Usefulness of the methods

In contrast to formerly used pain models, pain relief measured with our methods correlates well with clinical results. Nevertheless our approach in volunteers does not serve as a substitute for trials in patients. Our methods are, however, more accurate, faster and less expensive in establishing the dose-response and time-effect relationships of new drugs or new drug formulations. This helps to save time and money in designing adequate patient studies. Moreover our models can provide data for proof of concepts promptly and for the discrimination of candidate drugs or drug combinations. For evaluated compounds see link at bottom of page!

Principle of the methods

• Standardised pain induction: Defined contact free CO2 laser pulses are applied to normal or irritated skin(capsaicin or UV exposure).
• Objective quantitative algesimetry: Pain is assessed by averaged stimulus related somatosensory potentials from Vertex-EEG.
• Subjective quantitative algesimetry: In addition pain is evaluated by subjective rating (VAS) and stimulus dependent psychophysics. Induction of hyperalgesia by the exposure with UV or capsaicin makes it possible to discriminate moderately different analgesic effects with higher resolution.
• Concomitant measurement of anti-inflammatory effects: In case of NSAIDs their anti-inflammatory effect can be quantitatively measured by skin reflection spectrometry after a UV or capsaicin exposure.

Reference data

Both central and peripheral analgesic drug effects were demonstrated and differentiated. More than 40 studies were carried out. Data are available for systemically administered analgesics, antiepileptics, antidepressants, benzodiazepines and NSAIDs as well as for topical antihistamines and local anaesthetics.

Advantages of the methods

The methods show, in contrast to pain models in patients, very low variation. Thus small differences in the analgesic effect of drugs or doses of a drug can be proven with small study groups at low cost. This is due to the following features of our methods.

• The laser pain stimulus can be kept constant.
• The stimulus intensity is adjusted to the individual pain threshold.
• Vigilance is kept stable by a pursuit tracking task and a superimposed ear noise.
• The objective recordings of pain by evoked potentials show by nature smaller variation than subjective ratings.
  

Up to 30 measurements per hour can be made. Thus the time course of an analgesic effect can be measured with high resolution ( e. g. fast onset ).
Laser induced pain - in contrast to that initiated by electrical stimulation - is not subject to habituation. Therefore, long lasting analgesic effects can reliably be measured ( e.g. of slow release preparations).
Our short (50-80 ms) laser pulses selectively stimulate the nociceptors (TRPVR 1-3) via heat activated ion channels (A-delta and C-fibres). Thus, in contrast to electrical stimulation, it is possible to measure peripheral analgesic effects (e.g. in UV skin) in addition and separately from central ones (e.g. in capsaicin skin).

Options

• Discrimination of moderately different analgesic effects of drugs or doses of a drug.
• Measurement of the time course of the analgesic effect of drugs or special formulations (fast onset or slow release ).
• Establishing the dose effect relationship of investigational drugs.
• Assessment of the contribution of single drugs to the analgesic effect of drug combinations.
• Concomitant assessment of effects on inflammation or vigilance and performance or of pharmacokinetics.
  

The capsaicin model for induction of neurogenic inflammation and hyperalgesia combined with objective and quantitative pain relief measurement by the laser-algesimetry

Usefulness of the methods

In many different clinical painful inflammatory states neurogenic inflammation and hyperalgesia play a significant role. Moreover all clinical diseases causing long-lasting pain involve central mechanisms of hyperalgesia. Application of capsaicin on or into the skin is a broadly accepted model for induction of neurogenic inflammation and hyperalgesia which involves a strong central component. An inhibitory effect of any investigational compound on neurogenic inflammation and hyperalgesia would cast light on its potential efficacy in such different clinical settings.

Principle of the methods

At HPR the capsaicin is not injected intra-dermally because this (traumatic) application, which is suitable for achieving valuable scientific results, does not produce a homogenous area of skin hyperalgesia large enough to perform as many repeated measurements as necessary for quantitative cohort studies as intended by HPR. The institute, therefore, prefers an application of capsaicin to the surface of the skin by ash less filter paper via an occlusive dressing (1% capsaicin for 30 min).
At HPR eventual effects of an investigational drug on pain and hyperalgesia due to neurogenic inflammation can be measured using the objective quantitative method of laser algesimetry (see description of algesimetry on extra page), the redness of the capsaicin-induced neurogenic inflammation can be quantified by skin reflection spectrometry (erythema) and the size of the capsaicin-induced flare area can be determined by computer planimetry.

Reference data

At HPR the capsaicin model has been successfully used as a standard for the investigation of unspecific COX-inhibitors, COX2-inhibitors, centrally acting analgesics (opiates, opioids), antidepressants and histamine H1-blocking agents.

Advantages of the methods

The state of capsaicin-induced hyperalgesia is very close to neuropathy and to clinical situations in which long-lasting pain provokes a strong central component of hyperalgesia which adds to a peripheral component of hyperalgesia. Combining the capsaicin model with the laser algesimetry (with its additional kindling) allows to imitate natural states of chronic pain, stimulate close to neuropathy, and to utilise the advantages of the laser algesimetry, i.e. objectivity, reproducibility and repeatability of pain measurement.

Options

Utilise the state of capsaicin-induced hyperalgesia for the following measurements:

• Discrimination of moderately different analgesic effects of drugs or doses of a drug, especially with regard to major influences on central hyperalgesia
• Measurement of the time course of the analgesic effect of drugs or special formulations (fast or slow release)
• Establishing the dose effect relationship of investigational drugs
• Assessment of the contribution of single drugs to the analgesic effect of drug combinations
• Concomitant assessment of effects on inflammation or vigilance and performance or of pharmacokinetics

Influence of a NSAID on spontaneous and post laser-session rated (subjective) pain (VAS)

12h Hyperalgesia development and stability in subjective (VAS) and objective (Laser) measurement

Effect on capsaicin hyperalgesia by subchronic NARI (left) and acute/subchronic H1-antagonist (right)

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link to efficacy of evaluated compounds in laser model