|Year : 2012 | Volume
| Issue : 1 | Page : 26-30
Effect of cold stimulation-induced pain on pharmacodynamic responses in healthy human volunteers
Sunil Kumar Reddy Khambam, Madireddy Umamaheshwar Rao Naidu, Pingali Usha Rani, Takallapalli Ramesh Kumar Rao
ICMR Advance Center for Clinical Pharmacodynamics, Departments of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, Andhra Pradesh, India
|Date of Submission||27-May-2011|
|Date of Acceptance||18-Jun-2011|
|Date of Web Publication||23-Feb-2012|
Pingali Usha Rani
Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad 500 082, Andhra Pradesh
Source of Support: Indian Council of Medical Research., Conflict of Interest: None
| Abstract|| |
Aims: The aim of the present study was to quantify the changes in pharmacodynamic response during cold stimulation-induced pain. Materials and Methods: In the present study we evaluated the effect of cold stimulation (immersion of hand into cold water, 1 ± 0.5°C) in 24 healthy human subjects. Change in skin conductance (in the form of galvanic skin response), skin temperature, and heart rate were recorded using the Data Acquisition System (Biopac mp 150). Results: There was significant increase in skin conductance (P<0.001) from 0.22 ± 0.19 microSiemens to 0.32 ± 0.27 microSiemens, with 58.3% increase from the baseline. The heart rate also significantly increased by 8.3% (P<0.001) from 85.6 ± 15.1 bpm to 92.2 ± 14.2 bpm. There was no significant change in skin temperature. Conclusion: The findings of this study showed that an increase in skin conductance seemed to be a good indicator of acute pain. The changes in skin conductance were influenced by acute pain; therefore, monitoring skin conductance could be used as a pharmacodynamic parameter in the evaluation of analgesic agents.
Keywords: Cold pain, galvanic skin response, heart rate, skin conductance, skin temperature
|How to cite this article:|
Reddy Khambam SK, Rao Naidu MU, Rani PU, Kumar Rao TR. Effect of cold stimulation-induced pain on pharmacodynamic responses in healthy human volunteers. Int J Nutr Pharmacol Neurol Dis 2012;2:26-30
|How to cite this URL:|
Reddy Khambam SK, Rao Naidu MU, Rani PU, Kumar Rao TR. Effect of cold stimulation-induced pain on pharmacodynamic responses in healthy human volunteers. Int J Nutr Pharmacol Neurol Dis [serial online] 2012 [cited 2019 Aug 23];2:26-30. Available from: http://www.ijnpnd.com/text.asp?2012/2/1/26/93129
| Introduction|| |
Immersion of limbs in cold water has long been known to induce pain. On immersion of the hand in cold water, there is an initial sensation of cold followed by pain, which rapidly increases in intensity reaching a maximum within about a minute.  Cold stimulation is known to produce significant changes in pharmacodynamic responses in both the cardiovascular as well as central nervous systems. , Autonomic reactions such as tachycardia, hypertension, sweating, and lacrimation, although non-specific, are always regarded as signs of nociception or inadequate analgesia. Autonomic monitoring techniques, therefore, may help to quantitate reactions of the autonomic nervous system. , As pain is always subjective,  the evaluation of pain intensity has to rely on the patients' self-assessment. Therefore, one may fail to assess pain intensity correctly in small children, unconscious or delirious patients. ,,, Especially in the above-mentioned patients, a monitor that measures the stress caused by pain, as a surrogate for pain, may help to improve the management of postoperative pain. 
Pain and stress are known to influence sweat production, which can be monitored by measuring the psycho galvanic response of the skin.  An increase in sweat production causes a decrease in the electrical resistance of the skin.  The skin conductance peak is specific to the stimulus that induces the response and is evident within one to two seconds after stimulation.  The physiological reactions during the change in skin conductance stimulate the sympathetic nerve to release acetylcholine, which acts on the muscarinic receptors, with a subsequent release of sweat, leading to an increase in skin conductance,  and is not influenced by the neuromuscular blockade, adrenergic receptor active agents, or changes in the blood volume. ,
The main objective of the present study is to quantify the changes in skin conductance, heart rate, and skin temperature during the pain induced by cold stimulation.
| Materials and Methods|| |
Twenty four healthy participants (6 females and 18 males, age range 21 - 35 years) were included in the study. The volunteers were healthy, based on the history, physical examination, and laboratory tests. They had no history of drug abuse and did not take any OTC products. The protocol was approved by the institutional ethics committee, and all participants provided a written informed consent before any study-related procedure was performed. All pharmacodynamic assessments were conducted at the same time of the day between 8:00 a.m. and 11:00 a.m. by the same observer. The cold stimulation technique was indigenously developed in the department and performed on the participant's non-dominant arm as per the method described by Garcia de Jalon et al.  and Ammon et al.  The Galvanic Skin Response (GSR), Heart Rate (HR), and Skin Temperature were recorded before, during the cold stimulation, and four minutes after the cessation of cold stimulation on the contralateral dominant arm. This entire cold stimulation procedure was repeated thrice with a 10-minute interval between tests. The mean of the three readings was noted and considered for analysis.
Cold stimulation technique
A deflated blood pressure cuff was placed on the non-dominant arm of the subject. After a 30-second rest, the subject placed his hand upto the wrist into the warm-water bath (at 35°C ± 0.5°C) for exactly two minutes. Fifteen seconds before transferring the forearm into the cold water bath (at 1 ± 0.5°C with constant water circulation), a blood pressure cuff was inflated to 20 mm Hg below the diastolic blood pressure. The subject placed his/her forearm upto the wrist in a fixed position with the fingers wide apart into the cold water bath (for a maximum period of 120 seconds) until they perceived the sensation as intolerable (pain tolerance). The subject was then asked to put his/her hand immediately into the warm water bath, at this time the cuff pressure was released and constant flexion and extension movements were made for 20 seconds.
All experiments were performed with the subjects in the sitting position, after a good overnight sleep, and at least eight hours of fasting. Recordings of electrocardiogram, electrodermal activity, and skin temperature were performed using a BIOPAC MP 150 system (BIOPAC Systems, Goleta, CA, USA) with Acknowledge 4.0 software, for data acquisition. The recording was done in a quiet, temperature and humidity controlled room.
Three disposable Ag/AgCl electrodes were positioned in an Einthoven Lead I configuration and connected to the BIOPAC amplifier module ECG100C. The electrocardiogram (ECG) signal was digitized at a rate of 1000 Hz.
The cavities of two Ag/AgCl finger electrodes (TSD203, BIOPAC Systems) were filled with isotonic electrode paste and attached onto the palmar sides of the medial phalanges of the index and middle fingers of the dominant hand. The electrode leads were connected to the BIOPAC amplifier module GSR100C. The signal was filtered by an analog 1 Hz first order low pass and then digitized at a rate of 1000 Hz.
A surface temperature thermistor probe (TSD202D, BIOPAC Systems) was attached to the forehead of the subject and connected to the BIOPAC amplifier module SKT100C. The signal was digitized at the rate of 1000 kHz.
The data are represented as mean ± SD. One way ANOVA and Paired t-test was applied within the group. Out of 24 subjects, 22 could perform the cold stimulation test thrice, thus, the final data was calculated from 22 subjects. In all tests performed, P value <0.05 was considered to be significant.
| Results|| |
Twenty-four healthy subjects with a mean age of 27.2 years, mean height 167.3 cm, and a mean weight of 64.4 kg were enrolled in the present study. The demographic characteristics are presented in [Table 1].
The mean value of the skin conductance was 0.22 ± 0.19 microSiemens before the cold stimulation, which increased significantly by 58% during cold stimulation to 0.32 ± 0.27 microSiemens (P<0.001). The skin conductance returned to a near baseline value of 0.19 ± 0.21 microSiemens, four minutes after the cessation of cold stimulation [Figure 1].
|Figure 1: Skin conductance: Before, during the cold stimulation, and four minutes after the cessation of cold stimulation (P<0.001)|
Click here to view
The mean value of the heart rate was 85.6 ± 15.1 beats/minute before the cold stimulation, which increased during cold stimulation to a statistically significant value of 92.2 ± 14.2 beats/minute (8.3% increase), (P<0.001) and later returned to the baseline value of 83.6 ± 13.7 beats/minute, after cessation of the cold stimulation test procedure [Figure 2].
|Figure 2: Heart rate: Before, during the cold stimulation and four minutes after the cessation of cold stimulation (P<0.001)|
Click here to view
Initially, the skin temperature of the subjects' forehead was 33.9 ± 2.7°C, which slightly decreased during cold stimulation to 33.4 ± 2.7°C, with a 2.5% decrease; the difference was statistically non-significant [Figure 3].
|Figure 3: Skin temperature: Before, during the cold stimulation, and four minutes after the cessation of cold stimulation|
Click here to view
| Discussion|| |
In the present study we have recorded pharmacodynamic responses like skin conductance, heart rate, and skin temperature during cold stimulation in healthy subjects.
As pain is always subjective, evaluation of pain intensity normally relies on the subject's perception of pain on various self-assessment scoring systems. They rely on the patients cooperation and have limitations in patients with speaking, hearing, and language difficulty and subjects with cognitive impairment may also fail to assess pain intensity. ,,, When patients cannot verbally communicate the pain, a fast reacting, objective, sensitive, specific, continuous, and online method to monitor pain is needed. 
Although the method of monitoring changes in the electro galvanic properties of the skin had been described by Fere as early as in 1888, it had not been used as a tool for the assessment of pain until recent publications found a strong relationship between postoperative pain and the skin conductance parameter. ,, Our investigation focused on the skin conductance parameter, that is, skin conductance level and the healthy subjects' cold stimulation of hand significantly changed the skin conductance level.
The pressure used in the sphygmomanometer during cold stimulation was 20 mm Hg below the diastolic blood pressure, sufficient to produce a temporary occlusion of the venous return during stimulation, avoiding the normal loss of heat and adaptative reactions.
The skin conductance peak is specific for the stimulus, which induces the response and is evident within one to two seconds after stimulation. Change in skin conductance may therefore be a sensitive and specific tool for predicting pain intensity. The intra-individual variability of the skin conductance activity is highly dependent on the emotional state and pain. 
Skin conductance shows the emotional state as reflected in changes in the sympathetic nervous system. Each time this part of the sympathetic nervous system is activated, the palmar and planter sweat glands fill up, the skin conductance increases, and before the sweat is removed the skin conductance decreases. An increase in the number of skin conductance fluctuations (NSCF) and amplitude of skin conductance fluctuations (ASCF), although less influenced when compared to the skin conductance level, can therefore be interpreted as increased activity in this part of the sympathetic nervous system.  This method is specific to the stimuli that induce the stress response. Skin conductance fluctuations have been used to evaluate pain response in preterm infants. The pain stimuli induced an immediate increase in emotional sweating and skin conductance fluctuations, and when the pain stimuli terminated, the skin conductance fluctuations decreased immediately.  In our present study when we terminated the pain stimulus the pharmacodynamic responses came back to the baseline, which was in accordance with the study reported by H. Strom. 
Over the past 10 years various non-invasive techniques such as electroencephalography (EEG), magnetoencephalography, positron emission tomography, functional magnetic resonance imaging, and transcranial magnetic stimulation, as also a number of reports on pain perception using these techniques have been published. ,,,
The changes in skin conductance may be a promising tool for monitoring pain. It is different from heart rate and blood pressure, which are influenced by both the sympathetic and parasympathetic nervous systems. Skin conductance is only influenced by the sympathetic nervous system.  Skin sympathetic activity is extremely responsive to noxious or arousal stimuli. The findings in healthy subjects suggest that an increase in cardiac sympathetic activity should be reflected by the heart rate response.  Also, a high heart rate was noticed in some of the volunteers before the trial, which increased significantly during the cold stimulation and decreased below the baseline value after the completion of the trial.
Different studies show that the hemodynamic responses do not correlate well to noxious stimulus.  Lidderg and Wallin describe a positive correlation between the amplitude of the skin resistance fluctuation and the strength of the sympathetic nervous burst to the skin. 
A clear limitation of the skin conductance method to assess pain is the fact that skin conductance reflects palmar sweat gland filling, hence, ultimately a sympathetic tone. Therefore, all factors that influence the sympathetic tone (e.g., anxiety, nausea) might theoretically alter the reaction of skin conductance or its parameters, to painful stimuli. , Despite these limiting factors, our results suggest a strong relationship between skin conductance and acute pain. In future, skin conductance monitoring can add information on the pain and discomfort situation.
| Conclusion|| |
Simultaneous evaluation of skin conductance and heart rate during cold stimulation pain in healthy subjects can be used as a simple and sensitive method for evaluation of analgesic drugs. By repeating the cold stimulation at various time points, it is also possible to find out the onset and duration of analgesia.
| Acknowledgment|| |
The study was supported by a grant from the Indian Council of Medical Research (ICMR), Government of India. We also thank The Director, Nizam's institute for providing us the necessary infrastructure.
| References|| |
|1.||Posner J, Telekes A, Crowley D, Phillipson R, Peck AW. Effects of an Opiate on Cold-induced Pain and the CNS in Healthy Volunteers. Pain 1985;23:73-82. |
|2.||Mitchell LA, MacDonald RA, Brodie EE. Temperature and the Cold Pressor Test. J Pain 2004;5:233-8.3. |
|3.||Ledowski T, Bromilow J, Wu J, Paech MJ, Storm H, Schug SA. The assessment of postoperative pain by monitoring skin conductance: Results of a prospective study. Anaesthesia 2007;62:989-93. |
|4.||Bruno Guignard. Monitoring analgesia. Best Pract Res Clin Anaesthesiol 2006;20:161-80. |
|5.||Merskey H, Bogduk N. Classification of Chronic Pain. 2 nd ed. Seattle: IASP Press; 1994. |
|6.||Bosenberg A, Thomas J, Lopez T, Kokinsky E, Larsson LE. Validation of a six-graded faces scale for evaluation of postoperative pain in children. Pediatr Anesth 2003;13:708-13. |
|7.||Rodriguez CS, McMillan S, Yarandi H. Pain measurement in older adults with head and neck cancer and communication impairments. Cancer Nurs 2004;27:425-33. |
|8.||Sessler CN, Grap MJ, Ramsay MA. Evaluating and monitoring analgesia and sedation in the intensive care unit. Crit Care 2008;12:1-13. |
|9.||Ledowski T, Ang B, Schmarbeck T, Rhodes J. Monitoring of sympathetic tone to assess postoperative pain: Skin conductance vs surgical stress index. Anaesthesia 2009;64:727-31. |
|10.||Hampf G. Influence of cold pain in the hand on skin impedance, heart rate, and skin temperature. Physiol Behav 1990;47:217-8. |
|11.||Storm H. Changes in skin conductance as a tool to monitor nociceptive stimulation and pain. Curr Opin Anaesthesiol 2008;21:796-804. |
|12.||Hagbarth KE, Hallin RG, Hongell A, Torebjork HE, Wallin BG. General Characteristics of Sympathetic Activity in Human Skin Nerves. Acta Physiol Scand 1972;84:164-76. |
|13.||Wallin BG, Sundlof G, Delius W. The effect of carotid sinus nerve stimulation on muscle and skin nerve sympathetic activity in man. Pflugers Arch 1975;358:101-10. |
|14.||Garcia de Jalon PD, Harrison FJ, Johnson KI, Kozma C, Schnelle K. A modified cold stimulation technique for evaluation of analgesic activity in human volunteers. Pain 1985;22:183-9. |
|15.||Ammon S, Marx C, Behrens C, Hofmann U, Mürdter T, Griese EU, et al. Diclofenac does not interact with codeine metabolism in vivo: A study in healthy volunteers. BMC Clin Pharmacol 2002;2:1-10. |
|16.||Hullett B, Chambers N, Preuss J, Zamudio I, Lange J, Pascoe E, et al. Monitoring Electrical Skin Conductance. A tool for the assessment of postoperative pain in children? Anesthesiology 2009;111:513-7. |
|17.||Ledowski T, Bromilow J, Wu J, Paech MJ, Storm H, Schug SA. Monitoring of skin conductance to assess postoperative pain intensity. Br J Anaesth 2006;97:862-5. |
|18.||Kunimoto M, Kirno K, Elam M, Karlsson T, Wallin BG. Non-linearity of skin resistance response to intraneural electrical stimulation of sudomotor nerves. Acta Physiol Scand 1992;146:385-92. |
|19.||Storm H. Skin conductance and the stress response from heel stick in preterm infants. Arch Dis Child Fetal Neonatal Ed 2000;83:F143-7. |
|20.||Torquati K, Pizzella V, Babiloni C, Del Gratta C, Della Penna S, Ferretti A, et al. Nociceptive and non-nociceptive sub-regions in the human secondary somatosensory cortex: An MEG study using fMRI constraints. Neuroimage 2005;26:48-56. |
|21.||Adler LJ, Gyulai FE, Diehl DJ, Mintun MA, Winter PM, Firestone LL. Regional brain activity changes associated with fentanyl analgesia elucidated by positron emission tomography. Anesth Analg 1997;84:120-6. |
|22.||Alkire MT, White NS, Hsieh R, Haier RJ. Dissociable brain activation responses to 5-Hz electrical pain stimulation: A high-field functional magnetic resonance imaging study. Anesthesiology 2004;100:939-46. |
|23.||Tamura Y, Hoshiyama M, Inui K, Nakata H, Qiu Y, Ugawa Y, et al. Facilitation of A[delta]-fiber-mediated acute pain by repetitive transcranial magnetic stimulation. Neurology 2004;62:2176-81. |
|24.||Strom H, Myre K, Rostrup M, Stokland O, Lien MD, Raeder JC. Skin conductance correlates with perioperative stress. Acta Anaesthesiol Scand 2002;46:887-95. |
|25.||Victor RG, Leimbach WN Jr, Seals DR, Wallin BG, Mark AL. Effects of the cold pressor test on muscle sympathetic nerve activity in humans. Hypertension 1987;9:429-36. |
|26.||Storm H, Shafiei M, Myre K, Raeder J. Palmar skin conductance compared to a developed stress score and to noxious and awakening stimuli on patients in anaesthesia. Acta Anaesthesiol Scand 2005;49:798-803. |
|27.||Lidberg L, Wallin BG. Sympathetic skin nerve discharges inrelation to amplitude of skin resistance responses. Psychophysiology 1981;18:268-70. |
[Figure 1], [Figure 2], [Figure 3]