Curcumin Treatment Attenuates Pain and Enhances Functional Recovery after Incision

Sahbaie, Peyman MD*†; Sun, Yuan MD, PhD*†; Liang, De-Yong PhD*†; Shi, Xiao-You MD*; Clark, J. David MD, PhD*†

doi: 10.1213/ANE.0000000000000189
Pain and Analgesic Mechanisms: Research Report

BACKGROUND: Acute pain after surgery remains moderate to severe for 20% to 30% of patients despite advancements in the use of opioids, adjuvant drugs, and regional anesthesia. Depending on the type of surgery, 10% to 50% of patients experience persistent pain postoperatively, and there are no established methods for its prevention. Curcumin (diferuloylmethane) is one of the phenolic constituents of turmeric that has been used in Eastern traditional medicine as an antiseptic, antioxidant, anti-inflammatory, and analgesic agent. It may be effective for treating postoperative pain.

METHODS: We used the hindpaw incision model with C57BL/6 mice. Sensitization to mechanical and thermal stimuli as well as effects on edema and temperature were measured up to 7 days after surgery. Spontaneous pain after incision was assessed by using conditioned place preference (CPP), and alterations in gait function were assessed using multiparameter digital gait analysis.

RESULTS: Curcumin (50 mg/kg) significantly reduced the intensity of mechanical and heat sensitization after hindpaw incision in mice. No effects of curcumin on baseline nociceptive thresholds were observed. Curcumin also reduced hindpaw swelling after incision, suggesting an anti-inflammatory effect. In addition, perioperative curcumin treatment attenuated hyperalgesic priming due to incision when mice were subsequently challenged with hindpaw prostaglandin E2 application. Furthermore, while vehicle-treated mice had evidence of spontaneous pain 48 hours after incision in the CPP paradigm, no evidence of ongoing pain was observed in the mice treated with curcumin. Likewise, hindpaw incision caused changes in several gait-related indices, but most of these were normalized in the curcumin-treated animals. The peri-incisional levels of several pronociceptive immune mediators including interleukin (IL)-1β, IL-6, tumor necrosis factor α, and macrophage inflammatory protein-1α were either not reduced or were even augmented 1 and 3 days after incision in curcumin-treated mice. The anti-inflammatory cytokine IL-10 was unchanged, while transforming growth factor-β levels were enhanced under the same conditions.

CONCLUSIONS: Our studies suggest that curcumin treatment is effective in alleviating incision-induced inflammation, nociceptive sensitization, spontaneous pain, and functional gait abnormalities. Augmented transforming growth factor-β production provides one possible mechanism. These preclinical findings demonstrate curcumin’s potential as a preventative strategy in postoperative pain treatment.

Published ahead of print April 22, 2014

From the *Department of Anesthesia, Stanford University School of Medicine, Stanford, California; and Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California.

Accepted for publication January 31, 2014.

Published ahead of print April 22, 2014

Funding: VA Biomedical Lab R&D 9003.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Peyman Sahbaie, MD, Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, Anesthesiology Service (112-A), Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304. Address e-mail to

Article Outline

Acute pain after surgery remains moderate to severe for 20% to 30% of patients despite advancements in the use of opioids, adjuvant drugs and regional anesthesia.1,2 Depending on the type of surgery, 10% to 50% of patients experience persistent pain postoperatively and there are no well-established methods for its prevention.3–5 Complementary and alternative medicine treatments may provide novel analgesic treatment options and preventative strategies. Curcumin (diferuloylmethane) is one of the phenolic constituents of turmeric that has been used in Eastern traditional medicine as an antiseptic, analgesic, anti-inflammatory, antioxidant and antimalarial.6 Curcumin is very well tolerated in large doses, has been used in several clinical trials and is under study as treatment for arthritis, cancer, pain and other conditions.7

Several studies support more systematic investigation into curcumin’s analgesic mechanisms. For example, systemic curcumin has been shown consistently to produce significant reductions in the second phase of formalin-induced nocifensive behaviors in animals indicating inhibition of central sensitization.8–10 Curcumin has also shown efficacy in models of neuropathic pain. For example, using the streptozotocin model of diabetic neuropathy curcumin reduced thermal hyperalgesia as well as serum levels of the proinflammatory, pronociceptive cytokine tumor necrosis factor alpha (TNFα).11,12 Curcumin reduced cisplatin-induced peripheral neuropathy and the elevation of sciatic nerve neurotensin levels, thereby exerting neuroprotective effects.13 Moreover, in the chronic constriction injury model of neuropathic pain systemic curcumin administration had antihyperalgesic effects, possibly by modulating adrenergic and serotonergic descending inhibition from the brainstem.14 Recently, an oral curcumin preparation was shown to provide analgesia in a small cohort of patients with pain of several etiologies of magnitude similar to that observed when acetaminophen was administered.15 In addition, a controlled study involving the use of curcumin in osteoarthritis patients demonstrated reduced Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores and improved treadmill capabilities after 8 months of treatment. Serum markers of inflammation were also reduced.16

Postsurgical pain is a complex phenomenon involving multiple mechanisms including those involved in inflammatory and neuropathic pain.17,18 The known pharmacology of curcumin suggests that this agent might be effective in reducing pain, moderating inflammation and improving functional recovery after surgery. The aim of the present study was to evaluate the effects of curcumin treatment in a mouse model of postsurgical pain with respect to analgesic potential, anti-inflammatory activity and functional outcomes. Physiological, behavioral, and biochemical approaches were used in order to strengthen our investigations.

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Animal Care and Use

All experimental protocols were reviewed and approved by Veterans Affairs Palo Alto Healthcare System Institutional Animal Care and Use Committee before beginning the work. Male mice 8 to 11 weeks old of the C57Bl/6J strain obtained from Jackson Laboratories (Bar Harbor, MA) were kept in our facility a minimum of 1 week before initiating the experiments. All mice were kept under standard conditions with a 12-hour light/dark cycle and an ambient temperature of 22°C ± 1°C and were allowed food and water ad libitum.

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Hindpaw Incision

The mouse model of hindpaw incision was used as previously described to study cytokine levels and analgesic effects after incision.19–22 Briefly, mice were anesthetized using isoflurane 2% to 3% delivered through a nose cone. After sterile preparation, a 5-mm longitudinal incision was made with a number 11 scalpel on the plantar surface of the right hindpaw. This incision was sufficiently deep to divide deep tissues. After controlling bleeding, a single 6-0 nylon suture was placed through the midpoint of the wound, and antibiotic ointment was applied. Testing took place at time points up to 7 days after incision.

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Drug Administration

Curcumin 50 mg/kg (Sigma Chemicals, St. Louis, MO) or vehicle was administered by intraperitoneal injections. Curcumin dosage chosen was based on preliminary experiments and previously published reports.23,24 Mice received curcumin 24 and 2 hours before incision and once daily for 4 days after incision. Vehicle injections followed the same schedule. Hyperalgesic priming was assessed 14 days after incision (7 days after full nociceptive recovery) with an intraplantar challenge of 100 ng prostaglandin E2 (PGE2, Cayman Chemical) injected into the surgical hindpaw. PGE2 stock solutions were made in 100% ethanol and diluted in 0.9% saline before use in a volume of 15 μL per hindpaw.

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Nociceptive Assays

Mechanical sensitivity was assayed according to the “up-down” algorithm described by Chaplan et al.25 Previously we have applied this technique to detect sensitivity in mice after incision by using nylon von Frey filaments.19,22 Mice were acclimated on the testing wire mesh platforms inside clear plastic enclosures (10 cm D × 40 cm in H). Subsequently, sequential fibers with increasing stiffness were applied 1 mm lateral to the central wound edge and left in place 5 seconds. A response was defined as the withdrawal of hindpaw from the fiber and then a less stiff fiber was applied; if no response was obtained, the next stiffest fiber in the series was applied. Testing ended when 4 fibers had been applied after first response obtained. Mechanical withdrawal threshold was determined by a data-fitting algorithm for significance analysis.26

The method described by Hargreaves et al. modified for mice was used to determine heat sensitivity.27–29 After acclimation on a temperature-controlled glass platform (23.5°C) in a plastic enclosure with the same dimensions as above, the hindpaw was presented with a beam of light from the heat source. To prevent tissue damage, a 15-second cutoff was used. Withdrawal latency of the paw from the heat source was measured; three evaluations were made per paw separated by several minutes.

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Assessment of Paw Edema and Temperature

A laser (4381 Precicura, Limab, Goteborg, Sweden) sensor technique was used to measure the dorsal-ventral thickness of the hindpaw.30 After rapid and brief anesthesia with isoflurane, the mouse was held vertically with hindpaw resting on a tabletop under the laser. Using optical triangulation, a distance-measuring sensor (200 mm range, 0.01 mm resolution) was used to determine the difference of the distance from the top of the hindpaw to the tabletop (dorsal-ventral paw thickness). Three measurements were made per paw per animal.

For hindpaw temperature measurements, a fine wire thermocouple (Omega, Stamford, CT) was used. Briefly, both hindpaws were placed on an insulating block, and 3 sites were tested: the space between the first and second metatarsals (medial), the second and third metatarsals (central), and the fourth and fifth metatarsals (lateral). The same site was immediately tested in the contralateral hindpaw in alternate fashion beginning with right medial and ending with left lateral. The 6 measurements for each hindpaw were averaged for the mean temperature and compared.

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Conditioned Place Preference

To assess the effects of curcumin on the affective component of incision-induced nociception, a single trial counterbalanced conditioned place preference (CPP) test was used, similar to techniques described previously.31–33 The CPP experiments were done using standard conditioning chambers placed inside sound-attenuating chambers with controlled lighting. Video recordings were analyzed by TopScan (Clever Sys., Reston, VA) for time spent in each of the 2 active association compartments. Each experiment started with 2 preconditioning (PC) days when the mice had free access to the 3 chambers for 30 minutes of exploration. On PC day 2, mice underwent surgery for unilateral hindpaw incision after chamber explorations. On PC day 3, mice had free chamber exploration for 15 minutes and were video recorded. Any mouse that spent >80% or <20% of the total experiment time in either of the association compartments was excluded. On day 4, mice received saline injections and were assigned to either one of the association compartments for 50 minutes. Next, mice were placed in the opposite side after 4 hours, immediately after morphine (0.3 mg/kg) administration. On day 5, mice were placed in the middle neutral compartment of the apparatus and were assessed for time spent in outer compartments for 15 minutes. Curcumin or vehicle treatments were given after conclusion of daily procedures. Drug or vehicle injection and chamber assignments were randomized and counterbalanced between groups.

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Gait Analysis

To assess functional locomotor changes after incision, analysis of gait was done using the DigiGait (Mouse Specifics, Boston, MA). To accomplish these analyses, mice walked on a motor-driven treadmill, and a high-speed digital video camera captured images of the underside of the animals, providing a digital record of temporal and geometric components of gait. Automated software calculated various dynamic gait variables such as stride time, swing duration, stance duration, braking duration, and stride frequency. The mouse was acclimated to the treadmill compartment for 5 minutes (belt speed = 0), 1 day before initiation of tests. Mice were evaluated at baseline and daily after hindpaw incision, with analyses based on comparing gait indices of injured limb to contralateral paw. Recordings were done at a set speed of 30 cm/s. Curcumin or vehicle treatments were given daily after the conclusion of evaluations.

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Cytokine Analysis

Mouse plantar hindpaw skin was collected at baseline and days 1 to 3 after incision and frozen immediately on dry ice. Skin tissue was later transferred to ice-cold phosphate buffered saline containing protease inhibitors (CompleteTM, Roche Applied Science, Indianapolis, IN) and homogenized using a Polytron device (Brinkman Instruments Inc., Westbury, NY). Homogenates were centrifuged at 12,000 times gravity at 4°C for 10 minutes. Supernatant fractions were stored at −80°C. Later, to normalize mediator levels, protein assay (DC Protein Assay, Bio-Rad Laboratories, Hercules, CA) of aliquots were performed. Mouse bio-plex Luminex cytokine arrays were performed in the Human Immune Monitoring Center at Stanford University. Assay kits (Affymetrix, Santa Clara, CA) were used for sample preparation, and plates were read using a Luminex 200 (Austin, TX) instrument, both following manufacturers’ recommendations. Standard curves for each of the analyzed cytokines were included in the run. All samples were run in duplicate, and protein concentration was reported as pg/mg total protein.

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Data Analysis

All data are presented as mean ± SEM. To determine significant differences in the nociceptive assays, edema and temperature measurements, multiple t tests with Bonferroni correction (no assumption of same scatter) was used. For the above measurements, groups of mice were randomly assigned to treatment groups and followed across days until recovery. Therefore, measurements for each subject were done for 9 time points in the nociceptive assays, 7 time points for the priming experiments, 5 time points in edema, and 4 time points in temperature measurements. Comparisons were made between curcumin (n = 7) and vehicle (n = 8) treatment groups after incision, or curcumin (n = 7) and vehicle (n = 6) treatment groups without incision after nociceptive assays. For CPP data, the difference time scores (ttest − tpreconditioning) at 48 hours were first calculated, and 1-way analysis of variances were used to determine significant score differences between treatment (morphine ± incision ± curcumin) groups followed by post hoc Tukey tests (95% confidence interval of differences and α = 0.05). The single limb indices from the gait evaluations of the incised limb were compared with the contralateral limb and analyzed by paired 2-sided t tests. Separate groups of mice were used for each time point in cytokine analysis experiments. Subsequently, the differences in cytokine level expression in each group (no treatment, curcumin/vehicle and incision) were analyzed by 1-way analysis of variance, followed by Bonferroni post hoc tests (95% confidence interval of differences plus significance: α = 0.05). For all analyses, P < 0.05 was taken to be significant.

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Postincisional Nociceptive Sensitization

Baseline mechanical (day 0: vehicle/no incision = 1.35 ± 0.14; curcumin/no incision = 1.43 ± 0.10, P = 0.61) or heat (day 0: vehicle/no incision = 11.91 ± 0.38; curcumin/no incision = 11.54 ± 0.35, P = 0.48) paw nociceptive sensitivity was not significantly different after curcumin treatment in uninjured animals (Fig. 1). Curcumin treatment reduced the magnitude of mechanical hypersensitivity (Fig. 1A) and reduced the magnitude and duration of heat hypersensitivity in the incised mice, compared with the vehicle group (Fig. 1B).

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Incisional Hyperalgesic Priming

After complete recovery from postincisional nociceptive sensitization, separate groups of mice were evaluated on day 14 by a challenge of local PGE2 for hyperalgesic priming. Mice treated with curcumin at the time of incision displayed significantly attenuated hyperalgesic priming effects compared with controls (Fig. 2).

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Paw Edema and Temperature

To determine the ability of curcumin treatment to reduce indices of the inflammatory response in incised animals, we measured changes in paw thickness and temperature for up to 7 days after incision. There were significant differences between the incised curcumin-treated animals and controls in the measure of paw edema at the 1 to 3 day time points (Fig. 3A). Curcumin compared with vehicle treatment did not significantly reduce paw temperature (day 1: P = 0.17; day 2: P = 0.08; Fig. 3B). Curcumin by itself had no effects on baseline paw thickness (P = 0.38) or temperature (P = 0.63) compared with vehicle treatment.

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Conditioned Place Preference

To determine the effects of agents on nonevoked spontaneous pain after incision, the CPP paradigm was used. Initial assessments revealed no chamber preference bias for mice tested (data not shown). Curcumin 50 mg/kg or morphine 0.3 mg/kg treatment failed to induce preference in uninjured animals (Curcumin versus vehicle: P = 0.50; Morphine versus Vehicle: P = 0.66, Fig. 4, A–B). In addition, a single injection of 0.3 mg/kg morphine had no effect on mechanical nociceptive thresholds in intact (P = 0.49) or mechanical allodynia in incised (P = 0.69) mice (Fig. 4C). The morphine dose used here has been shown to produce place preference after carrageenan inflammation due to a reduction in ongoing pain but to lack reinforcing properties on its own.33 Next, mice received 0.3 mg/kg of morphine 48 hours after surgery and were conditioned to a random chamber. When tested the following day, the mice showed preference for the morphine-paired chamber (P < 0.05), indicating in incised mice the presence of ongoing pain relieved by morphine. However, incised mice treated perioperatively with curcumin failed to acquire morphine-induced place preference (P = 0.96; Fig. 4B). The absence of a morphine effect in curcumin-treated incised mice is consistent with the absence of ongoing pain in those animals.

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Gait Analysis

Evaluation of gait after incision demonstrated significant differences in 9 of 19 gait indices compared with controls 48 hours postincision (Table 1). The swing duration and the percent duration of swing were significantly longer in the incised compared with the contralateral limbs (P < 0.001). The brake duration and the percent duration of swing were unaffected, while both the propulsion duration and percentage were significantly shorter in the incised limbs (P < 0.01). Also, the stance duration and percentage were significantly shorter (P < 0.01 and P < 0.001, respectively), and paw area was significantly increased (P < 0.001) for the incised limbs. Curcumin treatment prevented functional abnormalities in 8 of the 9 gait indices found to be changed after incision alone with no effect on indices not found to be abnormal in the incised animals.

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Cytokine Analysis

Analysis of immune mediators in the skin surrounding the wounds did not demonstrate significant differences in proinflammatory mediator production of interleukin (IL)-1β (P = 0.31) and IL-6 (P = 0.99) at day 1 for curcumin- or vehicle-treated groups (Fig. 5, A–B). At the same time point, the levels of both TNF-α (P < 0.05) and macrophage inflammatory protein-1α (P < 0.01) were higher in curcumin-treated mice (Fig. 5, C–D). On day 1, the level of anti-inflammatory cytokine IL-10 was unchanged (P = 0.99), and transforming growth factor-β (TGF-β) was increased (P < 0.001) after curcumin treatment (Fig. 5, E–F).

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Postoperative pain remains a problematic issue despite the use of preventative strategies, opioids, nonsteroidal anti-inflammatory drugs, acetaminophen, and regional anesthesia.1,2 Well-tolerated supplements to our current postoperative pain armamentarium would, therefore, be welcomed. Making matters more complex is the growing appreciation that, depending on the type of surgery, postoperative pain can persist in a significant number of patients.3–5 Few strategies have been proven effective in preventing this type of pain, and novel strategies are required. Finally, analgesic strategies offering advantages of functional outcomes are of great interest to the field of anesthesiology as well as surgical specialists. Surgeries on the extremities designed to restore function including improved gait might particularly benefit from analgesics, supporting improved functional recovery in the convalescent period. In the present studies, we tested multiple facets of the analgesic activity of curcumin, a naturally derived substance used in traditional medicine. We found that curcumin not only reduced nociceptive sensitization in commonly used evoked pain assays but also reduced the priming of nociceptive sensitization after recovery from incision, spontaneous pain, and alterations in gait induced by hindpaw incision.

Curcumin has a history of use from ancient times as a treatment for pain, though rigorous evaluation of the compound as an analgesic is lacking. Several laboratory studies and a limited number of clinical trials support more systematic investigation into curcumin’s analgesic mechanisms. The systemic and intrathecal effects of curcumin on formalin-induced behaviors in animals have been studied, with findings of significant inhibition of central sensitization and the spinal cord and dorsal root ganglion sensory neurons as potential sites of action.8,9,34,35 In an animal model of peritoneal inflammatory pain, curcumin showed substantial analgesic action alone and enhanced analgesic effects of morphine.36 Additional studies in neuropathic pain conditions demonstrate curcumin to be effective in reducing thermal hyperalgesia in a model of diabetic neuropathy while reducing elevated serum levels of the pronociceptive cytokine TNFα.11,12 Curcumin administration exerted a neuroprotective effect in cisplatin-induced peripheral neuropathy by elevating sciatic nerve neurotensin levels.13,37 The antihyperalgesic effects of curcumin in a chronic constriction injury model of neuropathic pain appear to be due to modulatory effects on brainstem adrenergic and serotonergic systems,14 and its antineuroinflammatory effects.38 Curcumin has not, however, been evaluated using a model of postoperative pain. One placebo controlled study on cholecystectomy patients found that patients taking oral curcumin reported lower average pain scores and consumed fewer analgesics during follow-up.39 Also, a preparation of curcumin with improved oral bioavailability provided significant analgesia in a small group of patients with a mix of painful conditions.15 These observations helped to provide the rationale for our studies.

Though detailed explorations of curcumin’s mechanism(s) of action were beyond the scope of the present work, it is nevertheless relevant that curcumin has several potential mechanisms of action that could help it to regulate postoperative pain. These include its ability to regulate epigenetic mechanisms, its anti-inflammatory capabilities, and its modulation of transient receptor potential (TRP)/ion channels. Curcumin has significant activity against enzymes involved in epigenetic modifications of DNA and histone proteins, namely histone acetyltransferases and DNA methyltransferases.40,41 Epigenetic mechanisms are of rapidly growing interest to the field of pain management and research.42,43 Our group recently demonstrated that mechanical sensitization after incision is regulated by the Cxcr2 receptor whose spinal expression is under tight epigenetic control.44 Likewise, curcumin has been shown to reduce levels of pain-related inflammatory cytokines and chemokines in some settings, the same mediators found in surgical wounds.45–47 In the present studies, we found that our curcumin administration protocol was not associated with decreases in the levels of peri-incisional proinflammatory mediators in skin, despite reducing hindpaw edema. However, curcumin treatment was associated with increases in the level of TGF-β in incised skin. It has been demonstrated that TGF-β has an inhibitory role in normal nociception as well as in inflammatory and neuropathic pain models.48 In addition, the antihyperalgesic effects of curcumin may be attributed to its modulation of the spinal descending monoamine system.14 Finally, interactions between curcumin and the well-established pain-related receptors TRPA1 and TRPV1 have been proposed as targets related to its analgesic properties.49–51 Thus, several potential mechanisms need to be considered in exploring curcumin’s analgesic properties related to postincisional pain.

The value of pharmacological pain studies can be limited by incomplete behavioral characterizations and the lack of specific analysis of drug effects on continuing pain and function.31,52 Rigorous preclinical analgesic studies might therefore include models of (1) protective/reflexive nociception, (2) ongoing pain, (3) measures of priming for persistent pain states, and (4) assessment of effects on functional impairments. This broad approach has been promoted for improving the translational value of preclinical studies and to help refine the understanding of the specific analgesic mechanisms of the compounds under study.53–56 Our studies were designed to address these goals, and the data obtained were consistent in demonstrating a broad potential spectrum of analgesic activity. For example, our first observations provided evidence of curcumin’s ability to reverse both thermal and mechanical sensitization for several days after incision. These data are important because the mechanisms responsible for the thermal and mechanical effects are in part mechanistically distinct.18 Moreover, curcumin reduced the hyperalgesic priming observed after recovery of nociceptive thresholds after incision. This form of latent sensitization is believed to be mediated by both peripheral effects in the primary afferent fiber nerve terminals and neuroplastic events within the spinal cord.44,57,58 With respect to ongoing pain, curcumin was effective in eliminating evidence of ongoing pain in the CPP paradigm. Detailed electrophysiological studies have linked spontaneous afferent discharges and sensitization to spontaneous pain-related behaviors after hindpaw incision.59 It is interesting to note that 50% effective dose values for morphine analgesia using standard thermal and mechanical testing are typically several milligrams per kilogram in mice,60 yet a much lower (0.3 mg/kg) dosage of morphine produced strong place preference after incision while no analgesia to mechanical stimuli in incised mice. These data, consistent with other observations,61 suggest that estimates of pharmacological potency may depend greatly on the particular testing paradigm used and may involve drug effects on different components of a pain syndrome’s mechanisms. Finally, our studies are some of the first to document not only gait disturbances after hindpaw incision but the prevention of those alterations by virtue of curcumin administration. This type of treadmill analysis is used in the evaluation of disease status in models of arthritis and chronic pain.62,63 Including gait analysis in rodent incisional pain studies may refine our characterizations of candidate analgesics by providing quantitative functional information.

Curcumin is a naturally occurring substance used in various forms by many cultures for the treatment of a wide range of ailments. It has been studied extensively in both animals and humans and is very well tolerated in large doses when used in clinical trials. Our studies used a broad range of pain and function-related outcome measures to carefully assess the potential of curcumin as an analgesic to be used in the perioperative setting. Within the limitations of these laboratory studies, our data support pursuing curcumin as an adjuvant perioperative analgesic. Future studies would logically be focused on better understanding curcumin’s specific mechanisms of analgesic action and designing therapies more selectively targeting those mechanisms. However, it is possible that curcumin’s real value is as a safe, single molecule, multimodal analgesic.

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Name: Peyman Sahbaie, MD.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

Attestation: Peyman Sahbaie has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Yuan Sun, MD, PhD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Attestation: Yuan Sun has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: De-Yong Liang, PhD.

Contribution: This author helped design the study.

Attestation: De-Yong Liang approved the final manuscript.

Name: Xiao-You Shi, MD.

Contribution: This author helped conduct the study.

Attestation: Xiao-You Shi has seen the original study data and approved the final manuscript.

Name: J. David Clark, MD, PhD.

Contribution: This author helped design the study and write the manuscript.

Attestation: J. David Clark reviewed the analysis of the data and approved the final manuscript.

This manuscript was handled by: Jianren Mao, MD, PhD.

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