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Mechanisms and Pathways of Pain Photobiomodulation: A Narrative Review
KevinCheng*Laurent F.Martin*†Marvin J.Slepian§¶?#Amol M.Patwardhan*†‡??Mohab M.Ibrahim*†‡
doi : 10.1016/j.jpain.2021.02.005
Volume 22, Issue 7, July 2021, Pages 763-777
A growing body of evidence supports the modulation of pain by light exposure. As such, phototherapy is being increasingly utilized for the management of a variety of pain conditions. The modes of delivery, and hence applications of phototherapy, vary by wavelength, intensity, and route of exposure. As such, differing mechanisms of action exist depending upon those parameters. Cutaneous application of red light (660 nm) has been shown to reduce pain in neuropathies and complex regional pain syndrome-I, whereas visual application of the same wavelength of red light has been reported to exacerbate migraine headache in patients and lead to the development of functional pain in animal models. Interestingly visual exposure to green light can result in reduction in pain in variety of pain conditions such as migraine and fibromyalgia. Cutaneous application typically requires exposure on the order of minutes, whereas visual application requires exposure on the order of hours. Both routes of exposure elicit changes centrally in the brainstem and spinal cord, and peripherally in the dorsal root ganglia and nociceptors. The mechanisms of photobiomodulation of pain presented in this review provide a foundation in furtherance of exploration of the utility of phototherapy as a tool in the management of pain.
Effect of Topical Analgesia on Desensitization Following 8% Topical Capsaicin Application
Janne D.Christensen*SilviaLo Vecchio*Hjalte H.Andersen*JesperElberling†LarsArendt-Nielsen*
doi : 10.1016/j.jpain.2021.01.005
Volume 22, Issue 7, July 2021, Pages 778-788
To prevent pain associated with 8% capsaicin application, pretreatment with local anesthetics, such as EMLA (eutectic mixture of lidocaine 2.5% and prilocaine 2.5%), is considered an option. However, there is contradicting evidence regarding the effects of local analgesia on capsaicin-induced desensitization. In session 1, 2 skin areas in each forearm of 24 healthy volunteers were randomized to 2-hour pretreatment with EMLA/placebo cream. After pretreatment, 8% capsaicin patches were applied for 3 hours in 1 placebo and 1 EMLA pretreated area, obtaining the following four areas: Capsaicin?+?EMLA, Capsaicin?+?Placebo, EMLA alone, and Placebo. Pain intensity scores were assessed during the 3-hour application of capsaicin. Warmth detection, heat pain sensitivity, and microvascular reactivity were measured after the removal of capsaicin. After 24 hours, in session 2, all tests were repeated followed by histamine application in each area to examine itch intensity and neurogenic flare.
Experimental Hand and Knee Pain Cause Differential Effects on Corticomotor Excitability
David ARice*†Gwyn NLewis*ThomasGraven-Nielsen‡RufusLuther*Peter JMcNair*
doi : 10.1016/j.jpain.2021.01.006
Volume 22, Issue 7, July 2021, Pages 789-796
Acute pain elicits a well-known inhibitory effect on upper limb corticomotor excitability, whereas the temporal effects of lower-limb experimental pain and pain in a remote limb are less clear. The aim of this study was to compare the temporal corticomotor excitability changes in the upper and lower limbs in response to acute upper and lower limb pain. In a cross-over design, 13 participants (age 29 ± 9 years; 12 male) attended 2 sessions where experimental pain was induced by injecting hypertonic saline into either the first dorsal interosseous (FDI) muscle or infrapatellar fat pad at the knee, inducing a short-lasting pain experience scored on a numerical rating scale (NRS). Motor evoked potentials (MEPs) in response to transcranial magnetic stimulation were recorded in the FDI and vastus lateralis (VL) muscles before, during, and following pain. Hand and knee pain NRS scores were not significantly different. Hand pain elicited a short duration inhibition of the FDI MEPs (P < .0001) together with a facilitation of VL MEPs (P?=?.001) that outlasted the duration of pain. Knee pain elicited a short-duration facilitation of VL MEPs (P?=?.003) with no significant effect in the FDI MEPs (P?=?.46). The findings indicate a limb-specific corticomotor response to experimental pain that may be related to limb function.
Reduction of Pain and Spinal Nociceptive Transmission by Working Memory is Load Dependant
ZohaDeldar*†IsabelleBlanchette‡MathieuPiché*†
doi : 10.1016/j.jpain.2021.02.001
Volume 22, Issue 7, July 2021, Pages 797-805
Working memory (WM) engagement produces pain inhibition. However, it remains unclear whether higher WM load increases this effect. The aim of this study was to investigate the interaction between WM load and pain inhibition by WM and examine the contribution of cerebrospinal mechanism. Thirty-eight healthy volunteers were assigned to one of 2 n-back groups for which WM load was different (2-back or 3-back). The experimental protocol comprised 5 counterbalanced conditions (0-back, n-back, pain, 0-back with pain, and n-back with pain). Pain and the nociceptive flexion reflex (NFR) were evoked by transcutaneous electrical stimulation of the sural nerve. Pain was significantly different between conditions, but not between n-back groups. Both the 0-back and n-back tasks reduced pain compared with pain alone, but the n-back task produced stronger pain inhibition compared with the 0-back task. NFR amplitude was significantly different between conditions but not between n-back groups. NFR was inhibited by the 0-back and n-back tasks, with no difference between the 2 tasks. These findings indicate that pain inhibition by WM is increased by WM load, but only to a certain point. NFR inhibition by WM suggests that inhibition of pain by WM depends, at least in part, on cerebrospinal mechanism.
Nociceptor Overexpression of NaV1.7 Contributes to Chronic Muscle Pain Induced by Early-Life Stress
PedroAlvarez*OliverBogen*†Paul G.Green*†‡Jon D.Levine*†§
doi : 10.1016/j.jpain.2021.02.003
Volume 22, Issue 7, July 2021, Pages 806-816
Adult rats previously submitted to neonatal limited bedding (NLB), a model of early-life stress, display muscle mechanical hyperalgesia and nociceptor hyperexcitability, the underlying mechanism for which is unknown. Since voltage-gated sodium channel subtype 7 (NaV1.7) contributes to mechanical hyperalgesia in several preclinical pain models and is critical for nociceptor excitability, we explored its role in the muscle hyperalgesia exhibited by adult NLB rats. Western blot analyses demonstrated increased NaV1.7 protein expression in L4-L5 dorsal root ganglia (DRG) from adult NLB rats, and antisense oligodeoxynucleotide (AS ODN) targeting NaV1.7 alpha subunit mRNA attenuated the expression of NaV1.7 in DRG extracts. While this AS ODN did not affect nociceptive threshold in normal rats it significantly attenuated hyperalgesia in NLB rats. The selective NaV1.7 activator OD1 produced dose-dependent mechanical hyperalgesia that was enhanced in NLB rats, whereas the NaV1.7 blocker ProTx-II prevented OD1-induced hyperalgesia in control rats and ongoing hyperalgesia in NLB rats. AS ODN knockdown of extracellular signal-regulated kinase 1/2, which enhances NaV1.7 function, also inhibited mechanical hyperalgesia in NLB rats. Our results support the hypothesis that overexpression of NaV1.7 in muscle nociceptors play a role in chronic muscle pain induced by early-life stress, suggesting that NaV1.7 is a target for the treatment of chronic muscle pain.
Effects of Dry Needling on Muscle Stiffness in Latent Myofascial Trigger Points: A Randomized Controlled Trial
JorgeS?nchez-Infante*†AlfredoBravo-S?nchez*FernandoJiménez*JavierAbi?n-Vicén*
doi : 10.1016/j.jpain.2021.02.004
Volume 22, Issue 7, July 2021, Pages 817-825
The aim of this study was to analyze the effects of dry needling (DN) in upper trapezius latent trigger points (LTrPs) on muscle stiffness. A total of 51 recreational physically active subjects with LTrPs in the upper trapezius volunteered to participate and were randomly divided into a DN-group (n?=?27) and a sham-DN group (n?=?24). Volunteers received 1-session of DN or placebo treatment. Muscle stiffness, measured with strain and shear-wave elastography, pressure pain threshold (PPT), post-needling soreness, and muscle thickness were evaluated before treatment, and at 30-min, 24-hours, and 72-hours follow-up after treatment. The DN-group showed lower values from baseline for muscle stiffness measured with shear-wave elastrography at 24-hours (from 44.44 ± 15.97 to 35.78 ± 11.65 kpa; P < .01) and at 72-hours (35.04 ± 12.61 kpa; P < .01) and with strain elastography at 72-hours (from 1.75 ± 0.50 to 1.36 ± 0.40 AU; P < .01). The DN-group showed higher values of PPT than the sham-DN group at 72-hours (4.23 ± 0.75 vs. 5.19 ± 1.16 kg/cm2; P < .05). There was a progressive decrease in post-needling soreness compared to pain during needling of 33.13 ± 21.31% at 30-min, 80.92 ± 10.06% at 24-hours, and a total decrease in post-needling soreness in all participants at 72-hours. DN therapy is effective in reducing short-term muscle stiffness and increasing the PPT in volunteers with LTrPs in the upper trapezius after a treatment session.
Pain Prevalence, Chronicity and Impact Within Subpopulations Based on Both Hispanic Ancestry and Race: United States, 2010-2017
Richard L.Nahin
doi : 10.1016/j.jpain.2021.02.006
Volume 22, Issue 7, July 2021, Pages 826-851
We provide national surveillance estimates of pain chronicity, severity and impact in adult subpopulations defined by both Hispanic Ancestry and Race. Data are from 144,434 adults who completed validated questionnaires in the 2010–2017 National Health Interview Survey asking about pain status within the last 3 (N?=?84,664) or 6 months (N?=?59,770). Multivariable logistic regression was used to assess the relationship between pain and ethnicity/race. Compared to White Puerto Rican participants, White participants with Central/South American and Mexican ancestry had reduced odds of reporting Category 3–4 pain and High-Impact Chronic Pain (HICP), while those of Cuban ancestry had reduced odds of only HICP - eg, White participants with Mexican ancestry had 32% lower odds of having Category 3-4 pain and 50% lower odds of having HICP. While no differences were seen between White Puerto Rican and White Non-Hispanic participants for Category 3-4 pain, White Non-Hispanics had 40% lower odds of reporting HICP. Asian Non-Hispanic and Black Non-Hispanic participants had significantly lower odds of reporting Category 3-4 pain and HICP compared to White Puerto Rican participants, eg, Black Non-Hispanic participants had 26% lower odds off having Category 3-4 pain and 42% lower odds of having HICP.
Prospective Associations of Frequent Pain Symptoms With Suicidal Behavior in Adolescents
XianchenLiu*Zhen-ZhenLiu†‡YanyunYang§Cun-XianJia†
doi : 10.1016/j.jpain.2021.02.007
Volume 22, Issue 7, July 2021, Pages 852-863
Chronic pain and suicidal behavior are prevalent in adolescents. This longitudinal study examined the associations between pain symptoms and suicidal behavior in adolescents. A total of 7,072 adolescents participated in a follow-up study of behavior and health in Shandong, China. A self-administered structured questionnaire was used to assess pain symptoms (headache, stomachache, and other nonspecific pain), insomnia, anxiety/depression, substance use, stressful life events, prior suicidal behavior, and family environment in November-December in 2015. One year later, a follow-up survey was conducted. Mean age of the sample was 14.6 years, and half were female. Of the sample, 44.8% and 8.4% reported having one or more pain symptoms “sometimes” and “often”, respectively. A total of 22.4% and 10.6% reported having lifetime suicidal behavior at baseline and subsequent suicidal behavior over the 1-year follow-up, respectively. Frequent pain was significantly associated with increased risk of suicidal behavior at baseline (OR=1.64, 95%CI=1.32-2.03) and during the subsequent year (OR=1.50, 95%CI=1.17-1.93) while adjusting for adolescent individual and family covariates. Among adolescents without a history of prior suicidal behavior, frequent pain was significantly associated with an approximately 70% increased risk of incident suicidal behavior (OR= 1.69, 95%CI=1.14-2.51). In conclusion, frequent pain appears to be predictive of adolescent suicidal behavior one year later.
Pre-Exposure, But Not Overshadowing, Inhibits Nocebo Hyperalgesia
B.Colagiuri*J.Park*K.Barnes*L.Sharpe*R.A.Boakes*L.Colloca†E.J.Livesey*
doi : 10.1016/j.jpain.2021.02.008
Volume 22, Issue 7, July 2021, Pages 864-877
Nocebo hyperalgesia is a pervasive problem that significantly adds to the burden of pain. Conditioning is a key mechanism of nocebo hyperalgesia and recent evidence indicates that, once established, nocebo hyperalgesia is resistant to extinction. This means that preventive strategies are critical. We therefore tested whether two novel strategies – overshadowing (Experiment 1) and pre-exposure (Experiment 2) – could inhibit conditioned nocebo hyperalgesia. Overshadowing involves introducing additional cues during conditioning that should compete with and overshadow learning about the target nocebo cue. Pre-exposure involves pre-exposing the target nocebo cue in the absence of pain, which should diminish its ability to become associated with pain later. In both studies, healthy volunteers (N?=?141) received exposure to a series of electrocutaneous pain stimuli with and without a sham electrode ‘activated’, which they were led to believe was a genuine hyperalgesic treatment. Nocebo conditioning was achieved by pairing sham activation with high pain prior to testing at equivalent pain intensity. In both studies, standard nocebo conditioning led to clear nocebo hyperalgesia relative to natural history controls. In Experiment 1, there was no evidence that overshadowing attenuated nocebo hyperalgesia. Importantly, however, Experiment 2 found that pre-exposure successfully attenuated nocebo hyperalgesia with post hoc analysis suggesting that this effect was dose-dependent. These findings provide novel evidence that pre-exposure, but not overshadowing, could be a cheap and effective way for mitigating the substantial harm caused by conditioned nocebo hyperalgesia in clinical settings.
