Intra-subject variability in pain scoring and the consequences for analgesia treatment

Predicting the analgesic effect of pain medication is an important topic in
chronic pain research, especially in the field of neuropathic pain. Treating
neuropathic pain is based on a trial-and-error principle where the probability
of effective treatment is low (about 30% per treatment per patient).1 Both pain
responses and efficacy of treatment display a large between-subject but also
within-subject variability. This large variability is difficult to explain. In
recent years research behavioral tools have been developed that allow (some)
prediction of analgesic effect in chronic pain patients. One such tool is
quantitative sensory testing.2 With this method sensory profiles are produced
of patients with a certain chronic pain syndrome. Profile characteristics may
be used to predict analgesic properties.

In acute pain relief large variability exists in the analgesic properties of
pain medication. For example, in post-operative patients variability is present
in the amount of opioid dose necessary (up to factor 10 difference) to induce
adequate pain relief after surgery in patients with equivalent weights. In
experimental studies on acute pain similar effects are observed, where some
subject experience profound analgesia after the administration of an analgesic
where others experience no to little effect (dosage administered is adjusted to
weight).

In a recent study on capsaicine patches (Dahan, data on file) for the treatment
of painful diabetic neuropathy many predicting markers were obtained prior to
treatment. A finding of major interest in that study was that the amount of
pain relief produced by the capsaicine patch could be predicted by the amount
of variability of the pre-treatment spontaneous pain scores of the patients.
Patients with a high variability in pre-treatment spontaneous pain scores had a
high probability to experience pain relief opposed to patients with a low
variability in spontaneous pain scores who had a low chance to experience any
pain relief.

Furthermore, postoperative analgesia is difficult to establish stably in
obesitas patients and it is indicated that these patients are unable to score
pain consistantly.
.

In the current study we want to further explore the predictability of
pre-treatment pain variability on the probability to experience pain relief.
Knowledge on the understanding of individual differences in analgesic
properties of a drug is of importance to individualize pain treatment.
Specified individual treatment regimens will eventually lead to more adequate
pain relief in patients and an improvement of effect-side effect ratios. We
hypothesize that a high variability in pre-treatment experimental pain scores
is a predictive marker of pain relief. To this end we will determine
variability on experimentally induced heat and electrical pain stimuli to
determine its predictive potential for opioid-induced analgesia (i.e.
alfentanil). Furthermore, variability tests will be repeated after opioid
administration to evaluate the effect of opioids on pain variability.
For obese patients, variability in pain scoring will be established, and
furthermore a questionnaire will be filled out to assess variables that might
influence the patients' ability to score pain.
Furthermore we will evaluate endogenous pain mechanisms in the obese subjects.

Protocol outline
The study will be performed using a double-blind, randomized, placebo
controlled design. Subjects will be tested on 2 separate occasions with a
wash-out period of at least one week. Upon arrival subjects will be
familiarized with the heat and electrical pain tests and baseline pain test
will be performed to determine the lower and upper boundaries (pain stimulus
inducing a score of 0 out of 10 and 10 out of 10 respectively on a visual
analogue scale) of the heat and electrical stimuli. These boundaries will be
used for the remainder of the study. Next, baseline pain variability will be
determined by applying 10 random temperatures and 10 electrical potentials
between the pre-defined boundaries as described below.

After baseline pain variability is determined, an intravenous canule will be
placed in one of the arms for drug administration. Alfentanil will be
administered using target controlled infusion at analgesic plasma
concentrations for 120 minutes. The first 30 minutes will be used to induce a
stable alfentanil plasma concentration. In the remaining 90 minutes heat and
electrical pain variability tests will be re-assessed to determine the effect
of alfentanil on pain variability and the analgesic effect of the drug. Using
the TCI system alfentanil concentrations will be set at 100 ng/ml, 200 ng/ml
in 2 groups of 10 subjects.

For the post-operative patient group subjects will be tested prior to the
surgery where only the pain variability tests will be performed (no alfentanil
will be administered). 1-2 hours after surgery the pain variability tests will
be repeated and the amount of opioid necessary to induce adequate pain relief
will be registered for 24 hours post-operative.

Conditioned pain modulation, offset analgesia and temporal summation will be
measured in the obese subject group by means of heat pain stimuli and
electrical pain stimuli. Endogenous pain modulation will be evaluated this way.

Alfentanil. Alfentanil is a µ-opioid receptor agonist used for the treatment of
acute pain. Using the TCI system alfentanil concentrations will be set at 100
ng/ml, 200 ng/ml in 2 groups of 10 subjects. Blood samples will be obtained
at 20 min intervals to assess the stability of the alfentanil concentration
over time.

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