The Effect of Palmitylethanolamide on Central and Peripheral Sensitization After Heat-induced Hyperalgesia
Condition: Pain, Chronic; Pain, Acute; Central Sensitisation; Neuroinflammatory Response
MeSH terms: Hyperalgesia; Acute Pain; Chronic Pain
Study type: Interventional

Summary: 
      This planned study is based on a randomized, placebo-controlled cross-over design.

      Palmityhlethanolamide (PEA) is an endogenous fatty acid amide from the group of
      N-Acetylethanolamides, which analgesic, anti-inflammatory and neuroprotective effects can be
      attributed to this. In clinical studies, PEA has mainly been used as an adjuvant in pain
      therapy. The previous data show clinical efficacy without conclusions that can be drawn about
      the underlying mechanisms - these have not yet been investigated in a human experiment.

      The planned study, which demonstrates the mode of action of PEA using an established pain
      model on healthy volunteers, will help to assign the efficacy to peripheral or central
      nervous systems. These mechanisms allow to establish mechanism-oriented therapy approaches.
      These findings are essential for a better understanding of the clinical efficacy and to
      evaluate the correct fields of application.
    

Detailed description: 
      Palmityhlethanolamide (PEA) is an endogenous fatty acid amide from the group of
      N-Acetylethanolamides, which analgesic, anti-inflammatory and neuroprotective effects can be
      attributed to this. It is referred to as "dietary Food for special medical purposes".
      Different mechanisms of action have been described, including an effect on mast cells,
      ATP-sensitive K channels and TRP channels. In an animal study in mice it could be shown that
      the antinociceptive properties of PEA can be blocked by a CB2-cannabinoid antagonist.
      Overall, PEA seems to play a relevant role in the body's own regulation of neurogenic
      inflammation.

      In clinical studies, PEA has mainly been used as an adjuvant in pain therapy. In a recent
      metaanalysis of studies in which PEA was used to treatment of neuropathic or chronic pain, a
      significant effect can be shown. Remarkably none of the 1188 patients who took PEA for up to
      60 days had reported side effects.

      "Repetitive phasic heat application" is a validated method to generate a short-term
      peripheral and central sensitization. As a non-invasive human pain model, it is therefore
      well suited to examine analgesic and antihyperalgesic effects of pharmaceuticals.

      The data of the above meta-analysis show clinical efficacy without conclusions that can be
      drawn about the underlying mechanisms - these have not yet been investigated in a human
      experiment. Our planned study, which demonstrates the mode of action of PEA using an
      established pain model on healthy volunteers, will help to assign the efficacy to peripheral
      or central nervous systems. These mechanisms allow to establish mechanism-oriented therapy
      approaches. These findings are essential for a better understanding of the clinical efficacy
      and to evaluate the correct fields of applikation. If there is peripheral efficacy, this
      would qualify PEA for use in acute pain. However, if the effect is explained by central
      mechanisms, PEA can be useful in the area of chronic pain, and also in neuropathic pain.
      Accordingly, the results of this experimental human study are groundbreaking for the planning
      of future application studies or clinical use.

      Questions:

      In this study four questions were to be answered:

        1. Can spontaneous pain after repetitive phasic heat application be reduced by the intake
           of PEA?

        2. Can central sensitization be influenced by the intake of PEA?

        3. Can peripheral sensitization be influenced by the intake of PEA?

        4. Can the endogenous pain inhibition be influenced by the intake of PEA?

      The following methods are used to answer these questions.

        1. Spontaneous pain is measured using Visual Analog Scale (VAS).

        2. To assign an effect to central sensitization, the sensitivity to mechanical stimuli,
           i.e. Pinprick hyperalgesia or allodynia is the established marker.

        3. Efficacy on peripheral sensitization can be assessed by measuring the heat- thresholds.

        4. The endogenous pain inhibition is tested by the examination of the "conditioned pain
           modulation".

      Hypotheses

      Null hypothesis:

      Taking PEA 3x400mg for 28 days changes, compared to placebo spontaneous pain after repetitive
      phasic heat application.

      Alternative hypothesis:

      Taking PEA 3x400mg for 28 days changes, compared to placebo spontaneous pain after repetitive
      phasic heat application.

      Secondary hypotheses:

      There is a significant difference in the size of mechanical allodynia distance after
      repetitive phasic heat application compared to placebo intake.

      PEA induces a change in Pinprick hyperalgesia compared to placebo after repetitive phasic
      heat application.

      PEA induces a change in thermal perception and pain threshold compared to placebo after
      repetitive phasic heat application.

      PEA induces a change in "conditioned pain modulation" compared to placebo.

      Method:

      This study is based on a randomized, placebo-controlled cross-over design. The patients take
      either the test substance or placebo for 28 days according to a randomization generated via
      "randomizer.at". Both the patients and the study staff responsible for collecting the
      measurement parameters are blinded by the order in which the tablets are taken, as the
      individual tablets are stored in doses that are only marked with a code, that does not allow
      to identify whether they are verum or placebo preparations. A staff member not participating
      in the study will dissolve the code at the end of the study.

      After recruitment, information and inclusion of the subjects in the study, the first baseline
      measurement is performed. This is followed by randomization into 2 groups. After 28 days,
      during which either the verum or study substance is taken, the influence on the "conditioned
      pain modulation" is measured. The repetitive phasic heat application according to the
      published procedures follows. A 3x3cm area on the volar forearm is heated repeatedly using a
      TSA-II NeuroSensoryAnalyser. The thermode starts at 32.0°C and heats up to 48.0°C at 10°C/sec
      and cools down to 32.0°C after 6 seconds. This is repeated 6 times in total. This is followed
      by a 30 second pause and then 6 more heatings. A total of 10 blocks with 6 heatings each are
      performed.

      At the end of the last block, spontaneous pain is determined using the Visual Analogue Scale.

      Since primary and secondary hyperalgesia is most pronounced at 1 hour after repetitive phasic
      heat application, 60 minutes after the last heating, the measurement of allodynia distance
      and pinprick hyperalgesia is performed in immediate temporal sequence and the heat pain and
      perception threshold is determined.

      After an 8-week wash-out phase, a new baseline measurement is taken before the other
      substance is taken for 28 days. This is followed by a new examination of the conditioned pain
      modulation, a repetitive phasic heat application and the recording of the measurement
      parameters according to the sequence described above.

      Statistics:

      In cooperation with the Institute for Medical Informatics, Statistics and Documentation of
      the Medical University of Graz, the T-test for paired samples was defined for biometric
      planning, the planned evaluation is based on a linear mixed model.

      Study substance The volunteers will each receive 90 tablets containing either
      palmitoylethanolamide 400mg (OptiPEA.) or an optically identical placebo manufactured by our
      institutional pharmacy. The study substance is supplied by the company Innexus
      Nutraceuticals. It is taken at 8-hour intervals. The last dose is taken in the morning before
      the study visit. To increase the adherence to the therapy, an electronic reminder is given
      via cell phone.

      Parameter

      Spontaneous pain:

      Directly after the last heat application, the spontaneous pain is recorded using the VAS
      scale, which is used throughout the LKH Univ.-Klinikum Graz.

      Allodynia:

      Starting from the center of the thermal application, a von Frey filament (128 mN) is applied
      to the skin in 4 radial lines at a 5 mm interval, first from the inside to the outside, then
      from the outside to the inside, and the distance at which an unpleasant pointed sensation
      first occurs is determined. The 8 measurements are averaged.

      Pinprick hyperalgesia:

      By means of a pinprick with 256 mN a pointed stimulus is applied. The test site is 5 cm
      proximal to the center of the thermal stimulation area. A numerical scale (0-100) is used to
      measure how painful this stimulus is.

      Heat pain and perception threshold:

      The heat detection threshold and the heat pain threshold are determined according to the
      guidelines of the German Research Association for Neuropathic Pain, which involves heating
      the skin with TSA-II NeuroSensoryAnalyser. The test person can stop the heatig by pressing a
      stop button. This should be done at the first time he/she notices that the skin is warming up
      (heat detection threshold) or at the time he/she notices a pulling, burning or pricking
      sensation in addition to the feeling of heat (heat pain threshold). The measurements are
      taken 3 times each and the results are averaged.

      Conditioned pain modulation Conditioned pain modulation describes the function of the
      descending, pain-inhibiting system. First, the force with which pressure on the adductor
      pollicis brevis muscle of the non-dominant hand is not only perceived as pressure, but also
      as a stabbing, burning or pulling sensation is determined using a pressure gauge.
      Subsequently, the contralateral hand is immersed in ice water until the subject feels a pain
      intensity of NRS 40 (101-part scale). The pressure pain threshold is then immediately raised
      again.

      Adverse effects:

      Possible adverse effects are assessed and documented at each study visit. In addition, the
      subjects are informed about the necessity of immediate telephone contact in case of the
      occurrence of undesirable side effects.

      Sample Size The sample size was calculated by Mag. Schwantzer, Institute for Medical
      Informatics, Statistics and Documentation (IMI), Medical University of Graz. The database was
      based on the study by Jurgens et al, in which repetitive phasic heat application was tested
      in healthy volunteers.

      In this publication, the mean value for maximum pain was 72.2, the standard deviation was
      given as 5.4. Assuming more conservative baseline numbers for case number estimation
      (SD=10.8), a sample size of 12 on a paired sample T-test with alpha=5% would have 80% power
      to detect a difference of 10 VAS units. To compensate for any drop-outs, a sample size of 14
      subjects is included in the study. Statistical evaluation is performed by the T-test for
      paired samples or the Wilcoxon sign test, depending on the central tendency.

      Recruitment of test persons / education Recruitment is done by posting on notice boards at
      the ÖH an der KF-Uni Graz (main building, Resowi, Wall building).

      Subjects are asked orally whether they participate in another study at the same time or
      whether a required period of time has elapsed since participation in another study. They
      confirm this with their signature.

      An anesthesiologist involved in the study will provide the information. Consent is then given
      by signing a written information sheet.

      PEA is sold as "dietary food for special medical purposes". In a recent literature analysis,
      no side effects were reported in 1188 patients who took PEA for up to 60 days. Nevertheless,
      the company Innexus Nutraceuticals describes in an information leaflet that PEA "slows down
      intestinal function". Some people may suffer from constipation or a feeling of fullness as a
      result".

      The investigation of pain and perception thresholds according to the specifications of the
      "German Research Association for Neuropathic Pain" is an established procedure in both human
      research and clinical investigation. No danger is to be expected for the individual test
      person.

      The application of "repetitive phasic heat application" is an established human pain model.
      The maximum heat exposure of 48°C does not lead to skin damage. The changes in pain
      sensitivity are locally very limited and normalize within a few hours.

      If the individual test person is willing to be exposed to a pain stimulus for a limited
      period of time, there is no foreseeable risk for him/her.
    

Intervention name(s): Palmithylethanolamid; placebo
Intervention type(s): Dietary Supplement; Other
Intervention description(s): PEA 3x/d; placebo 3x/d
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: doubleblind, placebo-controlled,prospective crossover study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment