[Nocebo--the antipode to placebo]

It is well documented that placebo represents Pavlovian conditioned reflexes activated by positive anticipation of healing. The pain-relieving effects of placebo are due to a psychical activation of the endogenous opioid-serotonergic, pain-inhibitory descending system. The opposite effect is nocebo, a term introduced in 1961 by Kennedy. Nocebo-effects similarly appear to be produced by conditioned reflexes, but are activated by negative expectations (Figure 1). A number of examples of nocebo are given. Nocebo-stimuli, such as anxiety, fear, mistrust and doubt, may reduce a placebo-effect; it may induce negative side-effects in placebo-treatment; it may produce new aversive symptoms; and it may reverse symptoms from positive ones to negative ones (e.g. revert an analgesic response to hyperalgesia). In its most extreme, nocebo-stimuli may cause death, as in voodoo-death in primitive societies, an example of the fear-paralysis reflex. Whether the outcome is positive or negative is determined, inter alia, by the subject's possibility of coping with the situation. In a setting where the animal has no control over an aversive stimulus, as in inescapable foot shocks, nocebo-effects predominate. It is postulated that noradrenergic neurons in locus coeruleus in the brain stem are involved in the production of nocebo-effects. The "placebo-system" and the "nocebo-system" exert a reciprocal inhibition at a brainstem level (Figure 3).