Placebo Analgesic Effect Research Articles

The contribution of suggestibility and expectation to placebo analgesia phenomenon in an experimental setting

This study reports how placebo analgesia was produced by conditioning whereby the intensity of electric stimulation was surreptitiously reduced in order to examine the contribution of psychological factors of suggestibility and expectancy on placebo analgesia. This strategy was used in order to manipulate expectancy for pain reduction. The magnitudes of the placebo effects were estimated after a manipulation procedure and during experimental trials in which stimulus intensities were reset to original baseline levels. Individual differences in suggestibility, verbal expectancy for drug efficacy and manipulation procedure for pain reduction were tested as possible mediators of placebo analgesia. The following dependent variables were measured: (a) subjective expectancy for drug efficacy in pain relief, (b) expected pain intensity and unpleasantness, (c) concurrent pain intensity and unpleasantness and (d) remembered pain intensity and unpleasantness. Statistically significant placebo effects on sensory and affective measures of pain were obtained independently of the extent of the surreptitious lowering of stimulus strength during manipulation trials. The pairing of placebo administration with painful stimulation was sufficient to produce a generalized placebo analgesic effect. However, verbal expectancy for drug efficacy and individual differences in suggestibility were found to contribute significantly to the magnitude of placebo analgesia. The highest placebo effect was shown by the most pronounced reductions in pain ratings in highly suggestible subjects who received suggestions presumed to elicit high expectancy for drug efficacy. The results also demonstrated that placebo effects established on remembered pain were at least twice as great as those obtained on concurrent placebo effects. This was mainly because baseline pain was remembered as being much more intense than it really was. Moreover, remembered placebo effects, like the concurrent placebo effects, were highly correlated with expected pain scores obtained just after manipulation trials. These results indicate that multiple factors contribute to the placebo effect, including suggestibility, expectancy and conditioning, and that the judgement of placebo analgesia is critically determined by whether pain relief is assessed concurrently or after treatment.

Response expectancies in placebo analgesia and their clinical relevance

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.

Pharmacology (82)

Gabapentin enhances the analgesic effect of morphine in healthy volunteers. (Dr. Margarete Fischer Bosch Institut fuer Klinische Pharmakologie, Stuttgart, Germany) Anesth Analg 2000;91:185–191.This randomized, placebo‐controlled, double‐blinded study investigated the pharmacodynamic and pharmacokinetic interaction of Gabapentin (GBP) and morphine in 12 healthy male volunteers. Morphine (60 mg, controlled release) or placebo was administered at 8:00 a.m., and GBP (600 mg) or placebo was administered at 10:00 a.m., thus comparing the analgesic effect of placebo + GBP (600 mg) with placebo + placebo and morphine (60 mg) + GBP in comparison to morphine plus placebo by using the cold pressor test. The duration and intensity of the side effects were assessed by using visual analog scales. The analgesic effect was evaluated by the change in the area under the curve of pain tolerance. Placebo + GBP did not present any significant analgesic effect compared with placebo + placebo. A siginificant increase in pain tolerance was observed comparing the combination of morphine and GBP with morphine and placebo. The observed adverse events after placebo + GBP were not significantly different compared with placebo + placebo. Morphine + placebo led to the expected opioid‐mediated side effects. They were significantly more pronounced compared with placebo + placebo, but did not differ significantly compared with the combination of morphine + GBP. Concerning the pharmacokinetic variables of morphine and its glucuronides, no significant difference between morphine + placebo and morphine + GBP was observed, whereas the area under the curve of GBP significantly increased, and apparent oral clearance and apparent renal clearance of GBP decreased when morphine was administered concomitantly. These results suggest 2 different sites for the pharmacokinetic interaction—1 at the level of absoption and the other at the level of elimination. The study reveals both a pharmacodynamic and pharmacokinetic interaction between morphine and GBP, leading to an increased analgesic effect of morphine + GBP. These results and the good tolerability of GBP should favor clinical trials investigating the clinical relevance of the combination of morphine and GBP for treating severe pain.

Gabapentin Enhances the Analgesic Effect of Morphine in Healthy Volunteers

The most effective group of drugs for the treatment of severe pain is opioid analgesics. Their use, however, is limited by decreased effects in neuropathic and chronic pain as a result of increased pain and development of tolerance. Gabapentin (GBP) is effective in both experimental models of chronic pain and clinical studies of neuropathic pain. Therefore, we investigated, in a randomized, placebo-controlled, double-blinded study, the pharmacodynamic and pharmacokinetic interaction of GBP and morphine in 12 healthy male volunteers. Morphine (60 mg, controlled release) or placebo was administered at 8:00 am, and GBP (600 mg) or placebo was administered at 10:00 am, thus comparing the analgesic effect of placebo + GBP (600 mg) with placebo + placebo and morphine (60 mg) + GBP in comparison to morphine plus placebo by using the cold pressor test. The duration and intensity of the side effects were assessed by using visual analog scales. The analgesic effect was evaluated by the change in the area under the curve (h × %; 0% baseline before Medication 1) of pain tolerance. Placebo + GBP (18.9% × h, 95% confidence interval [CI]: −2.5 to 40.3) did not present any significant analgesic effect compared with placebo + placebo (4.7% × h, 95% CI: −16.7 to 26.1). A significant increase in pain tolerance was observed comparing the combination of morphine and GBP (75.5% × h, 95% CI: 54.0–96.9) with morphine + placebo (40.6% × h, 95% CI: 19.2–62.0). The observed adverse events after placebo + GBP were not significantly different compared with placebo + placebo. Morphine + placebo led to the expected opioid-mediated side effects. They were significantly more pronounced compared with placebo + placebo but did not differ significantly compared with the combination of morphine + GBP. Concerning the pharmacokinetic variables of morphine and its glucuronides, no significant difference between morphine + placebo and morphine + GBP was observed, whereas the area under the curve of GBP (43.9 ± 5.3 vs 63.4 ± 16.2 μg · h-1 · mL-1, P < 0.05) significantly increased, and apparent oral clearance (230.8 ± 29.4 mL/min vs 178 ± 97.9 mL/min, P = 0.06) and apparent renal clearance (86.9 ± 20.6 vs 73.0 ± 24.2 mL/min, P = 0.067) of GBP decreased when morphine was administered concomitantly. These results suggest two different sites for the pharmacokinetic interaction—one at the level of absorption and the other at the level of elimination. Our study reveals both a pharmacodynamic and pharmacokinetic interaction between morphine and GBP, leading to an increased analgesic effect of morphine + GBP. These results and the good tolerability of GBP should favor clinical trials investigating the clinical relevance of the combination of morphine and GBP for treating severe pain. Implications In a randomized, placebo-controlled, double-blinded trial with 12 healthy volunteers, we studied the interaction of morphine and gabapentin using the cold pressor test. The anticonvulsant gabapentin enhanced the acute analgesic effect of morphine. Furthermore, the plasma concentration of gabapentin was increased when morphine was administered concomitantly. Therefore, the well tolerated combination of gabapentin and morphine may improve pain therapy, especially in pain states, like chronic and neuropathic pain, which respond poorly to opioids.

The specific effects of prior opioid exposure on placebo analgesia and placebo respiratory depression

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.

Where are the causes of placebo analgesia?: A behavioral experiential analysis

Environmental conditions that foster a placebo analgesic effect include prior exposure to an effective analgesic treatment and contextual cues associated with such treatment. This evidence for the role of classical conditioning in placebo analgesia suggests the potential use of animal models for studying this phenomenon and the possibility of understanding it at the level of neural mechanisms. In addition, cognitive dimensions, such as desire for and expectation of pain relief, can potentially extend explanations of how placebo analgesia occurs. Importantly, these experiential factors are measurable and could be incorporated into analyses of human placebo analgesia. Measures of experiential factors that may directly cause placebo analgesia, multiple measures of the different dimensions of pain, and adequate controls for the natural history could permit a refined analysis of the nature and mechanisms of placebo analgesia. Measurement of the critical experiential factors that cause placebo responses may have far-reaching implications for the evaluation of placebo effects in human clinical studies.

The placebo effect of transcutaneous electrical stimulation

The placebo effect of transcutaneous electrical stimulation was studied in 93 patients in a double-blind cross-over trial using a genuine stimulator and a placebo machine. Placebo analgesic effect occurred in 32% of trials, as compared with 48% for actual stimulation. The placebo effect of the transcutaneous electrical stimulator is similar to the placebo effect that is noted in other double-blind studies in which medications are used.

A Single Dose Study Comparing the Analgesic Effects of Diflunisal, Acetylsalicylic Acid, and Placebo in Pain following Meniscectomy

A single dose experiment was used to evaluate the analgesic effect of diflunisal, a new salicylic acid derivative. Three dose levels of diflunisal (125 mg, 250 mg, and 500 mg) were compared to one dose level of acetylsalicylic acid (ASA) (600 mg) and placebo. The maximal analgesis induced by 500 mg diflunisal was comparable to that of 600 mg ASA. The onset of action was slightly more rapid with ASA but the duration of the analgesic effect was far longer for diflunisal, extending beyond 8 hours after administration. Diflunisal is a promising drug for the treatment of post-operative pain because of its long-lasting effect.