The Role of Learning in Nocebo Hyperalgesia
Condition: Nocebo Effects; Hyperalgesia; Chronic Pain; Pain Syndrome
MeSH terms: Hyperalgesia; Chronic Pain
Study type: Interventional

Summary: 
      Nocebo effects are adverse effects induced by patients' expectations. Nocebo effects on pain
      may underlie several clinical conditions, such as chronic pain. These effects can be learned
      via classical conditioning mechanisms. In the lab, nocebo effects are commonly studied via
      conditioning with continuous reinforcement (CRF) during which 100 percent of unconditioned
      pain stimuli are paired to conditioned stimuli (i.e., the activation of a mock medical
      device). Partial reinforcement (PRF) provides a more uncertain pairing during conditioning,
      where less than 100 percent of unconditioned pain stimuli are paired to conditioned stimuli.
      This method provides a potentially more clinically relevant learning platform to study how
      nocebo effects on pain are induced. In this study, the efficacy of conditioning with PRF,
      CRF, and sham-conditioning in inducing nocebo effects on pain will be compared. Furthermore,
      a counterconditioning method will be compared to an extinction method for the attenuation of
      nocebo effects on pain. Given the relevance of nocebo effects for patients, it is important
      to ascertain effective & clinically relevant methods to understand how nocebo effects may be
      formed and attenuated. This study is conducted by Leiden University.
    

Detailed description: 
      Main planned analyses:

      Primary Outcome; Comparing the effectivity of conditioning with PRF, conditioning with CRF,
      and sham conditioning, in inducing nocebo effects on pain:

      The magnitude of the induced nocebo effect during the first evocation phase (dependent
      variable), will be compared between induction groups (independent variable). The pain ratings
      for the first control trial will be measured against the pain ratings for the first
      reinforced trial, yielding the magnitude of the nocebo effect. A 3x2 mixed model Analysis of
      Variance (ANOVA) will be used, treating group as the between-subjects factor with three
      levels (PRF, CRF, sham) and magnitude of the nocebo effect on pain as a within-subjects
      measure with two levels (first control and first reinforced trial). Planned contrasts will be
      conducted.

      Secondary Outcome; Comparing the effectivity of counterconditioning and extinction in
      attenuating nocebo effects on pain:

      The nocebo effect still present in the second evocation phase (dependent variable) will be
      compared between attenuation groups (independent variable). This effect will be measured as
      the change in pain ratings reported in the first reinforced trial of the first evocation
      phase (after induction) and pain ratings reported in the first reinforced trial of the second
      evocation phase (after attenuation). This effect will be further analysed by measuring any
      change in pain reports for the control trials (second dependent variable) in the same way.
      The effect of induction group will also be further explored. A 2x2 mixed model ANOVA will be
      conducted, with attenuation group as the between-subjects factor (counterconditioning and
      extinction) and the degree to which the nocebo effect has been attenuated as the
      within-subjects measure with two levels (first and second evocation phase for the first
      reinforced trials). Further secondary analyses will be conducted.
    

Intervention name(s): Conditioning with partial reinforcement; Conditioning with continuous reinforcement; Counterconditioning; Extinction; Sham Conditioning
Intervention type(s): Behavioral; Behavioral; Behavioral; Behavioral; Behavioral
Intervention description(s): Conditioning with partial reinforcement (PRF) provides an uncertain pairing of unconditioned high pain stimuli and conditioned stimuli (i.e., on-screen messages signaling the activation of a mock medical device). During PRF only 70 percent of unconditioned stimuli are paired to conditioned stimuli. Pain of only moderate intensity is used for control stimuli that are paired to the deactivation of the mock device and are also used in the 30 percent of unreinforced trials.; During conditioning with continuous reinforcement (CRF) unconditioned high pain stimuli are paired to conditioned stimuli (i.e., on-screen messages signaling the activation of a mock medical device) in 100 percent of conditioning trials. Pain of only moderate intensity is used for control stimuli that are paired to the deactivation of the mock device.; During counterconditioning, the previously conditioned nocebo effects on pain are attenuated by pairing the same conditioned stimuli (i.e., on-screen messages signaling the activation of a mock medical device) to thermal pain stimuli of low intensity.; During extinction, the previously conditioned nocebo effects on pain are attenuated by pairing the same conditioned stimuli (i.e., on-screen messages signaling the activation of a mock medical device) only to control stimuli of moderate intensity (previously paired to the deactivation of the mock device).; In the sham group, participants receive different instructions (namely, that the activation of the device is not expected to affect their pain sensitivity). Additionally, during sham conditioning unconditioned stimuli are not consistently paired to conditioned stimuli, thereby preventing the formation of an association between high pain stimuli and the activation of the mock medical device. In the attenuation phase participants undergo an extinction procedure.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This study employs a 2-by-2 design (i.e.,2 conditioning induction groups and 2 attenuation groups), with an additional control group (i.e., sham conditioning). Participants are thus allocated in 1 out of 5 groups.
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Nocebo; Pain; Conditioning; Counterconditioning; Partial reinforcement; Learning