Conditioned Pain Modulation

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Conditioned Pain Modulation (CPM) represents a fundamental aspect of the body's endogenous pain regulatory system, often described as the "pain inhibits pain" phenomenon (see also Nociception). Physiologically, CPM is considered the human psychophysical correlate of Diffuse Noxious Inhibitory Controls (DNIC), a mechanism observed in animal models where a noxious stimulus applied to one part of the body inhibits pain responses in a remote area. This inhibition is mediated by a complex spino-bulbo-spinal feedback loop involving brainstem structures like the periaqueductal gray and rostral ventromedial medulla, utilizing neurotransmitters such as noradrenaline and serotonin.

A related concept is Conditioned Pain Facilitation. Conceptually the opposite of CPM, looking at situations where a simultaneous noxious stimulus increases the perception of pain from another site (an abnormal phenomenon in some chronic pain conditions). See also Pain Oriented Sensory Testing.

Neurophysiology

The neurophysiological mechanism underlying Conditioned Pain Modulation (CPM) in humans is largely understood through its animal model correlate, Diffuse Noxious Inhibitory Controls (DNIC). The process involves a complex interaction between ascending nociceptive pathways and descending modulatory systems, orchestrated primarily via a spino-bulbo-spinal loop:

Ascending Input (Conditioning Stimulus): The application of a noxious conditioning stimulus (CS) activates peripheral nociceptors. Signals are transmitted via primary afferent fibers (Aδ and C fibers) to second-order neurons in the dorsal horn of the spinal cord. This nociceptive information then ascends, primarily via the spinothalamic and spinoreticular tracts, towards higher brain centers.

Brainstem Processing: The ascending signals reach key nuclei within the brainstem, which act as critical integration and relay centers for pain modulation. The most implicated structures include:

• Periaqueductal Gray (PAG): Located in the midbrain, the PAG receives ascending nociceptive input and plays a pivotal role in coordinating descending pain control. It is rich in opioid receptors and neurons, suggesting involvement of endogenous opioids in its activation, although their precise role in DNIC/CPM remains complex. The PAG projects heavily to the RVM.
• Rostral Ventromedial Medulla (RVM): Situated in the medulla oblongata, the RVM receives input from the PAG and other areas (like the locus coeruleus). It is considered the primary output station for descending modulation relevant to DNIC/CPM. The RVM contains distinct populations of neurons, including "ON-cells" (which facilitate nociception) and "OFF-cells" (which inhibit nociception). Activation of the descending inhibitory pathway involves increasing the activity of OFF-cells and/or decreasing the activity of ON-cells. Descending Inhibition: From the RVM (and potentially other brainstem nuclei like the locus coeruleus), descending pathways travel down the spinal cord, primarily within the dorsolateral funiculus. These pathways synapse in the dorsal horn, near the terminals of primary afferent fibers and the cell bodies of second-order projection neurons that are processing input from the test stimulus (TS).

Spinal Cord Modulation: The descending pathways release key neurotransmitters into the dorsal horn synaptic environment:

• Noradrenaline (Norepinephrine): Released from projections originating mainly in the locus coeruleus and other noradrenergic cell groups, often synapsing near RVM neurons or receiving input from them. Noradrenaline primarily acts via α2-adrenergic receptors on presynaptic primary afferent terminals (reducing neurotransmitter release) and postsynaptic second-order neurons (hyperpolarizing them, reducing excitability).
• Serotonin (5-HT): Released from projections originating in the RVM (specifically the nucleus raphe magnus). Serotonin's effects are complex and receptor-dependent; it can be inhibitory (via 5-HT1A, 5-HT1B/D receptors) or facilitatory (via 5-HT2A, 5-HT3 receptors). However, within the context of CPM, its net effect via the descending pathways from the RVM is predominantly inhibitory.
• Endogenous Opioids: While central opioid signaling is crucial in PAG/RVM function, descending opioid pathways may also contribute directly to spinal inhibition, although serotonin and noradrenaline are considered the principal mediators of the final inhibitory output at the spinal level for CPM.

Outcome ("Pain Inhibits Pain"): The net effect of this descending barrage of noradrenaline and serotonin at the dorsal horn is the inhibition of the neuronal circuitry processing the test stimulus. This reduces the transmission of nociceptive signals related to the TS up to the brain, resulting in the psychophysical perception of decreased pain intensity or an increased pain threshold – the CPM effect.The efficiency of this entire loop can be influenced by supraspinal factors, including attention, expectation, mood (anxiety, depression), and catastrophizing, likely through modulation of activity within the PAG-RVM circuitry and related limbic structures. Therefore, while the core mechanism is the spino-bulbo-spinal reflex, the magnitude of the CPM response reflects the integrated state of an individual's endogenous pain regulatory system.

Clinical Value

When looking at a patients pain modulation profile, one also looks at the balance between pain inhibitory (e.g. CPM) and facilitatory (e.g. temporal summation) processes (see articles on hyperpathia and temporal summation of pain for facilitatory processes).

Individuals exhibiting a predominantly pro-nociceptive profile, marked by inefficient CPM and/or enhanced TS, often experience greater pain morbidity and may be at higher risk for developing chronic pain. Conversely, an anti-nociceptive profile, characterized by efficient CPM, is associated with lower pain morbidity.

Clinically, CPM is gaining recognition as a potentially valuable biomarker. Research indicates that the efficiency of an individual's CPM response, essentially the magnitude of pain inhibition they can generate, is relevant to chronic pain conditions. Impaired or less efficient CPM has been observed in various chronic pain populations, including those with fibromyalgia, irritable bowel syndrome, osteoarthritis. Interestingly though it is not predictably impaired in chronic low back pain, and painful diabetic peripheral neuropathy.

The potential clinical utility of CPM assessment lies in its capacity to serve multiple roles: characterizing the pathophysiology underlying specific pain syndromes, predicting the likelihood of developing chronic pain following acute events like surgery, and, most relevantly for this report, predicting or guiding the selection of appropriate treatments.

While the association between impaired CPM and established chronic pain is robust, it is important to note that this relationship is largely correlational. It remains an open question whether impaired CPM is a predisposing factor for chronic pain or a consequence of the ongoing pain state. This has direct implications with whether targeting descending inhibition will be a useful strategy.

Evidence exists to support both possibilities: pre-surgical CPM has shown predictive value for post-operative pain development , yet CPM can also improve following successful pain treatment, suggesting it can be altered by the pain state itself.

The translation of CPM testing from research laboratories to routine clinical settings faces challenges, primarily related to cost, equipment complexity, and lack of standardized protocols. Many established CPM paradigms utilize sophisticated and expensive equipment for delivering controlled stimuli and measuring responses

Principles of CPM Testing

Test and Conditioning Stimuli

CPM testing fundamentally involves assessing the change in perception of a painful 'test stimulus' (TS) when a separate, noxious 'conditioning stimulus' (CS) is applied to a remote body area.

Test Stimulus (TS): This is the pain stimulus whose perception is measured before and during/after the application of the CS. Common TS modalities include thermal stimuli (heat or cold), mechanical pressure (using an algometer to determine PPT), or electrical stimulation. For low-cost clinical applications, PPT measured with a pressure algometer is a frequently used, reliable, and relatively simple TS. The TS is typically calibrated to elicit a mild to moderate level of pain (e.g., 40-60/100 on a Numerical Rating Scale) or is measured as the threshold at which pressure becomes painful (PPT).

Conditioning Stimulus (CS): This is the noxious stimulus applied to a different body part (heterotopic) to activate the descending inhibitory pathways. The CS must be sufficiently intense (noxious) to trigger the CPM effect; studies often aim for a pain intensity rating of >20/100 or typically 4-7/10 on an NRS. Common CS modalities include immersion of a limb in cold water (Cold Pressor Task - CPT), application of ischemic pressure via a cuff, or application of painful heat. CPT and cuff ischemia are often favored in lower-cost protocols due to relatively simple equipment requirements (water bath/container with ice and thermometer, or sphygmomanometer/tourniquet cuff).

Sequential vs Parallel Paradigms

The timing of the TS measurement relative to the CS application defines the paradigm. The choice between sequential and parallel paradigms can influence results, and consistency within a clinic is crucial. For initial clinical implementation, the sequential paradigm may be preferable due to its reduced potential for attentional confounds.

Sequential Paradigm: The baseline TS is measured first. Then, the CS is applied for a defined duration or until a target pain level is reached and subsequently removed. The TS is then measured again immediately after the CS cessation. This approach is often recommended to minimize potential confounding effects of distraction caused by the ongoing CS during the TS measurement.

Parallel Paradigm: The baseline TS is measured first. Then, the CS is applied, and the TS is measured while the CS is ongoing. While potentially susceptible to distraction effects (which could artificially inflate the apparent CPM effect), some studies suggest parallel paradigms might elicit slightly stronger CPM effects, though findings are inconsistent.

Calculating the CPM Effect

The CPM effect quantifies the change in TS perception induced by the CS. It is typically calculated as:

Absolute Difference: CPM Effect = Baseline TS measurement – Conditioned TS measurement. For threshold measures like PPT (where a higher value means less sensitivity), a positive difference indicates inhibition (less pain sensitivity during/after conditioning), while a negative difference indicates facilitation (more pain sensitivity). For pain intensity ratings (e.g., using NRS), a positive difference indicates inhibition (lower pain rating during/after conditioning).

Percentage Change: CPM Effect (%) = * 100. For PPT, a positive percentage indicates inhibition.

It is important to note that CPM responses vary widely among individuals, ranging from strong inhibition to no effect, or even facilitation (increased pain perception). A median CPM effect of around 29% inhibition has been reported in reviews of healthy volunteers using various protocols, but this figure lacks validation and significant heterogeneity exists.

Factors Influencing CPM

The magnitude of the CPM effect can be influenced by numerous factors, contributing to inter-individual variability and highlighting the need for standardized procedures:

Methodological Factors: The specific TS and CS modalities, intensities, durations, body sites tested, and paradigm (sequential vs. parallel) all impact the measured CPM effect.

Individual Factors: Age (CPM may decline with age), sex (some studies suggest differences, but findings are inconsistent), hormonal status (e.g., menstrual cycle phase), and genetics can influence CPM.

Psychological Factors: Pain catastrophizing, anxiety, depression, expectations, and attentional focus can modulate CPM responses, with higher negative affect or catastrophizing often associated with reduced CPM.

Low Cost Protocol Choice

Two low cost options are PPT + Cold Pressor Test, and PPT + Cuff Ischaemia. The latter is more practical in a clinic environment and is the focus of this article. The Cold Pressure Test requires setting up a well insulated water bath maintained at a temperature of 10-12 degrees. Another option is a finger pressure device.

Equipment for Low Cost Measurement: PPT + Cuff Ischaemia

Pressure Algometers Equipment

Pressure algometers measure the force required to elicit a pain sensation when applied to tissue. They are essential for PPT-based CPM protocols.

Manual (Analog/Dial) Algometers: These devices typically use a calibrated spring and display the applied force (often in kgf or lbs) or pressure (kPa) on a dial. They often feature a peak-hold function to record the maximum force applied. Examples include the Wagner FDK/FDI or Baseline Dolorimeter models.

• Pros: Lower initial cost, simple operation, portable, no power required.
• Cons: Relies heavily on examiner technique for consistent application rate (typically 40-50 kPa/s or ~1 kg/s is recommended ), potential for parallax error reading the dial, manual recording required.

Digital Algometers: These use electronic sensors to measure force/pressure and display the reading digitally. They often offer features like peak-hold, unit conversion (kg, lbs, N), and sometimes controlled application rate feedback or data output. Examples include Wagner FPX/FPIX, JTECH Commander Echo, Medoc AlgoMed. Some low-cost digital options adapted from scales or using syringe-based sensors are emerging but may require validation.

• Pros: Easier reading, potentially better consistency with rate feedback/control (though examiner skill still matters), data storage/output capabilities in some models.
• Cons: Higher cost than manual models, require batteries/power.

Key Features: A standard 1 cm² flat, rubber tip is crucial for consistent pressure application. Ensure the device measures in appropriate units (kgf or kPa preferred for PPT) and has a suitable range (e.g., up to 10kgf or ~1000 kPa is common for clinical pain testing ). Calibration certification or verification capability is important for reliability.

Cuff Ischaemia Equipment

This method uses a standard blood pressure cuff or tourniquet to induce ischemic pain.

Sphygmomanometer/Cuff System: A standard clinical sphygmomanometer (manual or automatic) with an appropriately sized cuff for the upper arm or leg is required. Automatic digital blood pressure monitors are widely available and relatively inexpensive, offering consistent pressure application. Manual sphygmomanometers are also suitable but require careful inflation to the target pressure. Ensure the device is calibrated and functions correctly.

Optional Handgrip Dynamometer: Some protocols incorporate repetitive handgrip exercises during cuff inflation to accelerate ischemia onset. A simple handgrip device can be used if required by the chosen protocol.

Computer-Controlled Cuff Algometry Systems: Specialized systems (e.g., LabBench CPAR+, older Nocitech CPAR, systems used in research ) offer precise, automated control over cuff pressure inflation rates and duration, enabling more complex protocols like temporal summation or standardized CPM assessment. These systems provide user-independent stimuli, improving reproducibility. However, they represent a significant cost increase (likely several thousand NZD) and are typically found in research settings rather than standard clinics. While offering advantages, they are beyond the scope of "low-cost" implementation for most clinics.

Low Cost Protocol: PPT + Cuff Ischaemia

This protocol uses PPT measured via algometry as the TS and ischemic pain induced by a pressure cuff as the CS.

Setup

Informed Consent: Obtain written informed consent, explaining the procedure, potential discomfort (pressure, ache, tingling from cuff), risks (rare, e.g., temporary numbness/tingling, skin irritation, very rare nerve/vascular issues), voluntary nature, and right to stop.  

Screening: Screen for contraindications: Significant peripheral vascular disease, history of deep vein thrombosis (DVT) or thrombophlebitis in the limb, severe uncontrolled hypertension, significant peripheral neuropathy affecting the limb, fragile skin, open wounds, infection, or lymphedema in the limb, sickle cell disease, known clotting disorders. Document screening.

Environment: Conduct in a quiet, temperature-controlled room.

Acclimatization: Allow 5-10 minutes of quiet rest.

Positioning: Seat the patient comfortably with the arm/leg for PPT testing supported and relaxed. Position the limb for cuff application comfortably (e.g., arm resting on a table, leg elevated slightly if needed).

Instructions: Clearly explain the procedure:

1. Explain PPT measurement: "I will apply pressure with this device. Please tell me at the very moment the sensation changes from pressure to pain or discomfort." Emphasize reporting the threshold of pain, not tolerance.
2. Explain Cuff Ischemia: "I will place this blood pressure cuff on your arm/leg and inflate it. It will feel tight, and your limb may start to feel heavy, tingly, or achy. Please tell me when the discomfort reaches a specific level on a 0-10 pain scale (e.g., 5/10 or 6/10) , OR I will keep the cuff inflated for a set time (e.g., 3 or 5 minutes). You can ask me to stop at any time if it becomes too uncomfortable."  
3. Explain the sequence (e.g., "First, I will measure the pressure pain on your shoulder/leg. Then I will inflate the cuff on your arm/leg for [duration/until target pain]. Immediately after I release the cuff / While the cuff is still inflated [specify based on sequential/parallel], I will measure the pressure pain again.").

Procedure

Baseline PPT Measurement (TS Pre-CS):

1. Select the PPT test site (e.g., contralateral upper trapezius muscle, tibialis anterior muscle, or forearm extensor muscle – consistency is key). Mark the site if necessary
2. Place the algometer tip (1 cm²) perpendicular to the skin at the chosen site.  
3. Apply pressure at a constant rate (target 40-50 kPa/s or ~1 kg/s). If using a manual algometer, practice achieving a consistent rate.  
4. Instruct the patient to indicate the moment the pressure sensation first becomes painful (PPT).
5. Record the pressure value (kPa or kgf).
6. Repeat the measurement 2-3 times at the same site, with a 20-30 second interval between measurements. Calculate the mean baseline PPT.  

Conditioning Stimulus (Cuff Ischemia):

1. Apply the appropriately sized cuff to the non-dominant upper arm (above elbow) or lower leg (below knee, e.g., around calf muscle heads). Ensure smooth application.
2. Inflate the cuff rapidly to a target pressure. Options include:
   1. Fixed Suprasystolic Pressure: e.g., 240-260 mmHg. Requires checking systolic BP first.
   2. Pain-Targeted Pressure: Inflate gradually, asking for NRS pain rating, until a target intensity (e.g., 5/10 or 6/10 NRS) is reached. Record the pressure required.
3. Maintain the cuff inflation for a predetermined duration (e.g., 3 minutes , 5 minutes, or 10 minutes ) OR until the target pain intensity is consistently reported. Start the timer once target pressure/pain is reached.  
4. Some protocols include standardized exercise (e.g., repetitive ankle flexion/extension or handgrips for 1 minute) immediately after inflation to accelerate ischemic pain onset. If used, specify clearly.  
5. Monitor the patient for excessive discomfort or adverse effects. Remind them they can stop at any time.
6. At the end of the conditioning period (for sequential), rapidly deflate the cuff completely.

Conditioned PPT Measurement (TS Post-CS):

1. Immediately after cuff deflation (within seconds), repeat the PPT measurement procedure (steps 5.2.1 b-e) at the same test site used for baseline.  
2. Record the post-CS PPT value(s) and calculate the mean.
3. (Alternative: Parallel Paradigm) If using a parallel design, perform the PPT measurement while the cuff remains inflated at the target pressure/pain level. This requires careful coordination.  

Calculation

Calculate Absolute and Relative CPM Effect

Absolute CPM Effect (kPa or kgf): Baseline Mean PPT – Post-CS Mean PPT. (Positive value = inhibition).

Relative CPM Effect (%): * 100. (Positive value = inhibition).

Using CPM for Treatment Selection

Preliminary evidence suggests that baseline CPM efficiency might predict the development of chronic postsurgical pain and influence the response to certain analgesic treatments. Only a few useful studies were found.

Weak CPM Profile

Duloxetine: The strongest evidence for CPM predicting pharmacological response comes from a seminal study by Yarnitsky and colleagues (2012) investigated patients with painful diabetic neuropathy (PDN) treated with duloxetine. They found a significant correlation between baseline CPM efficiency and treatment efficacy: patients with less efficient CPM at baseline (indicating impaired endogenous inhibition) experienced significantly greater pain relief with duloxetine. Baseline CPM was the sole predictor of drug efficacy in their regression model, outperforming factors like baseline pain intensity or depression levels. Furthermore, the study observed that duloxetine treatment led to an improvement in CPM efficiency, but this improvement was primarily seen in those patients who initially had less efficient CPM and who responded well clinically. This finding suggests that duloxetine may exert its analgesic effect, at least in part, by restoring deficient descending inhibitory function, and that baseline CPM reflects the potential for such restoration. This aligns with the known mechanism of SNRIs, which enhance descending inhibition by increasing synaptic availability of serotonin and norepinephrine. This work has been cited as a key example supporting mechanism-based prediction in pain medicine.

Exercise: The benefits of exercise in chronic pain may relate to Exercise-Induced Hypoalgesia. This is a phenomenon where exercise acutely reduces pain sensitivity.

An acute bout of isometric exercise was shown to restore (increase) impaired baseline CPM in both individuals with fibromyalgia (FMS) and healthy controls, particularly at body sites distal to the exercising muscle. Similarly, an 8-week exercise program for patients with subacromial pain syndrome (SAPS) resulted in increased CPM efficiency alongside reductions in clinical pain. These findings suggest that exercise interventions might enhance the body's endogenous pain inhibitory capacity.

However, the ability of baseline CPM to predict the clinical outcome of exercise therapy is less clear. In the SAPS study, while exercise improved CPM and pain, baseline CPM was not a significant predictor of pain reduction in the final regression model; instead, lower baseline pain intensity and lower temporal summation (less facilitation) predicted better outcomes. While exercise can influence CPM, and CPM may predict the acute EIH response, the evidence for baseline CPM consistently predicting overall clinical pain relief from exercise programs is currently limited

Strong CPM Profile

A study by Edwards and colleagues (2016) found that topical diclofenac gel for knee osteoarthritis was significantly more effective in those with higher baseline CPM scores (indicating more efficient endogenous pain inhibition) after one month of treatment. Baseline CPM emerged as a significant predictor of treatment outcome even after controlling for baseline pain levels, age, and gender.

It is possible that individuals with more robust central inhibition are in a less centrally sensitized state, making them more responsive to any analgesic intervention, or that efficient CPM reflects a healthier overall nervous system state that allows the peripheral benefits of the NSAID to be more fully realized.

Increased Temporal Summation

There doesn't appear to be any evidence looking at response to gabapentinoids with different CPM profiles. One study found that patients with chronic pancreatitis pain responded better to pregabalin if they had increased temporal summation.

Resources

CPM - Ibancos-Losada 2020.pdf - 1.4 MB (f)

CPM bedside test.pdf - 596 KB (f)

Psychophysical assessment pain - Granovsky 2013.pdf - 453 KB (f)

Treat impaired descending inhibition - Hayashida 2019.pdf - 700 KB (f)