Surgical treatments for postamputation pain: study protocol for an international, double-blind, randomised controlled trial.

BACKGROUND: Painful conditions such as residual limb pain (RLP) and phantom limb pain (PLP) can manifest after amputation. The mechanisms underlying such postamputation pains are diverse and should be addressed accordingly. Different surgical treatment methods have shown potential for alleviating RLP due to neuroma formation - commonly known as neuroma pain - and to a lesser degree PLP. Two reconstructive surgical interventions, namely targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI), are gaining popularity in postamputation pain treatment with promising results. However, these two methods have not been directly compared in a randomised controlled trial (RCT). Here, we present a study protocol for an international, double-blind, RCT to assess the effectiveness of TMR, RPNI, and a non-reconstructive procedure called neuroma transposition (active control) in alleviating RLP, neuroma pain, and PLP. METHODS: One hundred ten upper and lower limb amputees suffering from RLP will be recruited and assigned randomly to one of the surgical interventions (TMR, RPNI, or neuroma transposition) in an equal allocation ratio. Complete evaluations will be performed during a baseline period prior to the surgical intervention, and follow-ups will be conducted in short term (1, 3, 6, and 12 months post-surgery) and in long term (2 and 4 years post-surgery). After the 12-month follow-up, the study will be unblinded for the evaluator and the participants. If the participant is unsatisfied with the outcome of the treatment at that time, further treatment including one of the other procedures will be discussed in consultation with the clinical investigator at that site. DISCUSSION: A double-blind RCT is necessary for the establishment of evidence-based procedures, hence the motivation for this work. In addition, studies on pain are challenging due to the subjectivity of the experience and the lack of objective evaluation methods. Here, we mitigate this problem by including different pain evaluation methods known to have clinical relevance. We plan to analyse the primary variable, mean change in NRS (0-10) between baseline and the 12-month follow-up, using the intention-to-treat (ITT) approach to minimise bias and keep the advantage of randomisation. The secondary outcomes will be analysed on both ITT and per-protocol (PP). An adherence protocol (PP population) analysis will be used for estimating a more realistic effect of treatment. TRIAL REGISTRATION: ClincialTrials.gov NCT05009394.

Ultralow Dose of Naloxone as an Adjuvant to Intrathecal Morphine Infusion Improves Perceived Quality of Sleep but Fails to Alter Persistent Pain: A Randomized, Double-blind, Controlled Study.

INTRODUCTION: This randomized, cross-over, double-blind, controlled study of continuous intrathecal morphine administration in patients with severe, long-term pain addresses whether the supplementation of low doses of naloxone in this setting is associated with beneficial clinical effects. METHODS: All of the study subjects (n=11) provided informed consent and were recruited from a subset of patients who were already undergoing long-term treatment with continuous intrathecal morphine because of difficult-to-treat pain. The patients were (in a randomized order) also given intrathecal naloxone (40 ng/24 h or 400 ng/24 h). As control, the patients' ordinary dose of morphine without any additions was used. The pain (Numeric Rating Scale, NRS) during activity, perceived quality of sleep, level of activity, and quality of life as well as the levels of several proinflammatory and anti-inflammatory cytokines in the blood were assessed. The prestudy pain (NRS during activity) in the study group ranged from 3 to 10. RESULTS: A total of 64% of the subjects reported improved quality of sleep during treatment with naloxone at a dose of 40 ng per 24 hours as compared with 9% with sham treatment (P=0.024). Although not statistically significant, pain was reduced by 2 NRS steps or more during supplemental treatment with naloxone in 36% of subjects when using the 40 ng per 24 hours dose and in 18% of the subjects when using naloxone 400 ng per 24 hours dose. The corresponding percentage among patients receiving unaltered treatment was 27%. CONCLUSIONS: To conclude, the addition of an ultralow dose of intrathecal naloxone (40 ng/24 h) to intrathecal morphine infusion in patients with severe, persistent pain improved perceived quality of sleep. We were not able to show any statistically significant effects of naloxone on pain relief, level of activity, or quality of life.

Evaluation of the cost-effectiveness of buprenorphine in treatment of chronic pain using competing EQ-5D weights.

Background and aims Chronic pain is a life altering condition and common among elderly persons. The 7-day buprenorphine patch could be a suitable treatment for managing chronic pain of moderate severity in elderly patients in Sweden. The objective of this analysis was to investigate the cost-effectiveness of the 7-day buprenorphine patch, versus no treatment, in patients >50 years old who suffer from moderate pain in a health economic perspective. An additional aim was to evaluate how the cost-effectiveness is affected by the choice of EQ-5D weights. Methods The annual treatment cost and the potential gains in health-related quality of life (HRQoL) of buprenorphine, compared to no treatment, were evaluated. Original EQ-5D data were collected from four clinical reference studies at baseline and at the final visit. Treatment effects on HRQoL were then assessed using both UK and Swedish EQ-5D weights. Annual treatment costs were calculated based on costs of physician visits and pharmaceuticals. The optimal treatment dose was 10-15 µg/h and the analysis was hence performed on both a 10- and a 15 µg/h buprenorphine patch. Results The analysis of buprenorphine treatment resulted in improved HRQoL in all reference studies, irrespective of choice of EQ-5D weight set. The change in quality adjusted life years (QALYs) varied with a gain of 0.042-0.118 using the UK weights and 0.020-0.051 with the Swedish weights. The average annual treatment cost was SEK14454 for the 10µg/h patch and SEK17 017 for the 15 µg/h patch, while cost for the no-treatment alternative was SEK 9 960. The base case incremental cost-effectiveness ratios (ICER) with the UK weights were SEK 40000-SEK 170000 and SEK 90000-SEK 350000 when applying the Swedish weights. The corresponding ICER-span in the sensitivity analysis was SEK 15 000-SEK 400 000 when applying the UK weights and SEK 30 000-SEK 840 000 with the Swedish weights (SEK 100 is about €11). Conclusions The results imply that the 7-day buprenorphine patch may be a cost-effective treatment of moderate chronic pain in patients over 50 years of age. The UK and the Swedish EQ-5D weights generated vastly different HRQoL estimates but buprenorphine remains cost-effective regardless choice of weight set.

Opioid rotation in patients initiated on oxycodone or morphine: a register study.

PURPOSE: Strong opioids are recommended for the treatment of moderate to severe pain. However, some patients do not achieve a successful treatment outcome due to intolerable adverse events and/or inadequate analgesia, thus may benefit from switching to another opioid, a procedure known as "opioid rotation." The type of opioid at treatment initiation may influence the risk of opioid rotation and the objective of this study was to assess such rotation after treatment initiation with two alternative treatments, controlled-release (CR) oxycodone versus CR morphine in patients suffering from non-cancer pain. METHOD: The study reported here was a real-life study based on Swedish register data: the Prescribed Drug, National Patient, and Cause of Death registers. The captured data cover the entire Swedish population treated in specialist care. A statistical analysis plan was agreed and signed before data were accessed. RESULTS: Data from 50,223 cases were included in the analyses. The risk of rotation was 19% higher in patients initiating treatment with morphine compared with oxycodone (hazard ratio 1.19; 95% confidence interval 1.11-1.27; P < 0.001), after adjusting for such baseline variables that were both significantly correlated with the outcome variable (time to rotation) and significantly different between the groups; age at index date, osteoarthritis and number of pain-related drugs. CONCLUSION: Patients with non-cancer pain who initiated treatment with CR morphine had a higher risk of opioid rotation than patients initiated with CR oxycodone.

Inotropic support during experimental endotoxemic shock: part I. The effects of levosimendan on splanchnic perfusion.

BACKGROUND: Septic shock may cause splanchnic hypoperfusion. We hypothesized that levosimendan would improve systemic and hepatosplanchnic perfusion during endotoxemic shock. METHODS: In 16 anesthetized pigs (31.4 +/- 3.4 kg), a jugular vein, a carotid artery, the pulmonary artery (thermodilution), the portal vein, and a hepatic vein were cannulated for hemodynamic monitoring and blood sampling. Ultrasonic flowprobes were placed around the portal vein, the hepatic artery, and the superior mesenteric artery (SMA). In addition to 30 mL/kg of dextran 70 given before baseline, all animals received 10 mL x kg(-1) x h(-1) of IV fluids throughout the experiment. An endotoxin infusion (2 microg x kg(-1) x h(-1)) was given for 300 min; 100 min after the start of endotoxin, the pigs were randomized to receive levosimendan (50 microg x kg(-1) x h(-1), n = 8) or placebo (n = 8). To evaluate the isolated effects of endotoxemia, all data before randomization were pooled into one group. Data were analyzed by analysis of variance and presented as mean +/- sem. RESULTS: Endotoxemia (t = 90 min, pooled data) decreased systemic vascular resistance (SVR, 2526 +/- 203 to 1946 +/- 122 dyn x s x cm(-5), P = 0.003) and mean arterial blood pressure (MAP, 109 +/- 6 to 84 +/- 3 mm Hg, P < 0.05), whereas heart rate (66 +/- 4 to 98 +/- 8 bpm), and mean pulmonary arterial pressure (MPAP, 20 +/- 1 to 38 +/- 2 mm Hg) increased (P < 0.001). Cardiac output (CO, 3.4 +/- 0.2 L/min) and systemic oxygen delivery (414 +/- 33 mL/min) were unchanged, but blood flows in the SMA (575 +/- 34 to 392 +/- 38 mL/min) and the portal vein (881 +/- 62 to 568 +/- 39 mL/min) decreased (P < 0.001). Although hepatic arterial blood flows increased (36 +/- 8 to 219 +/- 38 mL/min), gut (114 +/- 11 to 84 +/- 7 mL/min) and hepatic (94 +/- 11 to 67 +/- 8 mL/min) oxygen deliveries decreased (P < 0.05). At t = 300 min, the levosimendan group showed lower MPAP (39 +/- 3 vs 49 +/- 2 mm Hg, P = 0.025), lower SVR (2158 +/- 186 vs 3069 +/- 370 dyn x s x cm(-5), P = 0.052), and lower MAP (55 +/- 9 vs 87 +/- 9 mm Hg, P < 0.001) than the control group. In both groups, CO, portal vein, and hepatic arterial blood flows decreased (P < 0.001); the mean values for the levosimendan group at t = 300 min were 2.0 +/- 0.4 L/min, 390 +/- 83 mL/min, and 36 +/- 12 mL/min, respectively. SMA blood flow decreased only in the levosimendan group (432 +/- 40 to 320 +/- 78 mL/min, P < 0.001), whereas gut oxygen delivery decreased in the levosimendan (85 +/- 12 to 63 +/- 12 mL/min, P < 0.001) and in the control (83 +/- 6 to 59 +/- 3 mL/min, P = 0.03) groups. CONCLUSION: Levosimendan administered after the establishment of endotoxemic shock to pigs receiving moderate fluid resuscitation prevented further increases in MPAP and maintained a low SVR. There were, however, no improvements in CO, MAP decreased, and levosimendan neither prevented the development of circulatory shock nor improved hepatosplanchnic perfusion.

Cardiovascular effects of levosimendan in the early stages of endotoxemia.

Sepsis-associated myocardial depression is associated with calcium desensitization and adrenergic uncoupling. We conducted a prospective randomized investigation on the effects of the calcium sensitizer, levosimendan, on hemodynamics, myocardial blood flow, and myocardial lactate metabolism during porcine endotoxemia. Twelve pigs were studied. Oxygen consumption was measured by indirect calorimetry, and myocardial blood flow was measured by retrograde thermodilution. Pulmonary, arterial, and venous indwelling catheters allowed measurements of cardiac output, vascular pressures, and blood sampling. Fluids were given at an average of 15 mL . kg . h. After baseline measurements (0 min), an infusion of Escherichia coli LPS (2 microg . kg . min) was started in all animals. Beginning at 100 min, six animals received levosimendan (50 microg . kg . h), whereas six control animals received placebo. The study lasted for 300 min. All animals responded to endotoxin with pulmonary hypertension, a transient decrease in cardiac output, tachycardia, and systemic hypotension. Levosimendan infusion decreased systemic vascular resistance (P = 0.001), coronary vascular resistance (P = 0.004), and mean arterial (P < 0.001) and coronary perfusion pressures (P < 0.001), whereas pulmonary hypertension was unaffected. Heart rate progressively increased in both groups and was significantly higher in the levosimendan group (P = 0.048). Myocardial blood flow remained unchanged in both groups; however, 80 min after the start of levosimendan infusion, left ventricular myocardial hypoxia ensued, as evidenced by a negative myocardial lactate gradient (P = 0.01). Two control and five levosimendan animals died before the end of the study. Early administration of levosimendan during porcine endotoxemia increased heart rate, caused arterial vasodilation, and decreased coronary perfusion pressure, resulting in myocardial hypoxia.

[Secondary prevention for police officers involved in job-related psychologically stressful or traumatic situations]. / Sekundärprävention bei schwerer Belastung und Traumatisierung durch beruflich bedingte Exposition im Polizeidienst.

OBJECTIVES: Police officers are at high risk of being exposed to psychologically straining situations and potentially psychotraumatic experiences. In this article, such situations are exemplified and categorized, and the role and significance of secondary prevention following traumatic experiences is discussed. METHODS: From 1994 to 2003, 649 police officers received secondary prevention after being involved in a total of 250 potentially traumatic or psychologically stressful incidents. Psychological support was provided by teams of specially trained professionals in the acute phase after the incident following careful psychological evaluation. In a retrospective evaluation, the diagnoses obtained were analyzed with regard to sex and age and correlated with the severity of the incident. Three clusters of potentially traumatic situations were formed: (1) Employment of fire-arms with danger for the officer, (2) Standard situations including violence towards a third party, (3) Suicide or attempted suicide of a police officer. RESULTS: Police officers who experienced events assigned to cluster (1), comprising situations with considerable traumatic potential, had the highest incidence of posttraumatic stress disorder (PTSD) or other mental illness. Compared to male officers, females were more often diagnosed with other mental illness, whereas males had a higher incidence of PTSD. Cluster (2), which comprised situations of an officer's daily professional life, was not associated with an increased risk of mental illness. Officers were apparently capable of coping with situations considered psychologically straining for the general public without detectable evidence of a traumatic reaction. In cluster (3), which reflects the most dramatic interference with team relations, other forms of mental illness were diagnosed at a higher incidence.