BACKGROUND AND PURPOSE: Placebo response rates in clinical trials vary considerably and are observed frequently. For new drugs it can be difficult to prove effectiveness superior to placebo. It is unclear what contributes to improvement in the placebo groups. We wanted to clarify, what elements of clinical trials determine placebo variability. METHODS: We analysed a representative sample of 141 published long-term trials (randomized, double-blind, placebo-controlled; duration > 12 weeks) to find out what study characteristics predict placebo response rates in various diseases. Correlational and regression analyses with study characteristics and placebo response rates were carried out. RESULTS: We found a high and significant correlation between placebo and treatment response rate across diseases (r =.78; p <.001). A multiple regression model explained 79% of the variance in placebo variability (F = 59.7; p < 0.0001). Significant predictors are, among others, the duration of the study (beta =.31), the quality of the study (beta =.18), the fact whether a study is a prevention trial (beta =.44), whether dropouts have been documented (beta =-.20), or whether additional treatments have been documented (beta =-.17). Healing rates with placebo are lower in the following diagnoses; neoplasms (beta =-.21), nervous diseases (beta =-.10), substance abuse (beta =-.14). Without prevention trials the amount of variance explained is 42%. CONCLUSION: Medication response rates and placebo response rates in clinical trials are highly correlated. Trial characteristics can explain some portion of the variance in placebo healing rates in RCTs. Placebo response in trials is only partially due to methodological artefacts and only partially dependent on the diagnoses treated.

BACKGROUND: Surgical treatment and its consequences expose patients to stress, and here we investigated the importance of the psychological component of postoperative pain based on reports in the clinical literature. DISCUSSION: Postoperative pain remains a significant clinical problem. Increased pain intensity with increased demand for opioid medication, and/or a relative unresponsiveness to pain treatment was reported both when the analgesia was administered by means of conventional nurse injection regimes and patient-controlled analgesia (PCA). Both the quality of the analgesia, and the sensitivity of postoperative models for assessing analgesic efficacy could be significantly influenced. The findings could be explained by increased penetration of an algesic anxiety-related nocebo influence (which we chose to call "anxiebo") relative to its analgesic placebo counterpart. To counteract this influence, the importance of psychological effects must be acknowledged, and doctors and attending nurses should focus on maintaining trustful therapist-patient relationships throughout the treatment period. The physical mechanism of anxiebo should be further explored, and those at risk for anxiebo better characterized. In addition, future systemic analgesic therapies should be directed towards being prophylactic and continuous to eliminate surgical pain as it appears in order to prevent the anxiebo effect. Addressing anxiebo is the key to developing reproducible models for measuring pain in the postoperative setting, and to improving the accuracy of measurements of the minimum effective analgesic concentration. SUMMARY: Anxiebo and placebo act as counterparts postoperatively. The anxiebo state may impair clinical analgesia and reduce the sensitivity of analgesic trials. Ways to minimize anxiebo are discussed.

Response expectancies have been proposed as the major determinant of placebo effects. Here we report that different expectations produce different analgesic effects which in turn can be harnessed in clinical practice. Thoracotomized patients were treated with buprenorphine on request for 3 consecutive days, together with a basal intravenous infusion of saline solution. However, the symbolic meaning of this basal infusion was changed in three different groups of patients. The first group was told nothing about any analgesic effect (natural history). The second group was told that the basal infusion was either a powerful painkiller or a placebo (classic double-blind administration). The third group was told that the basal infusion was a potent painkiller (deceptive administration). Therefore, whereas the analgesic treatment was exactly the same in the three groups, the verbal instructions about the basal infusion differed. The placebo effect of the saline basal infusion was measured by recording the doses of buprenorphine requested over the three-days treatment. We found that the double-blind group showed a reduction of buprenorphine requests compared to the natural history group. However, this reduction was even larger in the deceptive administration group. Overall, after 3 days of placebo infusion, the first group received 11.55 mg of buprenorphine, the second group 9.15 mg, and the third group 7.65 mg. Despite these dose differences, analgesia was the same in the three groups. These results indicate that different verbal instructions about certain and uncertain expectations of analgesia produce different placebo analgesic effects, which in turn trigger a dramatic change of behaviour leading to a significant reduction of opioid intake.

Several lines of evidence indicate that placebos produce analgesia through the activation of endogenous opioid systems. Recently, we showed that placebos may also produce respiratory depressant responses, a typical side-effect of narcotics, when a subject had a prior experience of respiratory depression in the course of narcotic treatment. In the present study, we report that the placebo respiratory depression can be induced after repeated administrations of the partial opioid agonist buprenorphine. The placebo respiratory depressant effect that resulted from the buprenorphine conditioning was completely blocked by a dose of 10 mg of naloxone, indicating that it was mediated by endogenous opioids. These findings show that placebos act, via the activation of opioid receptors, not only on pain mechanisms but on the respiratory centres as well, thus mimicking a typical side-effect of narcotics. In addition, the experimental procedure we used did not produce any expectation of respiratory depression and, similarly, the subjects did not notice any sign of respiratory discomfort. Thus, the placebo respiratory depression elicited in the present study cannot be explained on the basis of cognitive or motivational mechanisms. Rather, it appears to be a sequence effect due to learning, thus suggesting a conditioning mechanism mediated by endogenous opioids.

Although in most of the cases the placebo response appears to be unpredictable, several factors have been considered in order to explain the placebo analgesic effect. For example, it is widely recognized, albeit with little empirical evidence, that placebo analgesia is more likely to occur after a successful analgesic therapy. On the basis of this assumption, we tested the placebo response in a population of patients who were treated with buprenorphine the day before for relieving postoperative pain. However, due to the high variability of opioid responsiveness, buprenorphine was effective in some patients and poorly effective in some others. Similarly, buprenorphine produced respiratory depression with a large variability, ranging from mild depression to no effect. We found that the placebo analgesic response depended on the buprenorphine analgesic effectiveness of the previous day. Analogously, we found that a placebo respiratory depressant response was more pronounced in those patients with a respiratory depressant response to buprenorphine on the day before, irrespective of the analgesic effectiveness. These specific effects suggest that (1) the placebo effect is experience-dependent;(2) the mechanisms underlying placebo analgesia and placebo respiratory depression are independent from each other and, by considering the role of endogenous opioids in placebo analgesia, might involve different subpopulations of opioid receptors.

OBJECTIVE: This study was aimed at analyzing the degree of intercostal nerve impairment in posterolateral and muscle-sparing thoracotomy and at correlating the nerve damage to the severity of long-lasting postthoracotomy pain. METHODS: Neurophysiologic recordings were performed 1 month after either posterolateral or muscle-sparing thoracotomy to assess the presence of the superficial abdominal reflexes (mediated in part by the intercostal nerves), the somatosensory-evoked responses after electrical stimulation of the surgical scar, and the electrical thresholds for tactile and pain sensations of the surgical incision. RESULTS: The patients who underwent a posterolateral thoracotomy showed a higher degree of intercostal nerve impairment than the muscle-sparing thoracotomy patients as revealed by the disappearance of the abdominal reflexes, a larger reduction in amplitude of the somatosensory-evoked potentials, and a larger increase of the sensory thresholds to electrical stimulation for both tactile perception and pain. In addition, these neurophysiologic parameters were highly correlated to the postthoracotomy pain experienced by the patients 1 month after surgery, indicating a causal role for nerve impairment in the long-lasting postoperative pain. CONCLUSIONS: This study shows for the first time the pathophysiologic differences between posterolateral and muscle-sparing thoracotomy and suggests that the minor long-lasting postthoracotomy pain in muscle-sparing thoracotomy patients is partly due to a minor nerve damage. In addition, because nerve impairment is responsible for the long-lasting neuropathic component of postoperative pain, it is necessary to match specific treatments to the neuropathic pain-generating mechanisms.

The treatment of neuropathic pain with opioid analgesics is a matter of controversy among clinicians and clinician scientists. Although neuropathic pain is usually believed to be only slightly responsive to opioids, several studies show that satisfactory analgesia can be obtained if adequate doses are administered. In the present study, we tested the effectiveness of buprenorphine in 21 patients soon after thoracic surgery (nociceptive postoperative pain) and 1 month after surgery in the same 21 patients who developed postthoracotomy neuropathic pain with a burning, electrical and shooting quality. According to a double-blind randomized study, the analgesic dose (AD) of buprenorphine needed to reduce the long-term neuropathic pain by 50%(AD50) was calculated and compared to the AD50 in the immediate postoperative period. We found that long-term neuropathic pain could be adequately reduced by buprenorphine. However, the AD50 in neuropathic pain was significantly higher relative to the AD50 in the short-term postoperative pain, indicating a lower responsiveness of neuropathic pain to opioids. We also found a strict relationship between the short-term and long-term AD50, characterized by a saturating effect. In fact, if the AD50 soon after surgery was low, the AD50 increase in the long-term neuropathic pain was threefold. By contrast, if the AD50 soon after surgery was high, the AD50 in neuropathic pain was only slightly increased. This suggests that, though neuropathic pain is indeed less sensitive to opioids, in some neuropathic patients a large amount of opioid resistance is already present in other painful conditions.

BACKGROUND: Posterolateral thoracotomy can produce stretching of/or damage to the intercostal nerves and their branches. To assess intercostal nerve impairment after operation, we measured the superficial abdominal reflexes, which are mediated, at least in part, by the most inferior intercostal nerves. METHODS: Using electrophysiologic techniques, we made recordings from the left and right abdominal walls to study the responses evoked by mechanical stimulation of the skin after operation. In addition, we assessed postoperative pain intensity according to a numeric rating scale and recorded postoperative opioid dose. RESULTS: We found that the patients with complete disappearance of the superficial abdominal reflexes experienced more severe postoperative pain than those in whom the reflexes were maintained. Moreover, opioid treatment was less effective in the patients with no reflexes postoperatively. CONCLUSIONS: Our findings show a strict correlation between pain intensity after posterolateral thoracotomy and absence of abdominal reflexes. We suggest that the higher pain intensity together with the absence of reflexes may be due to intercostal nerve impairment, be it anatomic or functional, and thus to a larger neuropathic component of postoperative pain. This finding may be used as a predictor of patients with high analgesic requirements.

In patients who reported mild postoperative pain, we evoked a nocebo response, a phenomenon equal but opposite to placebo. Patients who gave informed consent to increase their pain for 30 min received a substance known to be non-hyperalgesic (saline solution) and were told that it produced a pain increase. A nocebo effect was observed when saline was administered. However, if a dose of 0.5 or 5 mg of the cholecystokinin antagonist proglumide was added to the saline solution, the nocebo effect was abolished. A dose of 0.05 mg of proglumide was ineffective. The blockade of the nocebo hyperalgesic response was not reversed by 10 mg of naloxone. These results suggest that cholecystokinin mediates pain increase in the nocebo response and that proglumide blocks nocebo through mechanisms not involving opioids. Since the nocebo procedure represents an anxiogenic stimulus and previous studies showed a role for cholecystokinin in anxiety, we suggest that nocebo hyperalgesia may be due to a cholecystokinin-dependent increase of anxiety.

BACKGROUND: Transcutaneous electrical nerve stimulation (TENS) has been used extensively to control postoperative pain, but its effects are controversial. This is probably due to the different types of operations performed and, therefore, to the varying intensity of postoperative pain. Here we present an extensive study with TENS in 324 patients who underwent different types of thoracic surgical procedures: posterolateral thoracotomy, muscle-sparing thoracotomy, costotomy, sternotomy, and video-assisted thoracoscopy. METHODS: Each patient cohort was randomly subdivided into three treatment groups: TENS, placebo TENS and control. The effectiveness of TENS was assessed by two factors: the time from the beginning of treatment to the request for further analgesia and the total medication intake during the first 12 hours after operation. RESULTS: Whereas posterolateral thoracotomy produced severe pain, muscle-sparing thoracotomy, costotomy, and sternotomy caused moderate pain, and video-assisted thoracoscopy caused only mild pain. The TENS treatment was not effective in the posterolateral thoracotomy group, but it was useful as an adjunct to other medications in the muscle-sparing thoracotomy, costotomy, and sternotomy groups. In contrast, representing the only pain control treatment with no adjunct drugs, it was very effective in patients having video-assisted thoracoscopy. CONCLUSIONS: These findings show that TENS is useful after thoracic surgical procedures only when postoperative pain is mild to moderate; it is uneffective for severe pain.

This case report presents data regarding endogenous opioid analgesia in a healthy female subject prior to developing chronic pain, and again 4 and 13months following onset of chronic daily back pain. At each assessment period, the subject underwent identical protocols involving two sessions one week apart with randomized double-blind crossover administration of saline placebo and naloxone, an opioid antagonist. Each session included a 5-min anger recall interview, followed by finger pressure and ischemic acute pain tasks. Increases in acute pain ratings induced by opioid blockade were interpreted as reflecting endogenous opioid analgesia. When the subject was healthy and pain-free, naloxone produced a mean overall 16% decrease in pain ratings relative to placebo. However, 4months after onset of chronic pain, a mean naloxone-induced increase of 22% in pain ratings over placebo was observed, consistent with presence of endogenous opioid analgesia. The mean magnitude of this opioid blockade effect for the finger pressure task exceeded the 99% confidence interval for the healthy control population based on a previous study using a similar opioid blockade protocol [4]. At 13-month follow-up, naloxone produced a mean 45% decrease in acute pain ratings compared to placebo, arguing against presence of endogenous opioid analgesia. Although results must be interpreted cautiously, findings are consistent with the hypothesis that chronic pain may initially be associated with upregulation of endogenous opioid analgesic systems which then may become dysfunctional over time.

Preventive analgesia produced by ketorolac and metamizol was evaluated during a prospective study randomized in two groups. One hundred twenty children were included aged from 3 to 6 years who underwent surgery by different procedures. Analgesic dose was applied 15 min prior to surgery by intravenous (i.v.) via. Technique used was inhaled general anesthesia; use of opioids was avoided. Pain evaluation at the end of surgery (and during the following 48 to 72 h) as well as bleeding time, platelet count, and alterations in white blood cell count were dependent variables. As soon as patients arrived in the recovery room, pain was measured by modified McGrath scales and the chromatic EVA. In ketorolac group, 40% of children showed no pain and 55% presented mild to moderate pain (1-6). In metamizol group, 40% of children referred no pain, while 55% evaluated pain as minimal to moderate. Analgesia produced by both drugs presented no significant statistical diference (p > 0.5). Troughout followup, maximum pain referred had a values of 6 and 7, respectively, for ketorolac and metamizol. Fifteen min after analgesic dose, pain was referred as 3 and 4. No alterations were observed in bleeding time, platelet count, and white blood cell count. We conclude that both analgesics prevent hyperalgesia during post-surgical period.

Placebo (PL) treatment is a method utilized as a control condition in clinical trials. A positive placebo response is seen in up to 50% of patients with Parkinson disease (PD), pain syndromes, and depression. The response is more pronounced with invasive procedures or advanced disease. Physiologic and biochemical changes have been studied in an effort to understand the mechanisms underlying placebo-related clinical improvement. In PD, objective clinical improvements in parkinsonism correlate with dopaminergic activation of the striatum, documented by PET and with changes in cell firings of the subthalamic nucleus documented by single cell recordings. Dopaminergic pathways mediating reward may underlie PL-mediated improvement in PD. In pain syndromes, endogenous opioid release triggered by cortical activation, especially the rostral anterior cingulated cortex, is associated with PL-related analgesia and can be reversed by opioid antagonists. Covert treatment of an analgesic is less effective than overt treatment, suggesting an expectation component to clinical response. In depression, PL partially imitates selective serotonin reuptake inhibitor-mediated brain activation. Diseases lacking major "top-down" or cortically based regulation may be less prone to PL-related improvement.

Non-opioide analgesics have different pharmacological effects and different profiles of their risks. The life-threatening side effects i.e. agranulocytosis after administration of Dipyrone (Metamizol) are rare, but the must be known and cautions must be considered. On the other hand information must be given about the severe side effects following the not-recommended use i.e. end-stage renal disease after misuse of non-opioid analgesics, because these diseases are preventable.

INTRODUCTION: The influence of different postoperative doses of intrathecal morphine on the time of first opioid request by orthopaedic patients was investigated. The first choice analgesic was dipyrone and a maximum dose of 6 mg/day was allowed. METHODS: A prospective, double-blind, placebo-controlled, clinical trial was conducted with 15 patients in each group receiving intrathecally either a placebo, 0.05 mg morphine, 0.1 mg morphine or 0.2 mg morphine in combination with a spinal anaesthesia with isobaric bupivacaine. RESULTS: The number of patients without opioid requirement during the first 24 h after surgery were 3, 8, 14 and 14 in the placebo group and after 0.05 mg (p=0.128), 0.1 mg (p=0.0001) and 0.2 mg (p=0.0001) intrathecal morphine, respectively. The average time until first opioid requirement increased in a dose-dependent manner from 10.3 h to 23.9 h (p<0.0001). CONCLUSION: In orthopaedic patients with dipyrone as the primary analgesic, the addition of 0.1 mg or 0.2 mg morphine to spinal anaesthesia provided a simple long-lasting postoperative analgesia and the use of additional opioids could be avoided during the 24h postoperative period.

In part 1 of this review, perioperative aspects of the use of non-opioids (acetaminophene, dipyrone, traditional NSAR, coxibs) were discussed. In part 2 the perioperative aspects of opioids (weak opioids: tramadol, tilidine with naloxone, strong opioids: morphine, piritramide, oxycodone, hydromorphone, fentanyl, methadone, buprenorphine) and coanalgesics (gabapentinoids; ketamine) will now be presented. The main aim of the review is to describe the use, risks and cost of some substances to facilitate the differential indication. New aspects concerning the use of gabapentinoids and ketamine are discussed.

In part 1 of this review the perioperative aspects of the use of non-opioids (acetaminophen, dipyrone, traditional NSAR, coxibs) and in part 2 of opioids (weak opioids: tramadol, tilidine with naloxone, strong opioids: morphine, piritramide, oxycodone, hydromorphone, fentanyl, methadone, buprenorphine) and coanalgesics (gabapentinoids, ketamine) will be discussed. The main aim is to describe the relationship between analgesic efficacy and side effects to make clinical decisions easier in patients with preoperative renal, gastrointestinal, cardiovascular and other diseases. Some new aspects concerning perioperative administration of gabapentinoids and ketamine in patients with perioperative neuropathic pain are discussed.

Recognition and treatment of pain are now important indicators of the quality of care being delivered to neonates. However, population-specific characteristics have to be considered, necessitating an integrated, population-specific approach. Such an approach starts with a systematic evaluation ofpain, using a validated pain-assessment instrument, and should be followed by effective interventions, mainly based on appropriate, i.e., safe and effective, administration of analgesics. We will illustrate the impact of age on the pharmacokinetics and metabolism of opioids using recently collected and reported observations of tramadol disposition in early neonatal life. Although distribution volume and clearance display age-dependent maturation, it is important to recognize that important, unexplained interindividual variability in drug metabolism is still observed. Research questions in the field of developmental pharmacokinetics of opioids should focus on covariables of relevance in the interindividual variability of both pharmacokinetics and pharmacodynamics of opioids in neonates and on long-term outcomes in preterm and term neonates to whom opioids were administered, with regard to behavioral consequences and effects on pain thresholds.