Postamputation pain and sensory changes in treatment-naive patients: characteristics and responses to treatment with tramadol, amitriptyline, and placebo

BACKGROUND: Pain after amputation is common but difficult to treat, and few controlled treatment studies exist. METHODS: In the current study, 94 treatment-naive posttraumatic limb amputees with phantom pain (intensity: mean visual analog scale score [0-100], 40 [95% confidence interval, 38-41]) were randomly assigned to receive individually titrated doses of tramadol, placebo (double-blind comparison), or amitriptyline (open comparison) for 1 month. Nonresponders were crossed over to the alternative active treatment. RESULTS: After 1 month, phantom pain intensity was 1 (0-2) in the 48 tramadol responders (mean dose, 448 mg [95% confidence interval, 391-505 mg]), 0 (0-0) in the 40 amitriptyline responders (55 [50-59] mg), and 0 (0-0) in the 2 placebo responders, with similar effects on stump pain. Cytochrome P-450 2D6 slow metabolizers derived greater analgesia from tramadol and less from amitriptyline compared with fast metabolizers in the first treatment week (P < 0.01). Electrical pain thresholds increased and pain during suprathreshold stimulation decreased markedly on the stump and, to a lesser extent, on the contralateral limb after 1 month of treatment with amitriptyline or tramadol. Adverse effects were minor in all groups, but more common with tramadol. CONCLUSIONS: In treatment-naive patients, both amitriptyline and tramadol provided excellent and stable phantom limb and stump pain control with no major adverse events. Both drugs demonstrated consistent and large antinociceptive effects on both the stump and the intact limbs.     

A Randomized Study of the Effects of Gabapentin on Postamputation Pain

Background: Pain after amputation is common but difficult to treat. Therefore, the authors examined whether postoperative treatment with gabapentin could reduce postamputation stump and phantom pain.

Methods: Forty-six patients scheduled to undergo lower limb amputation were randomly assigned to receive oral gabapentin or placebo. Treatment was started on the first postoperative day and continued for 30 days. The daily dose of gabapentin or placebo was gradually increased to 2,400 mg/day. The intensity of stump and phantom pain was recorded every day on a numeric rating scale (0-10) during the 30-day treatment period. Five interviews were performed after 7, 14, and 30 days and after 3 and 6 months.

Results: Results from 41 patients were included in the data analysis. The risk of phantom pain (gabapentin vs. placebo) was 55.0% versus 52.6% (risk difference, 2.4%; 95% confidence interval, -28.9 to 33.7%; P = 0.88; 30 days) and 58.8% versus 50.0% (risk difference, 8.8%; 95% confidence interval, -23.3 to 40.9%; P = 0.59; 6 months). The median intensity of phantom pain (gabapentin vs. placebo) was 1.5 (range, 0-9.0) versus 1.2 (range, 0-6.6) (P = 0.60; 30 days) and 1.0 (range, 0-6.0) versus 0.5 (range, 0-5.0) (P = 0.77; 6 months). The median intensity of stump pain was 0.85 (range, 0-8.2) versus 1.0 (range, 0-5.4) (P = 0.68; 30 days) and 0 (range, 0-8.0) versus 0 (range, 0-5.0) (P = 0.58; 6 months).     

Analgesic Effects of Intravenous Lidocaine and Morphine on Postamputation Pain: A Randomized Double-blind, Active placebo-controlled, Crossover Trial

Background: Phantom and stump pains, common sequelae of limb amputations, are significant impediments to rehabilitation of amputees. The pathophysiology and optimal treatment of postamputation pain states are unclear. While stump pain may result from neuromas in the stump, phantom pain is thought to be related to cortical reorganization. The authors hypothesized that morphine and lidocaine may have differential effectiveness on stump and phantom pains.

Methods: The authors conducted a randomized double-blind, active-placebo-controlled, crossover trial to compare the analgesic effects of intravenous morphine and lidocaine on postamputation stump and phantom pains. An intravenous bolus followed by an intravenous infusion of morphine (0.05 mg/kg bolus + 0.2 mg/kg infusion over 40 min), lidocaine (1 mg/kg bolus + 4 mg/kg infusion) and the active placebo, diphenhydramine (10 mg bolus + 40 mg infusion), were performed on three consecutive days. Phantom and stump pain ratings and sedation scores were recorded at 5-min intervals using a 0-100 visual analog scale. Pain measures were initiated 30 min before drug infusion and continued until 30 min after the end of infusion. Subjects' self-reported pain relief and satisfaction were assessed at the end of each infusion.

Results: Thirty-one of 32 subjects enrolled completed the study. Eleven subjects had both stump and phantom pains, 11 and 9 subjects had stump and phantom pain alone, respectively. Baseline pain scores were similar in the three drug groups. Compared with placebo, morphine reduced both stump and phantom pains significantly (P < 0.01). In contrast, lidocaine decreased stump (P < 0.01), but not phantom pain. The changes in sedation scores for morphine and lidocaine were not significantly different from placebo. Compared with placebo, self-reported stump pain relief was significantly greater for lidocaine (P < 0.05) and morphine (P < 0.01), while phantom pain relief was greater only for morphine (P < 0.01). Satisfaction scores were significantly higher for lidocaine (mean +/- SD: 39.3 +/- 37.8, P < 0.01) and morphine (45.9 +/- 35.5, P < 0.01) when compared with placebo (9.6 +/- 21.0).     

A randomized study of the effects of gabapentin on postamputation pain

BACKGROUND: Pain after amputation is common but difficult to treat. Therefore, the authors examined whether postoperative treatment with gabapentin could reduce postamputation stump and phantom pain. METHODS: Forty-six patients scheduled to undergo lower limb amputation were randomly assigned to receive oral gabapentin or placebo. Treatment was started on the first postoperative day and continued for 30 days. The daily dose of gabapentin or placebo was gradually increased to 2,400 mg/day. The intensity of stump and phantom pain was recorded every day on a numeric rating scale (0-10) during the 30-day treatment period. Five interviews were performed after 7, 14, and 30 days and after 3 and 6 months. RESULTS: Results from 41 patients were included in the data analysis. The risk of phantom pain (gabapentin vs. placebo) was 55.0% versus 52.6% (risk difference, 2.4%; 95% confidence interval, -28.9 to 33.7%; P = 0.88; 30 days) and 58.8% versus 50.0% (risk difference, 8.8%; 95% confidence interval, -23.3 to 40.9%; P = 0.59; 6 months). The median intensity of phantom pain (gabapentin vs. placebo) was 1.5 (range, 0-9.0) versus 1.2 (range, 0-6.6) (P = 0.60; 30 days) and 1.0 (range, 0-6.0) versus 0.5 (range, 0-5.0) (P = 0.77; 6 months). The median intensity of stump pain was 0.85 (range, 0-8.2) versus 1.0 (range, 0-5.4) (P = 0.68; 30 days) and 0 (range, 0-8.0) versus 0 (range, 0-5.0) (P = 0.58; 6 months). CONCLUSION: Gabapentin administered in the first 30 postoperative days after amputation does not reduce the incidence or intensity of postamputation pain.     

Analgesic effects of intravenous lidocaine and morphine on postamputation pain: a randomized double-blind, active placebo-controlled, crossover trial

BACKGROUND: Phantom and stump pains, common sequelae of limb amputations, are significant impediments to rehabilitation of amputees. The pathophysiology and optimal treatment of postamputation pain states are unclear. While stump pain may result from neuromas in the stump, phantom pain is thought to be related to cortical reorganization. The authors hypothesized that morphine and lidocaine may have differential effectiveness on stump and phantom pains. METHODS: The authors conducted a randomized double-blind, active-placebo-controlled, crossover trial to compare the analgesic effects of intravenous morphine and lidocaine on postamputation stump and phantom pains. An intravenous bolus followed by an intravenous infusion of morphine (0.05 mg/kg bolus + 0.2 mg/kg infusion over 40 min), lidocaine (1 mg/kg bolus + 4 mg/kg infusion) and the active placebo, diphenhydramine (10 mg bolus + 40 mg infusion), were performed on three consecutive days. Phantom and stump pain ratings and sedation scores were recorded at 5-min intervals using a 0-100 visual analog scale. Pain measures were initiated 30 min before drug infusion and continued until 30 min after the end of infusion. Subjects' self-reported pain relief and satisfaction were assessed at the end of each infusion. RESULTS: Thirty-one of 32 subjects enrolled completed the study. Eleven subjects had both stump and phantom pains, 11 and 9 subjects had stump and phantom pain alone, respectively. Baseline pain scores were similar in the three drug groups. Compared with placebo, morphine reduced both stump and phantom pains significantly (P < 0.01). In contrast, lidocaine decreased stump (P < 0.01), but not phantom pain. The changes in sedation scores for morphine and lidocaine were not significantly different from placebo. Compared with placebo, self-reported stump pain relief was significantly greater for lidocaine (P < 0.05) and morphine (P < 0.01), while phantom pain relief was greater only for morphine (P < 0.01). Satisfaction scores were significantly higher for lidocaine (mean +/- SD: 39.3 +/- 37.8, P < 0.01) and morphine (45.9 +/- 35.5, P < 0.01) when compared with placebo (9.6 +/- 21.0). CONCLUSIONS: Stump pain was diminished both by morphine and lidocaine, while phantom pain was diminished only by morphine, suggesting that the mechanisms and pharmacological sensitivity of stump and phantom pains are different.     

Systemic administration of local anesthetics to relieve neuropathic pain: a systematic review and meta-analysis

We reviewed randomized controlled trials to determine the efficacy and safety of systemically administered local anesthetics compared with placebo or active drugs. Of 41 retrieved studies, 27 trials of diverse quality were included in the systematic review. Ten lidocaine and nine mexiletine trials had data suitable for meta-analysis (n = 706 patients total). Lidocaine (most commonly 5 mg/kg IV over 30-60 min) and mexiletine (median dose, 600 mg daily) were superior to placebo (weighted mean difference on a 0-100 mm pain intensity visual analog scale = -10.60; 95% confidence interval: -14.52 to -6.68; P < 0.00001) and equal to morphine, gabapentin, amitriptyline, and amantadine (weighted mean difference = -0.60; 95% confidence interval: -6.96 to 5.75) for neuropathic pain. The therapeutic benefit was more consistent for peripheral pain (trauma, diabetes) and central pain. The most common adverse effects of lidocaine and mexiletine were drowsiness, fatigue, nausea, and dizziness. The adverse event rate for systemically administered local anesthetics was more than for placebo but equivalent to morphine, amitriptyline, or gabapentin (odds ratio: 1.23; 95% confidence interval: 0.22 to 6.90). Lidocaine and mexiletine produced no major adverse events in controlled clinical trials, were superior to placebo to relieve neuropathic pain, and were as effective as other analgesics used for this condition.     

Gabapentin in postamputation phantom limb pain: a randomized,double-blind,placebo-controlled,cross-over study

BACKGROUND AND OBJECTIVES: Severe phantom limb pain after surgical amputation affects 50% to 67% of patients and is difficult to treat. Gabapentin is effective in several syndromes of neuropathic pain. Therefore, we evaluated its analgesic efficacy in phantom limb pain. METHODS: Patients attending a multidisciplinary pain clinic with phantom limb pain were enrolled into this randomized, double-blind, placebo-controlled, cross-over study. Other anticonvulsant therapy was discontinued. Each treatment was 6 weeks separated by a 1-week washout period. Codeine/paracetamol was allowed as rescue analgesia. The daily dose of gabapentin was titrated in increments of 300 mg to 2400 mg or the maximum tolerated dose. Patients were assessed at weekly intervals. The primary outcome measure was visual analog scale (VAS) pain intensity difference (PID) compared with baseline at the end of each treatment. Secondary measures were indices of sleep interference, depression (Hospital Anxiety and Depression [HAD] scale), and activities of daily living (Bartel Index). RESULTS: Nineteen eligible patients (mean age, 56 years; range, 24 to 68 years; 16 men) were randomized, of whom 14 completed both arms of the study. Both placebo and gabapentin treatments resulted in reduced VAS scores compared with baseline. PID was significantly greater than placebo for gabapentin therapy at the end of the treatment (3.2 +/- 2.1 v 1.6 +/- 0.7, P =.03). There were no significant differences between placebo and gabapentin therapy in terms of the number of tablets of rescue medication required, sleep interference, HAD scale, or Bartel Index. The medication was well tolerated with few reports of adverse effects. CONCLUSIONS: After 6 weeks, gabapentin monotherapy was better than placebo in relieving postamputation phantom limb pain. There were no significant differences in mood, sleep interference, or activities of daily living, but a type II error cannot be excluded for these variables.     

Effects of anesthesia on pain after lower-limb amputation

OBJECTIVE: To evaluate the effects of epidural, spinal, and general anesthesia on pain after lower-limb amputation. DESIGN: Cross-sectional survey. SETTING: Postamputation clinic. PATIENTS: 150 patients who were evaluated one to 24 months after their lower-limb amputation. INTERVENTIONS: Patients received epidural, spinal, or general anesthesia for their amputation. MEASUREMENTS: Standardized questions were used to assess stump pain, phantom sensation, or phantom limb pain preoperatively and postoperatively. Pain intensity was assessed on a verbal rating scale of 0 to 10. After the interview, each patient's medical history and anesthetic record were assessed. RESULTS: Patients who had received epidural anesthesia and those who had received spinal anesthesia recalled significantly less pain in the week after their surgery (P < 0.05). After an average of 14 months, there was no difference in stump pain, phantom limb sensation, or phantom limb pain between patients who received epidural anesthesia, those who received spinal anesthesia, and those who received general anesthesia for their amputation. Phantom limb pain continued to be frequent and severe despite patients' use of opioid analgesics, amitriptyline, and gabapentin. CONCLUSIONS: Patients who received epidural anesthesia and those who received spinal anesthesia recalled better analgesia in the first week after their amputation than did patients who received general anesthesia. Anesthetic technique had no effect on stump pain, phantom limb sensation, or phantom limb pain at 14 months after lower-limb amputation.     

The analgesic effect of tramadol after intravenous injection in healthy volunteers in relation to CYP2D6

Tramadol analgesia results from a monoaminergic effect by tramadol itself and an opioid effect of its metabolite (+)-M1 formed by O-demethylation of tramadol by CYP2D6. In this study we sought to determine the impact of (+)-M1 on the analgesic effect of tramadol evaluated by experimental pain models. The effect of an IV injection of 100 mg tramadol on experimental pain was studied 15-90 min after dosing in volunteers, 10 extensive metabolizers with CYP2D6 and 10 poor metabolizers without CYP2D6 in 2 placebo-controlled trials. The pain tests included detection and tolerance threshold to single electrical sural nerve stimulation, pain summation threshold to repetitive electrical sural nerve stimulation (temporal summation), and the cold pressor test. In extensive metabolizers, tramadol reduced discomfort experienced during the cold pressor test (P = 0.002). In poor metabolizers, the pain tolerance thresholds to sural nerve stimulation were increased (P = 0.04). (+)-M1 could be detected in the serum samples from all extensive metabolizers except one, but (+)-M1 was below the limit of determination in all poor metabolizers. The opioid effect of (+)-M1 appears to contribute to the analgesic effect of tramadol, but the monoaminergic effect of tramadol itself seems to create an analgesic effect.     

Perioperative intravenous ketamine infusion for the prevention of persistent post-amputation pain: a randomized, controlled trial

We hypothesized that perioperative ketamine administration would modify acute central sensitization following amputation and hence reduce the incidence and severity of persistent post-amputation pain (both phantom limb and stump pain). In a randomized, controlled trial, 45 patients undergoing above- or below-knee amputation received ketamine 0.5 mg x kg(-1) or placebo as a pre-induction bolus followed by an intravenous infusion of ketamine 0.5 mg x kg(-1) x h(-1) or normal saline for 72 hours postoperatively. Both groups received standardized general anaesthesia followed by patient-controlled intravenous morphine. The surface area of allodynia over the stump was mapped at days 3 and 6. Postamputation pain was assessed at days 3 and 6 and at 6 months postoperatively. We found no significant difference between groups in the surface area of stump allodynia or in morphine consumption. There was an unexplained, but significant, increase in the incidence of stump pain in the ketamine group at day 3. At six-month review, the incidence of phantom pain was 47% in the ketamine group and 71% in the control group. This did not reach statistical significance (P=0.28) as the power of the study was based on the search for a large treatment effect. The incidence of stump pain at six months was 47% in the ketamine group and 35% in the control group (P=0.72). There were no significant between-group differences in pain severity throughout the study period. Ketamine at the dose administered did not significantly reduce acute central sensitization or the incidence and severity of post-amputation pain.     

Prevention of phantom pain after major lower limb amputation by epidural infusion of diamorphine, clonidine and bupivacaine.

Phantom limb pain may appear in up to 85% of patients after amputation. There is no effective treatment. Perioperative epidural infusion of morphine and bupivacaine, alone or in combination, is effective in preventing phantom limb pain in patients with pre-existing limb pain. Serious side-effects, however, make them difficult to manage on a general ward. Clonidine has been shown to be an effective postoperative analgesia when applied epidurally. To mitigate the potentially serious side-effects of all these drugs, we have studied their combined efficiency in preventing phantom limb pain in a prospective controlled study of 24 patients undergoing lower limb amputation. In the study group (n = 13), an epidural infusion containing bupivacaine 75 mg, clonidine 150 micrograms and diamorphine 5 mg in 60 ml normal saline was given at 1-4 ml/h 24-48 h preoperatively and maintained for at least 3 days postoperatively. The control group (n = 11) received on-demand opioid analgesia. Pain was assessed by visual analogue scale at 7 days, 6 months and 1 year. At 1 year follow-up, one patient in the study group and eight patients in the control group had phantom pain (P < 0.002) and two patients in the study group versus eight patients in the control group had phantom limb sensation (P < 0.05). There was no significant improvement in stump pain. We conclude that perioperative epidural infusion of diamorphine, clonidine and bupivacaine is safe and effective in reducing the incidence of phantom pain after amputation.     

Synergistic Antinociceptive Effect of Amitriptyline and Morphine in the Rat Orofacial Formalin Test

Background: Combination therapy is often used to increase the clinical utility of analgesic agents. The coadministration of two compounds may achieve analgesia at doses lower than those required for either compound alone, leading to enhanced pain relief and reduction of adverse effects. Herein, the authors describe the effect of coadministration of morphine and amitriptyline on cutaneous orofacial inflammatory pain in rats.

Methods: Amitriptyline, morphine, or the combination of amitriptyline and morphine was administered systemically to rats, and antinociceptive effects were determined by means of the rat orofacial formalin test. Isobolographic analysis was used to define the nature of the interactions between morphine and amitriptyline.

Results: Amitriptyline as well as morphine produced a dose-related inhibition in the first phase and the second phase of rubbing activity. ED50 values against rubbing behavior were 14.6 mg/kg (95% confidence interval, 10.2-33.5 mg/kg) and 1.3 mg/kg (95% confidence interval, 1.0-1.7 mg/kg) for amitriptyline and morphine, respectively. Combinations of increasing fractional increments of amitriptyline and morphine ED50 doses produced a synergistic effect against rubbing behavior, as revealed by isobolographic analysis.     

Phantom pain and posttraumatic pain conditions

After limb or body part amputation, three different types of perceptual sensitive phenomena can be recognized. They can be all named posttraumatic neuropathies: painless sensations in phantom limb, painful phantom limb and painful posttraumatic stump. Painless sensations in phantom limb can be seen in 90% of cases in resected body parts as soon as first postoperative day, less often during the first week, and its clinical characteristics are usually stabilized during the first year. Painful posttraumatic stump appears because of pain neuroma existing, that forms at the proximal end of amputational stump as a consequence of physiological nerve regeneration attempt. Frequency of pain significantly varies considering authors from 5-90%, depending on definition of this phenomena and criteria used. It is considered that 5-10% mast be under permanent medicament treatment. Phantom pain appears more often in elderly and people with specific affective personality construction. It can be permanent, burning, nettling, tearing (25%), or intermittent, lancerating, in the shape of electrical discharging (32%), but it can also have bizarre attributes. Phantom pain appearance usually announces its duration in the longer period. After two years it is present at 59% of patients, with decreasing intensity, and only 5-10% suffer severe pain. In our Institute in the period from 1980-2003, 48 patients have been treated, 36 patients with medicamentous treatment, local blockades and chronic stimulations, and 12 patients, who did not react at conservative treatment were operated. In operated group in 10 patients pain disappeared, one patient it was with decreasing intensity, and one patient was without change.     

Morphine versus Mexiletine for Treatment of Postamputation Pain: A Randomized, Placebo-controlled, Crossover Trial

Background: Stump and phantom pains are debilitating sequelae of amputations that are often resistant to treatment. The efficacy of pharmacologic therapies, including opioids and sodium channel blockers, for postamputation pain is uncertain.

Methods: The authors conducted a double-blind, randomized, placebo-controlled, crossover study in adult patients with postamputation pain of 6 months or longer and greater than 3 on a 0-10 numeric pain rating scale. Each of the three treatment periods (morphine, mexiletine, or placebo) included a 1-week drug-free interval followed by 4-week titration, 2-week maintenance, and 2-week drug-taper phases. The primary outcome measure was change in average pain intensity from the drug-free baseline to the last week of maintenance.

Results: Sixty amputees were enrolled; data were analyzed from 56 subjects for one drug period, 45 subjects for two drug periods, and 35 subjects who completed all three drug periods. The mean morphine and mexiletine dosages were 112 and 933 mg, respectively. Morphine treatment provided lower pain scores compared with placebo and mexiletine (P = 0.0003). The mean percent pain relief during treatment with placebo, mexiletine, and morphine was 19, 30, and 53%, respectively (P < 0.0001, morphine vs. placebo and mexiletine). The numbers needed to treat to obtain 50% and 33% decreases in pain intensity with morphine were 5.6 and 4.5, respectively. Treatment with morphine was associated with a higher rate of side effects.     

Randomized prospective study comparing preoperative epidural and intraoperative perineural analgesia for the prevention of postoperative stump and phantom limb pain following major amputation

BACKGROUND AND OBJECTIVES: Acute stump pain and phantom limb pain after amputation is a significant problem among amputees with a reported incidence of phantom limb pain in the first year following amputation as high as 70%. Epidural analgesia before limb amputation is commonly used to reduce postamputation acute stump pain in the immediate postoperative period and phantom pain in the first year. We investigated whether immediate postamputation stump pain and phantom pain in the first year is reduced by preoperative epidural block with bupivacaine and diamorphine compared with intraoperative placement of a perineural catheter infusing bupivacaine. METHODS: In a randomized prospective trial, 30 patients scheduled for lower limb amputation were randomly assigned epidural bupivacaine at the standard rate used in our hospital (0.166%, 2 to 8 mL/h) and diamorphine (0.2 to 0.8 mg/h) for 24 hours before and during operation (14 patients; epidural group) and 3 days postoperatively, or an intraoperatively placed perineural catheter (16 patients; perineural group) for intra and postoperative administration of bupivacaine (0.25%, 10 mL/h). All patients had general anesthesia for the amputation and were asked about stump and phantom pain in the first 3 days and then at 6 and 12 months by an independent examiner. Study endpoints were rate of stump and phantom pain, intensity of stump and phantom pain, and consumption of opioids. The groups were well matched in baseline characteristics. RESULTS: Stump pain scores in the first 3 days were significantly higher in the perineural group compared with the epidural group (P <.01). After 3 days, 4 (29%) patients in the epidural group and 7 (44%) in the perineural group had phantom pain (P =.32). Numbers of patients with phantom pain for epidural versus perineural group were: 5 (63%) versus 7 (88%) (P =.25) at 6 months; 3 (38%) versus 4 (50%) (P =.61) at 12 months. Stump pain and phantom sensation were similar in both groups at 6 and 12 months. CONCLUSIONS: Using our regimen, perioperative epidural block started 24 hours before the amputation is not superior to infusion of local anaesthetic via a perineural catheter in preventing phantom pain, but gives better relief of stump pain in the immediate postoperative period.     

A comparison of tramadol, amitriptyline, and meperidine for postepidural anesthetic shivering in parturients.

Tramadol is effective for treating shivering during epidural anesthesia in parturients. In addition to its low affinity to opioid receptors, tramadol exerts a modulatory effect on central monoaminergic pathways. In this respect, there are parallels between the mechanisms of the action of tramadol and antidepressants such as amitriptyline. Meperidine is often recommended for the treatment of postanesthetic shivering. This prospective, double-blinded, and randomized clinical study was performed to compare the antishivering effects and accompanying side effects among tramadol, meperidine, and amitriptyline for the treatment of postepidural anesthetic shivering. Forty-five parturients who shivered during cesarean delivery under epidural anesthesia and requested antishivering treatment were randomly allocated to one of three groups for IV treatment: Group T (n = 15) received tramadol 0.5 mg/kg, Group M (n = 15) received meperidine 0.5 mg/kg, and Group A (n = 15) received amitriptyline 15 or 20 mg. The response rate (shivering ceased after treatment in 15 min) was 87% and 93% for Groups T and M, respectively, compared with 13% in Group A (P < 0.01). The time that elapsed from treatment to the time shivering ceased was 5.1 +/- 3.6 min (mean +/- SD) for Group T and 4.2 +/- 2.3 min for Group M. There was a significantly more frequent incidence (33%) of somnolence in Group M when compared with Groups T (7%) and A (0%) (P < 0.01). However, no significant differences were shown for pruritus, nausea, vomiting, or Apgar scores of newborns. We concluded that both tramadol and meperidine show a significantly faster response rate in the treatment of postepidural anesthetic shivering when compared with amitriptyline in the dosage used; tramadol had a decreased incidence of somnolence when compared with meperidine. IMPLICATIONS: This study was performed to compare the antishivering and side effects among tramadol, amitriptyline, and meperidine for the treatment of postepidural anesthetic shivering in parturients. Both tramadol and meperidine show a significantly faster response rate in the treatment of shivering when compared with amitriptyline. Tramadol had a less frequent incidence of somnolence than meperidine.     

Effect of Perioperative Vitamin C on the Incidence of Complex Regional Pain Syndrome: A Systematic Review and Meta-Analysis

Complex regional pain syndrome type 1 (CRPS-I) is a complex complication that occurs after limb extremity surgeries. Controversy exists regarding the effectiveness of vitamin C in reducing that condition. Therefore, we conducted this systematic review and meta-analysis to assess the role of vitamin C on CRPS-I and functional outcomes after distal radius, wrist, foot, and ankle surgeries. We searched Medline (via PubMed), Embase, the Cochrane Library, Clinicaltrial.gov, and Google Scholar for relevant studies comparing perioperative vitamin C versus placebo after distal radius, wrist, foot, and ankle surgeries from infinity to May 2021. Continuous data such as functional outcomes and pain scores were pooled as mean differences, while dichotomous variables such as the incidence of complex regional pain syndrome and complications were pooled as odds ratios, with 95% confidence interval, using R software (meta package, version 4.9-0) for Windows. Eight studies were included. The timeframe for vitamin C administration in each study ranged from 42 to 50 days postinjury and/or surgical fixation. The effect size showed that vitamin C was associated with a decreased rate of CRPS-1 than placebo (odds ratio 0.33, 95% confidence interval [0.17, 0.63]). No significant difference was found between vitamin C and placebo in terms of complications (odds ratio 1.90, 95% confidence interval [0.99, 3.65]), functional outcomes (mean difference 6.37, 95% confidence interval [-1.40, 14.15]), and pain scores (mean difference -0.14, 95% confidence interval [-1.07, 0.79]). Overall, vitamin C was associated with a decreased rate of CRPS-I than placebo, while no significant difference was found regarding complications, functional outcomes, and pain scores. These results hold true when stratifying fracture type (distal radius, ankle, and foot surgeries) and vitamin C dose (500 mg or 1 g).     

Sind Tramadol-Enantiomere für die postoperative Schmerztherapie besser geeignet als das Racemat? Eine randomisierte, Plazebo- und Morphin-kontrollierte Doppelblindstudie*

The goal of this prospective, randomised and double-blind pilot-study was to investigate the analgesic potency and the side-effects of tramadol enantiomers in clinical practice. One hundred patients recovering from orthopaedic surgery with a postoperative pain intensity of more than 50 on a visual analogue scale 0–100 mm (Table 1) were recruited for the study. They were treated in a randomised, double-blind way with a maximal dose of 150 mg i.v. (+)-, (?)-tramadol, racemate, or 15 mg i.v. morphine or saline in the placebo group (5 groups, 20 patients each). The primary criterium of efficacy was the number of responders defined as patients with a pain reduction of at least 20 on VAS after 40 min. In case of pain, responders were allowed to continue with the double-blind drug up to six hours. The non-responders were treated with morphine as the rescue analgesic. The secondary criterium was the incidence and severity of side-effects. Six patients terminated the study prematurely. One patient was excluded because of an allergic reaction to morphine, one patient could not be treated sufficiently with morphine, four were excluded because of protocol violations. There were 8 responders in the (+)-tramadol-, 6 in the (?)-tramadol- and 6 in the racemate group, 16* (P<0,05) in the morphine group, and 5 in the placebo group. Pain intensity after 40 min was reduced by 20 (p<0,05), 17 (p<0,05), 17 (p<0,05), 36 (p<0,01 vs placebo, p<0,05 vs (+)-, (?)-tramadol, and racemate group) and 5 mm on the VAS in the (+)-, (?)-, (+/?)-tramadol-, morphine- and placebo-group, respectively. Thirty eight adverse events like nausea, vomiting, PCO2-increase, and urinary retention occurred in 20 patients, most frequently in the (+)-tramadol- and morphine group. Sedation was significantly less profound in the (?)-tramadol group 1–4 h postoperatively. There were no side-effect in the tramadol racemate group. The enantiomers were equal to the racemate in analgesic potency, but inferior by far to morphine. They showed more adverse events and, hence, can not be preferred to the racemate in postoperative pain therapy.     

Phantom pain and sensation among British veteran amputees

Using a mail-delivered questionnaire, we surveyed 590 veteran amputees concerning phantom pain, phantom sensation and stump pain. They were selected randomly from a population of 2974 veterans with long-standing limb amputation(s) using a computer random number generator. Eighty- nine percent responded and of these, 55% reported phantom limb pain and 56% stump pain. There was a strong correlation between phantom pain and phantom sensation. The intensity of phantom sensation was a significant predictor for the time course of phantom pain. In only 3% of phantom limb pain sufferers did the condition become worse. One hundred and forty-nine amputees reporting phantom pain discussed their pain with their family doctors; 49 were told that there was no treatment available. Transcutaneous electric nerve stimulation, analgesics and non-steroidal anti-inflammatory drugs were satisfactory methods for controlling phantom limb pain.      

Postoperative analgesia with tramadol and metamizol. Continual infusion versus patient controlled analgesia

OBJECTIVE: The study compares the i.v. analgesia of tramadol and dipyrone delivered either as continuous infusion or as patient controlled analgesia (PCA). METHODS: After approval by the local ethics committee and informed consent 203 patients recovering from abdominal surgery were randomly assigned to pain treatment either by PCA or continuous intravenous infusion.Both groups received the same analgesic drug combination of tramadol (20 mg/ml) and dipyrone (200 mg/ml).The PCA bolus was set to 1 ml, the continuous infusion varied between 0-8 ml/h according to individual needs.Demographic and surgery related data were compared between the treatment groups, as well as pain scores, analgesic consumption and response rates over a 48 hour study period.A patient was assessed as non responder when rescue medication was necessary during the study period or the patient rated analgesia as insufficient during the final interview. RESULTS: In total,data of 191 patients (infusion-group: 94, PCA-group: 97) could be analyzed.Tramadol consumption was higher in the infusion group compared to the PCA-group (48 hours: 1009.4+/-494.4 vs. 813.0+/-585.3 mg;p<0.001) with no difference in pain scores. In the infusion group, significantly more interventions were necessary to adjust the infusion rate to individual needs (min-max: 1-15 vs. 0-2).The number of non responders amounted to 30 (31.9%) and 18 (18.6%;p=0.03) in the infusion and PCA group, respectively. CONCLUSIONS: PCA with tramadol and dipyrone can be considered an alternative for postoperative pain management and provided a more individualized treatment approach with lower analgesic consumption and more responders compared to a continuous infusion.