Placebo and Endogenous Mechanisms of Analgesia

16 May

Abstract The discovery of the endogenous systems of analgesia has produced a large amount of research aimed at investigating their biochemical and neurophysiological mechanisms and their neuroanatomical localization. Nevertheless, the neurobiological acquisitions on these mechanisms have not been paralleled by behavioural correlates in humans—in other words, by the understanding of when and how these endogenous mechanisms of analgesia are activated. Until recent times one of the most studied behavioural correlates of endoge- nous analgesia was stress-induced analgesia, in which the activation of endogenous opioid systems is known to be involved. By contrast, today the placebo analgesic effect represents one of the best-described situations in which this endogenous opioid network is naturally activated in humans. Therefore, not only is placebo research helpful towards improving clin- ical trial design and medical practice, but it also provides us with a better understanding of the endogenous mechanisms of analgesia.

Keywords  Placebo · Endogenous opioids · Expectation · Conditioning · Clinical trials

Endogenous Mechanisms of Analgesia

Placebo administration has been found to activate the endogenous  mecha- nisms of analgesia, and today the placebo effect represents  one of the most interesting  models to help us understand when and how these mechanisms are activated (Petrovic et al. 2002; Wager et al. 2004; Colloca and Benedetti

2005). As most of our knowledge about placebo analgesia is based on opioid mechanisms, particular attention has been paid to the endogenous opioid sys-

tems. However, non-opioid mechanisms are also involved in placebo analgesia (Colloca and Benedetti 2005), although nothing is known about them. A re- cent comprehensive  review of the endogenous  mechanisms  of analgesia by

Millan (2002) clearly shows the complexity of this endogenous network, which includes both opioid and non-opioid systems. Thus, the opioid systems repre- sent a first step towards understanding the intricate mechanisms underlying

the placebo analgesic effect.

Opioid receptors can be found throughout the brain, brainstem and spinal cord (Pfeiffer et al. 1982; Wamsley et al. 1982; Atweh and Kuhar 1983; Sadzot et al. 1991; Fields and Basbaum 1999; Fields 2004). These receptors may exert analgesic effects through different mechanisms (Jensen 1997), such as mod- ulation at the spinal level and/or  control of cortical and brainstem  regions. The modulation  of the spinal cord is one of the best described (Fields and Basbaum 1999; Fields 2004). The opioid system in the brainstem  comprises different regions like the periaqueductal  grey (PAG), the parabrachial  nuclei (PBN) and the rostral ventromedial medulla (RVM) (Fields and Basbaum 1999; Fields 2004). Although the opioid receptors are less characterized in the cor- tex, autoradiographic studies indicate high concentrations of opioid receptors in the cingulate cortex and prefrontal  cortex (Wamsley et al. 1982; Pfeiffer et al. 1982; Sadzot et al. 1991), and one of the highest levels of opioid receptor binding  has been found in the anterior  cingulate cortex (ACC) (Vogt et al.

1993). Studies performed  by means of positron  emission tomography  (PET) and the radioactive opioid 11C-diprenorphine  confirm previous animal and human autoradiography findings (Jones et al. 1991; Willoch et al. 1999, 2004). In addition,  opioid receptor agonists such as remifentanil  and fentanyl have

been shown to act on several regions known to be involved in pain processing and containing high concentrations of opioid receptors (Firestone et al. 1996; Adler et al. 1997; Casey et al. 2000; Wagner et al. 2001; Petrovic et al. 2002).

One of the main problems of this endogenous opioid network is to under- stand when and how it is involved in analgesic effects. For example, it has long

been known that fear and stress play an important  role in the activation of the endogenous opioid system (Willer and Albe-Fessard 1980; Fanselow 1994). It has also been hypothesized that several other contexts may be important  for

the activation of the endogenous  opioid systems (Fields and Basbaum 1999; Price 1999). In this regard, today the placebo response is probably the best-

described situation in which this endogenous opioid network is naturally ac- tivated in humans (Colloca and Benedetti 2005). Therefore, placebo research is also important for the understanding of the endogenous  mechanisms  of analgesia.

The Placebo Effect

Methodology to Reveal Real Placebo Effects

The placebo effect is the effect that  follows the administration of an inert medical treatment  (the placebo), be it pharmacological  or not. In order for a placebo effect to be demonstrated, several other phenomena have to be ruled out (Table 1), as the placebo itself is not always the cause of the effect that is observed (Benedetti and Colloca 2004; Colloca and Benedetti 2005; Pollo and Benedetti 2004). For example, most painful conditions  show a spontaneous variation in pain intensity that is known as natural history (Fields and Levine

1984). If a subject takes a placebo just before his pain starts decreasing, he may believe that the placebo is effective although that decrease would have occurred anyway. This is not a placebo effect but a misinterpretation of the

cause–effect relationship. Regression to the mean represents another example. This is a statistical phenomenon in which individuals tend to receive their initial pain assessment when pain is near its greatest intensity, but their pain level is

likely to be lower when they return for a second assessment (Davis 2002). In this case also, the improvement cannot be attributed to any intervention they might have undergone. A further source of confusion is represented by false-positive

errors  made by the patient  according to signal detection theory (Allan and Siegel 2002). In other words, a patient may erroneously detect a symptomatic relief in response to an inert treatment. The ambiguity of the symptom intensity may also lead to biases following verbal suggestion of benefit. Sometimes

it is a co-intervention,  such as the mechanical stimulation  produced  by the insertion of a needle to inject an inert solution, which is responsible for the reduction  of pain (Pollo and Benedetti 2004). All these examples show that,

although an improvement may occur after the administration of a placebo, the placebo is not necessarily the cause of the effect that is observed.

In a clinical trial all these factors are present. Therefore, clinical trials do

not representa good model to study and to understand the mechanisms of the placebo effect. For example, it has been shown that many results obtained in the clinical trial setting (Hrobjartsson and Gotzsche 2001) differ from those obtained  in the laboratory  setting where strictly controlled  conditions  are adopted (Vase et al. 2002). In the laboratory setting, for instance, it is possible to comparea no-treatment group witha placebo group so that the spontaneous

Placebo and Endogenous Mechanisms of Analgesia

remission of the symptom can be identified. The difference between the no- treatment  group  and the placebo group  represents  the real placebo effect. In the laboratory  setting other  confounding  variables can be controlled  as well (Benedetti and Colloca 2004; Colloca and Benedetti 2005), like regression to the mean, which can be ruled out by using experimental  pain. Likewise, symptom detection ambiguity and subjects’ biases can be eliminated through the measurement  of objective physiological parameters.  Finally, the effects of a co-intervention  can be identified by using the appropriate experimental model.

The term placebo effect is generally considered to be different from placebo response. The former has been used to refer to any improvement  in the con-

dition  of a group  of subjects that  has received a placebo. By contrast,  the latter refers to the change in an individual caused by a placebo manipulation. However, these two terms can be used interchangeably.

The Role of Expectation, Motivation and Conditioning

When all the factors described above have been ruled out, the real placebo re- sponse is a psychobiological phenomenon whereby several brain mechanisms can be identified (Table 1). It is important  to realize that the administration of a placebo involves the complex psychosocial context around  the patient,

such as the doctor’s words, the hospital environment, the sight of a therapeutic apparatus  and the like. Therefore, the study of the placebo effect is basically the study of the psychosocial context that surrounds  the patient.

It has long been known that the placebo effect involves both cognitive factors and conditioning mechanisms. On the one hand the deceptive administration of a placebo treatment  can lead the subjects to believe that the treatment  is effective, such that the anticipation and expectation of analgesia lead to a sig- nificant placebo analgesic effect (Amanzio and Benedetti 1999; Benedetti et al.

1999b; Price et al. 1999; Pollo et al. 2001). Some studies show that different ver- bal instructions lead to different expectations and thus to different responses, and this plays a fundamental role in the placebo effect (Kirsch 1985; Kirsch and Weixel 1988; Kirsch 1990, 1999; Price and Fields 1997; Pollo et al. 2001). This occurs not only with placebos but even with active drugs such as epinephrine (Schachter and Singer 1962), amphetamine  and chloral hydrate (Lyerly et al.

1964), and carisoprodol  (Flaten et al. 1999). In other words, a typical drug effect can sometimes be reduced if the subjects are misinformed on the action

of the drug and, similarly, new side-effects can be elicited with the appropriate verbal instructions.  Motivation and desire for pain relief has also been found to play a role in placebo analgesia (Price and Fields 1997; Vase et al. 2003).

The context around a therapy may act not only through expectation and con-

scious anticipatory processes. There are some lines of evidence indicating that, at least in some circumstances, the placebo response is a conditioned response due to repeated associations between a conditioned  stimulus (e.g. shape and colour of pills and tablets) and an unconditioned stimulus (the active substance inside the pills and tablets) (Gleidman et al. 1957; Herrnstein 1962; Siegel 1985,

2002; Ader 1997; Voudouris et al. 1989, 1990; Wickramasekera  2001). In this case, it is the context itself that is the conditioned stimulus. However, even by considering a typical conditioning procedure, it has been shown that a condi- tioned placebo response can result from conditioning but is actually mediated by expectancy (Montgomery  and Kirsch 1997). In fact, conditioning  would lead to the expectation that a given event will follow another event, and this occurs on the basis of the information that the conditioned stimulus provides about the unconditioned stimulus (Reiss 1980; Rescorla 1988).

A recent study has investigated some physiological functions that are af- fected by placebos through anticipatory  conscious processes and some other functions that undergo an unconscious mechanism of conditioning (Benedetti et al. 2003b). For example, verbally induced expectations of either analgesia or hyperalgesia antagonize completely the effects of a conditioning procedure in experimentally induced pain. By contrast, verbally induced expectations of ei- ther an increase or decrease of growth hormone (GH) and cortisol do not have any effect on the secretion of these hormones. However, if a pre-conditioning is performed  with sumatriptan, a serotonin  agonist that stimulates GH and inhibits cortisol secretion, a significant GH increase and cortisol decrease can be found in plasma after placebo administration. These findings indicate that

verbally induced expectations have no effect on hormonal  secretion whereas they affect pain. This suggests that placebo responses are mediated by condi- tioning when unconscious  physiological functions, like hormonal  secretion, are involved, whereas they are mediated by expectation when conscious phys- iological processes, like pain, come into play. Thus the placebo effect is a phe- nomenon that can be learned either consciously or unconsciously, depending on the system that is involved.

The Neurobiology of the Placebo Effect

The recent explosion of research on the neurobiological mechanisms  of the placebo effect is paying dividends,  as we are beginning  to understand the cascade of events that occur following the administration of a placebo along with verbal suggestions of clinical benefit (Fig. 1). Most of our neurobiologi- cal knowledge comes from the field of pain and analgesia, and several lines of evidence suggest that placebo administration activates the endogenous mecha- nisms of analgesia described in Sect. 1. Today we know that placebo analgesia is mediated by both opioid and non-opioid mechanisms, depending on different factors.

Opioid Mechanisms

An important step in understanding the mechanisms of placebo-induced anal- gesia was made in the clinical setting when Levine et al. (1978) provided evi- dence that placebo analgesia is mediated by endogenous opioids. Other studies subsequently further confirmed this hypothesis (Grevert et al. 1983; Levine and Gordon 1984; Benedetti 1996). In addition, cholecystokinin was found to in- hibit placebo-induced  analgesia, as cholecystokinin  antagonists  are capable of potentiating  the placebo analgesic effect (Benedetti et al. 1995, 1996). In fact, cholecystokinin is an anti-opioid peptide which antagonizes endogenous opioid neuropeptides,  so that its blockade results in the potentiation of opioid effects (Benedetti 1997).

Fields and Levine (1984) were the first to hypothesize that the placebo re- sponse may be subdivided into opioid and non-opioid  components.  In fact, they suggested that different physical, psychological and environmental situa- tions could affect the endogenous opioid systems differently. This problem was recently addressed by Amanzio and Benedetti (1999), who showed that both expectation and a conditioning  procedure  could result in placebo analgesia. The former is capable of activating opioid systems whereas the latter activates specific sub-systems. In fact, if the placebo response is induced by means of strong expectation cues, it can be blocked by the opioid antagonist naloxone.

Placebo and Endogenous Mechanisms of Analgesia

Fig. 1  Events that  might  occur  following the  administration of a placebo  along  with verbal  suggestions  of  analgesia.  A descending  pain  inhibitory  network  that  involves the  rostral  anterior  cingulate  cortex,  the  orbitofrontal  cortex,  the  periaqueductal  grey and  the  pons/medulla   is  activated.  Endogenous  opioids  might  inhibit  pain  through this  descending  network  and/or  other  mechanisms.  The endogenous  opioids  also act

at  the  level of  the  respiratory  centres.  The  β-adrenergic  sympathetic  system  is  also

inhibited  during  placebo  analgesia,  but  the  mechanism  is  not  known  (it  might  in-

volve either  reduction  of the pain itself or direct action  of endogenous  opioids).  Non- opioid  mechanisms  also  play  a  role.  Cholecystokinin  (CCK) counteracts   the  effects of the  endogenous  opioids  thus  antagonizing  placebo  analgesia.  Placebo can  also af- fect  serotonin-dependent  hormone   secretion,  mimicking  the  effect  of  the  analgesic drug  sumatriptan.  GH, growth  hormone;  ACTH, adrenocorticotropic hormone;  5HT, serotonin

Conversely, if the placebo response is induced by means of a prior conditioning with a non-opioid drug, it is naloxone-insensitive.

Regional placebo analgesic responses can be obtained in different parts of the body (Montgomery and Kirsch 1996; Price et al. 1999), and these responses are naloxone-reversible  (Benedetti et al. 1999b). If four noxious stimuli are applied to the hands and feet and a placebo cream is applied to one hand only, pain is reduced only on the hand where the placebo cream had been applied. This effect is blocked by naloxone, suggesting that the placebo-activated en- dogenous opioids have a somatotopic organization (Benedetti et al. 1999b). An additional study supporting the involvement of endogenous opioids in placebo analgesia was performed by Lipman et al. (1990) in chronic pain patients. These authors  found that those patients who responded  to placebo showed higher concentrations of endorphins  in the cerebrospinal fluid compared with those patients who did not respond.

A likely candidate  for the mediation  of placebo-induced  analgesia is the opioid neuronal  network described in Sect. 1 (Fields and Price 1997; Fields

and Basbaum 1999; Price 1999). A recent brain imaging study that used PET supports this hypothesis (Petrovic et al. 2002). These authors found that both a placebo and the rapidly acting opioid  agonist remifentanil  affect similar regions  in the cerebral  cortex and  in the brainstem,  thus  indicating  a re-

lated mechanism  in placebo-induced  and opioid-induced  analgesia. In par- ticular, the administration of a placebo induced the activation of the rostral anterior  cingulate cortex (rACC) and the orbitofrontal  cortex (OrbC). More-

over, there was a significant co-variation  in activity between the rACC and the lower pons/medulla, and a sub-significant co-variation between the rACC and the PAG, thus suggesting that the descending rACC/PAG/brainstem pain-

modulating  circuit is involved in placebo analgesia. In another  study using functional magnetic resonance imaging (fMRI), it was also found that brain activation patterns in the prefrontal cortex changed in anticipation to analgesia following placebo administration (Wager et al. 2004).

Placebo-activated endogenous  opioids have also been shown to produce a typical side-effect of opioids, that is, respiratory depression (Benedetti et al.

1998; Benedetti et al. 1999a). After repeated administrations of analgesic doses

of buprenorphine in the post-operative phase, which induces a mild decrease of ventilation, a placebo is capable of mimicking the same respiratory depres- sant response. This respiratory placebo response can be blocked by naloxone, indicating that it is mediated by endogenous opioids. Thus, placebo-activated opioid systems act not only on pain mechanisms but also on the respiratory centres.

The involvement of other systems during placebo analgesia is further sup- ported by recent work in which the sympathetic and parasympathetic  control of the heart were analysed during placebo analgesia (Pollo et al. 2003). In the clinical setting, it was found that the placebo analgesic response to a noxious stimulus was accompanied  by a reduced heart rate response. In order to in-

vestigate this effect from a pharmacological  viewpoint, the same effect was reproduced  in the laboratory setting. It was found that the opioid antagonist naloxone completely antagonized both placebo analgesia and the concomitant

reduced heart rate response, whereas the β-blocker propranolol  antagonized the placebo heart rate reduction but not placebo analgesia. By contrast, both placebo responses  were present  during  muscarinic  blockade with atropine,

indicating no involvement of the parasympathetic system. A spectral analy- sis of the heart rate variability for the identification  of the sympathetic and parasympathetic components  showed that  the β-adrenergic  low-frequency spectral component  was reduced during placebo analgesia, an effect that was

reversed by naloxone. These findings indicate that opioid-mediated placebo analgesia also affects the cardiovascular  system, although  we do not know whether the placebo-activated  endogenous  opioids  inhibit  the sympathetic

system directly or—through  the reduction of pain—indirectly.


Non-opioid Mechanisms

Recently, some non-opioid  mechanisms have begun to be explored, although nothing is known about non-opioid  mediators  of placebo analgesia. In fact, the release of neurotransmitters, like dopamine, has been identified in other illnesses such as Parkinson’s disease. Nonetheless, it is important to emphasize that the integration between the findings in the field of pain and those obtained in other pathological conditions is necessary and essential to better understand the intricate mechanisms of the placebo effect.

As described in Sect. 2.2, by using the analgesic drug sumatriptan, a sero- tonin agonist of the 5-HT1B/1D receptors that stimulates GH and inhibits cor- tisol secretion, it was shown that a conditioning procedure is capable of pro- ducing hormonal placebo responses. In fact, if a placebo is given after repeated administrations of sumatriptan, a placebo GH increase and a placebo cor- tisol decrease can be found  (Benedetti et al. 2003b). Interestingly,  verbally induced  expectations  of increase/decrease  of GH and cortisol did not have any effect on the secretion of these hormones.  Therefore, whereas hormone secretion is not affected by expectations, it is affected by a conditioning pro- cedure. Although we do not know whether these placebo responses are really mediated by serotonin, a pharmacological pre-conditioning appears to affect serotonin-dependent hormone secretion. These new findings may help inves- tigate non-opioid mechanisms in placebo analgesia.

The verbal instructions that induce expectations may have either a hopeful and trust-inducing meaning, eliciting a placebo effect, or a fearful and stressful meaning, inducing a nocebo effect (Hahn 1985, 1997; Benedetti and Amanzio

1997; Moerman  2002a, b). In a study performed  in post-operative  patients (Benedetti et al. 1997), negative expectations  were induced  by injecting an inert  substance  along with the suggestion that  pain was going to increase.

In fact, pain increased and this increase was prevented  by the CCK antago- nist proglumide. This indicates that expectation-induced hyperalgesia of these patients  was mediated,  at least in part,  by CCK. The effects of proglumide were not antagonized  by naloxone, which suggests that endogenous  opioids were not involved. Since CCK plays a role in anxiety and negative expecta- tions themselves are anxiogenic, these results suggest that proglumide acted on a CCK-dependent increase of anxiety during the verbally induced negative expectations. Although this study analysed a nocebo procedure, the involve- ment of CCK in the nocebo effect might help better clarify the modulation  of pain by both positive and negative expectations.

The release of endogenous  substances  following a placebo procedure  is a phenomenon  which is not confined to the field of pain, but it is also present in motor disorders  such as Parkinson’s disease. As occurs with pain, in this case patients are given an inert substance (placebo) and are told that it is an anti-Parkinsonian drug that produces an improvement in their motor perfor- mance. Both clinical improvements (Shetty et al. 1999; Goetz et al. 2000; Pollo et a. 2002) and changes in the single-neuron firing pattern (Benedetti et al. 2004) have been found after placebo administration in Parkinson’s patients. A study used PET in order to assess the competition  between endogenous dopamine

and 11C-raclopride for D2/D3 receptors, a method that allows identification of endogenous dopamine release (de la Fuente-Fernandez et al. 2001). This study

shows that placebo-induced  expectation of motor improvement  activates en- dogenous dopamine in the striatum of Parkinsonian  patients, thus indicating

that endogenous substances other than opioids may be involved in the placebo response in other illnesses. De la Fuente-Fernandez  and Stoessl (2002) argue that  the expectation-induced release of dopamine  in Parkinson’s  disease is

related to reward mechanisms. According to these authors, dopamine release by expectation of reward, in this case the expectation of clinical benefit, could represent  a common biochemical substrate  in many pathological situations, including pain. It is worth noting that there is an important interaction  be-

tween dopamine  and opioid systems, and that endogenous  opioids are also involved in reward mechanisms (de la Fuente-Fernandez and Stoessl 2002).

Very recently, the neural mechanisms of placebo treatments have also been

studied in depression, although these studies need further research and confir- mation because they did not include appropriate control groups. Depressed pa- tients who received a placebo treatment showed both electrical and metabolic changes in the brain.  In the first case, placebos induced  electroencephalo- graphic changes in the prefrontal  cortex of patients  with major depression, particularly in the right hemisphere (Leuchter et al. 2002). In the second case, changes in brain glucose metabolism were measured by using PET in subjects with unipolar depression. Placebo treatments  were associated with metabolic increases in the prefrontal,  anterior  cingulate, premotor,  parietal, posterior insula, and posterior cingulate cortex, and metabolic decreases in the subgen- ual cingulate cortex, para-hippocampus and thalamus (Mayberg et al. 2002).

Interestingly, these regions also were affected by the selective serotonin reup- take inhibitor fluoxetine, a result that suggests a possible role for serotonin in placebo-induced antidepressant effects.

Therefore, although very little is known on the role of non-opioid  medi- ators  in placebo analgesia, the investigation  of the placebo effect in other illnesses demonstrates that other neurotransmitters—like CCK, serotonin and dopamine—may  contribute  to the modulation  of the placebo responses  in different circumstances and pathological conditions.

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