Temporal Summation of Pain

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Temporal summation (TS) of pain describes the phenomenon whereby the perception of pain intensity increases in response to repetitive noxious stimuli delivered at a constant intensity. This process typically occurs when stimuli are applied at frequencies exceeding approximately 0.2 to 0.33 Hz. Fundamentally, TS serves as the human psychophysical correlate of the 'wind-up' phenomenon observed in dorsal horn neurons of the spinal cord in animal models. Wind-up is characterized by a progressive increase in the firing frequency and magnitude of neuronal responses to repeated C-fiber activation (see also hyperpathia). Enhanced TS is increasingly recognized as an indicator, or proxy measure, of central sensitization – a state of heightened responsiveness within nociceptive pathways.

The combination of heightened pain sensitivity (potentially reflected by TS) and reduced pain inhibition (assessed via conditioned pain modulation, CPM) may confer a greater risk for pain persistence. See also Pain Oriented Sensory Testing.

Neurophysiology

The phenomenon of temporal summation is underpinned by specific neurophysiological processes occurring primarily within the spinal cord dorsal horn, driven by inputs from the peripheral nervous system.

C-Fiber Input and Wind-Up

The primary driver for TS and its underlying neuronal correlate, wind-up, is the repetitive activation of unmyelinated, slow-conducting C-fiber nociceptors at frequencies typically at or above 0.33 Hz. Thinly myelinated Aδ fibers can also contribute to the overall pain experience and potentially its summation. When these nociceptors are stimulated repeatedly, they release neurotransmitters into the synaptic cleft of the dorsal horn. This sustained, high-frequency input leads to a progressive increase in the excitability and discharge rate of second-order neurons, particularly wide-dynamic-range (WDR) neurons. This frequency-dependent increase in neuronal firing during the stimulus train is termed wind-up. Temporal summation is the perceptual experience resulting from this amplified neuronal signaling; the individual perceives the constant intensity stimuli as becoming increasingly painful. The critical frequency for eliciting wind-up and TS mirrors the natural firing frequencies observed in C-fibers during sustained noxious stimulation.

Role of NMDA Receptors

Central to the mechanism of wind-up and TS is the activation of N-methyl-D-aspartate (NMDA) receptors located on the postsynaptic membrane of dorsal horn neurons. Under normal resting conditions, the NMDA receptor channel is blocked by a magnesium ion (Mg2+). However, repetitive C-fiber activation leads to sustained release of excitatory neurotransmitters, primarily glutamate, and neuropeptides like Substance P and CGRP. This intense stimulation causes sufficient depolarization of the postsynaptic membrane to dislodge the Mg2+ block from the NMDA receptor channel. Once unblocked, glutamate binding allows influx of calcium ions (Ca2+) into the neuron. This Ca2+ influx triggers a cascade of intracellular signaling events that increase neuronal excitability and responsiveness, contributing significantly to the progressive amplification of signals characteristic of wind-up. The dependence of wind-up and TS on NMDA receptor activation has been confirmed in both animal studies, where NMDA antagonists attenuate wind-up, and human studies. Other neurotransmitters and neuromodulators, such as Brain-Derived Neurotrophic Factor (BDNF), also contribute to modulating synaptic efficacy in this context.  

Relationship to Central Sensitization

Temporal summation is widely considered a key psychophysical manifestation and experimental model of central sensitization. Central sensitization refers to an amplification of neural signaling within the central nervous system that enhances the processing of nociceptive information, leading to a state of hyperexcitability. This results in pain hypersensitivity where responses to noxious stimuli are exaggerated (hyperalgesia), and non-noxious stimuli may be perceived as painful (allodynia). Other clinical features associated with central sensitization include the spread of pain beyond the initial injury site (secondary hyperalgesia), prolonged pain after the stimulus ceases (aftersensations), and enhanced temporal summation itself. See the related concept of hyperpathia.

Clinical Value

The assessment of temporal summation extends beyond a purely research interest, offering potential clinical value in the evaluation and management of patients with musculoskeletal pain. Its ability to reflect central pain processing mechanisms provides insights that complement traditional structural assessments.

Association with Chronic Musculoskeletal Pain Conditions

A growing body of evidence demonstrates enhanced temporal summation in various chronic musculoskeletal pain populations compared to healthy controls. This includes conditions frequently encountered in clinical practice such as chronic low back pain (LBP), osteoarthritis (OA), particularly of the knee , fibromyalgia (FM), and temporomandibular disorders (TMD). The presence of heightened TS, often observed even when stimuli are applied at body sites remote from the primary area of pain , strongly suggests that alterations in central nervous system processing, indicative of central sensitization, contribute significantly to the pain experience in these conditions. In fibromyalgia, this central sensitization often appears widespread, affecting multiple body regions and potentially involving the entire spinal neuroaxis. Furthermore, demographic factors may influence TS; studies have reported ethnic differences in TS among individuals with knee OA and gender differences, with some studies suggesting greater TS in women, for example in TMD or generally. Additionally, pain originating from deeper tissues like muscle may evoke more pronounced TS compared to superficial skin stimulation, potentially highlighting the relevance of TS in musculoskeletal conditions.

Correlation with Clinical Features

The relationship between experimentally measured TS and clinically relevant patient-reported outcomes is an area of active investigation, with findings sometimes varying depending on the specific condition, outcome measure, and TS methodology employed.

Pain Intensity: Some studies have reported positive correlations between the magnitude of TS and clinical pain intensity or severity ratings in conditions like OA, LBP, and FM. For instance, individuals with knee OA reporting higher pain levels often exhibit more enhanced TS. However, this association is not universally observed; other research, including large cohort studies, has found weak or non-significant correlations between TS and overall clinical pain intensity. This discrepancy might stem from differences in TS protocols (e.g., mechanical vs. thermal stimuli, testing site), the specific pain measure used (e.g., average pain recall vs. pain evoked by movement), and patient population characteristics. Notably, evidence suggests that mechanical TS, particularly when assessed locally, may be a better predictor of movement-evoked pain severity in individuals with chronic LBP than general self-reported pain intensity.

Chronicity and Disability: Enhanced TS has been linked to pain chronicity and greater levels of functional disability in various musculoskeletal conditions. This connection is often interpreted through the lens of central sensitization, where amplified pain processing contributes to persistent symptoms and activity limitations. Psychological factors, such as pain catastrophizing, are also strongly associated with disability and may interact with physiological measures like TS. Risk stratification tools like the STarT Back Tool, which incorporates psychological factors, identify subgroups with differing prognoses for persistent disability; research suggests that individuals in the low-risk subgroup tend to exhibit lower pain sensitivity profiles, including potentially less pronounced TS.

Prognosis and Prediction: A potential clinical application of TS assessment lies in its prognostic value. Enhanced TS has been investigated as a predictor of future clinical pain severity, the development of chronic pain after acute injury or surgery, and functional outcomes. For example, in knee OA, mechanical TS at the knee has been shown to prospectively predict greater clinical pain ratings weeks later. Similarly, in chronic LBP, mechanical TS has prospectively predicted greater movement-evoked pain and poorer physical function. However, the predictive utility of TS, particularly for long-term outcomes, requires further validation, as evidence remains mixed and study methodologies vary considerably. The combination of heightened pain sensitivity (potentially reflected by TS) and reduced pain inhibition (assessed via conditioned pain modulation, CPM) may confer a greater risk for pain persistence.

Mechanism-Based Treatment: Identifying enhanced TS in a patient strongly suggests a contribution from central sensitization. This finding can prompt clinicians to consider treatments that target these central mechanisms, complementing therapies aimed solely at peripheral structural issues. Pharmacologically, this might involve agents acting on NMDA receptors (though clinical options are limited) or other centrally acting analgesics. Non-pharmacologically, interventions such as specific manual therapy techniques designed to modulate central processes, certain forms of therapeutic exercise, neuromodulation techniques (e.g., tDCS, rTMS), and cognitive-behavioral therapies addressing pain perception and coping may be particularly relevant.

Equipment Options

Pressure Algometers: These devices measure the pressure required to elicit pain (Pressure Pain Threshold, PPT) and can be used to apply repetitive pressure stimuli for TS assessment. Manual spring-loaded or hydraulic algometers are relatively affordable and portable. They allow quantification of the stimulus intensity (PPT), which can be used to standardize the initial pain level for the TS procedure. Digital algometers offer features like real-time feedback and automated protocols, enhancing standardization but increasing cost. The reliability of PPT measurement with algometers is generally reported as moderate to excellent. However, achieving consistent pressure application rate and duration during the repetitive stimuli needed for TS assessment with manual devices requires careful technique and training, and the reliability of TS measured this way can be more variable.

Von Frey Filaments / Pinprick Devices: Von Frey filaments are calibrated nylon monofilaments designed to buckle at specific forces, allowing assessment of mechanical detection thresholds. Heavier filaments or dedicated pinprick devices (e.g., weighted neurotips) can be used to deliver repetitive noxious punctate stimuli to assess TS. These tools are extremely low-cost, highly portable, and simple to use conceptually. However, ensuring consistent application force, frequency, and duration manually requires practice. While useful for screening for mechanical hyperalgesia or allodynia, the standardization and reliability of TS elicited via manual pinprick can be lower compared to pressure algometry or thermal methods, and may be more operator-dependent.

Other Low-Cost Approaches: Transcutaneous Electrical Nerve Stimulation (TENS) units have been explored as an affordable alternative to thermal stimulators for assessing both TS and CPM, leveraging electrical pulses as the noxious stimulus. While promising due to the low cost and widespread availability of TENS units, protocols are still under development and require validation. Very basic tools like cooled or heated objects (coins, test tubes) can screen for gross thermal hypo- or hyperalgesia but lack the control needed for reliable TS assessment.

Practical Low-Cost Protocol using Pressure Algometry

The following outlines a practical protocol for assessing TS using a manual pressure algometer, synthesizing common elements from research protocols adapted for clinical feasibility.

Preparation: Select a quiet, temperature-controlled room to minimize distractions. Clearly explain the procedure to the patient, ensuring they understand they will receive ten brief pressure applications of the same intensity and will need to rate the pain after the first and last stimulus. Provide a 0-10 Numerical Rating Scale (NRS) where 0 represents "no pain" and 10 represents "the worst pain imaginable". Conduct a brief familiarization trial (e.g., apply 1-3 stimuli without rating) to ensure the patient understands the sensation and the rating task.

Site Selection: Choose a standardized test site. For assessing generalized sensitization, a site remote from the primary pain area, such as the muscle belly of the tibialis anterior or forearm extensors, is often preferred. Alternatively, testing over a clinically relevant painful area (e.g., lumbar paraspinals for LBP, quadriceps for knee OA) can be performed, but interpretation should consider potential peripheral influences. Mark the chosen site clearly.

Stimulus Intensity Determination (PPT): Using the pressure algometer equipped with a standard 1 cm² probe tip, determine the patient's PPT at the selected site. Apply pressure perpendicular to the skin at a steady rate (aim for approximately 30-50 kPa/second or 0.3-0.5 kg/second) until the patient first reports the sensation changing from pressure to pain. Immediately release the pressure and record the value (e.g., in kg/cm² or kPa). Repeat this measurement 2-3 times with a brief rest between trials and calculate the average PPT. This average PPT value will be the target intensity for the repetitive stimuli during the TS procedure.

Temporal Summation Procedure: Apply a series of 10 consecutive pressure stimuli using the algometer at the previously determined PPT intensity. Each stimulus should be brief, aiming for a duration of approximately 1 second. Deliver the stimuli at a consistent frequency of 0.5 Hz (one stimulus every 2 seconds). Using a metronome or stopwatch can aid timing consistency. Immediately after delivering the first stimulus, ask the patient to rate the perceived pain intensity on the 0-10 NRS. Continue applying stimuli 2 through 9 without obtaining ratings. Immediately after delivering the tenth stimulus, ask the patient to rate the perceived pain intensity again on the 0-10 NRS.

Calculation and Interpretation: Calculate the TS score as the difference between the pain rating after the tenth stimulus and the pain rating after the first stimulus: TS Score = Pain Rating (10th) - Pain Rating (1st).

• A positive TS score indicates the presence of temporal summation.
• A higher positive score generally suggests greater central pain facilitation or sensitization. A score of zero or a negative score suggests no summation or potentially even habituation/inhibition in that pathway under these conditions.  
• Interpretation Caveat: Clinically significant cut-off values for TS measured with low-cost methods are not well-established and can be influenced by the specific protocol, population, and body site tested. Therefore, interpretation should focus on the presence and relative magnitude of summation within the individual patient, potentially tracking changes over time, rather than relying on strict diagnostic thresholds.  

Considerations: Ensure the algometer is applied perpendicular to the skin for each stimulus. Maintain consistent pressure application and duration, especially with manual devices. If time allows and the patient tolerates it, repeating the entire TS procedure after a rest period (e.g., 2-5 minutes) and averaging the TS scores can improve reliability. Be mindful of potential floor effects (if the first stimulus evokes zero pain) or ceiling effects (if the first stimulus evokes very high pain, leaving little room for summation). If floor effects are consistent, slightly increasing the stimulus intensity above PPT might be considered, but avoid inducing excessive pain with the initial stimulus.

Conclusion

Temporal summation of pain is a quantifiable psychophysical phenomenon reflecting frequency-dependent amplification of pain perception, mediated primarily by C-fiber input leading to wind-up of dorsal horn neurons via mechanisms involving NMDA receptor activation. It serves as a clinical indicator of central pain facilitation and is frequently observed to be enhanced in individuals suffering from chronic musculoskeletal conditions such as low back pain, osteoarthritis, and fibromyalgia, suggesting a significant contribution of central sensitization to their pain experience.

Assessing TS can provide clinicians with valuable insights into a patient's underlying pain mechanisms, complementing traditional structural and pathological evaluations. While the evidence is still evolving and sometimes inconsistent, enhanced TS shows potential associations with clinical features like movement-evoked pain severity and may hold prognostic value for certain outcomes or predict responses to specific mechanism-based treatments targeting central sensitization.

Resources

Temporal summation methods - Kielstra 2024.pdf - 2.65 MB (f)