Analysis of pathomechanisms involved in side effects of menthol treatment in respiratory diseases
Affiliation(s)
Department of Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin, Slovakia. Royal Gwent Hospital, Newport, UK.
Department of Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin, Slovakia. Royal Gwent Hospital, Newport, UK.
ABSTRACT
Menthol is frequently used in over the counter medications for common colds and coughs. It was formerly considered to be under the class of herbal medicine, but identification of menthol receptor (TRPM8) moved it from the class of herbal medicine to the molecular pharmacology. It has been documented that menthol reduces dyspnoea and nasal obstruction via stimulation of nasal cold or flow receptors. It has also antitussive and antiirritative effect. Menthol can also induce adverse reactions such as airway irritation, dyspnoea, chest tightness and potentially respiratory failure, mainly in children. The mechanisms responsible for adverse reactions of menthol are not known completely. The adverse reactions of menthol could be due to its effects on TRPA1 channel, relevant to airway irritation. Higher concentrations of menthol stimulate TRPA1 channel causing airway irritation. It also increases mucus production and at the same time reduces cilliary activity leading to mucus stagnation. As the adverse effects were reported mainly at the night it is supposed that suppressed cough reflex during sleep potentiated by menthol induced cough suppression might be responsible for lack of airway mucus clearing and obliteration of small airways. Adverse effects could also be due to consequences of reflexes induced by the menthol action on trigeminal afferents, like apnoea or bronchoconstriction. Menthol is effective in relieving respiratory symptoms, but cough and cold medications should be used with caution. Recommendations are low concentrations of menthol used locally (intranasal) and not combined with camphor or cineole, as they may have additive effects and should be avoided in children under 2 years. Further data are necessary to completely elucidate potential risks of over the counter menthol medication in children but based on the meta analysis of documented case reports, menthol can be used safely if its contraindications for use are followed as with any other over the counter medications.
Menthol is frequently used in over the counter medications for common colds and coughs. It was formerly considered to be under the class of herbal medicine, but identification of menthol receptor (TRPM8) moved it from the class of herbal medicine to the molecular pharmacology. It has been documented that menthol reduces dyspnoea and nasal obstruction via stimulation of nasal cold or flow receptors. It has also antitussive and antiirritative effect. Menthol can also induce adverse reactions such as airway irritation, dyspnoea, chest tightness and potentially respiratory failure, mainly in children. The mechanisms responsible for adverse reactions of menthol are not known completely. The adverse reactions of menthol could be due to its effects on TRPA1 channel, relevant to airway irritation. Higher concentrations of menthol stimulate TRPA1 channel causing airway irritation. It also increases mucus production and at the same time reduces cilliary activity leading to mucus stagnation. As the adverse effects were reported mainly at the night it is supposed that suppressed cough reflex during sleep potentiated by menthol induced cough suppression might be responsible for lack of airway mucus clearing and obliteration of small airways. Adverse effects could also be due to consequences of reflexes induced by the menthol action on trigeminal afferents, like apnoea or bronchoconstriction. Menthol is effective in relieving respiratory symptoms, but cough and cold medications should be used with caution. Recommendations are low concentrations of menthol used locally (intranasal) and not combined with camphor or cineole, as they may have additive effects and should be avoided in children under 2 years. Further data are necessary to completely elucidate potential risks of over the counter menthol medication in children but based on the meta analysis of documented case reports, menthol can be used safely if its contraindications for use are followed as with any other over the counter medications.
Cite this paper
Gavliakova, S. , Buday, T. , Shetthalli, V. and Plevkova, J. (2013) Analysis of pathomechanisms involved in side effects of menthol treatment in respiratory diseases. Open Journal of Molecular and Integrative Physiology, 3, 21-26. doi: 10.4236/ojmip.2013.31004.
Gavliakova, S. , Buday, T. , Shetthalli, V. and Plevkova, J. (2013) Analysis of pathomechanisms involved in side effects of menthol treatment in respiratory diseases. Open Journal of Molecular and Integrative Physiology, 3, 21-26. doi: 10.4236/ojmip.2013.31004.
References
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TRPM8 and TRPA1 in molecular logic of cold sensation. Molecular Pain, 1, 16. doi:10.1186/1744-8069-1-16 [7] Peier, A.M., Moqrich, A., Hergarden, A.C. et al. (2002) TRP channel that senses cold stimuli and menthol. Cell, 108, 705-715. doi:10.1016/S0092-8674(02)00652-9 [8] Malkia, A., Pertusa, M., Fernández-Ballester, G. et al. (2009) Differential role of the menthol-binding residue Y745 in the antagonism of thermally gated TRPM8 channels. Molecular Pain, 5, 62. doi:10.1186/1744-8069-5-62 [9] Karashima, Y., Daman, N., Prenen, J., Talavera, K., Segal, A., Volts, T. and Milins, B. (2007) Bimodal action of menthol on TRPA1 channel. Journal of Neuroscience, 27, 9874-9884. doi:10.1523/JNEUROSCI.2221-07.2007 [10] Cliff, M.A. and Green, B.G. (1994) Sensory irritation and coolness produced by menthol: Evidence for selective desensitization of irritation. Physiology and Behaviour, 56, 1021-1029. doi:10.1016/0031-9384(94)90338-7 [11] Story, G.M., Peier, A.M., Reeve, A.J., et al. (2003) ANKTM1 a TRP like channels expressed in nociceptive neurons, activated by cold temperature. Cell, 112, 819829. doi:10.1016/S0092-8674(03)00158-2 [12] Kenia, P., Houghton, T. and Beardsmore, C. (2008) Does inhaling menthol affect nasal patency of cough? Pediatric Pulmonology, 43, 532-537. doi:10.1002/ppul.20797 [13] Lindemann, J., Tsakiropoulou, E. and Scheithauer, M. (2008) Effect of menthol inhalation on nasal mucosal temperature and nasal patency. American Journal of Rhinology, 22, 402-405. doi:10.2500/ajr.2008.22.3194 [14] Naito, K., Komori, M. and Kondo, Y. (1997) The effect of L-menthol stimulation of the major palatine nerve on subjective and objective nasal patency. Auris Nasus Larynx, 24, 159-162. doi:10.1016/S0385-8146(96)00005-3 [15] Eccles, R. (2000) Role of cold receptors and menthol in thirst, the drive to breathe and arousal. Appetite, 34, 2935. doi:10.1006/appe.1999.0291 [16] Lande, E.A., Morice, A.H. and Grattan, T.J. (1994) The antitussive effects of menthol, camphor and cineole in conscious GP. Pulmonary Pharmacology, 7, 179-184. doi:10.1006/pulp.1994.1021 [17] Morice, A.H., Marshal, A.E., Higgins, K.S. and Grattan, T.J. (1999) Effect of inhaled menthol on citric acid induced cough in normal subjects. Thorax, 49, 10241026. doi:10.1136/thx.49.10.1024 [18] Paul, I.M. (2012) Therapeutic options for acute cough due to upper respiratory infections in children. Lung, 190, 41-44. doi:10.1007/s00408-011-9319-y [19] Buday, T., Brozmanova, M., Biringerova, Z., Gavliakova, S., Poliacek, I., Calkovsky, V., Shetthalli, M.V. and Plevkova, J. (2012) Modulation of cough response by sensory inputs from the nose—Role of trigeminal TRPA1 versus TRPM8 channels. Cough, 8, 11. doi:10.1186/1745-9974-8-11 [20] Abe, J., Hosakawa, H. and Okazawa, M. (2005) TRPM8 protein localisation in trigeminal ganglia and taste papillae. Molecular Brain Research, 136, 91-98. doi:10.1016/j.molbrainres.2005.01.013 [21] Xiang, H., Ling, X.J. and Chen. M. (2008) TRPM8 mechanisms of autonomic nerve response to cold in respiratory airways. Molecular Pain, 4, 22. doi:10.1186/1744-8069-4-22 [22] Haidl, P., Kemper, P. and Butnarasu, S.J. (2001) Does the inhalation of a 1% L-menthol solution in the premedication of fiberoptic bronchoscopy affect coughing and the sensation of dyspnea? Pneumologie, 55, 115-119. doi:10.1055/s-2001-12280 [23] Vertigan, A.E. and Gibson, P.G. (2011) Urge to cough and its application to the behavioural treatment of cough. Bratislavske Lekarske Listy, 112, 102-108. [24] Ito, S., Kume, H., Shiraki, A., Kondo, M., Makino, Y., Kamiya, K. and Hasegawa, Y. (2008) Inhibition by the cold receptor agonists menthol and icilin of airway smooth muscle contraction. Pediatric Pulmonology, 43, 532-537. [25] Schulz, V. (2004) Rational phytotherapy: A reference guide for physicians and pharmacists. Springer, Berlin. [26] Javorka, K., Tomori, Z. and Zavarska, L. (1980) Protective and defensive airway reflexes in premature infants. Physiol Bohemoslov, 29, 29-35 [27] Angel, J.J.E. and De Burgh Daly, M. (1972) Reflex respiratory and cardiovascular effects of stimulation of receptors in the nose of the dog. Journal of Physiology, 220, 673-696. [28] Melis, K., Bochner, A. and Janssens, G. (2008) Accidental nasal eucalyptol and menthol instillation. Pulmonary Pharmacology and Therapeutics, 21, 812-817. [29] Ipswich, M.A. (2009) Vicks Vapo-Rub—How dangerous for children? Child Health Alert, 27, 1064-4849. [30] Orani, G.P., Anderson, J.W., Sant’Ambrogio, G. and Sant’Ambrogio, F.B. (1991) Upper airway cooling and l-menthol reduce ventilation in the guinea pig. Journal of Applied Physiology, 70, 2080-2086. [31] Sekizawa, S., Tsubone, H., Kuwahara, M. and Sugano, S. (1996) Nasal receptors responding to cold and l-menthol airflow in the guinea pig. Respiration Physiology, 103, 211-219. doi:10.1016/0034-5687(95)00091-7 [32] Lesoline, W. (1965) Dangers and complications in the administration of menthol containing preparations in otorhinolaryngology. HNO, 13, 238-239. [33] Baraniuk, J.N. and Merck, S.J. (2008) Nasal reflexes: Imlications for exercise, breathing and sex. Current Allergy and Asthma Reports, 8, 147-153. doi:10.1007/s11882-008-0025-7 [34] Braunstahl, G.J., Kleinjan, A., Overbeek, S.E., Prins, J.B., Hooksteden, K.C. and Fokken, W.J. (2000) Segmental bronchial provocation induces nasal inflammation in allergic rhinitis patients. American Journal of Respiratory and Critical Care Medicine, 161, 2051-2057 [35] Levi, L.R., Tyler, G.R., Olson, L.G. and Saunders, N.A. (1990) Lack of airway response to nasal iritation in normal and asthmatic subjects. Australian & New Zealand Journal of Medicine, 20, 578-582. doi:10.1111/j.1445-5994.1990.tb01317.x [36] Littel, N.T., Carlisle, C.C., Millman, R.P. and Braman, S.S. (1990) Changes in airway resistance folloving nasal provocation. American Review of Respiratory Disease, 141, 580-583. doi:10.1164/ajrccm/141.3.580 [37] Martin, D., Valdez, J., Boren, J. and Mayersohn, M. (2004) Dermal absorption of camphor, menthol, and methyl salicylate in humans. Journal of Clinical Pharmacology, 44, 1151-1157. doi:10.1177/0091270004268409 [38] Flaman, Z., Pellechia-Clarke, S., Bailey, B. and McGuigan, M. (2001) Unintentional exposure of young children to camphor and eucalyptus oils. Paediatrics & Child Health, 6, 80-83.
[1] Schroeder, K. and Fahey, T. (2004) Over-the-counter medications for acute cough in children and adults in ambulatory settings. Cochrane Database of Systematic Reviews, 4, CD001831. [2] Abanses, J.C., Shinobu, A. and Rubin, B.K. (2009) Vicks VapoRub induces mucin secretion, decreases ciliary beat frequency, and increases tracheal mucus transport in the ferret trachea. Chest, 135, 143-148. doi:10.1378/chest.08-0095 [3] Eccles, R. (2003) Menthol: Effects on nasal sensation of airflow and the drive to breathe. Current Allergy and Asthma Reports, 3, 210-214. doi:10.1007/s11882-003-0041-6 [4] Eccles, R. (1994) Menthol and related cooling compounds. Journal of Pharmacy and Pharmacology, 46, 618-630. doi:10.1111/j.2042-7158.1994.tb03871.x [5] Galeotti, N., Di Cesare Mannelli, L., Mazzanti, G., Bartolini, A. and Ghelardini, C. (2002) Menthol: A natural analgesic compound. Neuroscience Letters, 322, 145-148. doi:10.1016/S0304-3940(01)02527-7 [6] McKemy, D.D. (2005) How cold is it? TRPM8 and TRPA1 in molecular logic of cold sensation. Molecular Pain, 1, 16. doi:10.1186/1744-8069-1-16 [7] Peier, A.M., Moqrich, A., Hergarden, A.C. et al. (2002) TRP channel that senses cold stimuli and menthol. Cell, 108, 705-715. doi:10.1016/S0092-8674(02)00652-9 [8] Malkia, A., Pertusa, M., Fernández-Ballester, G. et al. (2009) Differential role of the menthol-binding residue Y745 in the antagonism of thermally gated TRPM8 channels. Molecular Pain, 5, 62. doi:10.1186/1744-8069-5-62 [9] Karashima, Y., Daman, N., Prenen, J., Talavera, K., Segal, A., Volts, T. and Milins, B. (2007) Bimodal action of menthol on TRPA1 channel. Journal of Neuroscience, 27, 9874-9884. doi:10.1523/JNEUROSCI.2221-07.2007 [10] Cliff, M.A. and Green, B.G. (1994) Sensory irritation and coolness produced by menthol: Evidence for selective desensitization of irritation. Physiology and Behaviour, 56, 1021-1029. doi:10.1016/0031-9384(94)90338-7 [11] Story, G.M., Peier, A.M., Reeve, A.J., et al. (2003) ANKTM1 a TRP like channels expressed in nociceptive neurons, activated by cold temperature. Cell, 112, 819829. doi:10.1016/S0092-8674(03)00158-2 [12] Kenia, P., Houghton, T. and Beardsmore, C. (2008) Does inhaling menthol affect nasal patency of cough? Pediatric Pulmonology, 43, 532-537. doi:10.1002/ppul.20797 [13] Lindemann, J., Tsakiropoulou, E. and Scheithauer, M. (2008) Effect of menthol inhalation on nasal mucosal temperature and nasal patency. American Journal of Rhinology, 22, 402-405. doi:10.2500/ajr.2008.22.3194 [14] Naito, K., Komori, M. and Kondo, Y. (1997) The effect of L-menthol stimulation of the major palatine nerve on subjective and objective nasal patency. Auris Nasus Larynx, 24, 159-162. doi:10.1016/S0385-8146(96)00005-3 [15] Eccles, R. (2000) Role of cold receptors and menthol in thirst, the drive to breathe and arousal. Appetite, 34, 2935. doi:10.1006/appe.1999.0291 [16] Lande, E.A., Morice, A.H. and Grattan, T.J. (1994) The antitussive effects of menthol, camphor and cineole in conscious GP. Pulmonary Pharmacology, 7, 179-184. doi:10.1006/pulp.1994.1021 [17] Morice, A.H., Marshal, A.E., Higgins, K.S. and Grattan, T.J. (1999) Effect of inhaled menthol on citric acid induced cough in normal subjects. Thorax, 49, 10241026. doi:10.1136/thx.49.10.1024 [18] Paul, I.M. (2012) Therapeutic options for acute cough due to upper respiratory infections in children. Lung, 190, 41-44. doi:10.1007/s00408-011-9319-y [19] Buday, T., Brozmanova, M., Biringerova, Z., Gavliakova, S., Poliacek, I., Calkovsky, V., Shetthalli, M.V. and Plevkova, J. (2012) Modulation of cough response by sensory inputs from the nose—Role of trigeminal TRPA1 versus TRPM8 channels. Cough, 8, 11. doi:10.1186/1745-9974-8-11 [20] Abe, J., Hosakawa, H. and Okazawa, M. (2005) TRPM8 protein localisation in trigeminal ganglia and taste papillae. Molecular Brain Research, 136, 91-98. doi:10.1016/j.molbrainres.2005.01.013 [21] Xiang, H., Ling, X.J. and Chen. M. (2008) TRPM8 mechanisms of autonomic nerve response to cold in respiratory airways. Molecular Pain, 4, 22. doi:10.1186/1744-8069-4-22 [22] Haidl, P., Kemper, P. and Butnarasu, S.J. (2001) Does the inhalation of a 1% L-menthol solution in the premedication of fiberoptic bronchoscopy affect coughing and the sensation of dyspnea? Pneumologie, 55, 115-119. doi:10.1055/s-2001-12280 [23] Vertigan, A.E. and Gibson, P.G. (2011) Urge to cough and its application to the behavioural treatment of cough. Bratislavske Lekarske Listy, 112, 102-108. [24] Ito, S., Kume, H., Shiraki, A., Kondo, M., Makino, Y., Kamiya, K. and Hasegawa, Y. (2008) Inhibition by the cold receptor agonists menthol and icilin of airway smooth muscle contraction. Pediatric Pulmonology, 43, 532-537. [25] Schulz, V. (2004) Rational phytotherapy: A reference guide for physicians and pharmacists. Springer, Berlin. [26] Javorka, K., Tomori, Z. and Zavarska, L. (1980) Protective and defensive airway reflexes in premature infants. Physiol Bohemoslov, 29, 29-35 [27] Angel, J.J.E. and De Burgh Daly, M. (1972) Reflex respiratory and cardiovascular effects of stimulation of receptors in the nose of the dog. Journal of Physiology, 220, 673-696. [28] Melis, K., Bochner, A. and Janssens, G. (2008) Accidental nasal eucalyptol and menthol instillation. Pulmonary Pharmacology and Therapeutics, 21, 812-817. [29] Ipswich, M.A. (2009) Vicks Vapo-Rub—How dangerous for children? Child Health Alert, 27, 1064-4849. [30] Orani, G.P., Anderson, J.W., Sant’Ambrogio, G. and Sant’Ambrogio, F.B. (1991) Upper airway cooling and l-menthol reduce ventilation in the guinea pig. Journal of Applied Physiology, 70, 2080-2086. [31] Sekizawa, S., Tsubone, H., Kuwahara, M. and Sugano, S. (1996) Nasal receptors responding to cold and l-menthol airflow in the guinea pig. Respiration Physiology, 103, 211-219. doi:10.1016/0034-5687(95)00091-7 [32] Lesoline, W. (1965) Dangers and complications in the administration of menthol containing preparations in otorhinolaryngology. HNO, 13, 238-239. [33] Baraniuk, J.N. and Merck, S.J. (2008) Nasal reflexes: Imlications for exercise, breathing and sex. Current Allergy and Asthma Reports, 8, 147-153. doi:10.1007/s11882-008-0025-7 [34] Braunstahl, G.J., Kleinjan, A., Overbeek, S.E., Prins, J.B., Hooksteden, K.C. and Fokken, W.J. (2000) Segmental bronchial provocation induces nasal inflammation in allergic rhinitis patients. American Journal of Respiratory and Critical Care Medicine, 161, 2051-2057 [35] Levi, L.R., Tyler, G.R., Olson, L.G. and Saunders, N.A. (1990) Lack of airway response to nasal iritation in normal and asthmatic subjects. Australian & New Zealand Journal of Medicine, 20, 578-582. doi:10.1111/j.1445-5994.1990.tb01317.x [36] Littel, N.T., Carlisle, C.C., Millman, R.P. and Braman, S.S. (1990) Changes in airway resistance folloving nasal provocation. American Review of Respiratory Disease, 141, 580-583. doi:10.1164/ajrccm/141.3.580 [37] Martin, D., Valdez, J., Boren, J. and Mayersohn, M. (2004) Dermal absorption of camphor, menthol, and methyl salicylate in humans. Journal of Clinical Pharmacology, 44, 1151-1157. doi:10.1177/0091270004268409 [38] Flaman, Z., Pellechia-Clarke, S., Bailey, B. and McGuigan, M. (2001) Unintentional exposure of young children to camphor and eucalyptus oils. Paediatrics & Child Health, 6, 80-83.