Changes In Pain Sensitivity Research Articles

Developmental Changes in Pain and Spinal Immune Gene Expression after Radicular Trauma in the Rat.

Neuropathic pain is chronic pain that develops after nerve injury and is less frequent in infants and children than in adults. Likewise, in animal models of neuropathic pain, allodynia and hyperalgesia are non-existent or attenuated in the infant, with a “switch” during development by which acute nerve injury transitions to chronic pain. Concomitant with the delay in neuropathic pain, there is a parallel delay in the ability of nerve injury to activate the immune system. Models of neuropathic pain in the infant have used various ligation methods and find that neuropathic pain does not occur under after postnatal days 21–28 (PN21–PN28), linked to activation of immune processes and developmental regulation of anti-inflammatory cytokines. We applied a model of neuropathic pain in the adult using a transient compression of the cervical nerve or nerve root in infant rats (injured at 10, 14, 21, or 28 days of age) to define transition periods during which injury results in no change in thermal and mechanical pain sensitivity or in short-term changes in pain. There was little to no hyperalgesia when the injury was imposed at PN10, but significant thermal hyperalgesia and mechanical allodynia 1 day after compression injury when performed at PN14, 21, or 28. Thermal withdrawal latencies returned to near baseline by 7 days postsurgery when the injuries were at PN14, and lasted up to 14 days when the injury was imposed at PN28. There was mechanical allodynia following injury at 1 day postinjury and at 14 days after injury at PN14. Measurements of mRNA from spinal cord at 1, 7, and 14 days postinjury at PN14, 21, and 28 showed that both the magnitude and duration of elevated immune markers and chemokines/cytokines were greater in the older animals, corresponding to the development of hyperalgesia. Thus, we confirm the late onset of neuropathic pain but found no evidence of emergent hyperalgesia if the injury was before PN21. This may be due to the use of a transient, and not sustained, compression ligation model.

Peripheral Blood Flow Responses to Pain Following a Hypnosis Intervention in Sickle Cell Disease

Introduction: Vaso-occlusive pain crises are considered the "hallmark" of sickle cell disease (SCD). Persistent occurrence is thought to lead to changes in the peripheral and central nervous system, which can then in turn lead to changes in pain sensitivity. Imaging studies have shown that hypnotic analgesia can reduce activity in supraspinal areas of the "pain matrix." To date there are no published studies looking at the effectiveness of hypnosis in altering pain perception in patients with SCD. The purpose of this study was to investigate changes in peripheral blood flow in response to a 30-minute hypnosis intervention and its relationship to pain sensitivity.Methods: To assess the effectiveness of increasing vasodilation, a laboratory based, single session hypnosis protocol was administered to a sample of 14 SCD patients and 14 healthy controls. Continuous readings for SpO2, pulse rate and pulse waveform was monitored using a pulse oximetry transducer placed on the left thumb. Bio-behavioral pain measures were collected during a standardized pain protocol before and after a hypnosis session, performed by a trained therapist. The protocol consisted of assessing pain tolerance and threshold via a heat probe (˚C) for "pain task 1", preceded by an anticipation period. "Pain task 2" consisted of assessing pain intensity via the same heat probe (˚C) on a 1-100 visual analog scale (VAS), preceded by another anticipation period.Results: To investigate blood-flow responses to their respective baseline (baseline vs. hypnosis), all recorded signal following these two periods was normalized respectively. Independent sample t-tests between both normalized anticipation and pain responses periods revealed controls showed no response to hypnosis for anticipation period 1(t(23.42) = .184, p = .855, d = .072), but SCD patients showed a large increase in blood flow (t(16.99) = 4.189, p = .0006, d = 1.79). Neither controls (t(21.05) = .00, p = .994, d = .003) or SCD patients (t(19.99) =.718, p = .481, d = .305) showed an effect of hypnosis in response to pain task 1. Neither controls (t(23.96) = -.139, p = .890, d = -.05) or SCD patients (t(18.82) = 1.035, p = .313, d = .441) showed a response to anticipation period 2, but the effect size reveals that this may be due to a lack of power. Neither controls (t(16.52) = .258, p = .799, d = .101) or SCD patients (t(19.63) = p = .5375, d = .268) showed no changes in response to hypnosis for pain task 2. Independent sample t-tests revealed no significant difference in pain threshold (t(13) = 0.941, p = .364, d = .251) or tolerance (t(13) = 0.937, p = 0.366, d = 0.250) in SCD patients before and after hypnosis. Differences in pain ratings were marginal but showed a decrease with medium effect (t(13) = -1.5315, p = 0.150, d = 0.409). The same tests revealed significant decreases in controls for pain threshold (t(13) = 2.825, p = 0.01, d = .755), pain tolerance (t(13) = 2.482, p = 0.02, d = 0.664), and pain rating (t(13) = 2.950, p = 0.01, d = .789).Conclusion: Results revealed that hypnosis may be an effective treatment in helping manage vasoconstriction in SCD as a response to cognitive appraisals about pain, as well as reducing pain sensitivity. The data presented provide preliminary clinical evidence of the use of hypnosis as a treatment method to improve vasodilation in SCD patients and decreasing pain crises, thus increasing overall quality of life. DisclosuresNo relevant conflicts of interest to declare.

MicroRNA 320a Predicts Chronic Axial and Widespread Pain Development Following Motor Vehicle Collision in a Stress-Dependent Manner.

Study Design Prospective human cohort study combined with molecular studies. Background A microRNA is a small, noncoding RNA molecule that can play a role in disease onset. Recent studies found that circulating levels of microRNA 320a (miR-320a) are associated with musculoskeletal pain conditions and that miR-320a is stress responsive. Objectives To investigate whether circulating expression levels of miR-320a in the peritraumatic period predict persistent axial musculoskeletal pain 6 months after motor vehicle collision (MVC). Methods We evaluated whether (1) circulating miR-320a and related members of the miR-320a family predict axial musculoskeletal pain and other musculoskeletal pain outcomes 6 months following MVC, and (2) miR-320a regulates stress system and pain-related transcripts in cell culture. Given the wealth of data suggesting that biological mechanisms influencing pain outcomes are often sex and/or stress dependent, interactions between miR-320a, stress, and sex were evaluated. Results In primary analyses (n = 69), a significant crossover interaction was observed between the influence of circulating miR-320a and peritraumatic distress (β = -0.01, P = .002) on post-MVC axial musculoskeletal pain. Reduced peritraumatic miR-320a expression levels predicted axial musculoskeletal pain in distressed individuals (β = -0.12, P = .006) but not nondistressed individuals. In secondary analyses, miR-320a predicted widespread musculoskeletal pain, and related members of the miR-320a family also predicted axial and widespread musculoskeletal pain. In cell culture, miR-320a bound stress and pain-associated 3'UTR transcripts (FKBP5, ADCYAP1, PER2, and NR3C1). Conclusion These data suggest that miR-320a may help mediate regional and widespread changes in pain sensitivity after MVC. J Orthop Sports Phys Ther 2016;46(10):911-919. doi:10.2519/jospt.2016.6944.

Rewiring of Developing Spinal Nociceptive Circuits by Neonatal Injury and Its Implications for Pediatric Chronic Pain.

Significant evidence now suggests that neonatal tissue damage can evoke long-lasting changes in pain sensitivity, but the underlying cellular and molecular mechanisms remain unclear. This review highlights recent advances in our understanding of how injuries during a critical period of early life modulate the functional organization of synaptic networks in the superficial dorsal horn (SDH) of the spinal cord in a manner that favors the excessive amplification of ascending nociceptive signaling to the brain, which likely contributes to the generation and/or maintenance of pediatric chronic pain. These persistent alterations in synaptic function within the SDH may also contribute to the well-documented “priming” of developing pain pathways by neonatal tissue injury.

Effects of neonatal pain, stress and their interrelation on pain sensitivity in later life in male rats.

Neonatal pain and stress induce long-term changes in pain sensitivity. Therefore their interrelation is a topical subject of clinical and basic research. The present study investigated the effects of inflammatory peripheral pain and stress of maternal deprivation (MD)-isolation in 1-2- and 7-8-day-old Wistar rats (P1,2 and P7,8 respectively, ages comparable to preterm and full-term human babies) on basal pain and pain sensitivity in conditions of inflammatory pain (formalin test) during adolescence. The neonatal impacts were: pain (formalin injection, FOR in the paw), stress (a short 60-min MD), or pain+stress combination (FOR+MD), and appropriate controls. We found that stress of short-term maternal deprivation-isolation and inflammatory pain on P1,2 and P7,8 significantly increased the vulnerability of the nociceptive system to inflammatory pain. Maternal deprivation-isolation on P1,2 as compared with a similar impact on P7,8 had a greater effect on pain sensitivity of the adolescent rats, but the influence of early pain was independent of the injury age. Only adolescent rats with an early combination of pain and maternal deprivation-isolation showed hypoalgesia in the hot plate (HP) test. However licking duration (reflecting pain sensitivity) in these rats did not exceed licking duration in animals exposed only to maternal deprivation-isolation or pain. This study adds new data to the growing body of work demonstrating that early noxious impacts have long-term consequences for the functional activity of the nociceptive system. Our new findings may help to understand the impact of pain and maternal separation in the neonatal intensive care unit.

Optogenetic and chemogenetic strategies for sustained inhibition of pain.

Spatially targeted, genetically-specific strategies for sustained inhibition of nociceptors may help transform pain science and clinical management. Previous optogenetic strategies to inhibit pain have required constant illumination, and chemogenetic approaches in the periphery have not been shown to inhibit pain. Here, we show that the step-function inhibitory channelrhodopsin, SwiChR, can be used to persistently inhibit pain for long periods of time through infrequent transdermally delivered light pulses, reducing required light exposure by >98% and resolving a long-standing limitation in optogenetic inhibition. We demonstrate that the viral expression of the hM4D receptor in small-diameter primary afferent nociceptor enables chemogenetic inhibition of mechanical and thermal nociception thresholds. Finally, we develop optoPAIN, an optogenetic platform to non-invasively assess changes in pain sensitivity, and use this technique to examine pharmacological and chemogenetic inhibition of pain.

Effects of dry needling to the symptomatic versus control shoulder in patients with unilateral subacromial pain syndrome

BackgroundInitial reports suggest that treating myofascial trigger points in the infraspinatus with dry needling may be effective in treating patients with shoulder pain. However, to date, high quality clinical trials and thorough knowledge of the physiologic mechanisms involved is lacking. ObjectivesTo examine the effect of dry needling to the infraspinatus muscle on muscle function, nociceptive sensitivity, and shoulder range of motion (ROM) in the symptomatic and asymptomatic shoulders of individuals with unilateral subacromial pain syndrome. DesignWithin-subjects controlled trial. MethodsFifty-seven volunteers with unilateral subacromial pain syndrome underwent one session of dry needling to bilateral infraspinatus muscles. Outcome assessments, including ultrasonic measures of infraspinatus muscle thickness, pressure algometry, shoulder internal rotation and horizontal adduction ROM, and questionnaires regarding pain and related disability were taken at baseline, immediately after dry needling, and 3–4 days later. ResultsParticipants experienced statistically significant and clinically relevant changes in all self-report measures. Pressure pain threshold and ROM significantly increased 3–4 days, but not immediately after dry needling only in the symptomatic shoulder [Pressure pain threshold: 5.1 (2.2, 8.0) N/cm2, internal rotation ROM: 9.6 (5.0, 14.1) degrees, horizontal adduction ROM: 5.9 (2.5, 9.4) degrees]. No significant changes occurred in resting or contracted infraspinatus muscle thickness in either shoulder. ConclusionsThis study found changes in shoulder ROM and pain sensitivity, but not in muscle function, after dry needling to the infraspinatus muscle in participants with unilateral subacromial pain syndrome. These changes generally occurred 3–4 days after dry needling and only in the symptomatic shoulders.

Estrous cycle influences excitatory amino acid transport and visceral pain sensitivity in the rat: effects of early-life stress.

BackgroundEarly-life stress (ELS) is a recognized risk factor for chronic pain disorders, and females appear to be more sensitive to the negative effects of stress. Moreover, estrous cycle-related fluctuations in estrogen levels have been linked with alternating pain sensitivity. Aberrant central circuitry involving both the anterior cingulate cortex (ACC) and the lumbosacral spinal cord has also been implicated in the modulation of visceral pain in clinical and preclinical studies. Here we further investigate changes in visceral pain sensitivity and central glutamatergic systems in rats with respect to estrous cycle and ELS.MethodsWe investigated visceral sensitivity in adult female Sprague-Dawley rats, which had undergone maternal separation (MS) in early life or remained non-separated (NS), by performing colorectal distension (CRD). We also assessed excitatory amino acid uptake through excitatory amino acid transporters (EAATs) in the lumbosacral spinal cord and ACC.ResultsNS animals in proestrus and estrus exhibited reduced EAAT uptake and decreased threshold to CRD. Moreover, total pain behaviors were increased in these stages. MS rats exhibited lower pain thresholds and higher total pain behaviors to CRD across all stages of the estrous cycle. Interestingly, cortical EAAT function in MS rats was inhibited in the low estrogen state—an effect completely opposite to that seen in NS rats.ConclusionsThis data confirms that estrous cycle and ELS are significant factors in visceral sensitivity and fluctuations in EAAT function may be a perpetuating factor mediating central sensitization.

Electrical high-frequency stimulation of the human thoracolumbar fascia evokes long-term potentiation-like pain amplification.

Nociceptive long-term potentiation, a use dependent increase in synaptic efficacy in the dorsal horn of the spinal cord is thought to contribute to the development of persistent pain states. So far, no study has analyzed the effects of high-frequency stimulation (HFS) of afferents from deep tissues (muscle and fascia) on pain perception in the back in humans. In 16 healthy volunteers, the multifidus muscle and the overlying thoracolumbar fascia were stimulated with electrical high-frequency pulses (5 × 100 pulses at 100 Hz) through bipolar concentric needle electrodes placed at lumbar level (L3/L4). Electrical pain thresholds were lower (P < 0.001) and pain ratings were higher for fascia compared with muscle stimulation (P < 0.05). For both tissues, pain ratings increased significantly across the five 100 Hz trains (from 15 to 22 numerical rating scale for fascia, from 8 to 12 numerical rating scale for muscle; both P < 0.01). Fascia HFS increased fascia pain ratings 2.17 times compared with the unconditioned control site (P < 0.001), but had no significant effect on pain sensitivity of the muscle. The HFS in muscle had no significant effect on muscle pain, but decreased pain sensitivity of the overlying fascia by 20% (P < 0.05). In additional experiments using the same electrodes and followed over >60 minutes post-HFS, potentiation by fascia HFS was similar to that of skin HFS. These findings show that the spinal input from the fascia can induce long-term changes in pain sensitivity for at least 60 minutes making it a candidate potentially contributing to nonspecific low back pain.

Cohort Removal Induces Changes in Body Temperature, Pain Sensitivity, and Anxiety-Like Behavior

Mouse behavior is analyzed to elucidate the effects of various experimental manipulations, including gene mutation and drug administration. When the effect of a factor of interest is assessed, other factors, such as age, sex, temperature, apparatus, and housing, are controlled in experiments by matching, counterbalancing, and/or randomizing. One such factor that has not attracted much attention is the effect of sequential removal of animals from a common cage (cohort removal). Here we evaluated the effects of cohort removal on rectal temperature, pain sensitivity, and anxiety-like behavior by analyzing the combined data of a large number of C57BL/6J mice that we collected using a comprehensive behavioral test battery. Rectal temperature increased in a stepwise manner according to the position of sequential removal from the cage, consistent with previous reports. In the hot plate test, the mice that were removed first from the cage had a significantly longer latency to show the first paw response than the mice removed later. In the elevated plus maze, the mice removed first spent significantly less time on the open arms compared to the mice removed later. The results of the present study demonstrated that cohort removal induces changes in body temperature, pain sensitivity, and anxiety-like behavior in mice. Cohort removal also increased the plasma corticosterone concentration in mice. Thus, the ordinal position in the sequence of removal from the cage should be carefully counterbalanced between groups when the effect of experimental manipulations, including gene manipulation and drug administration, are examined using behavioral tests.

Gain control mechanisms in the nociceptive system.

The "gate control theory of pain" of 1965 became famous for integrating clinical observations and the understanding of spinal dorsal horn circuitry at that time into a testable model. Although it became rapidly clear that spinal circuitry is much more complex than that proposed by Melzack and Wall, their prediction of the clinical efficacy of transcutaneous electrical nerve stimulation and spinal cord stimulation has left an important clinical legacy also 50 years later. In the meantime, it has been recognized that the sensitivity of the nociceptive system can be decreased or increased and that this "gain control" can occur at peripheral, spinal, and supraspinal levels. The resulting changes in pain sensitivity can be rapidly reversible or persistent, highly localized or widespread. Profiling of spatio-temporal characteristics of altered pain sensitivity (evoked pain to mechanical and/or heat stimuli) allows implications on the mechanisms likely active in a given patient, including peripheral or central sensitization, intraspinal or descending inhibition. This hypothesis generation in the diagnostic process is an essential step towards a mechanism-based treatment of pain. The challenge now is to generate the rational basis of multimodal pain therapy algorithms by including profile-based stratification of patients into studies on efficacy of pharmacological and nonpharmacological treatment modalities. This review outlines the current evidence base for this approach.

Changes in Pain Sensitivity and Pain Modulation During Oral Opioid Treatment: The Impact of Negative Affect

Opioids are frequently prescribed for chronic low back pain (CLBP), but there are broad individual differences in the benefits and risks of opioid therapy, including the development opioid-induced hyperalgesia. This study examined quantitative sensory testing (QST) data among a group of CLBP patients undergoing sustained oral opioid treatment. We investigated whether individual differences in psychological characteristics were related to opioid-induced changes in pain perception and pain modulation. The six-month, open-label trial evaluated patients with low to high levels of negative affect (e.g., symptoms of distress, depression and anxiety); participants underwent QST at baseline (prior to initiating treatment) and during oral opioid treatment. A chronic pain management center. The 31 study participants had chronic discogenic back pain, with a pain intensity rating >3/10. Participants were divided into groups with high vs. low levels of Negative Affect (NA). In the previously-published manuscript describing the clinical outcomes of the trial, high NA patients achieved only about half of the analgesic effect observed in the low NA group (Wasan AD, Michna E, Edwards RR, et al. Psychiatric comorbidity is associated prospectively with diminished opioid analgesia and increased opioid misuse in patients with chronic low back pain. Anesthesiology 2015;123:861-72). The QST findings reported here suggested that tolerance to experimental (cold pressor) pain and conditioned pain modulation tended to decrease in the high NA group over the course of opioid treatment, while temporal summation of mechanical pain declined in the low NA group. These results reveal that while the low NA group seemed to exhibit a generally adaptive, analgesic pattern of changes during opioid management, the high NA group showed a pattern more consistent with opioid-induced hyperalgesic processes. A greater susceptibility to hyperalgesia-promoting changes in pain modulation among patients with high levels of distress may contribute to a lower degree of benefit from opioid treatment in high NA patients.

Subjective Sleep Quality Deteriorates Before Development ofPainful Temporomandibular Disorder.

There is good evidence that poor sleep quality increases risk of painful temporomandibular disorder (TMD). However, little is known about the course of sleep quality in the months preceding TMD onset, and whether the relationship is mediated by heightened sensitivity to pain. The Pittsburgh Sleep Quality Index was administered at enrollment into the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study. Thereafter the Sleep Quality Numeric Rating Scale was administered every 3months to 2,453 participants. Sensitivity to experimental pressure pain and pinprick pain stimuli was measured at baseline and repeated during follow-up of incident TMD cases (n=220) and matched TMD-free controls (n=193). Subjective sleep quality deteriorated progressively, but only in those who subsequently developed TMD. A Cox proportional hazards model showed that risk of TMD was greater among participants whose sleep quality worsened during follow-up (adjusted hazard ratio=1.73, 95% confidence limits=1.29, 2.32). This association was independent of baseline measures of sleep quality, psychological stress, somatic awareness, comorbid conditions, nonpain facial symptoms, and demographic characteristics. Poor baseline sleep quality was not significantly associated with baseline pain sensitivity or with subsequent change in pain sensitivity. Furthermore the relationship between sleep quality and TMD incidence was not mediated via baseline pain sensitivity or change in pain sensitivity. Subjective sleep quality deteriorates progressively before the onset of painful TMD, but sensitivity to experimental pain does not mediate this relationship. Furthermore, the relationship is independent of potential confounders such as psychological stress, somatic awareness, comorbid conditions, nonpain facial symptoms, and various demographic factors.

Feeling the burn: When it looks like it hurts, and belongs to me, it really does hurt more.

We examined changes in pain sensitivity in the rubber hand illusion (RHI). Experiment 1 investigated changes in pain tolerance immediately after a "healthy" and "wounded" RHI when immersing the hand in a cold pressor ice bath. There was 19% increased pain tolerance and increased perception detection threshold after the healthy RHI, but 11% reduction after the wounded RHI. Experiment 2 examined pain experience during the wounded RHI with capsaicin-induced hyperalgesia. Pain intensity and unpleasantness was higher on the illusion arm during the synchronous RHI, compared with asynchronous trials. There was no change in pain experience on the control arm, and both arms had similar pain sensitivity after the experiment. Our results highlight the impact of embodying a substitute limb on pain, with increased tolerance and reduced tactile sensitivity when the fake limb is healthy and apparently pain-free, but increased pain sensitivity when the self-attributed limb appears to be wounded.

Pregabalin and placebo responders show different effects on central pain processing in chronic pancreatitis patients.

BackgroundPain control in chronic pancreatitis is a major challenge; the mechanisms behind analgesic treatment are poorly understood. This study aims to investigate the differences in pain sensitivity and modulation in chronic pancreatitis patients, based on their clinical response (responders vs nonresponders) to placebo or pregabalin treatment.MethodsThis study was part of a randomized, double-blind, placebo-controlled trial evaluating the analgesic effects of pregabalin and placebo in chronic pancreatitis. Post hoc, patients were assigned to one of four groups, ie, responders and nonresponders to pregabalin (n=16; n=15) or placebo (n=12; n=17) treatment. Responders were defined as patients with >30% pain reduction after 3 weeks of treatment. We measured change in pain sensitivity before and after the treatment using electric pain detection thresholds (ePDT) in dermatomes C5 (generalized effects) and Ventral T10 (segmental effects). Descending endogenous pain modulation was quantified via conditioned pain modulation (CPM) paradigm.ResultsSixty patients were analyzed in a per-protocol analysis. ePDT change in C5 was significant vs baseline and greater in pregabalin (1.3 mA) vs placebo responders (−0.1 mA; P=0.015). This was not so for ePDT in Ventral T10. CPM increased more in pregabalin (9%) vs placebo responders (−17%; P<0.001). CPM changed significantly vs baseline only for pregabalin responders (P=0.006).ConclusionThis hypothesis-generating study provides the first evidence that pain relief with pregabalin is associated with anti-hyperalgesic effects and increased endogenous inhibitory modulation. No such effects were observed in patients experiencing pain relief with the placebo treatment. The mechanisms underlying analgesic response to placebo vs drug treatments are different and, together with their interactions, deserve further study.

Local and Systemic Changes in Pain Sensitivity After 4Weeks of Calf Muscle Stretching in a Nonpainful Population: A Randomized Trial.

Stretching is often used in clinical practice for a variety of purposes, including pain therapy. The possible mechanism behind the effect of stretching remains to be clarified. To investigate whether 4weeks of unilateral stretching of the calf muscles would affect local and central pain sensitivity. This study was a randomized assessor-blinded clinical study. Healthy participants (age 18 to 40) were included and randomized. Participants in the intervention group were instructed to perform 2 stretching exercises targeting the calf muscles; 3 times 30seconds, 7days a week for 4weeks on the dominant leg. Participants in the control group were instructed not to do any stretching for 4weeks. Pressure pain threshold (PPT) and temporal summation (TS) of pressure pain were measured on the stretched calf, the contra-lateral calf, and contra-lateral lower arm using a computerized cuff algometer. Analyses of variance on the per-protocol population (defined as participants that adhered to the protocol) were used to assess group differences in the changes from baseline. Forty healthy volunteers were included, of which 34 participants adhered to the protocol (15 intervention group/19 control group). No statistically significant group differences in the changes from baseline were found regarding PPT and TS measurements for the stretched calf, the contra-lateral calf, and the arm. Four weeks of regular stretching of the calf muscles does not affect pressure pain sensitivity, suggesting that pressure pain sensitivity is unaffected by stretching in a healthy population. The mechanisms underlying any benefits of regular stretching remain to be explained.

Increased pain sensitivity in chronic pain subjects on opioid therapy: a cross-sectional study using quantitative sensory testing.

The aim of this study was to compare the sensitivity to experimental pain of chronic pain patients on opioid therapy vs chronic pain patients on non-opioid therapy and healthy subjects by quantitative sensory testing (QST). There is a growing body of evidence demonstrating that chronic use of opioid drugs may alter pain sensitivity. Identifying the characteristic changes in thermal pain sensitivity in chronic opioid users will be helpful in diagnosing pain sensitivity alterations associated with chronic opioid use. Utilizing an office-based QST technique, we examined thermal pain threshold, tolerance, and temporal summation in 172 chronic pain subjects receiving opioid therapy, 121 chronic pain subjects receiving non-opioid therapy, and 129 healthy subjects. In chronic pain subjects receiving opioid therapy, there were detectable differences in QST characteristics compared with both chronic pain subjects receiving non-opioid therapy and healthy subjects. Specifically, in chronic pain subjects receiving opioid therapy, 1) sensitivity to heat pain was increased; threshold to heat pain was significantly lower; 2) tolerance to supra-threshold heat pain was significantly decreased; and 3) temporal pain summation was exacerbated, as compared with chronic pain subjects receiving non-opioid therapy. In a subgroup of chronic pain subjects receiving opioid therapy with increased heat pain sensitivity, their average opioid medication dosage was significantly higher than those who had an above-average heat pain threshold. Moreover, a subset of chronic pain subjects on opioid therapy exhibited a significant decrease in diffuse noxious inhibitory control (DNIC) compared with chronic pain subjects on non-opioid therapy. These findings suggest that a subset of QST parameters can reflect opioid-associated thermal pain sensitivity alteration, including decreased heat pain threshold, decreased cold and heat pain tolerance, diminished DNIC, and/or exacerbated temporal summation.

Age-related differences in conditioned pain modulation of sensitizing and desensitizing trends during response dependent stimulation

The current study evaluated age differences in conditioned pain modulation using a test stimulus that provided the opportunity to evaluate changes in heat pain sensitivity, sensitization, and desensitization within the same paradigm. During this psychophysical test, pain intensity clamping uses REsponse Dependent STIMulation (REDSTIM) methodology to automatically adjust stimulus intensity to maintain a desired pain rating set-point. Specifically, stimulus intensity increases until a pre-defined pain rating (the setpoint) is exceeded, and then decreases until pain ratings fall below the setpoint, with continued increases and decreases dictated by ratings. The subjects are blinded in terms of the setpoint and stimulus intensities. Younger and older subjects completed two test sessions of two REDSTIM trials, with presentation of conditioning cold stimulation between the trials of one session but not the other. The results indicated that conditioning cold stimulation similarly decreased the overall sensitivity of younger and older subjects, as measured by the average temperature that maintained a setpoint rating of 20 (on a scale of 0–100). The conditioning stimulus also significantly enhanced sensitization following ascending stimulus progressions and desensitization following descending stimulus progressions in older subjects relative to younger subjects. Thus, older subjects experienced greater swings in sensitivity in response to varying levels of painful stimulation. These results are discussed in terms of control over pain intensity by descending central modulatory systems. These findings potentially shed new light on the central control over descending inhibition and facilitation of pain.

Reliability of pain intensity clamping using response-dependent thermal stimulation in healthy volunteers.

BackgroundPain intensity clamping uses the REsponse-Dependent Stimulation (REDSTIM) methodology to automatically adjust stimulus intensity to maintain a desired pain rating set-point which is continuously monitored from a subject’s real-time pain ratings. REDSTIM blinds subjects regarding the pain intensity set-point, supporting its use for assessing intervention efficacy. By maintaining the pain intensity at a constant level, a potential decrease in pain sensitivity can be detected by an increase in thermode temperature (unknown to the subject) and not by pain ratings alone. Further, previously described sensitizing and desensitizing trends within REDSTIM provide a novel insight into human pain mechanisms overcoming limitations of conventional testing methods. The purpose of the present study was to assess the test-retest reliability of pain intensity clamping using REDSTIM during three separate sessions.MethodsWe used a method for testing changes in pain sensitivity of human subjects (REDSTIM) where the stimulus temperature is modulated to clamp pain intensity near a desired set-point. Temperature serves as the response variable and is used to infer pain sensitivity. Several measures were analyzed for reliability including average temperature and area under the curve (AUC). Intraclass correlation coefficients were calculated for each measure at pain rating set-points of 20/100 and 35/100.ResultsSixteen healthy individuals (mean age = 21.6 ± 3.9) participated in three experiments two days apart at both pain rating set-points. Most reliability coefficients were in the moderate to substantial range (r’s = 0.79 to 0.94) except for the negative AUC (r = 0.52), but only at the 20/100 pain rating set-point.ConclusionsThe present study supports the test-retest reliability of pain intensity clamping using the REDSTIM methodology while providing a novel tool to examine human pain modulatory mechanisms and overcoming common shortcomings of conventional quantitative sensory testing methods.

Adaptation of local muscle blood flow and surface electromyography to repeated bouts of eccentric exercise.

The aim of this randomized controlled crossover study was to investigate the effect of a bout of unaccustomed eccentric exercise (ECC) followed by a consecutive bout of the same intensity on local muscle blood flow, amplitude, and frequency of the electromyographic (EMG) signal from the exercised tibialis anterior muscle. Sixteen healthy male participants (age, 25.7 (0.6) years; body mass index 24.8 (1) kg·m(-2) participated in this study. Two identical bouts of high-intensity ECC were performed on the tibialis anterior muscle 7 days apart. Control sessions involving no exercise were performed 4 weeks either before or after the exercise sessions. Changes in local total blood flow [ΔtHb], EMG root mean square, and median power frequency were recorded during isometric maximum voluntary contraction of ankle dorsiflexion. Measurements were performed before, immediately after, and the day after both ECCs (ECC1 and ECC2). The participants rested quietly in a chair in the control session. Eccentric exercise 1 led to a significant decrease in [ΔtHb] on the day after (p ≤ 0.05), whereas ECC2 did not. Median power frequency decreased significantly in ECC2 compared with ECC1 (p < 0.01). Root mean square was unchanged in all the instants. The present study showed that adaptation is depicted in the local muscle blood flow and the frequency contents of the EMG after an unaccustomed ECC inducing muscle soreness. These alterations provide a potential mechanism for a rapid adaptation, which decreases susceptibility of the muscle to develop further soreness in the subsequent ECC bout.