M. Zenz

Long-term oral opioid therapy in patients with chronic nonmalignant pain

In contrast to the use of opioids for the treatment of acute and chronic cancer pain, the administration of chronic opioid therapy for pain not due to malignancy remains controversial. We describe 100 patients who were chronically given opioids for treatment of nonmalignant pain. Most patients experienced neuropathic pain or back pain. We used sustained-release dihydrocodeine, buprenorphine, and sustained-release morphine. Pain reduction was measured with visual analogue scales (VAS), and the Karnofsky Performance Status Scale was used to assess the patients function. Good pain relief was obtained in 51 patients and partial pain relief was reported by 28 patients. Only 21 patients had no beneficial effect from opioid therapy. There was a close correlation between the sum and the peak VAS values (r = 0.983; p less than 0.0001) and pain reduction was associated with an increase in performance (p less than 0.0001). The most common side effects were constipation and nausea. There were no cases of respiratory depression or addiction to opioids. Our results indicate that opioids can be effective in chronic nonmalignant pain, with side effects that are comparable to those that complicate the treatment of cancer pain.

Efficacy of acupuncture for the prophylaxis of migraine: a multicentre randomised controlled clinical trial

BACKGROUND Our aim was to assess the efficacy of a part-standardised verum acupuncture procedure, in accordance with the rules of traditional Chinese medicine, compared with that of part-standardised sham acupuncture and standard migraine prophylaxis with beta blockers, calcium-channel blockers, or antiepileptic drugs in the reduction of migraine days 26 weeks after the start of treatment. METHODS This study was a prospective, randomised, multicentre, double-blind, parallel-group, controlled, clinical trial, undertaken between April 2002 and July 2005. Patients who had two to six migraine attacks per month were randomly assigned verum acupuncture (n=313), sham acupuncture (n=339), or standard therapy (n=308). Patients received ten sessions of acupuncture treatment in 6 weeks or continuous prophylaxis with drugs. Primary outcome was the difference in migraine days between 4 weeks before randomisation and weeks 23-26 after randomisation. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN52683557. FINDINGS Of 1295 patients screened, 960 were randomly assigned to a treatment group. Immediately after randomisation, 125 patients (106 from the standard group) withdrew their consent to study participation. 794 patients were analysed in the intention-to-treat popoulation and 443 in the per-protocol population. The primary outcome showed a mean reduction of 2 .3 days (95% CI 1.9-2.7) in the verum acupuncture group, 1.5 days (1.1-2.0) in the sham acupuncture group, and 2.1 days (1.5-2.7) in the standard therapy group. These differences were statistically significant compared with baseline (p<0.0001), but not across the treatment groups (p=0.09). The proportion of responders, defined as patients with a reduction of migraine days by at least 50%, 26 weeks after randomisation, was 47% in the verum group, 39% in the sham acupuncture group, and 40% in the standard group (p=0.133). INTERPRETATION Treatment outcomes for migraine do not differ between patients treated with sham acupuncture, verum acupuncture, or standard therapy.

Direct conversion from oral morphine to transdermal fentanyl: a multicenter study in patients with cancer pain

&NA; Direct conversion from oral morphine to transdermal fentanyl with a ratio of oral morphine/transdermal fentanyl (100:1 mg) daily was examined in patients with cancer pain. Patients with a ‘stable and low level of cancer pain’ receiving a constant dosage of sustained release morphine during a pre‐study phase of 6 days were included in the study. Initial fentanyl dosage was calculated by a conversion table. The transdermal system was changed every 72 h and the dosage was adjusted to the needs of the patients according to the VAS scores and the requirement of liquid morphine, which was allowed to achieve sufficient pain relief. Regression analysis at the end of the study revealed a mean morphine/transdermal fentanyl ratio of 70:1. Pain relief during treatment with transdermal fentanyl was identical to sustained release morphine. However, significantly more patients took: supplemental medication with liquid morphine during transdermal fentanyl therapy. The number of patients suffering from pain attacks did not increase with transdermal fentanyl. Constipation and medication with laxatives decreased significantly during fentanyl therapy. Other side effects and vital signs were identical. Three patients suffered from a morphine withdrawal syndrom beginning within the first 24 h of transdermal fentanyl therapy. Cutaneous reactions to the patch were rare, mild and transient. Patients and physicians reported satisfaction with the transdermal therapy. 94.7% of the patients chose to continue the transdermal fentanyl therapy at the end of the study due to better performance in comparison to oral morphine. Due to these results an initial conversion from oral morphine to transdermal fentanyl with the ratio of 100:1 is safe and effective.

Quantitative sensory testing, neurophysiological and psychological examination in patients with complex regional pain syndrome and hemisensory deficits

&NA; Based on bed‐side neurological testing, it has recently been shown that 33% of chronic complex regional pain syndrome (CRPS) type I patients exhibit sensory impairments, which extend past the painful area of the affected limb in a hemisensory distribution (Pain, 80 (1999) 95). In the present study, the clinically observed changes in touch and temperature sensations on the side of the body ipsilateral to the affected limb were investigated quantitatively. Neurophysiological and psychological examinations were conducted to detect changes in the peripheral and central nervous system as well as psychopathological abnormalities. In 40 patients with CRPS, a bed‐side neurological examination was performed. Quantitative sensory testing was conducted at five locations on each side of the body. The evaluation of touch thresholds was performed using von Frey filaments (n=40). To measure cool, warm and heat pain thresholds quantitatively, a thermal stimulator using a Peltier‐element was used (n=28). With respect to clinical findings, the initiating trauma and severity of abnormalities on nerve conduction testing, three patients were diagnosed as having a reliable CRPS II (causalgia) and five patients a possible CRPS II. Thirty‐two patients were diagnosed as having a CRPS I. On clinical examination, 15 patients revealed generalized sensory deficits on the side of the body ipsilateral to the affected limb (hemisensory deficit, n=12; sensory impairment in the upper quadrant of the body, n=3). Patients with these generalized sensory deficits had a significantly longer illness duration (P<0.05) and a significantly higher percentage of mechanical allodynia/hyperalgesia than patients with spatially restricted sensory deficits (n=25) (P<0.05). In patients with generalized sensory impairment, thresholds for touch, warm and cold sensations, and for heat pain were significantly increased at all five locations tested ipsilaterally compared with the contralateral body side, except for the cool threshold on the chest and the heat pain threshold distally on the affected limb. In patients with sensory deficits limited to the affected limb, the touch threshold was significantly higher only in the distal part of the affected limb when compared with the contralateral limb. In these patients, thermal testing revealed almost no differences in cool, warm and heat pain thresholds when comparing both sides. Repeated thermal testing conducted in five patients with generalized sensory impairment reproduced the significant differences between both sides for cool, warm and heat pain thresholds. However, the correlation between the results obtained in the first and second examinations was poor. Neurophysiological recordings revealed pathological results in 46% for nerve conduction studies, 24% for somatosensory evoked potentials and 39% for sympathetic skin response. For all methods applied, there was no statistically significant difference in the incidence of pathological results between patients with generalized and patients with spatially restricted sensory abnormalities. Psychological examination using the structured clinical interview on DSM‐IV (SKID) demonstrated a high frequency of affective and anxiety disorders, however, without significant differences between both groups. We conclude that hemisensory impairment in patients with CRPS Type I is probably related to functional disturbances in processing of noxious events in the thalamus and may be a clinical correlate of subcortical brain plasticity in chronic pain.

Hemisensory impairment in patients with complex regional pain syndrome.

The purpose of the present study was to investigate the extent and quality of sensory impairment and their relation to pain characteristics and movement disorders in patients suffering from complex regional pain syndrome (CRPS) type I. Neurological testing was performed independently by two examiners in 24 patients with CRPS type I. In eight patients (33%), a hemisensory impairment with decreased temperature and pinprick sensation ipsilateral to the limb affected by CRPS could be observed. In four patients (17%), a sensory deficit in the upper quadrant of the body could be demonstrated and in eight patients (33%), sensory impairment was limited to the limb affected by CRPS. Mechanical allodynia and mechanical hyperalgesia could be observed in a higher percentage of patients with hemisensory deficit or sensory impairment in the upper quadrant (92%), than in those patients with sensory impairment limited to the affected limb (17%) (P < 0.005). In patients with left-sided CRPS, sensory abnormalities in the upper quadrant or hemisensory impairment were more frequently demonstrated (77%) than in patients with right-sided CRPS (18%) (P < 0.005). There was a high correlation (92%) for the sensory findings between the two examiners, and hemisensory abnormalities were stable over a period of 3-6 months in all six patients with repeated examinations. Motor impairment (contractures, weakness, tremor or difficulties in initiating movement) could be observed in a higher percentage in patients with sensory abnormalities in the upper quadrant or hemisensory impairment (83%) than in patients with sensory impairment limited to the affected limb (42%) (P < 0.05) and was significantly correlated with allodynia/hyperalgesia (P < 0.005). The results demonstrated that sensory deficits in patients with CRPS, frequently extend past the painful area of the affected limb. The increased frequency of mechanical allodynia and movement disorders in patients with hemisensory impairment or sensory deficits in the upper quadrant, might indicate that central mechanisms are involved in the pathogenesis of CRPS in these patients.

Preoperative alpha2-adrenergic receptor agonists prevent the deterioration of renal function after cardiac surgery: results of a randomized, controlled trial.

OBJECTIVE To evaluate the influence of the alpha2-adrenergic receptor agonist clonidine on creatinine clearance as a measure of renal function. DESIGN Prospective, double-blind, randomized, placebo-controlled clinical trial. SETTING University hospital. PATIENTS Patients undergoing coronary artery bypass graft surgery (n = 48) with normal risk. INTERVENTIONS Administration of clonidine (4 micrograms/kg iv)) or placebo 1 hr before induction of anesthesia. MEASUREMENTS AND MAIN RESULTS Induction and maintenance of anesthesia (etomidate, midazolam, and fentanyl) and cardiopulmonary bypass technique (nonpulsatile, normothermic, intermittent cold blood cardioplegia) were standardized in all patients. The night before surgery and the first and third night after surgery, creatinine clearance was calculated from a 12-hr urine collection period. Venous blood samples for determination of plasma antidiuretic hormone (ADH) concentrations were taken the evening before surgery, immediately before induction of anesthesia and the evening after surgery (n = 16). Arterial catecholamine plasma concentrations were determined (high-performance liquid chromatography) before induction, 15 mins after induction of anesthesia, immediately after sternotomy, before initiation of cardiopulmonary bypass, as well as 5, 15, and 30 mins after initiation of cardiopulmonary bypass (n = 16). The total amount of anesthetics, infusions, transfusions, diuresis, and blood loss was not different between the groups. Creatinine clearance decreased over the first postoperative night from 98 +/- 18 (preoperatively) to 68 +/- 19 mL/min (p < .05) in placebo-treated patients. Creatinine clearance remained unchanged in clonidine-treated patients (90 +/- 19 [preoperatively] to 92 +/- 17 mL/min). There was a significant difference in creatinine clearance between the groups during the first postoperative night (p < .05; Mann-Whitney U test). In the third postoperative night, mean creatinine clearance of both groups was not different (75 +/- 31 vs. 86 +/- 28 mL/min). ADH concentrations were not different between the groups at any time, while plasma catecholamine concentrations were always significantly lower in clonidine-treated patients. CONCLUSIONS Preoperative treatment with clonidine (4 microgram/kilogram) prevents the deterioration of renal function after cardiac surgery. This effect might be due to clonidine-induced reduction in the sympathetic nervous system response to coronary artery bypass graft surgery.

Influence of the N-methyl-d-aspartate antagonist memantine on human motor cortex excitability

The aim of our study was to investigate the effect of the N-methyl-D-aspartate (NMDA) antagonist memantine on motor excitability in humans. Seven healthy volunteers received memantine or placebo, respectively, over a period of 8 days. At day 8, transcranial magnetic stimulation (TMS) was performed using a paired pulses paradigm in order to assess intracortical inhibition and facilitation. Additionally, motor threshold and silent period duration after TMS were measured as well as M waves, F waves and peripheral silent period after electrical peripheral nerve stimulation. Intracortical inhibition was enhanced, and intracortical facilitation reduced after memantine ingestion in comparison to placebo, whereas no significant difference could be observed regarding the other neurophysiological parameters. We conclude that the NMDA receptor is involved in the regulation of excitability of intracortical interneuronal circuits.

The Quality of Pain Management in German Hospitals

BACKGROUND The Pain-Free Hospital Project was initiated in 2003 with the aim of improving pain management throughout Germany. We assessed the current state of pain management in German hospitals. METHODS From 2004 to 2006, data were obtained anonymously from 2252 patients who had undergone surgery, and 999 who had been treated non-surgically, in a total of 25 hospitals. They were interviewed about the intensity of pain they had experienced and about the effectiveness of its treatment. RESULTS No pain at all was reported by 12.4% of patients who had undergone surgery and by 16.7% of the non-surgically treated patients. Moderate to severe pain at rest was reported by 29.5% of the surgical group and 36.8% of the non-surgical group. More than 50% of the overall group reported pain on movement. 55% of the surgical group, and 57% of the non-surgical group, were dissatisfied with their pain management. Peak pain tended to occur outside normal working hours. No analgesic treatment at all was given to 39% of patients in the non-surgical group, even though they were in pain; the corresponding figure for the surgical group was 15% (a significant difference, p<0.001). Inadequately effective pain management was reported by 45.6% of patients in the non-surgical group and 29.6% in the operative group (again, a significant difference. Cancer patients were treated more often with potent opioids. CONCLUSION Severe postoperative pain is still too common among hospitalized patients, particularly pain that is induced by movement. Patients being treated on non-surgical wards also often suffer severe pain needlessly. Pain management seems to be worse for non-surgical patients (cancer patients excepted) than for surgical patients: waiting times for medication are longer, and ineffective medications are given more often. On the other hand, a number of hospitals provide positive examples of the potential effectiveness of pain management for both surgical and non-surgical patients.

Long-Term Treatment of Cancer Pain With Transdermal Fentanyl

The long-term therapy of 51 patients using transdermal fentanyl was evaluated. The transdermal therapy was performed for 158 days (range, 15-855 days). The need for increasing dosages of transdermal fentanyl was caused by the progression of the underlying cancer disease (mean initial dose, 69.5 micrograms fentanyl/hr; mean final dose, 167.7 micrograms fentanyl/hr). The transdermal system was changed every third day. Application intervals had to be shortened in 23.5% of the patients. Pain reduction was good throughout the study. Severe side effects did not occur. Constipation and the need for laxatives occurred less frequently than with previously administered oral morphine. Skin tolerance of the transdermal system was good. The treatment of cancer pain with transdermal fentanyl can be performed as a long-term therapy and result in good pain relief. Considering its specific pharmacokinetic properties, it is an alternative medication on step III of the World Health Organizations guidelines for cancer pain management.

Efficacy of the NMDA-receptor antagonist memantine in patients with chronic phantom limb pain - results of a randomized double-blinded, placebo-controlled trial

&NA; Phantom limb pain (PLP) associated neuroplastic changes are partly mediated by excitatory amino acids at NMDA receptor sites. This study was undertaken to deduce if NMDA‐receptor antagonists may be effective in patients with chronic PLP. Therefore a four week double‐blinded, randomized placebo‐controlled trial was performed to evaluate the efficacy of 30 mg memantine/day, an orally administrable NMDA receptor antagonist. Thirty‐six patients, 18 per group, with a history of at least 12 months PLP and an average pain of at least 4 on the 11‐point numeric rating scale (NRS) were enrolled. The patients completed a standardized questionnaire before the trial. PLP intensity and the level of eight complaints were assessed during the trial. Number needed to treat (NNT) was calculated based on the average PLP during the 3rd week (steady state). In both groups, PLP declined significantly in comparison with the baseline (verum: 5.1 (±2.1) to 3,8 (±2,3), placebo from 5.1 (±2.0) to 3.2 (±1,46) NRS) without a re‐rising of the PLP during the washout period. Mean pain relief was 47% in the memantine group (10 patients reported more than 50% relief), 40% in the placebo group (6>50%): NNT were 4.5 (KI: 2.1–10.6). Analysis of covariance demonstrated a significant impact only on the prior PLP intensity, but no treatment effect. Two patients have demonstrated long‐term pain relief under memantine until now (16 months). The total number of slight adverse events were comparable in both groups, but the overall number of severe events was higher in the memantine group (P<0.05). This trial failed to demonstrate a significant clinical benefit of the NMDA‐receptor antagonist memantine in chronic PLP. The administration of a higher dosage is probably not tolerable.