Post-fracture Pain Research Articles

Cannabidiol and Cannabigerol, Nonpsychotropic Cannabinoids, as Analgesics that Effectively Manage Bone Fracture Pain and Promote Healing in Mice.

Bone fractures are among the most prevalent musculoskeletal injuries, and pain management is an essential part of fracture treatment. Fractures heal through an early inflammatory phase, followed by repair and remodeling. Nonsteroidal anti-inflammatory drugs (NSAIDs) are not recommended for fracture pain control as they potently inhibit the inflammatory phase and, thus, impair the healing. Opioids do not provide a better alternative for several reasons, including abuse potential. Accordingly, there is an unmet clinical need for analgesics that effectively ameliorate postfracture pain without impeding the healing. Here, we investigated the analgesic efficacy of two nonpsychotropic cannabinoids, cannabidiol (CBD) and cannabigerol (CBG), in a mouse model for tibial fracture. Mice with fractured tibiae exhibited increased sensitivity to mechanical, cold, and hot stimuli. Both CBD and CBG normalized pain sensitivity to all tested stimuli, and their analgesic effects were comparable to those of the NSAIDs. Interestingly, CBD and CBG promoted bone healing via multiple mechanisms during the early and late phases. During the early inflammatory phase, both cannabinoids increased the abundance of periosteal bone progenitors in the healing hematoma and promoted the osteogenic commitment of these progenitors. During the later phases of healing, CBD and CBG accelerated the fibrocartilaginous callus mineralization and enhanced the viability and proliferation of bone and bone-marrow cells. These effects culminated in higher bone volume fraction, higher bone mineral density, and improved mechanical quality of the newly formed bone. Together, our data suggest CBD and CBG as therapeutic agents that can replace NSAIDs in managing postfracture pain as both cannabinoids exert potent analgesic effects and, at the same time, promote bone healing. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Ultrasound-guided supra-inguinal fascia Iliaca compartment block for older adults admitted to the emergency department with hip fracture: a randomized controlled, double-blind clinical trial

BackgroundHip fracture is common in older adults, and can cause severe post-fracture pain. Fascia iliaca nerve block has consequently been used for preoperative analgesia.MethodsWe performed a randomized, controlled, double-blind clinical trial and recruited older patients with hip fractures. These patients were randomized into two groups and received ultrasound-guided fascia iliaca compartment block using either the supra-inguinal approach (group F) or the classical approach (group C). Heart rate, blood pressure, and resting and exercising visual analog scales were recorded before the procedure and at 30 min, and 6, 12, and 24 h after completion of the procedure. We recorded the duration of the procedure—as well as complications such as bleeding, hypotension, and intractable vomiting; the sleep duration in a 24 h period was also documented.ResultsA total of 38 patients completed the trial, and we observed no differences in the baseline characteristics or pre-procedural measurements between the two groups. Compared with the patients in group C, patients in group F exhibited significantly lower exercising VAS scores at 6 and 12 h after the procedure, faster heart rates at 6 and 24 h after the procedure, a longer procedural duration, and a longer sleep duration. There were no differences in the frequencies of complications between the two groups. The percentages of patients who took oral analgesics and the numbers of medications consumed were also not different between the two groups.ConclusionsThe supra-inguinal FICB provided effective analgesia and improved exercise tolerance compared with the classical approach.Trial registrationThe trial was registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2100045644, registration date: 2021 April 20).

The Relationship Between Fragility Fractures and Pain Experience: A Systematic Review

Purpose: This systematic review is conducted to explore the relationship between fragility fractures and pain experience.Methods: We searched for relevant studies on Pubmed, Embase, Web of Science, and the Cochrane library without restrictions on language from inception until February 4th, 2021. The risk of bias and methodological quality was evaluated using the Newcastle-Ottawa Scale and ROBINS-I tool.Results: Twenty-one studies were included in this systematic review. The so-called study reported participants with continuous post-fracture pain. The included studies showed that post- fractured pain can decrease with time, however, the continual pain can last at least 1 year even longer, and some participants would need to self-manage pain. Moreover, the limited range of motion was considered as a factor that might distress the normal development of daily activities.Conclusions: The current evidence could not fully support that pain continues to influence patients' lives after a fragility fracture. However, it still showed the pain might come with fracture. The findings also could be useful to help health care providers better recognize and manage this clinical consequence of fractures. Nonetheless, future large-scale longitudinal studies will be required to evaluate the long-term effects of pain in fragility fractures.

Assessment, Quantification, and Management of Fracture Pain: from Animals to the Clinic.

Fractures are painful and disabling injuries that can occur due to trauma, especially when compounded with pathologic conditions, such as osteoporosis in older adults. It is well documented that acute pain management plays an integral role in the treatment of orthopedic patients. There is no current therapy available to completely control post-fracture pain that does not interfere with bone healing or have major adverse effects. In this review, we focus on recent advances in the understanding of pain behaviors post-fracture. We review animal models of bone fracture and the assays that have been developed to assess and quantify spontaneous and evoked pain behaviors, including the two most commonly used assays: dynamic weight bearing and von Frey testing to assess withdrawal from a cutaneous (hindpaw) stimulus. Additionally, we discuss the assessment and quantification of fracture pain in the clinical setting, including the use of numeric pain rating scales, satisfaction with pain relief, and other biopsychosocial factor measurements. We review how pain behaviors in animal models and clinical cases can change with the use of current pain management therapies. We conclude by discussing the use of pain behavioral analyses in assessing potential therapeutic treatment options for addressing acute and chronic fracture pain without compromising fracture healing. There currently is a lack of effective treatment options for fracture pain that reliably relieve pain without potentially interfering with bone healing. Continued development and verification of reliable measurements of fracture pain in both pre-clinical and clinical settings is an essential aspect of continued research into novel analgesic treatments for fracture pain.

Effect of NSAID Use on Bone Healing in Pediatric Fractures: A Preliminary, Prospective, Randomized, Blinded Study.

This study aimed to investigate if nonsteroidal anti-inflammatory drugs (NSAIDs) used in the acute phase of bone healing in children with fractures result in delayed union or nonunion as compared with patients who do not take NSAIDs for pain control during this same time period. In this prospective, randomized, parallel, single-blinded study, skeletally immature patients with long bone fractures were randomized to 1 of 2 groups for their postfracture pain management. The NSAID group was prescribed weight-based ibuprofen, whereas the control group was not allowed any NSAID medication and instead prescribed weight-based acetaminophen. Both groups were allowed to use oxycodone for breakthrough pain. The primary outcome was fracture healing assessed at 2, 6, and 10 weeks. One-hundred-two patients were enrolled between February 6, 2014 and September 23, 2016. Ninety-five patients (with 97 fractures) completed a 6-month follow-up (46 patients with 47 fractures in the control group and 49 patients 50 fractures in the NSAID group). None achieved healing at 1 to 2 weeks. By 6 weeks, 37 of 45 patients (82%) of control group and 46 out of 50 patients (92%) of ibuprofen group had healed fractures (P=0.22). At 10 to 12 week follow-up, 46 (98%) of the control group fractures were healed and 50 (100%) of the ibuprofen group fractures were healed. All were healed by 6 months. Healing was documented at a mean of 40 days in the control group and 31 days in the ibuprofen group (P=0.76). The mean number of days breakthrough oxycodone was used was 2.4 days in the control group and 1.9 days in the NSAID group (P=0.48). Ibuprofen is an effective medication for fracture pain in children and its use does not impair clinical or radiographic long bone fracture healing in skeletally immature patients. Level I-therapeutic.

Disability and Pain are the Best Predictors of Sick Leave After a Distal Radius Fracture in Men

Purpose Distal radius fracture often compromises working ability, but clinical implications are less studied in men due to its lower incidence. This study therefore describes sick leave in men with distal radius fracture, specifically exploring the impact of patient- and fracture-related factors. Methods Professionally active men aged 20–65 with distal radius fracture were followed prospectively for 1-year (n = 88). Data included treatment method, radiographic parameters pre/post treatment, complications, health, lifestyle and occupational demand. Patient outcomes were self-reported sick leave; Disability of the Arm, Shoulder and Hand (DASH) score; pain (5 likert scale); SF-36: Physical Component Scale (PCS) and Mental Component Scale (MCS). Results Median sick leave was 4 weeks (IQR 0; 8); almost a third reported taking no sick leave. Categorizing sick leave into 3 groups (0–6, 7–12 and > 12 weeks), men with the longest sick leave had 22 points higher DASH score (p = 0.001) and 5 points lower PCS (p = 0.02) at 1 week and the difference remained over time; they were also older and more often treated surgically. The strongest predictors of length of sick leave were one-week post-fracture DASH score (rs = 0.4, p < 0.001), pain intensity (rs = 0.4, p < 0.001) and PCS (rs = − 0.4, p = 0.002). The correlation between sick leave and pain was even stronger analyzing treatment groups separately (closed reduction and cast rs = 0.56, p = 0.007, surgery rs = 0.42, p = 0.04). Conclusions Self-reported disability, pain and global health measurements as early as 1 week post-fracture are the strongest predictors of length of sick leave regardless of treatment; an important finding easily transferrable to clinical management of distal radius fractures.

Tibial post fracture pain is reduced in kinin receptors deficient mice and blunted by kinin receptor antagonists

BackgroundTibial fracture is associated with inflammatory reaction leading to severe pain syndrome. Bradykinin receptor activation is involved in inflammatory reactions, but has never been investigated in fracture pain.MethodsThis study aims at defining the role of B1 and B2-kinin receptors (B1R and B2R) in a closed tibial fracture pain model by using knockout mice for B1R (B1KO) or B2R (B2KO) and wild-type (WT) mice treated with antagonists for B1R (SSR 240612 and R954) and B2R (HOE140) or vehicle. A cyclooxygenase (COX) inhibitor (ketoprofen) and an antagonist (SB366791) of Transient Receptor Potential Vaniloid1 (TRPV1) were also investigated since these pathways are associated with BK-induced pain in other models. The impact on mechanical and thermal hyperalgesia and locomotion was assessed by behavior tests. Gene expression of B1R and B2R and spinal cord expression of c-Fos were measured by RT-PCR and immunohistochemistry, respectively.ResultsB1KO and B2KO mice demonstrated a reduction in post-fracture pain sensitivity compared to WT mice that was associated with decreased c-Fos expression in the ipsilateral spinal dorsal horn in B2KO. B1R and B2R mRNA and protein levels were markedly enhanced at the fracture site. B1R and B2R antagonists and inhibition of COX and TRPV1 pathways reduced pain in WT. However, the analgesic effect of the COX-1/COX-2 inhibitor disappeared in B1KO and B2KO. In contrast, the analgesic effect of the TRPV1 antagonist persisted after gene deletion of either receptor.ConclusionsIt is suggested that B1R and B2R activation contributes significantly to tibial fracture pain through COX. Hence, B1R and B2R antagonists appear potential therapeutic agents to manage post fracture pain.

Understanding osteoporotic pain and its pharmacological treatment: supplementary presentation.

Osteoporosis, a disorder that affects millions of people worldwide, is characterized by decreased bone mass and microstructural alterations giving rise to an increased risk of fractures. Osteoporotic fractures can cause acute and chronic nociceptive and neuropathic pain that mainly affects elderly patients with multiple comorbidities and commonly on different drug regimens. Central sensitization seems to play a pivotal role in developing and maintaining chronicity of post-fracture pain in osteoporosis. Antiosteoporosis drugs are able to partially control pain, but additional analgesics are always necessary for pain due to bone fractures. Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors reduce acute pain but with a poor effect on the chronic neuropathic component of pain and with relevant side effects. Opioid drugs can control the whole spectrum of acute and chronic bone pain, but they differ with respect to their efficacy on neuropathic components, their tolerability and safety. Chronic pain after osteoporotic fractures requires a multifaceted approach, which includes a large spectrum of drugs (antiosteoporosis treatment, acetaminophen, NSAIDs, selective COX-2 inhibitors, weak and strong opioids) and non-pharmacological treatment. Based on a better understanding of the pathogenesis of osteoporotic and post-fracture pain, a guided stepwise approach to post-fracture osteoporotic pain will also better meet the needs of these patients.

Understanding osteoporotic pain and its pharmacological treatment.

Osteoporosis, a disorder that affects millions of people worldwide, is characterized by decreased bone mass and microstructural alterations giving rise to an increased risk of fractures. Osteoporotic fractures can cause acute and chronic pain that mainly affects elderly patients with multiple comorbidities and commonly on different drug regimens. The aim of this paper is to summarize the pathogenesis and systemic treatment of osteoporotic pain. This narrative review summarizes the main pathogenetic aspects of osteoporotic pain and the cornerstones of its treatment. Osteoporotic fractures induce both acute and chronic nociceptive and neuropathic pain. Central sensitization seems to play a pivotal role in developing and maintaining chronicity of post-fracture pain in osteoporosis. Antiosteoporosis drugs are able to partially control pain, but additional analgesics are always necessary for pain due to bone fractures. Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors reduce acute pain but with a poor effect on the chronic neuropathic component of pain and with relevant side effects. Opioid drugs can control the whole spectrum of acute and chronic bone pain, but they differ with respect to their efficacy on neuropathic components, their tolerability and safety. Chronic pain after osteoporotic fractures requires a multifaceted approach, which includes a large spectrum of drugs (antiosteoporosis treatment, acetaminophen, NSAIDs, selective COX-2 inhibitors, weak and strong opioids) and non-pharmacological treatment. Based on a better understanding of the pathogenesis of osteoporotic and post-fracture pain, a guided stepwise approach to post-fracture osteoporotic pain will also better meet the needs of these patients.

Long-term experiences of pain after a fragility fracture.

We characterized perspectives on long-term pain among men and women who had sustained a fragility fracture. We conducted a secondary analysis of qualitative data from 67 individuals recruited in three primary studies (47-89years old; 55 women, 12 men). Eligible individuals from the primary studies were those who had reported pain related to their fracture beyond 6months. Data about reported pain were re-analyzed using qualitative description as articulated by Sandelowski. Thirty-four individuals (47-89years old; 4 men; 8 had sustained a vertebral fracture) reported pain related to their fracture in the primary studies. Thirty-one (91%) participants had sustained a fragility fracture at least 1year previously (range 1-13years). Patients described long-term pain beyond typical fracture healing times, generally unrelieved by analgesics, which affected their mobility, functional activity, independence, sleep, and energy. Health care providers were perceived to under-estimate timelines regarding the decrease of post-fracture pain and to not manage that pain. Participants reported that pain management was inadequate and that they developed their own strategies to respond to it. Pain continues to influence many patients' lives more than 1year after a fragility fracture. Patient narratives could be useful to help health care providers to better recognize and manage this long-term consequence of fractures.

Passive transfer autoimmunity in a mouse model of complex regional pain syndrome.

It has been proposed that complex regional pain syndrome (CRPS) is a posttraumatic autoimmune disease, and we previously observed that B cells are required for the full expression of CRPS-like changes in a mouse tibia fracture CRPS model. The current study used the mouse model to evaluate the progression of postfracture CRPS-like changes in wild-type (WT) and muMT fracture mice lacking B cells and antibodies. The pronociceptive effects of injecting WT fracture mouse serum antibodies into muMT fracture mice were also evaluated. Postfracture pain behaviors transitioned from being initially dependent on both innate and autoimmune inflammatory mechanisms at 3 weeks after fracture to being entirely mediated by antibody responses at 12 weeks after fracture and spontaneously resolving by 21 weeks after fracture. Furthermore, serum IgM antibodies from WT fracture mice had pronociceptive effects in the fracture limb when injected into muMT fracture mice. IgM antibody levels gradually increased in the fracture limb hind paw skin, sciatic nerve, and corresponding lumbar cord, peaking at 12 to 18 weeks after fracture and then declining. Immunohistochemistry localized postfracture IgM antibody binding to antigens in the fracture limb hind paw dermal cell nuclei. We postulate that fracture induces expression of neoantigens in the fracture limb skin, sciatic nerve, and cord, which trigger B cells to secret IgM antibodies that bind those antigens and initiate a pronociceptive antibody response. Autoimmunity plays a key role in the progression of nociceptive and vascular changes in the mouse fracture model and potentially contributes to the CRPS disease process.

Pain and fracture-related limitations persist 6months after a fragility fracture.

Our objective was to examine the experience of pain after a fracture beyond the conventional healing duration of 6months. We conducted a phenomenological study in participants who were deemed high risk for future fracture and recruited through an urban fracture clinic in Toronto, Canada. In-depth interviews were conducted with questions addressing the experience of pain, the status of recovery from the fracture, ways in which the fracture affected one's daily activities, and interactions with health care providers. Two researchers coded the transcripts within the phenomenological perspective to develop a structure of the pain experience, promoting rigour through the use of multiple analysts, searching for negative cases, and supporting claims with direct quotations from participants. We interviewed 21 participants who had sustained fractures of the wrist (n=4), hip (n=6), vertebrae (n=2), and multiple or other locations (n=9). All patients were ambulatory, had a range of socioeconomic status, and lived in the community. Eleven of the 21 participants reported persistent pain at the site of the fracture. Of the 10 participants who reported no pain, four indicated they had ongoing difficulties with range of motion and specific activities and two others described persistent pain from a previous fracture or reliance on a scooter for mobility. Our study demonstrated that over two-thirds of older adults reported fracture-related pain and/or limitations at, or beyond, 6months post-fracture. We suggest that health care providers ask questions about post-fracture pain and/or limitations when assessing fracture status beyond 6months.

Prospective study of predictive factors of changes in pain and hip function after hip fracture among the elderly.

Our study identified pre-fracture variables, such as home status or function, that are directly or indirectly associated with frailty status before fracture. The prevention in the deterioration of those variables would improve the prognosis of those hip fractured, being this an important issue for the societies with increasingly aging population. This study was designed to identify predictors of pain and declines in function among elderly patients following a fall-related hip fracture. Patients aged 65 or older with a fall-related hip fracture retrospectively completed pre-fracture status questionnaires (T0; n = 740) and were then prospectively followed for 6months (T1; n = 546). Of these, 474 were randomly selected to complete an additional 18months of follow-up (T2; n = 356). Primary outcome measures were changes in the pain and function dimensions of the Western Ontario and McMaster Universities Osteoarthritis Index questionnaire's short form (WOMAC-SF). Potential predictors included sociodemographic variables, in-hospital and clinical pre- and post-fracture data, and activities of daily living at baseline and follow-up. Multivariate logistic regression was used for analysis. Predictors of worsening pain at T1 and/or T2 included living in a home care situation or nursing home before the fracture (OR at T1, 1.515; OR at T2, 2.749), and low pre-fracture pain (OR at T1, 1.028; OR at T2, 1.027). Predictors of deterioration in function at T1 and/or T2 included age ≥85years (OR at T1, 2.714; OR at T2, 4.762), lower income (OR at T1, 1.755), high pre-fracture hip function (OR at T1, 1.029; OR at T2, 1.028), referral to rehabilitation upon discharge (OR at T1, 2.378; OR at T2, 2.881), and longer delay between fall and surgery (OR at T1, 1.133; OR at T2, 1.124). Frailty before hip fracture is a predictor of greater post-fracture pain and deterioration in function. Given that exercise programs help prevent frailty, promoting exercise in elderly may improve the prognosis of hip fracture.

Facilitated spinal neuropeptide signaling and upregulated inflammatory mediator expression contribute to postfracture nociceptive sensitization.

Tibia fracture induces exaggerated substance P (SP) and calcitonin gene-related peptide (CGRP) signaling and neuropeptide-dependent nociceptive and inflammatory changes in the hind limbs of rats similar to those seen in complex regional pain syndrome. Inflammatory changes in the spinal cord contribute to nociceptive sensitization in a variety of animal pain models. This study tested the hypothesis that fracture-induced exaggerated neuropeptide signaling upregulates spinal inflammatory mediator expression, leading to postfracture hind limb nociceptive sensitization. At 4 weeks after performing tibia fracture and casting in rats, we measured hind limb allodynia, unweighting, warmth, edema, and spinal cord neuropeptide and inflammatory mediator content. The antinociceptive effects of intrathecally injected neuropeptide and inflammatory mediator receptor antagonists were evaluated in fracture rats. Transgenic fracture mice lacking SP or the CGRP RAMP1 receptor were used to determine the effects of neuropeptide signaling on postfracture pain behavior and spinal inflammatory mediator expression. Hind limb allodynia, unweighting, warmth, edema, increased spinal SP and CGRP, and increased spinal inflammatory mediator expression (TNF, IL-1, IL-6, CCL2, and nerve growth factor) were observed at 4 weeks after fracture in rats. Fracture-induced increases in spinal inflammatory mediators were not observed in fracture mice lacking SP or the CGRP receptor, and these mice had attenuated postfracture nociceptive sensitization. Intrathecal injection of selective receptor antagonists for SP, CGRP, TNF, IL-1, IL-6, CCL2, or nerve growth factor each reduced pain behaviors in the fracture rats. Collectively, these data support the hypothesis that facilitated spinal neuropeptide signaling upregulates the expression of spinal inflammatory mediators contributing to nociceptive sensitization in a rodent fracture model of complex regional pain syndrome.

(287) Facilitated spinal neuropeptide signaling and upregulated inflammatory mediator expression contributes to post-fracture nociceptive sensitization

Tibia fracture induces exaggerated substance P (SP) and CGRP signaling and neuropeptide-dependent nociceptive and inflammatory changes in the hindlimbs of rats similar to those seen in complex regional pain syndrome (CRPS). Inflammatory changes in the spinal cord also contribute to nociceptive sensitization in a variety of animal pain models. This study tested the hypothesis that fracture induced exaggerated neuropeptide signaling upregulates spinal inflammatory mediator expression, leading to post-fracture hindlimb nociceptive sensitization. At 4 weeks after tibia fracture and casting we measured hindlimb allodynia, unweighting, warmth, edema, and spinal cord neuropeptide and inflammatory mediator content. The antinociceptive effects of intrathecally injected neuropeptide and inflammatory mediator receptor antagonists were evaluated in fracture rats. Transgenic fracture mice lacking SP or the CGRP RAMP1 receptor were used to determine the effects of neuropeptide signaling on post-fracture pain behavior and spinal inflammatory mediator expression. Hindlimb allodynia, unweighting, warmth, edema, increased spinal SP and CGRP, and increased spinal inflammatory mediator expression (TNF-α, IL-1β, IL-6, CCL2, NGF) were observed at 4 weeks after fracture in rats. Fracture induced increases in spinal inflammatory mediators were not observed in fracture mice lacking SP or the CGRP receptor and these mice had attenuated post-fracture nociceptive sensitization. Intrathecal injection of selective receptor antagonists for SP, CGRP, TNF-α, IL-1β, IL-6, CCL2, or NGF each reduced pain behaviors in the fracture rats. Collectively, these data support the hypothesis that facilitated spinal neuropeptide signaling upregulates the expression of spinal inflammatory mediators contributing to nociceptive sensitization in a rodent fracture model of CRPS.

Evaluation of a fracture pain model in domestic pigeons (Columba livia)

To validate a model of postfracture pain in perching birds. 21 adult domestic pigeons (Columba livia). In each bird, a standardized osteotomy of 1 femur was performed and the fracture was immobilized with an intramedullary pin. Degree of postoperative pain was evaluated 6 times/d for 4 days by use of 3 methods: an electronic perch for assessment of weight-bearing load differential of the pelvic limbs, 4 numeric rating pain scales for assessment of pain (all of which involved the observer in the same room as the bird), and analysis of video-recorded (observer absent) partial ethograms for bird activity and posture. Measurements obtained were compared with data collected before the surgery to evaluate the ability of these methods to detect pain. The weight-bearing load differential was a sensitive, specific, reliable, and indirect measure of fracture-associated pain in the model used. Two of 4 tested pain scales (fractured limb position and subjective evaluation of degree of pain) were sensitive and specific for detecting pain and were reliable in a research setting. Interobserver reliability of the 4 pain scales was excellent. Partial ethograms were sensitive for identifying pain-associated behavior in pigeons, particularly during the first 2 days after surgery. The fracture pain model was reliable and reproducible and may be useful for experimental studies involving postsurgical pain in pigeons. Weight-bearing load differential was the most sensitive and specific means of determining degree of pain in pigeons during the first 4 days after hind limb fracture induction.

The Effect of Nonsteroidal Anti-Inflammatory Drug Administration on Acute Phase Fracture-Healing: A Review

The analgesic efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) is well established, and these agents often form an integral part of posttraumatic pain management. However, potentially deleterious effects of resulting prostaglandin suppression on fracture-healing have been suggested. A systematic literature review involving searches of electronic databases and online sources was performed to identify articles exploring the influence of NSAIDs on fracture-healing. A structured search approach identified 316 papers as potentially relevant to the topic, and these were manually reviewed. The majority described small-scale studies that were retrospective or observational in nature, with limited control of potentially confounding variables, or presented little key information that was not also present in other studies. Although increasing evidence from animal studies suggests that cyclooxygenase-2 (COX-2) inhibition suppresses early fracture-healing, in vivo studies involving human subjects have not provided convincing evidence to substantiate this concern. We found no robust evidence to attest to a significant and appreciable patient detriment resulting from the short-term use of NSAIDs following a fracture. The balance of evidence in the available literature appears to suggest that a short-duration NSAID regimen is a safe and effective supplement to other modes of post-fracture pain control, without a significantly increased risk of sequelae related to disrupted healing.

Neuropeptide Deficient Mice Have Attenuated Nociceptive, Vascular, and Inflammatory Changes in a Tibia Fracture Model of Complex Regional Pain Syndrome

BackgroundDistal limb fracture in man can induce a complex regional pain syndrome (CRPS) with pain, warmth, edema, and cutaneous inflammation. In the present study substance P (SP, Tac1−/−) and CGRP receptor (RAMP1−/−) deficient mice were used to investigate the contribution of neuropeptide signaling to CRPS-like changes in a tibia fracture mouse model. Wildtype, Tac1−/−, and RAMP1−/− mice underwent tibia fracture and casting for 3 weeks, then the cast was removed and hindpaw mechanical allodynia, unweighting, warmth, and edema were tested over time. Hindpaw skin was collected at 3 weeks post-fracture for immunoassay and femurs were collected for micro-CT analysis.ResultsWildtype mice developed hindpaw allodynia, unweighting, warmth, and edema at 3 weeks post-fracture, but in the Tac1−/− fracture mice allodynia and unweighting were attenuated and there was no warmth and edema. RAMP1−/− fracture mice had a similar presentation, except there was no reduction in hindpaw edema. Hindpaw skin TNFα, IL-1β, IL-6 and NGF levels were up-regulated in wildtype fracture mice at 3 weeks post-fracture, but in the Tac1−/− and RAMP1−/− fracture mice only IL-6 was increased. The epidermal keratinocytes were the cellular source for these inflammatory mediators. An IL-6 receptor antagonist partially reversed post-fracture pain behaviors in wildtype mice.ConclusionsIn conclusion, both SP and CGRP are critical neuropeptide mediators for the pain behaviors, vascular abnormalities, and up-regulated innate immune responses observed in the fracture hindlimb. We postulate that the residual pain behaviors observed in the Tac1−/− and RAMP1−/− fracture mice are attributable to the increased IL-6 levels observed in the hindpaw skin after fracture.

Ondansetron does not block paracetamol-induced analgesia in a mouse model of fracture pain

BackgroundThe aim of this study was to assess any interaction between ondansetron and paracetamol on a model of post-fracture pain in mice. MethodsIn protocol A, after fracture of the tibia, mice were assigned to four groups: paracetamol 30 mg kg−1, paracetamol 50 mg kg−1, paracetamol 100 mg kg−1, or a saline vehicle i.p. In protocol B, after fracture of the tibia, mice were randomized to receive either paracetamol (100 mg kg−1) plus saline (vehicle), paracetamol (100 mg kg−1) plus ondansetron (1 mg kg−1), paracetamol (100 mg kg−1) plus ondansetron (2 mg kg−1), saline plus ondansetron (2 mg kg−1), or saline plus saline i.p. Three tests were used to assess pain behaviour: von Frey filament application, hot-plate test, and a subjective pain scale. Rescue analgesia with morphine was administered as necessary. ResultsIn protocol A, paracetamol (100 mg kg−1)-treated animals had less mechanical nociception, thermal nociception, and a lower subjective pain scale rating, when compared with those receiving paracetamol at 30 or 50 mg kg−1 or saline [ED50 paracetamol=46.3 (6.34) mg kg−1]. No difference was found between paracetamol (30 mg kg−1) and saline-treated animals. In protocol B, the mechanical withdrawal threshold, the thermal withdrawal latency, and the subjective pain scale were lower after injection of paracetamol (100 mg kg−1)+saline, paracetamol (100 mg kg−1)+ondansetron (1 mg kg−1), and paracetamol (100 mg kg−1)+ondansetron (2 mg kg−1), whereas in mice receiving saline+ondansetron (2 mg kg−1) or saline+saline, there was no difference. ConclusionWe found that paracetamol 100 mg kg−1 blocked the development of hyperalgesia and allodynia after fracture pain and ondansetron did not modify the antinociceptive effect of paracetamol in this model.

Mouse Model of Fracture Pain

The aim of this study was to validate a model of postfracture pain in mice, which was evaluated in the presence and the absence of morphine and ketoprofen. The study was divided into two parts: protocol A, the effects of closed fracture; and protocol B, the effects of morphine and ketoprofen on fracture pain. In protocol A, mice were assigned to three groups: group 1, sham incision; group 2, sham pinning; or group 3, fracture. In protocol B, mice were randomly assigned to four groups to receive morphine (3 or 10 mg/kg body weight), ketoprofen (50 mg/kg body weight), or placebo (vehicle). Three tests were used to assess pain behavior: von Frey filament application, hot plate test, and a subjective pain scale. In protocol A, thermal nociception, mechanical nociception, and subjective pain were significantly modified in group 3 (fractured) compared with control groups 1 and 2 (sham groups). In protocol B, when tests were repeated for 240 min in morphine-treated animals and in ketoprofen-treated animals, reduction of mechanical nociception, thermal nociception, and subjective pain scale score were observed. Morphine and ketoprofen administration provided the same effect on behavioral testing on postoperative days 1 and 2. This mouse model seems to be a reliable and reproducible tool to investigate the effect of closed bone fracture on several parameters, such as pain, remodeling, and recovery. Moreover, it allows studying the effects of various pharmacologic treatments as well as the involvement of various systems using different genetically modified strains of mice.