence and a method for finding the optimal combination.

The evidence of the usefulness of drug combinations in pain management is reviewed and the problem of finding the optimal combination is presented. For post-operative pain, adding a non-steroidal anti-inflammatory drug (NSAID) or paracetamol to intravenous morphine is beneficial. Adding ketamine to intravenous morphine may be advantageous, but ketamine has a narrow therapeutic window. The combination paracetamol-NSAID is probably superior to either component alone. For post-operative epidural analgesia, combinations of low doses of a local anaesthetic, an opioid and adrenaline (epinephrine) are superior to single-drug regimens. There are virtually no data on the advantages of combinations over single drugs in neuropathic and chronic musculoskeletal pain. Adding NSAIDs or ketamine to opioids may be useful in cancer pain. Because of the enormous number of possible combinations, randomized controlled trials may fail to test the optimal combination. A stepwise optimization model that has been applied in clinical investigations is presented.