Medication For Skin-exciting Therapy

New methods for objectifying the pharmacological effects of nonivamide, nicoboxil and their combinations.

Skin-exciting or irritating measures in the treatment of traumatic injuries, muscle, joint and nerve pains have been known for decades. Objectifying the effects of this kind of cutaneously-transmitted influence on joint effusions, strains and contusions, as well as muscle hardening and tenseness with the sensations of "pain" and "functional impairment" mainly felt by the patient, have encountered methodological difficulties, since their registration has for the most part been based exclusively on subjective assessment methods. The effects of skin exciting therapy are, in the light of new methods of investigation, now measurable objectively and, on the basis of the latest result in relation to the so-called capsaicin-sensitive pain receptors and the neuronal processing of their signals, they are better understood. This paves the way to most interesting therapeutic approaches, by which, using a topical application, a direct path is opened for influencing neuronal pain perception and pain assimilation.

Noxious stimuli acting on the skin are registered by nerve endings of the Ad and C-fibres. Some 90% of the C-Fibres react as polymodal afferents to various stimuli - namely, to heat, as well mechanical and chemical noxes. The density of these polymodal C-fibres ranges between 3 and 10 fibres per mm2 skin surface. As the actual pain sensors, C- and Ad -fibres conduct the pain signal to the spinal cord. There the signal is transferred synaptically to ascending pain pathways.

Peripherally as well as spinally, pain inhibition centres are localised and can be influenced by impulses from the periphery. Various connected neurons and a series of pain modulators are involved. With the excitation of a pain receptor, a release out of pain modulators, for example, the neuropeptide substance P at the peripheral end (axon reflex), can in addition occur alongside the release of transmitters and modulators at the spinal end in the spinal cord.

An excitation of a sub-population of these cutaneous nociceptors, especially the polymodal MH (mechanoheat) -C -fibres or the MHI and MHII fibres belonging to the thin myelinated Ad -fibres, can also be achieved by topical application of skin-sensitising or irritating substances, such as the naturally-occurring capsaicin (N-vanillyl-8-methly-6-nonenamide) and the synthetic capsaicin analogue nonivamide (N-vanillyl-nonamide). Both are homovanillin acid derivatives, which differ slightly in their alkyl chain. Their pharmacological effects are identical.

Capsaicin receptors have been located in the membranes, in the proximal as well as in the distal areas of capsaicin-sensitive pain fibres. Other cutaneous primary afferences, such as A8-fibres, are capsaicin-insensitive. With the isolation of resiniferatoxin from Euphorbia Resinifera, a highly potent capsaicin analogue ,and the synthesis of capsazepin, the first competitive capsaicin antagonists (8), came the breakthrough in understanding the fundamental cellular and molecular mechanisms.

By the linking of capsaicin or capsaicin analogues to specific receptors, nonselective cation channels are opened, which permit the inflow of Na+ and Ca2+ ions into the cell. This leads to a distinct depolarisation of the neuron and, due to the dual (sensory-efferents) character of this polymodal nociceptors, to the calcium-dependent release of substance P and other neuropeptides.The initial, painful and erythematous irritation to be observed with topical application is attributable to this initial excitation of the nociceptor.

The increase of intracellular calcium concentration resulting from the Ca2+ inflow inhibits as it develops the voltage-gated calcium channels responsible for the release of neuropeptides from the peripheral nerve endings. This inhibition causes a reduction of neurogenic plasma extravasation, while an analgesia is caused by the blockade of the synaptic transmission, reversible with topical application (for example, by depletion of the neurotransmitter, noradrenalin, stored in the presynaptic vesicles). This depolarisation, which continues for hours, sometimes days, is responsible for the inexcitability of the neurons and the complete blockade of the conduction of pain stimuli and is perceived as analgesia.

The analgesic effect of these skin-exciting or irritating substances thus differs fundamentally from the mechanism of action of non-steroidal antirheumatics or antiphlogistics, where the joint principle of action lies in the inhibition of cyclooxygenase (C0Xl and COX2) and thus in the inhibition of the prostaglandin synthesis.

The treatment of painful soft tissue affections with skin-exciting medication to be applied topically rests on the principles described, which are widely used in rheumatology and sports medicine. As described above, they evoke a sustained analgesic effect and a stronger blood supply of the skin and muscle, conveyed by a C and Ad fibre excitation. The increased blood supply leads to a relaxation of the musculature and an increase in cell metabolism. This produces an alleviation of chronic pain conditions in degenerative and inflammatory rheumatic disease of the skeleton and the musculature. Those pains are also influenced which are attributable to muscular tension or a trauma, and the course of healing is shortened.

With FinalgonS as a cream, liniment, extra strong ointment and as a thermal plaster, proven medication for skin-exciting therapy has been available for some decades. The areas of application include the symptomatic treatment of muscular, joint and nerve pains, such as sciatica and lumbago, of muscle hardening and tension, contusions, bruises, muscle and ligament strains, sprains, wrenches and joint effusions, as well as the improvement in circulation of the musculature before physical exercises and the treatment of tendovaginitis and non-vascular peripheral circulatory disturbances . FinalgonS as ointment, cream and liniment contains the capsaicin analogue, nonivamide, and the nicotinic acid ester, nicoboxil (2-butoxyethyl nicotinate). The effect of these two substances rests on different pharmacological mechanisms. nonivamide possesses antinociceptive (analgesic) characteristics, by which it directly stimulates sensitive nerve endings in the skin. An axon reflex leads parallel to a dilatation of the vessels in the affected skin area. This local improvement in perfusion additionally supports the healing course in the damaged tissue. This requires adequate organisational and functional reactions in the microcirculation. These processes are probably directly encouraged by the stimulated polymodal C-fibres, by which these fibres with the appropriate cutaneous stimulation release neuropeptides, such as substance P, neurokinin A and CGRP (calcitonin gene-related peptide), which have the effect of promoting growth on cells of different tissue. Excitation of cuto-visceral reflex arcs causes an increase in blood supply, spasmolysis and pain-relief in the depth of the tissue and the segmentally-related organs. In addition, muscular circulation is reflexly increased. These effects are accompanied by an intensive and long-sustained feeling of warmth. The nicotinic acid ester nicoboxil acts directly to dilate the blood vessels of the skin. The action of the nicotinic acid ester occurs within minutes. This means that, in the administrative forms which both substances contain, the rapid vasodilation by using nicoboxil is synergistic for the effect of nonivamide. The effect of the combination exceeds those of the individual components. Proof of the effectiveness of nonivamide and nicoboxil has in the past been produced by a series of clinical investigations by means of subjective assessments by the doctor and/or patients. These were supplemented by measurements of the increase in skin perfusion, the resultant increase in skin temperature or the appearance of erythema

Since an erythema and subjective heat sensation at the application location appear as the result of the increased blood supply, these local reactions can be quantified by the rise in skin temperature (thermometry), the area of the erythema (planimetry), the heat conductivity of the skin (fluvometry), discolouration of the skin (colorimetry) and circulation measurements by means of Doppler sonography), as well as lately laser Doppler scanning for high-precision area measurement of skin perfusion. For objectivisation of the effect on cutaneous micro circulation, a non-invasive measuring method is available with laser Doppler scanning, for precise recording of two dimensional changes. Furthermore, musculature circulation reflectively increased by skin stimulation can be measured.

New methods of examination into clinical pharmacological effects

Twelve volunteers with healthy skins were examined by Stiicker et. al in the course of a double blind, randomised and controlled clinical cross-over trial. The authors chose a pharmacodynamic test system, by which the reactions after administration of nonivamide (0.4%), nicoboxil (2.5%) and their combination in FinalgonS ointment were measured against a placebo (ointment base) by means of laser Doppler scanning. In addition, the skin temperature, the colour change in the skin and the area of the erythema were measured.

To exclude an urticarial reaction, in the first measurement the skin thickness in the field of measurement was determined sonographically before and 30 min. after application of FinalgonS ointment. Provided a urticarial reaction (increase in the sonographically measured skin thickness by more than 15%) could be excluded, the actual examination was carried out in a second series of measurements after a period of four days (washout period) free of treatment. The volunteers (5 women and 7 men between the ages of 25-34 years) acclimatised themselves in the prone position for 20 min. at room temperature (220C). Following the measurement of the baseline values in the four circular fields of measurement each of 1.3 cm diameter on the back, the four test substances were applied in randomised Order and the skin reaction measured after 15, 30, 45, 60, 120, 240 and 480 min. 0.03 ml of each substance was applied for each field. The fields lay in each case 5 cm paravertebral and 3 cm above and below the connecting line of the two iliac crests. All measurements followed in order of laser Doppler scanning, colorimetry, planimetry and skin temperature.

Laser Doppler scanning

The laser Doppler scanning method used here offers, by comparison to the conventional laser Doppler flowmetry, the advantage that not only the blood flow can be measured in a closely circumscribed localisation but also the distribution of the blood flow intensities over the area in question.

The measuring principle is based on the fact that monochromatic light is subjected to the so-called Doppler's effect, as soon as it is reflected in the moving erythrocytes in the microvascular bed. The reflected light is converted into a signal through a photodetector or photo multiplier, which correlates linear with the tissue perfusion. Due to the wide variability of blood circulation in the skin, this measuring process is especially suitable for following two-dimensional spatial changes over time. There is a further advantage in that the scanner head need not be brought into direct contact with the skin. A mirror system directs a HeNe laser (wavelength 632.5 rim) with two stepper motors meander-shaped over the field of measurement. The reflected light signal is recorded by a photodetector in the scanner head and. the signals are transformed to a two-dimensional perfusion picture. A false-colour coding with six colours encodes the flow values, which in addition can be quantified for each one of the 4,096 measuring points.

Colorimetry

Changes in skin colour were registered with a colorimeter. The appliance works with a pulse xenon arc lamp and six silicon photocells, of which three receive the light sent out and three the reflected light. The value pairs for blue (1 = 450 rim), green (1 = 550 nm) and red (1 = 660 rim) are selected by filters and grouped into one colour, which are characterised by their brightness (L), colour base and colour saturation on the green-red axis (A) and on the blue-yellow axis.

Planimetry

Planimetry was used to measure the erythema area. For this, a transparent foil was laid on the skin and the reddening circled with a signer. The areas so transferred are evaluated by image analysis, by which the transparent foil is laid under a microscope and the image read into a computer through a video camera. By this means, the area, the circumference and diameter can be determined.

Skin Temperature

The skin temperature was registered with a thermometer with a resolution of 0. 10C and an accuracy of measurement of 0.03% of the reading in the measuring range of -300C to +500C.

Results

In all the volunteers, a noticeable increase in skin blood circulation was measured with laser Doppler scanning in the fields of measurement with active test substances. After 15 min. the mean flow in the entire hyperaemic area showed statistically significant differences between the test substances and placebo, as well as between [email protected] and nonivamide (p < 0.0002).

The maximum mean flow also showed statistically significant differences between the three active test substances and placebo, as well as between [email protected] and nonivamide (p < 0.05).

Diagram 1 represents the maximum flow over time of the hyperaemic reactions (as mean value in an area of 6 x 6 pixel).

If the extent of the hyperaemic reaction (Diagram 2) is considered, there is a much more pronounced reaction for the combination compared to the individual substances (in each case p < 0. 000 1), as well as for nonivamide and nicoboxil alone compared to placebo (p < 0.0002; p < 0.0001). The effectiveness of skin stimulation clearly showed the expansion of the hyperaemic area far beyond the point of application (1.3 cm, diameter). The combination produced a hyperaemic area of approx. 18 cm2, nonivamide of 7 cm2 and nicoboxil of approx. 9 cm2. Whereas FinalgonS and nicoboxil achieved maximum effect after About 30 min., this took about 60 min. with nonivamide. Diagram 3 shows the hyperaemic reaction (laser Doppler scanning) of the three tested active substances and of placebo after 45 minutes.

These findings agree very well with the data from planimetry. If the maximum extent of the reddened skin area is considered, the three test preparations are significantly superior to placebo, as well as the combination of the individual substances nonivamide (p < 0. 000 1) and nicoboxil (p < 0. 00 1). Between the individual substances, there are differences with regard to the time taken for reaction with a more rapid effect of the combination and of nicoboxil compared to nonivamide. The diameter of the erythema after application of the combination reached about 6 cm, compared to nonivamide with about 3 cm and nicoboxil with about 4 cm (Diagram 4). These values are lower in comparison to those of the hyperaemic area. This can be explained that, through the laser Doppler scanning, the erythrocyte flow was measured, not in the superficial capillaries but in the deeper layers of the skin, the sub-papillary plexus, by contrast the erythema was determined by the blood circulation on the skin surface.

With colorimetric recording of the skin colour, the A-value represents the skin reddening and thus the blood supply. Again, significant differences can be demonstrated between the active test substances and placebo, as well as between the combination and the individual substances (Diagram 5). The maximum achievable A-value reaches a statistically significantly higher value on application of the combination than with nonivamide (p < 0.05) and nicoboxil (p < 0.05). The precise measurements of the flow in the hyperaemic area by means of laser Doppler scanning correlate well with the colorimetric results.

The rise in skin temperature after application of the three active test substances also indicates an increase in blood circulation. While the combination raised the skin temperature by more than 10C, nonivamide and nicoboxil achieved a rise of approx. 0.50C (Diagram 6). Even in this parameter, FinalgonS was superior to the two individual substances, statistically significant in the case of nonivamide (p < 0.05). With regard to the maximum measured temperature, similar differences showed between the active test substances and placebo. The application of the ointment base free of effective substances produced a cooling effect and thus led to a decrease in the skin temperature of approx. 0.60C. In addition to the clearly superior effect, a more rapid appearance of the reaction and a longer effective period of the combination compared to the individual substances nonivamide and nicoboxil was on the whole apparent from the time course of all parameters.

New examination results and known clinical and clinical-pharmacological results in comparison Skin temperature, erythema and heat conductivity

Thilenius undertook extensive measurements on the rise in skin temperature after application of nonivamide (0.6%), nicoboxil (5%) and their combinations. At various parts of the body (breast, abdomen, upper and lower arm, hand, thigh and leg), nonivamide raised the skin temperature on average by 1. WC, nicoboxil by 2.70C and the combination by 3.10C. The effect of nicoboxil occurred with a delay of 3-10 min and continued for 30-60min.

After nonivamide, the latency period amounted to 8-50 min and the duration of effect 30-70 min. The combination united the rapid effect (3-10 min.) with a long duration of action (40-90 min.)

Similar results were achieved by Tronnier in the measurement of the erythema caused by the individual substances and by the combination. After the application of nicoboxil ointment (2.5%), the maximum was reached after about 12 min;. the effect faded within 2 hours. After nonivamide ointment (0.4%), the maximum effect was reached after about 60 min here also the effect continued for 2 hours. For the combination, there appeared a roughly additive course of effectiveness.

By measuring the heat conductivity of the skin (as Hensel and, others) the blood circulation can be indirectly determined. The findings received by this method from the inner side of the thigh confirm the results stated above. After the application of 0.5 g nicoboxil ointment (2.5%), the effect occur-red after about 5 min., reached its maximum after about 30 min. and continued for 1-2 hours.

After nonivamide ointment (0.4%), the effect occur-red after about 30 min, reached its maximum after 1 hour and continued for 1.5-3 hours. For the combination, the effect was ascertained after about 5 min., the maximum effect was reached after about 20 min. and the duration of action exceeded 2hours.

Influence on muscle blood circulation

Josenhans applied FinalgonS ointment in the vertebral prominence zone to 60 patients with brachialgia in osteochondrosis of the cervical spinal column, which is often accompanied by peripheral blood supply disturbances. He registered a rise in skin temperature of 2.50c at the point of application. With the same patients, there occurred an increase in skin temperature of 3.40C at the end of the index finger. With a further 10(control) patients group, the application of a placebo ointment induced at the point of application a rise in temperature of 0.20C, against which at the end of the index finger with these patients a temperature decrease of LTC was measured.

In two further studies, the reflectory influence of muscle blood supply was examined. Paintner was able to show that, after the application of FinalgonS ointment to the calf in the underlying musculature, the blood supply was increased. He assumed that this occurred by reflex action, since he could prove that, after paravertebral application in the area of the 4th. lumbar vertebra to the 1 sacral vertebra, a rise in circulation of the calf muscles resulted, measured as a decrease of an intramuscularly injected J131 depot. Similar results were obtained by Holzapel, who applied the ointment paravertebral between the 3rd. and 5th. lumbar vertebrae and registered a rise in skin temperature at the leg.

Clinical Results

All in all, there exist reports of results on 1,791 patients with illnesses of the rheumatic form circle, neuritides, pleuritides, soft tissue contusions and peripheral blood supply disturbances, on the application of FinalgonS ointment in skin-exciting therapy.

Brill, Haase & Haslreiter,Furtenbach, Geyer and others,Lemke and Chitil & Ortner unanimously report on the intensive heat effect which occurs after a short while and lasts for up to 6 hours. The feeling of warmth is accompanied by a relief from pain and a relaxation of the tense musculature. On the first application, the heat sensation was felt by some patients as burning, which lost in intensity, however, with subsequent embrocations. This burning feeling led in only a few cases to cessation of the therapy. Furthermore, it was reported several times that the heat sensation occurred again after fading of the initial effect with the influence of external warmth (bed, bath) or muscle work.

Benz reports on 1,234 patients in his chiropractic activity. By the application of FinalgonS , he achieved with his patients a satisfactory reversal of muscle tenseness and the myalgic zones, so that with most patients it resulted in permanent freedom from complaint.

In a randomised study, Hume-Kendall (33) compared the effect of FinalgonS and another hyperaemial (methyl-nicotinate) against placebo with patients with osteoarthritis of the lumbar spinal column. The preparations were applied for 2 weeks in each case. Out of 40 patients, 21 said that FinalgonS was the most effective treatment, 11 the comparable preparation and 8 placebo. An objective improvement in mobility was established in 11 patients (5 FinalgonS , 3 each the comparable preparation and placebo). New clinical studies also confirm the effectiveness of topical application of capsaicin to patients with osteoarthritis (knee and finger) and patients with rheumatoid arthritis.

The influence of FinalgonS on sports injuries was examined by Hainbock. In 70 cases of contusions, bruises, muscle and ligament strains, sprains or joint effusions he established immediate relief of pain-reflex muscle tension, a rapid absorption of effusions and oedema, and a faster restoration of tissue lesions. An earlier start with active exercises was therefore possible.

With 50 sports students (30 man and 20 women) and 121 sports people, Kochner examined the preventive effect of a twice-daily application (in the morning before practice commenced and evenings) for avoiding aching muscles. The embrocations were applied over a large areas of the arms, shoulders and legs. No undesirable reaction of the skin, the circulation, the breathing or digestive organs was observed. No participant experienced muscle cramp or injuries during the training which occupied 6 hours daily. Inflammatory irritations on sinews and joints faded rapidly under the therapy.

In a further 56 cases, the therapeutic application in the case of sport injuries (muscle strains, effusions of blood, sprains, joint effusions, luxations and bone fractures) was examined. In all cases, there was a surprisingly rapid absorption of haematoma and oedema, and a clear reduction of muscular tension.

Conclusion

The results of the new studies with laser Doppler scanning confirm the results from the earlier examinations with FinalgonS ointment and its component substances and are in agreement with therapeutic experience over decades. The acknowledged curves on the time scale for hyperaemic reactions make a clear distinction between nicoboxil and nonivamide as to commencement of effectiveness. In combination, both modes of action complement each other into one overall effect, starting within minutes and continuing for hours, which clearly exceed the effects of the individual substances in their intensity.

The requirements are thus met, which have, for example, been set up in EU Guideline 75/318 for the evaluation and admission of fixed drug combinations. Fixed drug combinations are regarded in this regulation as clinically advantageous, when each combination partner makes a positive contribution to the overall effect. The combination of nicoboxil and nonivamide in FinalgonS has proved its worth on the touchstone of the most modern methods of investigation and has provided proof of the meaningful interplay of two different effective mechanisms.

For this skin-exciting therapy on the basis of the combination , there are also most interesting therapeutic approaches through the action mechanism transmitted by capsaicin receptors in conjunction with effects of nicoboxil, by which, by means of topical application, there is a direct way to influence pain perception and pain assimilation. Furthermore, going beyond the indications described, it appears to open a new therapeutic access to a whole series of illnesses, characterised by a dysfunction of primary afferent neurones.

Dr. B. Aicher
Dr. Karl Thomae GmbH
Dept. for Medical Science,88397 Biberach

Dr. M. Shicker, Prof. Dr. P.Altmeyer,
Dermatological Clinic of the Ruhr University, Bochum,
St. Josefs Hospital, Bochum.

For technical reasons diagrams and abstracts have not been included in this paper.

Extract from the Pharmacist's Journal. Vol. 11/96. 18th Year. Pages 44-50.

Personal Note:
My family and I have used Finalgon ointment to very good effect for many years.....When the painful area is cold to touch we use a combination of Finalgon and heat wheat bags..........Simon Strauss

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