Lene Vase

A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia

&NA; A previous meta‐analysis of clinical analgesic trial studies showed generally low magnitudes of placebo analgesia (N. Engl. J. Med. 344 (2001) 1594). However, as studies included in their analysis used only placebo as a control condition, we conducted two meta‐analyses, one in which 23 studies used only placebo as a control condition, and one in which 14 studies investigated placebo analgesic mechanisms. Magnitudes of placebo analgesic effects were much higher in the latter (mean effect size=0.95) as compared to the former (mean effect size=0.15) and were significantly different (P=0.003). This difference as well as differences in effect sizes within studies of placebo mechanisms may be parsimoniously explained by differences in expected pain levels produced by placebo suggestions and by conditioning. Furthermore, some of the studies of placebo analgesic mechanisms indicate that the magnitude of placebo analgesia is higher when the placebo analgesic effect is induced via suggestion combined with conditioning than via suggestion alone or conditioning alone. Based on these findings, we suggest that placebo analgesic effects are most optimally conceptualized in terms of perception of the placebo agent, and therefore a new definition of placebo response is proposed.

The contributions of suggestion, desire, and expectation to placebo effects in irritable bowel syndrome patients. An empirical investigation

In order to investigate external factors that may influence the magnitude of placebo analgesia as well as psychological factors that mediate placebo analgesia, 13 irritable bowl syndrome (IBS) patients rated evoked rectal distension and cutaneous heat pain under the conditions of natural history (NH), rectal placebo (RP), rectal nocebo (RN), rectal lidocaine (RL) and oral lidocaine (OL). Patients were given verbal suggestions for pain relief and rated expected pain levels and desire for pain relief for both evoked visceral and cutaneous pain, respectively. Large reductions in pain intensity and pain unpleasantness ratings were found in the RP, RL and OL condition as compared to the natural history condition, whereas no significant difference in pain reduction between the three treatment conditions was found. Ratings during RN and NH were not statistically different. Compared to a previous study, which shows that rectal lidocaine reverses visceral and cutaneous hyperalgesia, these results suggest that adding a verbal suggestion for pain relief can increase the magnitude of placebo analgesia to that of an active agent. Since IBS patients rate these stimuli as much higher than do normal control subjects and since placebo effects were very large, they probably reflect anti‐hyperalgesic mechanisms to a major extent. Expected pain levels and desire for pain relief accounted for large amounts of the variance in visceral pain intensity in the RP, RL, and OL condition (up to 81%), and for lower amounts of the variance in cutaneous pain intensity. Hence, the combination of expected pain levels and desire for pain relief may offer an alternative means of assessing the contribution of placebo factors during analgesia.

Increased placebo analgesia over time in irritable bowel syndrome (IBS) patients is associated with desire and expectation but not endogenous opioid mechanisms

&NA; A study was conducted to determine whether changes in expected pain levels, desire for pain relief, or anxiety contribute to an increase in placebo analgesia over time as well as to determine whether placebo analgesic effects of IBS patients are related to endogenous opioid mechanisms. Twenty‐six women with IBS were exposed to rectal stimulation (35 or 55 mmHg for 30 s) and tested under natural history (NH), rectal placebo (RP) and rectal lidocaine (RL) conditions. During all conditions, 16 patients were given saline intravenously (to test for a placebo effect) and 10 patients were given naloxone intravenously (to test naloxone antagonism of the placebo effect) on a double blind basis. Patients rated expected pain level, desire for pain relief and anxiety at 2 and 22 min after the onset of NH, RP, and RL conditions and they rated actual pain intensity at 5‐min intervals for 40 min. There was a large and significant placebo effect (P<0.001) that increased over time. Ratings of expected pain levels, desire for pain relief and anxiety decreased over time and contributed to more variance in placebo and lidocaine responses during the last half of the session. These changes suggest that a reduction in negative emotions may be central to placebo effects. There was no significant difference between psychological mediators (desire, expectation, anxiety) or the placebo effect in the saline and naloxone groups, indicating that neither the psychological mediators nor the placebo analgesic effect were associated with endogenous opioids in this clinically related paradigm.

A systematic review of adverse events in placebo groups of anti-migraine clinical trials

ABSTRACT In analgesic clinical trials, adverse events are reported for the painkiller under evaluation and compared with adverse events in the placebo group. Interestingly, patients who receive the placebo often report a high frequency of adverse events, but little is understood about the nature of these negative effects. In the present study, we compared the rates of adverse events reported in the placebo arms of clinical trials for three classes of anti‐migraine drugs: NSAIDs, triptans and anticonvulsants. We identified 73 clinical trials in 69 studies describing adverse events in placebo groups: 8 were clinical trials with NSAIDs, 56 were trials with triptans, and 9 were trials with anticonvulsants. Studies were selected of all Medline/PubMed or CENTRAL referenced trials published until 2007. Adverse event profiles of the three classes were compared using a systematic review approach. We found that the rate of adverse events in the placebo arms of trials with anti‐migraine drugs was high. In addition, and most interestingly, the adverse events in the placebo arms corresponded to those of the anti‐migraine medication against which the placebo was compared. For example, anorexia and memory difficulties, which are typical adverse events of anticonvulsants, were present only in the placebo arm of these trials. These results suggest that the adverse events in placebo arms of clinical trials of anti‐migraine medications depend on the adverse events of the active medication against which the placebo is compared. These findings are in accordance with the expectation theory of placebo and nocebo effects.

Factors contributing to large analgesic effects in placebo mechanism studies conducted between 2002 and 2007.

ABSTRACT Recent meta‐analyses find various magnitudes of placebo analgesia effects in placebo mechanism trials versus placebo control trials, which have led to debate. To further investigate the magnitude of placebo analgesia in placebo mechanism trials the databases “PubMed”, “PsycINFO” and “Web of Science” (2002–2007) were searched with the term “placebo analgesia”. Twenty‐one articles including 24 studies fulfilled the selection criteria (concerning: mechanisms, control, placebo treatment, randomization and pain measures). The validity of studies was assessed by the authors and effect sizes were calculated via difference scores. The magnitude of placebo analgesia in placebo mechanism studies was large (d = 1.00) and about five times larger than placebo analgesia effects in placebo control studies (d = 0.15–0.27). Differences in magnitude between the two types of studies appear to result from different types of suggestions given for pain relief. The magnitude of placebo effects was larger in studies that used long‐term pain stimuli >20 s (d = 0.96) as opposed to short‐term stimuli (d = 0.81) and the largest placebo effects were found in studies wherein hyperalgesia was present (d = 1.88). These results replicate our previous finding that placebo analgesic effects are higher in mechanism studies than in placebo control studies. However, since magnitudes of placebo analgesic effects are highly variable it may be valuable to investigate the factors and mechanisms that contribute to this variability as well as differences in magnitudes across types of studies.

Cognitive-emotional sensitization contributes to wind-up-like pain in phantom limb pain patients

&NA; Peripheral mechanisms are known to play a role in phantom pain following limb amputation, and more recently it has been suggested that central mechanisms may also be of importance. Some patients seem to have a psychological sensitivity that predisposes them to react with pain catastrophizing after amputation of a limb, and this coping style may contribute to increased facilitation, impaired modulation of nociceptive signals, or both. To investigate how pain catastrophizing, independently of anxiety and depression, may contribute to phantom limb pain and to alterations in pain processing twenty‐four upper‐limb amputees with various levels of phantom limb pain were included in the study. Patients’ level of pain catastrophizing, anxiety and depression was assessed and they went through quantitative sensory testing (QST) of thresholds (mechanical and thermal) and wind‐up‐like pain (brush and pinprick). Catastrophizing accounted for 35% of the variance in phantom limb pain (p = 0.001) independently of anxiety and depression. Catastrophizing was also positively associated with wind‐up‐like pain in non‐medicated patients (p = 0.015), but not to pain thresholds. These findings suggest that cognitive‐emotional sensitization contributes to the altered nociceptive processing seen in phantom limb pain patients. The possible interactions between pain catastrophizing, wind‐up‐like pain, and peripheral input in generating and maintaining phantom limb pain are discussed.

Placebo manipulations reduce hyperalgesia in neuropathic pain

Summary Placebo effects in neuropathic pain were investigated. Placebo manipulations reduced the area of hyperalgesia, and this effect was related to low levels of negative affect. ABSTRACT Several studies have shown that placebo analgesia effects can be obtained in healthy volunteers, as well as patients suffering from acute postoperative pain and chronic pain conditions such as irritable bowel syndrome. However, it is unknown whether placebo analgesia effects can be elicited in chronic pain conditions with a known pathophysiology such as a nerve injury. Nineteen patients who had developed neuropathic pain after thoracotomy were exposed to a placebo manipulation in which they received either open or hidden administrations of lidocaine. Before the treatment, the patients rated their levels of spontaneous pain and expected pain and completed a questionnaire on their emotional feelings (Positive Affect Negative Affect Schedule) and went through quantitative sensory testing of evoked pain (brush and cold allodynia, heat pain tolerance, area of pinprick hyperalgesia, wind‐up‐like pain after pinprick stimulation). The placebo manipulation significantly reduced the area of pinprick hyperalgesia (P = .027), and this placebo effect was significantly related to low levels of negative affect (P = .008; R2 = 0.362) but not to positive affect or expected pain levels. No placebo effect was observed in relation to spontaneous pain or evoked pain, which is most likely due to low pain levels resulting in floor effects. This is the first study to demonstrate a placebo effect in neuropathic pain. The possible mechanisms underlying the placebo effects in hyperalgesia are discussed, and implications for treatment are outlined.

Randomised controlled trials may underestimate drug effects: balanced placebo trial design.

Background It is an inherent assumption in randomised controlled trials that the drug effect can be estimated by subtracting the response during placebo from the response during active drug treatment. Objective To test the assumption of additivity. The primary hypothesis was that the total treatment effect is smaller than the sum of the drug effect and the placebo effect. The secondary hypothesis was that non-additivity was most pronounced in participants with large placebo effects. Methods We used a within-subject randomised blinded balanced placebo design and included 48 healthy volunteers (50% males), mean (SD) age 23.4 (6.2) years. Experimental pain was induced by injections of hypertonic saline into the masseter muscle. Participants received four injections with hypertonic saline along with lidocaine or matching placebo in randomised order: A: received hypertonic saline/told hypertonic saline; B: received hypertonic saline+lidocaine/told hypertonic saline; C: received hypertonic saline+placebo/told hypertonic saline+pain killer; D: received hypertonic saline+lidocaine/told hypertonic saline+pain killer. The primary outcome measure was the area under the curve (AUC, mm2) of pain intensity during injections. Results There was a significant difference between the sum of the drug effect and the placebo effect (mean AUC 6279 mm2 (95% CI, 4936–7622)) and the total treatment effect (mean AUC 5455 mm2 (95% CI, 4585–6324)) (P = 0.049). This difference was larger for participants with large versus small placebo effects (P = 0.015), and the difference correlated significantly with the size of the placebo effect (r = 0.65, P = 0.006). Conclusion Although this study examined placebo effects and not the whole placebo response as in randomised controlled trials, it does suggest that the additivity assumption may be incorrect, and that the estimated drug effects in randomised controlled trials may be underestimated, particularly in studies reporting large placebo responses. The implications for randomised controlled trials and systematic reviews need to be discussed.

Expectations and positive emotional feelings accompany reductions in ongoing and evoked neuropathic pain following placebo interventions

Summary Large placebo but not nocebo effects were seen in ongoing and evoked neuropathic pain, and patients’ expectations about these treatments coexisted with emotional feelings. ABSTRACT Research on placebo analgesia and nocebo hyperalgesia has primarily included healthy subjects or acute pain patients, and it is unknown whether these effects can be obtained in ongoing pain in patients with chronic pain caused by an identifiable nerve injury. Eighteen patients with postthoracotomy neuropathic pain were exposed to placebo and nocebo manipulations, in which they received open and hidden administrations of pain‐relieving (lidocaine) or pain‐inducing (capsaicin) treatment controlled for the natural history of pain. Immediately after the open administration, patients rated their expected pain levels on a mechanical visual analogue scale (M‐VAS). They also reported their emotional feelings via a quantitative/qualitative experiential method. Subsequently, patients rated their ongoing pain levels on the M‐VAS and underwent quantitative sensory testing of evoked pain (brush, pinprick, area of hyperalgesia, wind‐up‐like pain). There was a significant placebo effect on both ongoing (P = .009 to .019) and evoked neuropathic pain (P = .0005 to .053). Expected pain levels accounted for significant amounts of the variance in ongoing (53.4%) and evoked pain (up to 34.5%) after the open lidocaine administration. Furthermore, patients reported high levels of positive and low levels of negative emotional feelings in the placebo condition compared with the nocebo condition (P ⩽ .001). Pain increases during nocebo were nonsignificant (P = .394 to 1.000). To our knowledge, this is the first study to demonstrate placebo effects in ongoing neuropathic pain. It provides further evidence for placebo‐induced reduction in hyperalgesia and suggests that patients’ expectations coexist with emotional feelings about treatments.

Music reduces pain and increases functional mobility in fibromyalgia

The pain in Fibromyalgia (FM) is difficult to treat and functional mobility seems to be an important comorbidity in these patients that could evolve into a disability. In this study we wanted to investigate the analgesic effects of music in FM pain. Twenty-two FM patients were passively exposed to (1) self-chosen, relaxing, pleasant music, and to (2) a control auditory condition (pink noise). They rated pain and performed the “timed-up & go task (TUG)” to measure functional mobility after each auditory condition. Listening to relaxing, pleasant, self-chosen music reduced pain and increased functional mobility significantly in our FM patients. The music-induced analgesia was significantly correlated with the TUG scores; thereby suggesting that the reduction in pain unpleasantness increased functional mobility. Notably, this mobility improvement was obtained with music played prior to the motor task (not during), therefore the effect cannot be explained merely by motor entrainment to a fast rhythm. Cognitive and emotional mechanisms seem to be central to music-induced analgesia. Our findings encourage the use of music as a treatment adjuvant to reduce chronic pain in FM and increase functional mobility thereby reducing the risk of disability.