Non-Invasive Objective Markers to Measure Pain: A Direction to Develop a Pain Device - A Narrative Review

Objective

This narrative review article will be a step forward to see the available current evidence about different pain-related markers for possible future development of pain devices.

Salivary biomarkers

The salivary glands contain various pain-associated biomarkers and they are connected to the neuroendocrine system.^[2] Studies have reported a correlation between salivary concentrations of biomarkers and pain. The substances P and glutamate are the most important neurotransmitters responsible for pain transmission and are present in saliva.^[3,4] Salivary concentration of substance P was significantly correlated with dental pain. The substance P level was higher in patients who had dental pain compared with patients who had no dental pain.^[5] High level of substance P and Glutamate in saliva has been reported in patients having high-intensity chronic migraine pain.^[6] High concentration of glutamate production within the posterior insula causes enhanced glutaminergic neurotransmission and this correlates with individual pain sensitivity and this may contribute a part to the pathophysiology of Fibromyalgia and central pain augmentation syndrome.^[7] It has been seen in a previous study that the level of saliva cortisol is directly associated with osteoarthritis related pain. The increased level of cortisol has been seen in women with greater pain severity.^[8] Self pain perception and salivary cortisol had a positive correlation in a study done by Alresayes et al. in adolescents with temporomandibular disorder.^[9] The salivary alpha amylases also correlate significantly with pain. Vahedi et al. reported that salivary alpha amylase concentration was significantly higher in patients with a headache when compared with control patients.^[10] A positive correlation has been shown in studies between salivary a-amylase and pain level in patients who were posted for surgery before and after.^[11,12] Studies have shown that secretory IgA (sIgA) levels may interfere with the pain experienced by the patient and it may have a negative correlation with pain.^[13] Both soluble tumour necrosis factor-α receptor II (sTNF-RII) and sIgA can be a reliable salivary biomarkers for pain assessment but sTNF-RII can be more accurate in diagnosing pain in people with advanced dementia.^[14] Alpha-amylase and IgA were present in higher amounts in the saliva of a patient with burning mouth syndrome^[15] and these markers could be used as pain biomarkers.^[16] The studies regarding pain assessment using salivary biomarkers are limited. As saliva is an easily obtained and non-invasive process, this technique could be a good option to assess pain objectively. More research should be focused on developing saliva-based biosensor technology to measure these biomarkers for pain assessment objectively.

Heart rate variability (HRV)

HRV is the physiological change in the time interval between heartbeats. Chronic pain produces changes in HRV and this chronic pain is influenced by both the sympathetic and parasympathetic nervous systems. This change in autonomic balance can be measured. The painful stimulation produces changes in time and frequency between successive heartbeats reflecting autonomic reactivity to painful stimulation.^[17,18] This is a simple and non-invasive variable that uses standard ECG monitoring and can also be used in both sedated and awake patients.^[19,20] However, breathing cycles fluctuates the heart rate and these considerations have improved the parameter accuracy.^[21]

Blood pressure (BP)

There is an inverse relationship between acute pain response and BP at rest in normotensive adults and adolescents without pain.^[22-26] Many studies reported that patients with chronic pain may have dysfunction of BP and hypoalgesia and this shows absence of inverse relationship between acute pain sensitivity and BP.^[27-31] Some studies have shown that there are some changes in descending inhibitory pathways due to chronic pain, for example, α2-adrenergic, baroreflex sensitivity, and endogenous opioids may be involved in altering the relation between BP and the pain modulatory system.^[30,31] Central sensitisation which involves the upregulation of ascending pain pathways may be involved in chronic pain patients.^[32]

Electroencephalography (EEG)

EEG device records the electrical activity of the brain. This is a non-invasive technique that uses electrodes that are placed over the scalp. Ionic current produces voltage fluctuations within the brain and this can be measured by EEG.^[33] Quantitative EEG has been applied to assess brain functioning in several chronic pain syndromes.^[34] The central and peripheral processing of painful input can be reflected by the signal amplitudes in EEG, that correlate with painful stimulus. These measured signal amplitudes are altered by analgesic medication;^[35-38] the precision required to know whether the stimulus is painful or non-painful can be debatable.^[38-43] At present, promising results have been shown by steady-state evoked potentials which quantify long lasting changes after a period of sensory stimulus and infrared laser evoked potentials,^[44-47] although do not show the neural coding of pain intensity.^[41] In this situation, a subjective way of pain estimation which is estimated by gamma-band oscillations can be a promising alternative.^[48] At present, this way of measuring pain intensity via EEG is within the research setting and it requires careful experimental studies. However, with more clinical research on a larger population, these techniques may help measure pain objectively.

Nerve conduction velocity

The peripheral nervous system is composed of nerve fibres identified as A-beta, A-delta, and C-fibres. The A-delta and C nerve fibres are the main pain-conducting nerve fibres systems.^[49] The various approaches to measure the function of pain pathways for A-delta and C-fibres are electrically, mechanically, and thermally. These three sensory tests are called quantitative sensory testing that measures the function of the small nerve fibres.^[50] The pathways of the pain are made up of nerves and the pain function could be measured electrically. Kall et al. invented an electrical device called Pain-Matcher that allows an objective way of performing pain measurement and provides a measurement value of pain.^[51] Many mechanical instruments have been used clinically to measure the function of nerve fibers of pain, that is, Muscle Pain Detection Device and PainTest™ FPX 25 Algometer.^[52,53] The nerve A-delta and C-nerve fibres play an important role in pain transmission and temperature sensation. The range of temperature through the device using warm and cold perception threshold can measure the functions of pain.^[54] Various devices have been developed for the quantitative thermal sensory nerve pathway testing, that is, CASE IV thermal testing probe, Marstock stimulator, Glasgow system, Middlesex Hospital thermal testing system, PATH-tester MPI 100, Thermal sensory analyser TSA-2001, Painmouse and Thermal sensitivity tester.^[55-62]

Galvanic skin response (GSR)

The change in the electrical property of the skin is called GSR. Painful stimuli activate autonomic nervous system which causes sweating and decrease the skin’s electrical resistance and thereby its conductance increases. The frequency of skin conductance and amplitude has been measured by various devices. This frequency and amplitude can be used to correlate with pain stimulus.^[63] To measure GSR, the constant voltage needs to be applied on a person’s skin and the skin conductance is measured with the help of Ohm’s Law by calculating the flow of current. Self-adhesive electrodes have to be applied to the palm or sole for measurement. The GSR amplifier delivers a small voltage through the person’s skin which is not perceived by humans but amplification can detect the response.^[64]

Respiratory rate (RR)

It has been reported in previous studies that the RR was evaluated when pain increases in the animals.^[65] A positive correlation between pain intensity and RR was also found in human studies. Many studies have noted that RR increases during the pain and it may be the most frequent physiological indicator of pain.^[66,67] Significant changes had been reported in RR during nociceptive procedures. Erden et al. observed a positive correlation between RR and pain intensity in patients admitted to the intensive care unit.^[68] Dantas et al. also reported the same results in children. They reported a significant increase in RR (P = 0.001) due to pain.^[69]

Oxygen saturation

Oxygen saturation is routinely measured by pulse oximeter and it can slightly vary with physiological changes occurring in the human body. Evaluating oxygen saturation and RR changes can be a valuable tool to measure pain objectively. Measuring pain in neonates or non-verbal patients is a difficult task. The study reported low sensitivity and specificity of oxygen saturation to evaluate neonatal pain and used only as an auxiliary method.^[70] Saleh et al. reported no statistically significant relationship between oxygen saturation before and after analgesia.^[71] Further research on a larger population is required to correlate the association between oxygen saturation and pain assessment and this noninvasive method can be used to measure pain objectively.

Surgical plethysmographic index (SPI)

The device SPI has been used to monitor the hemodynamic responses to analgesic medications and surgical stimuli during anaesthesia. This device records the increased sympathetic activity as a reaction to painful nociceptive stimuli and can be used to assess acute nociceptive stimuli. The mechanism is based on the photoplethysmographic waveforms of oxygen saturation measurements to analyse pulse wave interval and amplitude. A linear scale number from 0 to 100 is generated and the pain is considered if the values are more than 50.^[72] SPI can be useful in predicting postoperative pain, if obtained before patient arousal and correlated significantly with arousal.^[73] Thee et al. studied the relationship between the numeric rating scale and SPI and a significant correlation with total opioid consumption was found.^[74]

Pupillometry

Noxious stimuli can cause sympathetic stimulation which leads to pupillary dilatation. Various devices are used to measure the diameter of the pupil involving the noninvasive infrared principle. These pupillary responses could be influenced by several other factors such as drugs, environmental luminance, age, and other disease conditions.^[75,76] However these pupillary changes could be an important marker to analyse pain in non-verbal patients and neonates. Pupillometry has been reported as a technique to assess the pain objectively and to assess the pharmacodynamics of opioids.^[77,78] The nociceptive signal through autonomic innervations of iris muscles can be detected by pupil dilatation extension and the pharmacological effect in the central nervous system is provided by attenuation extension in pupillary response during opioid exposure.^[79]

Electromyography

Electromyography is a device to measure the response of the muscle to a nerve’s stimulation and has been used as an alternative method for the assessment of muscular pain.^[80] Gruss et al. used the EMG as one of the markers of a physiological signal to measure pain intensity.^[81] Candotti et al. reported a significant difference between the enrolled population with pain and no pain in the upper trapezius using surface electromyography. The lower force value has been reported in people with pain.^[80,82] Ambroz et al. outlined a significant correlation between surface electromyography and objective pain assessment in chronic low back pain patients. Muscle activity was threefold higher in these patients with pain when compared to patients without pain. Surface electromyography may be a useful objective diagnostic tool for the assessment of chronic lower back pain.^[83] The study reported by Mieronkoski et al. used surface electromyography to detect facial expressions during pain.^[84]

Limitation

We feel adding more databases could have given more insight into the current narrative review. Critical appraisals about each and every article were not included in this narrative review. Systematic review could have given robust evidence on the current topic. Invasive methods of measuring pain were not considered.

Systematic review for future studies on the current topic including all the parameters irrespective of invasive or noninvasive will give concrete evidence to move forward in making a device to measure pain objectively.