SYSTEM FOR PAIN MANAGEMENT

USING OBJECTIVE PAIN MEASURE

CLAIM OF PRIORITY

[0001] This application claims the benefit of priority under 35 U.S.C. §

119(e) of U.S. Provisional Patent Application Serial Number 62/400,336, filed on September 27, 2016, which is herein incorporated by reference in its entirety.

CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application is related to commonly assigned U.S. Provisional

Patent Application Serial No. 62/400,313, entitled "SYSTEMS AND

METHODS FOR CLOSED-LOOP PAIN MANAGEMENT", filed on

September 27, 2016 and U.S. Provisional Patent Application Serial No.

62/395,641, entitled "METHOD AND APPARATUS FOR PAIN

MANAGEMENT USING HEART SOUNDS", filed on September 16, 2016, which are incorporated by reference in their entirety.

TECHNICAL FIELD

[0003] This document relates generally to medical devices and more particularly to a pain management system that uses sensed physiological and/or functional parameters to produce an objective measure for pain.

BACKGROUND

[0004] Pain may result from an injury, a disease (e.g., arthritis,

fibromyalgia), or even a medical treatment (e.g., certain cancer treatment).

Various treatments are applied for pain management, such as medication, psychotherapy, electrical stimulation, thermal therapy, and their various combinations. Examples of electrical stimulation for pain management include Transcutaneous Electrical Nerve Stimulation (TENS) delivered by a TENS unit and Spinal Cord Stimulation (SCS) that may be delivered by an implantable neuromodulation systems. Pain treatment may be prescribed based on an assessment of a patient's symptoms and underlying conditioning and titrated based on the patient's response to the treatment. As pain is not directly measurable by a machine, the assessment of the condition and the titration of the therapy may depend on questioning the patient.

SUMMARY

[0005] An example (e.g., "Example 1") of a system for managing pain of a patient may include a pain monitoring circuit, a pain relief device, and a control circuit. The pain monitoring circuit may include a parameter analyzer and a pain score generator. The parameter analyzer may be configured to receive and analyze at least two parameters selected from a physiological parameter indicative of a physiological function or state of the patient, a functional parameter indicative of a physical activity or state of the patient, or a patient parameter including subjective information provided by the patient. The pain score generator may be configured to compute a composite pain score using an outcome of the analysis. The composite pain score may indicate a degree of the pain. The pain relief device may be configured to deliver one or more pain- relief therapies. The control circuit may be configured to control the delivery of the one or more pain-relief therapies using the composite pain score and therapy parameters.

[0006] In Example 2, the subject matter of Example 1 may optionally be configured such that the parameter analyzer is configured to produce a signal metric using the at least two parameters, and the pain score generator is configured to compute the composite pain score using the signal metric.

[0007] In Example 3, the subject matter of Example 2 may optionally be configured such that the parameter analyzer is configured to generate one or more weighting factors and is configured to produce the signal metric using the at least two parameters with the one or more weighting factors each applied to a parameter of the at least two parameters.

[0008] In Example 4, the subject matter of Example 3 may optionally be configured such that the parameter analyzer is configured to adjust the one or more weighting factors by automatic adaptation to the patient over time.

[0009] In Example 5, the subject matter of any one or any combination of Examples 1 to 4 may optionally be configured such that the pain monitoring circuit further include: one or more physiological signal sensors configured to sense one or more physiological signals from the patient, a physiological signal sensing circuit configured to process the one or more physiological signals, a physiological parameter generator configured to generate the physiological parameter using the processed one or more physiological signals, one or more functional signal sensors to sense one or more functional signals from the patient, a functional signal sensing circuit configured to process the one or more functional signals, and a functional parameter generator configured to generate the functional parameter using the processed one or more functional signals.

[0010] In Example 6, the subject matter of Example 5 may optionally be configured such that the one or more physiological signal sensors include a sensor configured to sense a physiological signal indicative of change in sympathetic activity, and the physiological parameter generator is configured to generate a physiological parameter being a measure of the change in sympathetic activity.

[0011] In Example 7, the subject matter of Example 5 may optionally be configured such that the one or more physiological signal sensors include a sensor configured to sense a physiological signal indicative of a neural activity, and the physiological parameter generator is configured to generate a

physiological parameter being a measure of the neural activity.

[0012] In Example 8, the subject matter of Example 5 may optionally be configured such that the one or more functional signal sensors include a sensor configured to sense a function signal indicative of a measure of movement or posture, and the functional parameter generator is configured to generate a functional parameter quantitatively indicative the measure of movement or posture.

[0013] In Example 9, the subject matter of any one or any combination of Examples 1 to 8 may optionally be configured to include a patient information input device configured to receive patient information related to pain, a patient information processing circuit configured to process the patient information, and a patient parameter generator configured to generate the patient parameter using the processed patient information.

[0014] In Example 10, the subject matter of any one or any combination of Examples 1 to 9 may optionally be configured such that the pain relief device includes a neuromodulator to deliver a neuromodulation therapy including electrical stimulation. [0015] In Example 11, the subject matter of any one or any combination of Examples 1 to 10 may optionally be configured such that the pain relief device includes a drug pump.

[0016] In Example 12, the subject matter of any one or any combination of Examples 1 to 11 may optionally be configured to include an implantable medical device including the pain monitoring circuit, the pain relief device, and the control circuit, and the control circuit includes an implant control circuit.

[0017] In Example 13, the subject matter of Example 12 may optionally be configured to include an external device configured to be communicatively coupled to the implantable medical device. The external device includes the patient information input device including a patent input device configured to receive a parameter representative of intensity of the pain specified by the patient.

[0018] In Example 14, the subject matter of Example 13 may optionally be configured such that the external device is configured to receive the composite pain score, to produce a notification using the composite pain score, to determine one or more recipients of the notification using the composite pain score, and to control delivery of the notification to each of the one or more recipients.

[0019] In Example 15, the subject matter of Example 14 may optionally be configured such that the external device is configured to produce external commands for adjusting the therapy parameters using the composite pain score and the patient information and transmit the external commands to the implantable medical device, and the implant control circuit is configured to adjust the therapy parameters using the external commands.

[0020] An example (e.g., "Example 16") of a method for managing pain of a patient is also provided. The method may include receiving and analyzing at least two parameter selected from a physiological parameter indicative of a physiological function or state of the patient, a functional parameter indicative of a physical activity or state of the patient, and a patient parameter related to the pain automatically using a processor, the patient parameter including subjective information provided by the patient, computing a composite pain score using the processor based on an outcome of the analysis, the composite pain score indicating of a degree of the pain, delivering one or more pain-relief therapies using a pain relief therapy device, and controlling the delivery of the one or more pain-relief therapies from the pain relief therapy device automatically using the processor based on the composite pain score and therapy parameters.

[0021] In Example 17, the subject matter of Example 16 may optionally further include generating one or more weighting factors, and the subject matter of analyzing the at least two parameters as found in Example 16 may optionally include generating a signal metric using the at least two parameters with the one or more weighting factors each applied to a parameter of the at least two parameters, and the subject matter of computing the composite pain score as found in Example 16 may optionally include computing the composite pain score using the signal metric.

[0022] In Example 18, the subject matter of Example 17 may optionally further include adjusting the one or more weighting factors by automatic adaptation to the patient over time.

[0023] In Example 19, the subject matter of any one or any combination of Example 16 may optionally further include sensing one or more physiological signals from the patient using one or more physiological signal sensors, generating the physiological parameter based the one or more physiological signals using the processor, sensing one or more functional signals from the patient using one or more functional signal sensors, generating the functional parameter based the one or more functional signals using the processor, and receiving a parameter representative of intensity of the pain from the patient.

[0024] In Example 20, the subject matter of generating the physiological parameter as found in Example 19 may optionally include generating a measure of the change in sympathetic activity.

[0025] In Example 21, the subject matter of generating the physiological parameter as found in any one or any combination of Examples 19 and 20 may optionally include generating a measure of the neural activity.

[0026] In Example 22, the subject matter of generating the functional parameter as found in any one or any combination of Examples 19 to 21 may optionally include generating a functional parameter quantitatively indicative of a measure of movement or posture.

[0027] In Example 23, the subject matter of any one or any combination of Examples 16 to 22 may optionally include producing a notification using the composite pain score, determining one or more recipients of the notification using the composite pain score and one or more specified thresholds, and delivering the notification to each of the one or more recipients.

[0028] In Example 24, the subject matter of delivering the one or more pain-relief therapies using the pain relief therapy device as found in any one or any combination of Examples 16 to 23 may optionally include delivering one or more of a neuromodulation therapy including electrical stimulation or a drug therapy from an implantable medical device.

[0029] In Example 25, the subject matter of Example 24 may optionally further include adjusting the therapy parameters using the composite pain score and a patient command entered by the patient using an external device communicatively coupled to the implantable medical device.

[0030] This Summary is an overview of some of the teachings of the present application and not intended to be an exclusive or exhaustive treatment of the present subject matter. Further details about the present subject matter are found in the detailed description and appended claims. Other aspects of the disclosure will be apparent to persons skilled in the art upon reading and understanding the following detailed description and viewing the drawings that form a part thereof, each of which are not to be taken in a limiting sense. The scope of the present disclosure is defined by the appended claims and their legal equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The drawings illustrate generally, by way of example, various embodiments discussed in the present document. The drawings are for illustrative purposes only and may not be to scale.

[0032] FIG. 1 illustrates an embodiment of a pain analyzer.

[0033] FIG. 2 illustrates an embodiment of a pain monitoring circuit including a pain analyzer such as the pain analyzer of FIG. 1.

[0034] FIG. 3 illustrates an embodiment of a pain management system and portions of an environment in which the system operates.

[0035] FIG. 4 illustrates an embodiment of a method for pain

management such as may be performed by the pain management system of FIG. [0036] FIG. 5 illustrates another embodiment of a pain management system and portions of an environment in which the system operates.

[0037] FIG. 6 illustrates an embodiment of a method for pain

management such as may be performed by the pain management system of FIG. 5.

[0038] FIG. 7 illustrates an embodiment of an implantable medical device of a pain management system such as the pain management system of FIG. 5.

[0039] FIG. 8 illustrates an embodiment of an external device of a pain management system such as the pain management system of FIG. 5.

[0040] FIG. 9 illustrates an embodiment of a remote device of a pain management system such as the pain management system of FIG. 5.

DETAILED DESCRIPTION

[0041] In the following detailed description, reference is made to the accompanying drawings which form a part hereof, and in which is shown by way of illustration specific embodiments in which the invention may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, and it is to be understood that the embodiments may be combined, or that other embodiments may be utilized and that structural, logical and electrical changes may be made without departing from the spirit and scope of the present invention. References to "an", "one", or "various" embodiments in this disclosure are not necessarily to the same embodiment, and such references contemplate more than one embodiment. The following detailed description provides examples, and the scope of the present invention is defined by the appended claims and their legal equivalents.

[0042] This document discusses a pain management system that provides a quantitative measure of a patient's pain (or pain-related condition or symptom) for diagnostic, monitoring, and/or therapeutic purposes. The International Association for the Study of Pain (IASP, Washington, DC, U.S.A.) defines pain as an "unpleasant sensory and emotional experience that is associated with the actual or potential tissue damage or described in such terms." While also experienced by healthy people, elevated levels of pain are experienced by many patients suffering from various types of injuries and diseases. Managing pain is a top priority of physicians and nurses. In a clinic, pain is often quantified by questioning the patient using the visual analog scale (VAS) or numeric rating scale ( RS). VAS allows the patient to indicate a point representing the perceived pain level in a continuum from no pain to the worst imaginable pain. NRS allows to patient to select a number between 0 and 10 representing the perceived pain level from no pain ("0") to the worst imaginable pain ("10"). However, the pain value as indicated by the patient is a subjective measure. One patient's "10" could be another patient's "1". In addition, monitoring and quantifying chronic pain presents additional challenges as the patient's perception of pain can change over time. Furthermore, some patients such as infants and disabled may have a challenge communicating their perception of pain. A lack of an objective measure of pain results in many challenges in healthcare besides such examples.

[0043] The subjective pain value can lead to challenges such as over and under dosing of analgesics (especially opioids), misdiagnosis, suboptimal therapy, extended hospital stay, and increased healthcare cost. Patients and their care providers can both benefit from a more objective measure of pain. Many measureable parameters are known to relate to pain (see Table 1). Such parameters, individually or in combination, may be measured in the present pain management system discussed in this document. In various embodiments, one or more of such parameters can be acquired to produce a pain score being a quantitative measure of pain. In various embodiments, this pain score can be used to adjust or optimize a pain relief therapy in a closed-loop pain

management system. For example, a pain monitoring system producing such a pain score can be integrated into a closed-loop pain management system to titrate a pain control therapy. Examples of such pain control therapy can include any one or any combination of spinal cord stimulation (SCS), dorsal root ganglia (DRG) stimulation, deep brain stimulation (DBS), motor cortex stimulation (MCS), transcranial direct current stimulation (tDCS), transcutaneous spinal direct current stimulation (tsDCS), trigeminal nerve stimulation, occipital nerve stimulation, vagus nerve stimulation (VNS), sacral nerve stimulation, pudendal nerve stimulation, sphenopalatine ganglion stimulation, sympathetic nerve modulation, multifidus muscle stimulation, adrenal gland modulation, carotid baroreceptor stimulation, transcutaneous electrical nerve stimulation (TENS), transcranial magnetic stimulation (TMS), tibial nerve stimulation, transcranial magnetic stimulation (TMS), radiofrequency ablation (RFA), pulsed

radiofrequency ablation, ultrasound therapy, high-intensity focused ultrasound (HIFU), optical stimulation, optogenetic therapy, magnetic stimulation, other peripheral tissue stimulation therapies, other peripheral tissue denervation therapies, drug therapy (such as delivered from a drug pump), and nerve blocks or injections (such as pharmaceuticals or biologies). .

[0044] Pain alters various physiological and functional signals that can be sensed from the patient invasively or non-invasively. Such signals can be used to quantify the patient's pain levels. Physiological signals such as heart rate, blood pressure, respiration rate, and skin conductance, as well as signals derived from these such as heart rate variability, may show abnormal patterns when the patient experiences pain, due to the patient's sympathetic activity elevated by pain. The physiological signals indicative of level of sympathetic activity can therefore be collected via invasive and/or non-invasive means for analysis of the patient pain state. Pain is felt by the patient through transmission of neural signals in the patient's nervous system. Thus, pain can be measured more directly by sensing the patient's neural activities. Pain alters neuronal connection, resulting in predictable changes in electrical activity in the nervous system that can be captured by, for example, electroencephalography (EEG) and electromyography (EMG), which can be analyzed to assess the patient's pain by evaluating neural function. Functional signals such as those indicative of a measure of movement (e.g., activity level, gait pattern, range of motion, or sleep) or posture can also indicate the patient's pain state, because pain can impact various functional aspects of the patient's daily activities when the patient has to compensate for discomfort during the activities. For example, the patient may try to reduce pain with irregular gait patterns and/or lower activity levels. Such functional signals can also be monitored for analyzing the patient pain state. In various embodiments, such physiological and functional parameters when used individually or in various combinations can provide for an objective and quantitative measure of the patient's pain.

[0045] In addition to the physiological and/or functional parameters, the analysis of pain can also include subjective input from the patient. For example, the patient's mood and mental state such as stress level and sleep quality can impact the patient's perception of pain. Furthermore, the analysis of pain can also include environmental parameters such as temperature, humidity, and/or air pressure, which may influence discernment of pain. Time of day, which may capture circadian influence on pain, can also be included in the analysis of pain.

[0046] In various embodiments, the present pain management system can sense pain-indicating physiological and functional signals and analyze the signals using an objective method to produce a quantitative measure

representative of the pain state of the patient, to control therapy delivery, and to evaluate efficacy of therapeutic intervention for pain. In various embodiments, outcomes of the analysis can include an objective pain measure based on one or more physiological parameters and one or more function parameter. In various embodiments, the objective pain measure is further combined with relevant medical history of the patient and/or input received from the patient or their caregivers to produce a composite pain score. This pain score represents the patient's pain intensity and can be reported to the patient and/or a care provider, and can be used to start, stop, and adjust pain management therapies.

[0047] While various physiological or functional parameters have been studied for indicating or measuring pain, the present pain management system combines both physiological and functional parameters to better capture the patient's pain experience and quantify the pain experience into an objective pain value (e.g., the composite pain score). For example, the system can include sensors for sensing the physiological and functional signals, a patient information input to receive patient information such as subjective pain level perceived by the patient and/or pain-related information in the patient's medical history, a processing circuit to produce the physiological and functional parameters by extracting relevant information from the sensed signals and computing the composite pain score based on the physiological and functional parameters and the patient information. The composite pain score as well as the algorithm for its computation can be updated continuously, periodically, according to other schedules, or as needed to reflect the changes in the physiological and functional parameters and the patient information. The composite pain score can be used for monitoring the patient's pain state and/or titrating one or more pain relief therapies the patient receives. [0048] FIG. 1 illustrates an embodiment of a pain analyzer 100 that can include a parameter analyzer 102 and a pain score generator 104. In the illustrated embodiment, parameter analyzer 102 receives and analyzes one or more physiological parameters each indicative of a physiological function or state of a patient, one or more functional parameters each indicative of a physical activity or state of the patient, and one or more patient parameters related to the pain, such as a parameter representative of intensity of the pain specified by the patient. Pain score generator 104 computes a composite pain score using an outcome of the analysis. The composite pain score indicates a degree of the pain. In various embodiments, parameter analyzer 102 can receive and analyze at least one physiological parameter and one functional parameter. Pain score generator 104 can compute a composite pain score using an outcome of the analysis.

[0049] In various embodiments, parameter analyzer 102 can produce a signal metric using one or more physiological parameters, one or more functional parameters, and/or the one or more patient parameters. In one embodiment, parameter analyzer 102 produces the signal metric using at least one parameter selected from the one or more physiological parameters, the one or more functional parameters, or the one or more patient parameters. In one embodiment, parameter analyzer 102 produces the signal metric using at least two parameters selected from the one or more physiological parameters, the one or more functional parameters, or the one or more patient parameters. In one embodiment, parameter analyzer 102 produces the signal metric using at least one physiological parameter and one functional parameter. In one embodiment, parameter analyzer 102 produces the signal metric using at least two parameters selected from a physiological parameter, a functional parameter, and a patient parameter. In one embodiment, parameter analyzer 102 produces the signal metric using the one or more physiological parameters and the one or more functional parameters. In one embodiment, parameter analyzer 102 produces the signal metric using the one or more physiological parameters and the one or more patient parameters. In one embodiment, parameter analyzer 102 produces the signal metric using the one or more functional parameters and the one or more patient parameters. In one embodiment, parameter analyzer 102 produces the signal metric using the one or more physiological parameters, the one or more functional parameters, and the one or more patient parameters.

[0050] The signal metric can be a linear or nonlinear combination of the one or more physiological parameters, the one or more functional parameters, and/or the one or more patient parameters. In various embodiments, parameter analyzer 102 can produce the signal metric using the one or more physiological parameters, the one or more functional parameters, and/or the one or more patient parameters with the weighting factors each applied to one of these parameters. In various embodiments, parameter analyzer 102 can adjust the weighting factors through automatic learning and adaptation to the patient over time (e.g., based on stored parameters and/or outcomes of analysis, such as features extracted from the parameters). In various other embodiments, parameter analyzer 102 can allow the weighting factors to be adjusted manually. In various other embodiments, the weighting factors can be adjusted according to a calibration schedule or as needed, and the adjustment can be performed by a user such as a physician or other authorized care provider in a clinic, or initiated by the patient and performed by parameter analyzer 102 automatically at home. In various embodiments, the weighting factors can be patient-specific and dynamically changed based on the patient's conditions and/or activities, such as source of pain, type of pain, related pathological condition, physical condition (e.g., bed-ridden), time of day, and/or physical activity (e.g., patient being sleeping or walking).

[0051] In various embodiments, pain score generator 104 can compute the composite pain score using the signal metric. In one embodiment, pain score generator 104 trends the signal metric and computes the composite pain score based on the resulting trending of the signal metric.

[0052] FIG. 2 illustrates an embodiment of a pain monitoring circuit 210.

In the illustrated embodiment, pain monitoring circuit 210 includes one or more physiological signal sensors 212, a physiological signal sensing circuit 214, a physiological parameter generator 216, one or more functional signal sensors 218, a functional signal sensing circuit 220, a functional parameter generator 222, a patient information input device 224, a patient information processing circuit 226, a patient parameter generator 228, and pain analyzer 100. In various embodiments, pain monitoring circuit 210 can include at least one or more physiological signal sensors 212, physiological signal sensing circuit 214, physiological parameter generator 216, one or more functional signal sensors 218, functional signal sensing circuit 220, functional parameter generator 222, and pain analyzer 100.

[0053] In various embodiments, one or more physiological signal sensors

212 can each sense one or more physiological signals, and can each be a noninvasive, percutaneous, or implantable sensor. Physiological signal sensing circuit 214 can process the one or more physiological signals. Physiological parameter generator 216 can generate the one or more physiological parameters using the processed one or more physiological signals. Examples of the one or more physiological parameters can include one or more measures of physiologic manifestations of change in the patient's sympathetic activity (referred to as "autonomic measures"), one or more direct measures of neuronal activity (referred to as "neuron/brain measures"), and/or one or more chemical or analyte parameters derived from body tissue, fluid, and/or excretion collected from the patient.

[0054] Examples of the one or more autonomic measures can include (1) heart rate and heart rate variability, including time and frequency domain measures, statistic metrics in the time domain including standard deviation of the baseline normal R-R intervals to assess changes from baseline, the square root of mean squared differences of successive R-R intervals over different time windows, q-factors for spectral peaks at very low frequency (VLF), low frequency (LF), and high frequencies (HF), ratio of power in the different frequency bands (LF/FIF), changes in frequency of maximum peaks over time, and complexity metrics derived from these signals; (2) blood pressure measures including systolic and diastolic blood pressure, pulse transit time, wave amplitude, and volume (the blood pressure measures can be obtained using heart sounds such as by leveraging the second heart sound (S2) as a strong surrogate for pressure readings through either invasive or noninvasive means, or can also be acquired using blood pressure cuffs or photoplethysmograms (PPGs)); and (3) galvanic skin response, including time and frequency domain measures.

Additional examples of the one or more autonomic measures can be found in Table 1 (e.g., under "Autonomic Measures"). Examples of the neuron/brain measures can include (1) electroencephalogram (EEG) based pattern analysis and frequency domain measures; (2) electromyogram (EMG) based time (amplitude and latency) and frequency domain measures; and (3) response to specific evoked potentials (EPs) that are affected under cognitive tasks, mental state changes, mood variation, presence of depression, and/or presence of different levels of pain. Additional examples of the one or more neuron/brain measures can be found in Table 1 (e.g., under "Neuron/Brain Measures"). In various embodiments, physiological parameter generator 216 can generate any one or any combination of these examples as the one or more physiological parameters. Examples of the one or more chemical or analyte parameters can include parameters derived from the patient's blood, sweat, saliva, breath, tissue, etc. Additional examples one or more chemical or analyte parameters can be found in Table 1 (e.g., under "Blood Draw/Concentration Measures").

[0055] In various embodiments, one or more functional signal sensors

218 can sense one or more functional signals, and can each be a non-invasive, percutaneous, or implantable sensor. Functional signal sensing circuit 220 can process the one or more functional signals. Functional parameter generator 222 can generate the one or more functional parameters using the processed one or more functional signals. Examples of the one or more functional signals can include measures of (1) movement (e.g., activity level, gait pattern, range of motion, or sleep) and (2) posture. Additional examples of the one or more functional parameters can be found in Table 1 (e.g., under "Functional

Measures"). In various embodiments, physiological parameter generator 222 can generate any one or any combination of these examples as the one or more functional parameters.

[0056] In various embodiments, patient information input device 224 can receive patient information related to pain. Patient information processing circuit 226 can process the patient information. Patient parameter generator 228 can generate one or more patient parameters using the processed patient information. Examples of the one or more patient parameters can (1) parameters derived from input from the patient such as perceived pain levels, mood, and stress levels (including external interactions, such as interactions with another person) as a way to quantify non-physical activity); and (2) parameters derived from the patient's medical history record (e.g., demographic data, diagnoses, procedures applied, and prescriptions). Some additional examples of the parameters derived from the patient's medical history record can be found in Table 1 (e.g., under "Blood Draw/Concentration Measures"). In various embodiments, patient parameter generator 228 can generate any one or any combination of these examples as the one or more patient parameters.

[0057] FIG. 3 illustrates an embodiment of a pain management system

330 and portions of an environment in which system 330 operates. System 330 can include sensors 332, a portable device 334, a network 338 communicatively coupled to portable device 334 via a communication link 336, and a medical facility 340 communicatively coupled to network 338. A pain monitoring circuit such as pain monitoring circuit 210 can be distributed in sensors 332 and portable device 334. In various embodiments, portable device 334 can be implemented as a dedicated device or in a generic device such as a smartphone, a laptop computer, or a tablet computer.

[0058] For example, sensors 332 may include at least one sensor of physiological sensor(s) 212 and one sensor of functional signal sensor(s) 218, and portable device 334 can include the remaining components of pain monitoring circuit 210. The composite pain score as well as other data acquired by portable device 334 can be transmitted to network 338 via communication link 336 to be stored, further analyzed, and/or inform the patient's healthcare provider. When the composite pain score and/or the other data indicate that the patient needs medical attention, a notification will be transmitted to medical facility 340 from network 338. In various embodiments, sensor(s) 332 can include external, percutaneous, and/or implantable sensors that communicate with portable device 334 via wired and/or wireless links, and communication link 336 can be a wired or wireless link.

[0059] FIG. 4 illustrates an embodiment of a method 400 for pain management. In one embodiment, system 330 is configured to perform method 400 for a patent.

[0060] At 402, one or more physiological parameters and one or more functional parameters are generated. The one or more physiological parameters are each indicative of a physiological function or state of the patient. The one or more functional parameters are each indicative of a physical activity or state of the patient. Examples of such one or more physiological parameters can include the physiological parameters that can be generated by physiological parameter generator 216 as discussed above with reference to FIG. 2 and Table 1.

Examples of such one or more functional parameters can include the functional parameters that can be generated by functional parameter generator 222 as discussed above with reference to FIG. 2 and Table 1.

[0061] Optionally at 404, patient input is received. Optionally at 406, patient history is received. The received patient input and/or patient history include one or more patient parameters related to the pain of the patient.

Examples of such one or more patient parameters can include the patient parameters that can be generated by patient parameter generator 228 as discussed above with reference to FIG. 2 and Table 1. In various embodiments, the one or more patient parameters can include one or more parameters directly entered by the patient or another person attending the patient as well as one or more parameters derived from information entered by the patient or another person attending the patient and the patient's medical history. In one embodiment, the one or more patient parameters includes a parameter representative of intensity of the pain specified by the patient based on his or her perception of the pain.

[0062] At 408, the parameters generated and/or received at 402, 404, and

406 are analyzed. In various embodiments, the analysis can result in a signal metric using one or more physiological parameters, one or more functional parameters, and/or the one or more patient parameters. In one embodiment, the analysis results in the signal metric using at least one parameter selected from the one or more physiological parameters, the one or more functional parameters, or the one or more patient parameters. In one embodiment, the analysis results in the signal metric using at least two parameters selected from the one or more physiological parameters, the one or more functional parameters, or the one or more patient parameters. In one embodiment, the analysis results in the signal metric using at least one physiological parameter and one functional parameter. In one embodiment, the analysis results in the signal metric using at least two parameters selected from a physiological parameter, a functional parameter, and a patient parameter. In one embodiment, the analysis results in the signal metric using the one or more physiological parameters and the one or more functional parameters. In one embodiment, the analysis results in the signal metric using the one or more physiological parameters and the one or more patient parameters. In one embodiment, the analysis results in produces the signal metric using the one or more functional parameters and the one or more patient parameters. In one embodiment, the analysis results in produces the signal metric using the one or more physiological parameters, the one or more functional parameters, and the one or more patient parameters.

[0063] In various embodiments, weighting factors can be generated, and the signal metric can be produced using the one or more physiological parameters, the one or more functional parameters, and/or the one or more patient parameters with the weighting factors each applied to one of these parameters. In another embodiment, one or more of the one or more

physiological parameters, the one or more functional parameters, and the one or more patient parameters are preprocessed to extract relevant pain information features before generating the weighting factors to be applied to these features. In another embodiment, the weighting factors are generated using one or more machine learning techniques such as neural network, fuzzy logic, support vector machines, and/or generalized linear or non-linear regressions.

[0064] At 410, a composite pain score is computed. In various embodiments, the composite pain score can be computed using the signal metric. In various embodiments, additional parameters such as environmental parameters and time can be used in computing the composite pain score, such as by including in the analysis that results in the signal metric. The environmental parameters, such as temperature, humidity, and/or air pressure, may influence discernment of pain. In various embodiments, such environmental parameters can be measured by system 300 and/or obtained from weather forecasts based on location (e.g., specified manually or using a global positioning system) to anticipate or predict their impact to the composite pain score. One or more weighting factors can be determined based on the reliability of these

environmental parameters (e.g., depending on how they are obtained) and applied in computing the composite pain score. Time of day may capture circadian influence on pain. There are still additional parameters that can affect pain, and can be used in computing the composite pain score, such as by including in the analysis that results in the signal metric. Examples can include, but are not limited to, amount and/or quality of sleep (e.g., as measured by system 330), amount and/or type of activity during a preceding period of time (e.g., the previous day or week, and measured by system 330), personal events that may have positive impact or negative impact on pain, medication changes, time of year (e.g., birthday and holidays), personal events that may have positive impact or negative impact on pain (e.g., church and socialization activities making for consistent good moods on Sunday with a let down on Monday, as monitored and recognized as a pattern by system 330), and/or deviation from patterns determined by system 330 (e.g., regular activity around lunch time because walking to a cafeteria stops due to changes in pain perception not identified by other parameters). In one embodiment, the signal metric is trended, and the composite pain score is computed based on the trend.

[0065] At 412, the algorithm used to compute the composite pain score is calibrated. In various embodiments, the calibration can include adjusting the one or more weighting factors manually, automatically by learning and adapting to the patient's circumstances and conditions over time, and/or adjusting the weighting factors based on changes in the physiological and functional parameters. The weighting factors can be adjusted according to a calibration schedule or as needed. In various embodiments, the calibration can be a continuous process. For example, calibration can be performed over the course of minutes or longer, e.g., days, to encompass a range of activities. Calibration can be a prompted activity or scheduled to occur intermittently, for example. Different weighting factors can be used for various activities, such as sleeping and walking. In various embodiments, the weighting factor can be linear or nonlinear in nature.

[0066] At 414, whether medical intervention is required is determined, such as by comparing the composite pain score to one or more thresholds. If intervention is not required as determined at 414, the one or more physiological parameters and one or more functional parameters are generated again (i.e., their values are updated) for continued monitoring of the patient.

[0067] At 416, the result of the computation, including at least the composite pain score, is displayed to the patient or a caregiver. At 418, if intervention is required as determined at 414, relevant medical personnel is notified for appropriate action that can be dependent on the composite pain score. Examples of the appropriate action can include instructing the patient to take medication, instructing the patient to visit a clinic, or sending medical personnel to visit the patient.

[0068] FIG. 5 illustrates another embodiment of a pain management system 530 and portions of an environment in which system 530 operates.

System 530 can include an implantable medical device 542, a portable device 534 communicatively coupled to implantable medical device 542 via a wireless communication link 544, network 338 communicatively coupled to portable device 534 via communication link 336, and medical facility 340

communicatively coupled to network 338. A pain monitoring circuit such as pain monitoring circuit 210 can be distributed in implantable medical device 542 and portable device 534, and implantable medical device 542 can deliver one or more pain relief therapies. In various embodiments, portable device 534 can be implemented as a dedicated device or in a generic device such as a smartphone, a laptop computer, or a tablet computer.

[0069] For example, implantable medical device 542 may include at least one sensor of physiological sensor(s) 212 and one sensor of functional signal sensor(s) 218, and portable device 534 can include the remaining components of pain monitoring circuit 210. The composite pain score as well as other data acquired by portable device 534 can be transmitted to network 338 via communication link 336 to be stored, further analyzed, inform the patient's healthcare provider, and/or used to control delivery of one or more pain relief therapies from implantable medical device 542. When the composite pain score and/or the other data indicate that the patient needs medical attention, such as when system 530 is unable to automatically adjust the one or more pain relief therapies for a satisfactory result as indicated by the composite pain score, a notification will be transmitted to medical facility 340 from network 338.

[0070] FIG. 6 illustrates an embodiment of a method 600 for pain management. In one embodiment, system 530 is configured to perform method 600 for a patent. Method 600 can be performed for monitoring pain of the patient and delivering one or more pain relief therapies to the patient with closed-loop control. As illustrated in FIG. 6, method 600 includes steps 402, 404, 406, 408, 410, and 412 of method 400.

[0071] At 614, the composite pain score is compared to a therapy threshold indicating a need for adjusting a pain relief therapy. If the composite pain score does not exceed the therapy threshold as determined at 614, the one or more physiological parameters and one or more functional parameters are generated again (i.e., their values are updated) for continued monitoring of the patient. Examples of the pain relief therapy can include neuromodulation therapies (e.g., SCS, PNS, DBS, and TMS) and drug therapies.

[0072] At 616, when the composite pain score exceeds the therapy threshold as determined at 614, the pain relief therapy is adjusted. The adjustment can include starting a therapy, increasing intensity (e.g.,

neurostimulation energy or drug dose), switching to a different type therapy, or adjusting any therapy parameters. Examples of therapy parameters for various types of neuromodulation therapies can include pulse frequency, burst frequency, pulse width, waveform shape, anode/cathode configurations, and current fractionalization.

[0073] At 618, whether the composite pain score exceeds a notification threshold is determined. At 620, if the pain exceeds the notification threshold as determined at 618, relevant medical personnel is notified for appropriate action that may be dependent on the composite pain score and/or the record of delivery of the pain relief therapy. Examples of the appropriate action can include instructing the patient to take medication, instructing the patient to visit a clinic, or sending medical personnel to visit the patient. If the pain does not exceed, the notification threshold as determined at 618, no notification to relevant medical personnel is necessary. In any case, the one or more physiological parameters and one or more functional parameters are continued to be generated (i.e., their values are updated) for continued assessment of the patient pain level.

[0074] FIG. 7 illustrates an embodiment of an implantable medical device 742, which represents an example of implantable medical device 542. Implantable medical device 742 can include a pain monitoring circuit 710, an implant communication circuit 752, and a pain relief device 754. Pain monitoring circuit 710 represents an example of pain monitoring circuit 210 as implemented in an implantable medical device. When the one or more patient parameters are used by pain analyzer 100, patient information input device 224 can receive the patient information from an external device communicatively coupled to implantable medical device 742 via communication link 544. [0075] Implant control circuit 746 controls the operation of implantable medical device 742 and can include a communication controller 748 and a therapy controller 750. Communication controller 748 can control transmission of the composite pain score the external device, such as on a periodical basis or according to another specified schedule, when the composite pain score exceeds a specified threshold, when change in the composite pain score exceeds a specified threshold, or when the rate of change in the composite pain score exceeds a specified threshold. Therapy controller 750 can control the delivery of the one or more pain-relief therapies using the composite pain score and therapy parameters. Implant communication circuit 752 allow implantable medical device 742 to communicate with the external device via communication link 544. Pain relief device 754 can deliver one or more pain-relief therapies. In various embodiments, pain relief device 754 can include a neuromodulator to deliver electrical stimulation (such as SCS, PNS, DBS, and/or TMS) and/or a drug pump to deliver one or more pain suppression agents.

[0076] FIG. 8 illustrates an embodiment of an external device 834, such as may be implemented in portable device 534. External device 834 can include an external user interface 856, an external control circuit 862, and an external communication circuit 868. In various embodiments, external device 834 can be implemented in a portable device such as a hand-held or wearable device.

[0077] External user interface 856 can include a user input device 858 and a presentation device 860. User input device 858 can receive patient information such as a subjective input from the patient to indicate the degree of the pain as perceived by the patient. Presentation device 860 can include a display screen and/or other audio and/or visual presentation devices. In one embodiment, a touchscreen is used as user input device 858 and presentation device 860. External control circuit 862 controls operation of external device 834 and can include a notification controller 864 and a therapy controller 866. Notification controller 864 can receive the composite pain score from

implantable medical device 742, produce a notification using the composite pain score, determine one or more recipients of the notification using the composite pain score, and control delivery of the notification to each of the one or more recipients. The recipients can include the patient and/or various users of a pain management system such as system 530. In various embodiments, notification controller 864 can present the notification using presentation device 860. The notification can include the composite pain score, one or more indicators representing the pain score, an alert or alarm message regarding the patient's pain state, and/or instructions for actions to be taken by the patient. In various embodiments, notification controller 864 can produce and present the notification when the composite pain score exceeds a specified threshold, when change in the composite pain score exceeds a specified threshold, or when the rate of change in the composite pain score exceeds a specified threshold.

Therapy controller 866 can produce external commands for adjusting the therapy parameters using the composite pain score and the patient information and transmit the external commands to implantable medical device 742 via communication link 544. External communication circuit 868 allow external device 834 to communicate with implantable medical device 742 via

communication link 544 and to communicate with a remote device via communication link 336.

[0078] FIG. 9 illustrates an embodiment of a remote device 970, such as may be implemented in network 338 and/or medical facility 340. Remote device 970 can be used for patient monitoring and therapy control, and can include a remote user interface 972, a remote control circuit 978, and a remote

communication circuit 984.

[0079] Remote user interface 972 can include a user input device 974 and a presentation device 976. User input device 974 can receive patient information such as patient history stored in network 338 and/or medial facility 340, and can also receive user commands for adjusting the one or more pain- relief therapies. Such user command may be determined based on updated knowledge about the patient's conditions and/or results of one or more pain- relief therapies received by the patient. Presentation device 976 can include a display screen and/or other audio and/or visual presentation devices. In one embodiment, a touchscreen is used as user input device 974 and presentation device 976. Remote control circuit 978 can include a notification controller 980 and a therapy controller 982. Notification controller 980 can receive the notification transmitted from external device 834, determine one or more further recipients of the notification, and control delivery of the notification to each of the one or more further recipients. Such further recipients can include physicians and/or other caregivers attending the patient, a hospital, and a medical emergency response facility. Therapy controller 982 can produce remote commands for adjusting the delivery of the one or more pain-relief therapies using the notification and the user commands. In various embodiments, therapy controller 866 of external device 834 can produce the external commands using the composite pain score, the patient information, and the remote commands. Remote communication circuit 984 can communicate with external device 834 via communication 336 and network 338.

[0080] In various embodiments, circuits of the present pain management system, including its various embodiments discussed in this document, may be implemented using a combination of hardware and software. For example, the circuits may be implemented using an application-specific circuit constructed to perform one or more particular functions or a general-purpose circuit

programmed to perform such function(s). Such a general-purpose circuit includes, but is not limited to, a microprocessor or a portion thereof, a microcontroller or portions thereof, and a programmable logic circuit or a portion thereof.

[0081] It is to be understood that the above detailed description is intended to be illustrative, and not restrictive. Other embodiments will be apparent to those of skill in the art upon reading and understanding the above description. The scope of the invention should, therefore, be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

disorder and a decrease in entropy alpha 1 Short term fractal scaling exponent ECG, PPG

measures the qualitative

characteristics and correlation

features of HR behavior.

Galvanic Skin SNA causes sweat glands to fill up Electrodes on 11, 12, 13, Response (GSR) and skin conductance increases the hand, 14

creating skin conductance measure fluctuations. conductivity

Photo- Reduction in the amplitude of PPG PPG 15, 16, 17,

Plethysmographic is caused by peripheral 18 (PPG) vasoconstriction and the

nociception response during

general anesthesia.

Vasoconstriction as a result of

increased SNA.

Pulse Rate Could be a replacement measure PPG 19, 20, 21 Variability (PRV) for HRV. Can be used to estimate

HRV at rest.

Blood Pressure Marker of sympathetic ton. PPG 22, 23 24, (BP) Increased ton causes 25

vasoconstriction and thus elevated

BP. Increased BP is associated with

increased pain levels

Pulse Transit Time Vasoconstriction is a physiological PPG, possible 26, 27, 28 & Pulse Wave response to pain which directly internal sensor

Amplitude impacts the pulse transit time and (at 2 locations to

(Alternative pulse wave amplitude. In the measure transit

measure for BP) presence of painful stimuli, both time)

pulse transit time and pulse wave

amplitude decrease.

Respiration Rate Measure of sympathetic tone. ECG, embedded 29, 30, 31, (RR) Elevated respiratory rate strain gauge

corresponds to increased pain.

Pupil Diameter Dilation of the pupil is indicative of *Imaging 32

sympathetic activation

Respiratory Sinus RSA is a physiological indicator 33, 34, 35, Arrhythmia (RSA) that may have implications for 36, 37 responses to pain and stress. It is

essentially the transfer function

from respiration rate to R-R

intervals. Another way to assess

cardiac autonomic function. Pain is

associated with an impairment of

neurocardiac integrity which can be

measured through RSA which

decreases in the presence of

increased sympathetic activity /

decreased parasympathetic activity.

Baroreceptor Increased baroreceptor response is BP monitoring 38, 39, 40, Sensitivity associated with decreased pain 41, 42, 43, levels. 44, 45, 46,

47

Normalized Pulse Sympathetic tone causes vascular Measured in the 48, 49 Volume (NPV) constriction. This vascular tone can outer ear or at

be measured in several locations on the finger tip

the body to indicate sympathetic

tone. NPV can be derived from the

fingertip using PPG. It can also be

derived from the bottom of the ear

canal.

Functional Measures

Activity Measuring activity in patients with Accel erometer 50, 51, 52 pain can be an indicator of pain

level with patients in severe pain

participating in less activity

Timed up-and-go Faster up-and-go time (shorter time Accel erometer

to complete task), less discomfort

and able to move more quickly.

Physical activity Increased physical activity is a sign Accel erometer

of decreased discomfort

Gait Patients with pain may have altered Accel erometer / 53, 54, 55, gait due to pain, such as a limp. gyroscope 56, 57, 58,

Velocity set distance to walk divided by time Accel erometer / 59, 60, it takes to walk the set distance gyroscope

Stride Length linear distance between the Accel erometer /

placement of both feet gyroscope

Swing Time time from the moment the foot lifts Accel erometer /

from the floor until it touches again gyroscope

Single Limb time from when the heel touches Accel erometer /

Support Time the flood until toes are lifted gyroscope

Gait autonomy maximum time a person can walk, Accel erometer /

taking into account the number and gyroscope duration of stops

Trunk-Pelvis Altered gait patterns are observed Gyroscope

Rotation, balance in patients with pain. Due to

pain/discomfort, the coordination

of the trunk and pelvis rotations

vary from healthy subjects. In a

healthy person, pelvis-thorax

coordination in the transverse plane

evolves gradually from in-phase

coordination towards antiphase

coordination with increasing

walking velocity. In patients with

pain these movements are more

rigid and less flexible coordination.

Facial expressions Particular facial expressions/cues Imaging 61

are associated with pain (Facial

Action Units) such as nose

wrinkling and cheek-raising Sleep Quality Poor sleep quality is often observed accelerometer, 62, 63, 64, when patients are in pain. More subjective 65 movement and wakefulness during

sleep.

Quality of Quality of life/mood can affect pain subjective 66 Life/Mood (Can be score. Better mood can decrease

subjective or pain perception/intensity

objective)

Stress - Subjective Stress levels can greatly affect ECG (HRV), 67, 68, measure HRV and sympathetic tone. subjective

Neuron/Brain Measures

Quantitative Method used to assess damage to Neurometer 69, 70, 71, Sensory Test (QST) the small nerve endings, which 72, 73, 74, detect changes in temperature, and 75, 76 large nerve endings, which detect

vibration

Warm Heat stimuli, subject reports Neurometer

temperature change or heat pain

threshold

Cold Cold stimuli, subject reports Neurometer

temperature change or cold pain

threshold

Vibration Measure sensation/sensitivity to Neurometer

vibration. Set frequency and change

amplitude to detect

threshold/sensitivity

Current Perception Also known as sensory nerve Neurometer

Threshold (CPT) conduction threshold testing.

Entails the quantification of the

sensory threshold to transcutaneous

electrical stimulation. CPT measure

represents the minimal amount of

painless, neuroselective

transcutaneous electrical stimulus

required to reproducibly evoke a

sensation.

Pain Perception PPT represents the minimum Neurometer

Threshold (PPT) current intensity that produced pain

Pain Tolerance PTT measure is the maximum Neurometer

Threshold (PTT) amount of neuroselective electrical

stimulus that a subject can tolerate

Tactile Stimulation of the index finger with Neurometer

Discrimination assessments of 2-point

Threshold discrimination thresholds as a

marker for tactile perception.

EEG Increased activity in the pain matrix EEG 77, 78, 79, of patients in a high pain state 80 versus low pain state

Spectral Power Increased spectral power is EEG

attributable to theta over activity.

Withdrawal Reflex activate an appropriate withdrawal

painless states. Biochemical Measures

Cytokine Profile Increased pro-inflammatory Blood draw 109

cytokines and decreased antiinflammatory cytokines can

increase pain/discomfort

proTNFa - applied to peripheral nerve Blood draw

inflammatory fibers in vitro and in-vivo

experiments leads to increased

electrical activity in patients with

pain. Increased TNFa in the blood

and thus endoneural environment

might also lead to increased C-fiber

activity and sensation of pain.

IL-2 - has shown both analgesic

and algetic effects. Elevated levels

associated with pro-algetic effect.

antiIL-4, IL-10. Roles in down Blood draw

inflammatory regulating the production of proinflammatory cytokines.

Heightened IL-4 & IL-10 protein

may reflect a natural analgesic

system regulating the activity and

sensitivity of the endogenous

opioid system.

Biochemical Neurotensin, oxytocin and Cortisol Blood draw 110, 111, Markers levels were increased after 112, 113 intervention (cervical and spinal

manipulation). This response

occurred immediately after

intervention and the differences

between the intervention and

control groups were gone at 2 hours

after intervention

MDA (malondialdehyde) is a

marker of oxidative stress and is

increased in pain states

DMS (dimethyl sphingosine) is a

small molecule byproduct of

cellular membranes in the nervous

system. This study was performed

in rats where elevated levels of

DMS were seen in rats with

neuropathic pain.

Biochemical mechanisms of

chronic pain and fatigue. Chronic

pain subjects had a reduction in

serum sodium, increase in levels of markers of tissue damage (ALT

(alanine aminotrasaminate) and

AST (aspartate aminotransferase))

and an increase in the tyrosine:

leucine ratio which represents

alterations in protein turnover.

Lactic acid and proteoglycans

(metabolic markers)

GABA Evidence that GABA transmission 114 is involved in the inhibition of

dysesthesia, allodynia, and other

signs of neuropathic pain

P2X4 Receptor After nerve injury P2X4 receptors 115 Expression Levels are upregulated in spinal microglia

by several factors at the

transcriptional and translational

levels increase HR and BP are

associated with increased burst

amplitude but not in all patients.

May have implications for

individual differences in CV

consequences of CP.

Salivary Levels of interleukin (IL)la, IL8, Saliva 116, 117 neuropeptide / AgRP, Cortisol, monocyte

cytokine / hormone chemotactic protein- 1 (MCP1),

detection

dynorphin A, prolactin, valine,

proline, hypoxanthine, propionate,

formate, and acetate in saliva

samples could be used to

distinguish between patients with

and without pain.

Hypothalamic-pituitary-adrenal

(HP A) axis, one of the main bodily

stress systems, function has been

found to be reduced in chronic pain

patients. Salivary Cortisol is

commonly used to assess HP A axis

function. Epinephrine and

norepinephrine levels could

potentially be used. glial cell-derived Concentrations of glial cell-derived CSF 119 neurotrophic factor neurotrophic factor in cerebrospinal

fluid (CSF) have been shown to be

higher in neuropathic pain patients.

Neuropeptide CSF levels of nociceptin/orphanin CSF 120 ligand: (N/OFQ) have been found to be

nociceptin/orphanin lower in patients treated with

(N/OFQ) morphine than those not being

treated with morphine.

Structural nerve Patients with sciatica and lumbar CSF 120 proteins disc herniation have shown high

CSF levels of neurofilament protein

and S-100 protein, which are

indicators of axonal damage and

Schwann cell injury.

Markers of Intervertebral disc damage has been Blood draw 120 collagen shown to be correlated with an

metabolism increase in collagen metabolism,

which can be monitored using

serum markers such as PICP and

CTX. cystatin C Upregulation of cystatin C has been CSF 120 demonstrated in animal models of

pain, and higher levels of cystatin C

has been found in CSF samples of

patients in pain compared to those

not in pain.

Purines Fibromyalgia patients show Blood draw 123 abnormal profile of purines in

plasma based on activity of

enzymes involved in purine

metabolism (adenosine deaminase,

dipeptidyl peptidase IV and prolyl

endopeptidase).

Peripheral tissue Peripheral pain mediators are Blood draw; 121 markers released in response to damage or Tissue Biopsy

disease, and induce sensitization

leading to chronic pain. Examples

include:

• Prostanoids

• Cytokines TNFa and IL- 1 β

• Nerve growth factor (NGF)

• Chemokines including CCL2, CCL3, and CXCL5

CNS plasticity Central sensitization is another step Blood draw; 121 markers in the process leading to chronic Tissue Biopsy

pain, and is mediated by NMDA

receptors.

Gene Expression Altered gene expression is Blood draw; 121, 122 associated with chronic pain. Tissue Biopsy

Affected genes include:

• Nociceptors (e.g., Ti VI,

TrpAl, GABA-Bl, 5-

HT3A)

• Ion channels regulating

nociceptor excitability (e.g.,

Navl .8 and other sodium

channel subunits, potassium

channel subunits)

• Transmitters and

modulators released

centrally (e.g., substance P,

BDNF, neuropeptide Y)

• μ-opioid receptor

• Genes involved in GABA

synthesis (e.g., GAD65,

GAD67, GABA-Bl)

Human genetic studies have shown

a correlation between GTP

cyclohydrolase 1 polymorphisms,

which decrease tetrahydrobiopterin

(BH4) levels, and reduced pain in

patients. Furthermore, excessive

BH4 is produced after nerve injury

in mice, and blocking the BH4

production reduces

hypersensitivity.

Epigenetic Epigenetic modifications is Blood draw; 121 modifications associated with the development of Tissue Biopsy

chronic pain • Hi stone acetyl ati on

- Histone deacetylase (HDAC) inhibitors (compounds that prevent the removal of acetyl groups from hi stones) can mitigate symptoms in animal models of inflammatory diseases (e.g., arthritis, colitis, and hepatitis), has also been shown to have clinical benefits arthritis

• DNA methylation

Methyl binding protein MeCP2 has been shown to promote abnormal upregulation of a group of genes in

inflammatory pain conditions

- intervertebral disc

degeneration, and the chronic pain associated with it, has been shown to correlate with increases in methylation at the SPARC gene promoter in both mice and humans.

• REST

- REST promoter binding is directly responsible for reduced expression of several genes known to be relevant for nociceptive processing in the DRG (e.g., μ- opioid receptor, Navl .8,

Table 1. Parameters indicative of level of pain.

BP Blood Pressure

BPV Blood Pressure Variability

CP Chronic Pain

CPT Current Perception Threshold

CV Cardiovascular

EEG El ectroencephal ography

EMG El ectromy ography

EP Evoked Potential

FM Fibromyalgia

GSR Galvanic Skin Response

HR Heart Rate

HRV Heart Rate Variability

LBP Low Back Pain

MSNA Muscle Sympathetic Nerve Activity

NPV Normalized Pulse Volume

NS Not significant

OPS Objective Pain Score

PA Plethysmogram Amplitude

PPG Plethysmogram

PPT Pain Perception Threshold

PTT Pain Tolerance Threshold

QST Quantitative Sensory Testing

RSA Respiratory Sinus Arrhythmia

SC Skin Conductance

SCS Spinal Cord Stimulation

SNA Sympathetic Nervous Activity

UsEn Ultra-short Entropy

Table 2. Abbreviations used in Table 1.

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Table 3. References cited in Table 1.