The analgesic effect of intraarticular OnabotulinumtoxinA in a female murine model of collagenase induced chronic degenerative monoarthritis.

PURPOSE: We previously reported the efficacy of intraarticular (IA) rimabotulinumtoxinB (BoNT/B) in a murine model of chronic degenerative arthritis pain. This study aimed to measure the analgesic effects of onabotulinumtoxinA (BoNT/A) on collagenase induced chronic degenerative arthritis joint pain. METHODS: Chronic degenerative arthritis was produced by IA injection of 10 µl collagenase (Col) (10 IU) into the left knee of C57BL/6J female mice 4 weeks prior to pain assessment. IA BoNT/A was injected 3 days before testing. Arthritis pain was measured as evoked pain scores (EPS) and spontaneous pain behaviors with an advanced dynamic weight bearing (ADWB) device. EPS was a tally of fights and vocalizations exhibited in one minute with knee palpation. Percent body weight and percent time spent on each limb was quantified. All mice were 12 weeks old at the time of examination. RESULTS: IA Col increased EPS and reduced ADWB measures of percent weight bearing on the left hind limb compared to naïve mice. BoNT/A treatment reduced EPS and increased weight bearing on the left hind limb. The improvements were not significant compared to the Col group. There was no significant difference in time spent on the left hind limb between any treatment groups. Forelimb ADWB measures of percent weight and time in arthritic mice significantly increased compared to nonarthritic animals. Treatment with BoNT/A in the arthritic limb decreased this offloading; however, statistical analysis only showed significance in weightbearing. CONCLUSION: IA Col monoarthritis increased evoked and spontaneous pain behaviors in female mice after four weeks. Treatment with IA BoNT/A decreased pain behaviors but only forelimb weight bearing showed a significant improvement. This led us to conclude that treatment with BoNT/A is not an effective analgesic for the treatment of chronic degenerative knee arthritis in murine models.

The Effect of Treatment with Resiniferatoxin and Capsaicin on Dynamic Weight Bearing Measures and Evoked Pain Responses in a Chronic Inflammatory Arthritis Murine Model.

OBJECTIVE: Capsaicin (CAP) and Resiniferatoxin (RTX) are vanilloid receptor agonists that can normalize Evoked Pain Scores (EPS) and Automated Dynamic Weight Bearing (ADWB) measures in murine acute inflammatory arthritis when given by intra-articular (IA) injection. To determine whether these vanilloid receptor agonists have benefit in Complete Freund's Adjuvant (CFA) induced chronic inflammatory arthritis pain, we measured changes in ADWB and EPS in arthritic mice with and without treatment with IA CAP and RTX. METHODS AND MATERIALS: Chronic inflammatory arthritis was produced by IA injection of 30 µl of Complete Freund's Adjuvant (CFA) into the left knee of C57BL6 male mice 3 weeks prior to pain behavior testing. Mice were injected with either low or high dose IA RTX (10µl of 0.001 or 0.003%), or IA CAP (10 µL of 0.01%) 7 days prior to pain behavior testing. RESULTS: Chronic Inflammatory arthritis pain produced increased EPS and reduced ADWB measures for weight bearing in the affected limb of arthritic mice compared to naïve mice. ADWB measurements for time in CFA when compared with Naive were not significantly different, but suggested off-loading the arthritic limb to the normal limb. Treatment with IA CAP or RTX 7 days prior to pain behavior testing produced significant improvement in EPS but no improvement in ADWB measures. Neither IA CAP nor IA RTX had any impact on EPS or ADWB measurements in non-arthritic mice when given 7 days prior to pain behavioral testing. CONCLUSION: Using ADWB and EPS, we quantified pain in a murine chronic inflammatory arthritis model. IA CFA caused a significant increase in EPS and decreased ADWB measures in the affected limb. Treatment with IA RTX and CAP produced significant improvement in EPS in mice with mono-articular inflammatory arthritis. IA vanilloid treatment produced no improvement in ADWB measurements for weight and for time.

The effect of intra-articular vanilloid receptor agonists on pain behavior measures in a murine model of acute monoarthritis.

Arthritis is the most common cause of disability in the US, and the primary manifestation of arthritis is joint pain that leads to progressive physical limitation, disability, morbidity, and increased health care utilization. Capsaicin (CAP) is a vanilloid agonist that causes substance P depletion by interacting with vanilloid receptor transient receptor potential V1 on small unmyelinated C fibers. It has been used topically for analgesia in osteoarthritis with variable success. Resiniferatoxin (RTX) is an ultra potent CAP analog. The aim of this study was to measure the analgesic effects of intra-articular (IA) administration of CAP and RTX in experimental acute inflammatory arthritis in mice. Evoked pain score (EPS) and a dynamic weight bearing (DWB) device were used to measure nociceptive behaviors in a murine model of acute inflammatory monoarthritis. A total of 56 C57B16 male mice underwent EPS and DWB testing - 24 nonarthritic controls and 32 mice with carrageenan-induced arthritis. The effects of pretreatment with 0.1% CAP, 0.0003% RTX, or 0.001% RTX were measured. Nociception was reproducibly demonstrated by increased EPS and reduced DWB measures in the affected limb of arthritic mice. Pretreatment with 0.001% RTX resulted in statistically significant improvement in EPS and DWB measures when compared with those observed in carrageenan-induced arthritis animals. Pretreatment with IA 0.0003% RTX and IA 0.01% CAP resulted in improvement in some but not all of these measures. The remaining 24 mice underwent evaluation following treatment with 0.1% CAP, 0.0003% RTX, or 0.001% RTX, and the results obtained were similar to that of naïve, nonarthritic mice.

A comparison of DigiGait™ and TreadScan™ imaging systems: assessment of pain using gait analysis in murine monoarthritis.

PURPOSE: Carrageenan-induced arthritis is a painful acute arthritis model that is simple to induce, with peak pain and inflammation occurring at about 3 hours. This arthritis model can be evaluated using semiquantitative evoked or non-evoked pain scoring systems. These measures are subjective and are often time- and labor-intensive. It would be beneficial to utilize quantitative, nonsubjective evaluations of pain with rapid assessment tools. We sought to compare the DigiGait™ and TreadScan™ systems and to validate the two gait analysis platforms for detection of carrageenan-induced monoarthritis pain and analgesic response through changes in gait behavior. METHODS: Non-arthritic mice and carrageenan-induced arthritic mice with and without analgesia were examined. A painful arthritic knee was produced by injection of 3% carrageenan into the knee joint of adult mice. Analgesic-treated mice were injected subcutaneously with 0.015 mg/mL (0.5 mg/kg) buprenorphine. Five-second videos were captured on the DigiGait™ or TreadScan™ system and, after calculating gait parameters, were compared using student's unpaired t-test. RESULTS: We found the DigiGait™ system consistently measured significantly longer stride measures (swing time, stance time, and stride time) than did TreadScan™. Both systems' measures of variability were equal. Reproducibility was inconsistent on both systems. While both systems detected alterations in some gait measures after carrageenan injection, none of the alterations were seen with both systems. Only the TreadScan™ detected normalization of gait measures after analgesia, but the system could not detect normalization across all measures that altered due to arthritis pain. Time spent on analysis was dependent on operator experience. CONCLUSION: Neither the DigiGait™ nor TreadScan™ system was useful for measuring changes in pain behaviors or analgesic responses in acute inflammatory monoarthritic mice.

Intraarticular botulinum toxin A for refractory painful total knee arthroplasty: a randomized controlled trial.

OBJECTIVE: To assess short-term efficacy of single intraarticular botulinum toxin (IA-BoNT/A) injection in patients with chronically painful total knee arthroplasty (TKA) in a randomized, placebo-controlled, triple-blind study. METHODS: Patients with chronic TKA pain (pain > 6 on 0-10 scale and > 6 months post-TKA) evaluated in and referred from orthopedic surgery clinics were recruited. The primary outcome, proportion of patients with clinically meaningful decrease of at least 2 points on 0-10 visual analog scale (VAS) for pain, was compared between treatment groups at 2 months using comparison of proportions test and for all efficacy timepoints (2, 3, and 4 months) using generalized estimating equations (GEE). Secondary outcomes of global assessment, function, and quality of life were compared using GEE, duration of pain relief by t-test, and adverse events by chi-square test. RESULTS: In total, 54 patients with 60 painful TKA were randomized, with main analyses restricted to one TKA per patient (49 TKA in 49 patients). Mean age was 67 years, 84% were men, and mean duration of TKA pain was 4.5 years. A significantly greater proportion of patients (71%) in the IA-BoNT/A group compared to IA-placebo (35%) achieved clinically meaningful reduction in VAS pain at 2 months (p = 0.028) and at all efficacy timepoints (p = 0.019). Duration of meaningful pain relief was significantly greater after IA-BoNT/A, 39.6 days (SD 50.4) compared to IA-placebo, 15.7 days (SD 22.6; p = 0.045). Statistically significantly better scores were seen in IA-BoNT/A vs IA-placebo for all efficacy timepoints for the following outcomes: "very much improved" on physician global assessment of change (p = 0.003); Western Ontario McMaster Osteoarthritis Index physical function (p = 0.026), stiffness (p = 0.004), and total scores (p = 0.024); and Short-Form 36 pain subscale score (p = 0.049). Number of total and serious adverse events was similar between groups, with no patients in either group with new objective motor or sensory deficits during followup. CONCLUSION: In this single-center randomized trial, single IA-BoNT/A injection provided clinically meaningful short-term improvements in pain, global assessment, and function in patients with chronic painful TKA. A multicenter trial is needed to confirm these findings.

Pain behavior measures to quantitate joint pain and response to neurotoxin treatment in murine models of arthritis.

OBJECTIVE: To evaluate the validity of newly developed pain behavior measures in two murine models of inflammatory arthritis and to determine the ability of these measures to evaluate the analgesic effectiveness of intra-articular (IA) botulinum toxin type A (BoNT/A) for treatment of arthritis pain. DESIGN: Acute inflammatory arthritis was produced in adult female mice by IA injection of carrageenan and chronic inflammatory arthritis by IA injection of CFA. The presence of arthritis was confirmed by the presence of swelling and erythema. A menu of pain behavior measures was devised for quantitating pain in these models including tenderness, and spontaneous nocturnal wheel running. Toxicity due to neurotoxin was measured as gross limb weakness and impaired functional ability during wheel running. RESULTS: Tenderness measures and spontaneous nocturnal wheel-running are valid measures of arthritis pain and are sensitive to the effects of analgesia. Narcotic analgesics are effective, but in fully analgesic doses impair wheel-running. IA BoNT/A is an effective analgesic for chronic arthritis pain, but not for acute arthritis pain. High doses can produce local limb muscle weakness, which impairs wheel-running function. Doses of botulinum toxin that are not toxic retain their analgesic function. CONCLUSIONS: Tenderness and spontaneous pain behavior measures are valid and sensitive for the measurement of pain and analgesia in murine models of inflammatory arthritis. Effective narcotic analgesia produces a decline in function in mice similar to that seen in humans. IA neurotoxin is a promising therapy for chronic inflammatory arthritis but may not be effective for acute arthritis pain.

Intra-articular botulinum toxin A for refractory shoulder pain: a randomized, double-blinded, placebo-controlled trial.

We compared the short-term efficacy and safety of intra-articular (IA) botulinum toxin A (BoNT/A) to IA-placebo in patients with chronic, refractory shoulder joint pain. Forty-three shoulder joints in patients with moderate-to-severe shoulder arthritis pain were randomized to receive (1) 100 units IA-BoNT/A + lidocaine or (2) IA-saline + lidocaine. The following outcomes were compared using analysis of covariance: (1) primary: change in pain severity on a visual analog scale at 1 month (VAS, 0 cm to 10 cm); (2) secondary: Shoulder Pain and Disability Index (SPADI) disability subscale, quality of life on short-form (SF)-36 subscales, percent of patients who achieved at least a 30% decrease or a 2-point reduction in VAS pain (clinically meaningful pain relief), and safety. Both BoNT/A (n = 21) and placebo (n = 22) groups were comparable at baseline. At 1 month post-injection, the VAS pain reduction was significantly more in the BoNT/A group versus the placebo group (-2.4 vs -0.8; P-value = 0.014). When comparing BoNT/A with the placebo group at 1 month, it was observed that 5 SF-36 subscale scores improved significantly (P

Intra-articular botulinum toxin A as an adjunctive therapy for refractory joint pain in patients with rheumatoid arthritis receiving biologics: a report of two cases.

We report the use of intra-articular Botulinum toxin A in two RA patients with persistently painful monoarthritis in ankle/feet joints. Both patients had monarticular pain despite a good response of all other joints to a combination therapy that included anti-tumor necrosis factor therapy. Both patients had failed intra-articular corticosteroid injections and declined surgical options. After a single, "off-label", intra-articular injection of Botulinum toxin A into the right ankle (100 unit) and left first metatarsophalangeal joint (25 unit), respectively, pain and function improved significantly (> or =40%) in both patients. Durable response with improvement of pain and function lasting 15-18 months was noted (follow-up continuing). Ankle joint swelling resolved by 15 months and MTP joint swelling by one month. Intra-articular BoNT/A may be an additional therapeutic option in RA patients with persistent monoarthritis. A randomized study is underway to confirm these findings.

Medical residents' beliefs and concerns about using opioids to treat chronic cancer and noncancer pain: a pilot study.

This study assessed and compared residents' beliefs and concerns about using opioids for treating pain in patients with cancer and noncancer low back pain (NLBP). Participants included 72 Internal Medicine and Medicine-Pediatrics residents who completed a survey questionnaire. Based on a scale of 0 = "No concern" to 10 = "Very concerned," residents expressed greater concern that treating NLBP with opioids, compared with cancer-related pain, causes addiction (6.01 vs 1.15), abuse (5.57 vs 1.39), and side effects (4.76 vs 2.87); limits other treatments (5.36 vs 1.30); draws criticism from faculty (4.33 vs 0.88); or risks sanctioning (state board 4.12 vs 1.12, legal 4.06 vs 1.17); p < 0.001 for each (paired t-tests). They had more comfort (8.94 vs 4.31) and more empathy (9.09 vs 6.79) using opioids to treat for cancer pain than NLBP and would give whatever doses necessary for pain control (8.41 vs 3.66); p < 0.001 for each. Our findings show that residents are far more concerned about using opioids to treat NLBP than cancer-related pain.

Opioid use by patients in an orthopedics spine clinic.

OBJECTIVE: Concerns regarding the efficacy, toxicity, tolerance, dependence, and abuse of opioids have limited their use for patients with chronic spine pain. In our previous study of rheumatology clinic patients, opioid analgesics were found to be highly effective, produced only mild side effects, and had few instances of opioid abuse. The purpose of this study was to replicate our previous study in another large cohort of patients with nonmalignant pain due to well-defined spinal diseases. METHODS: Opioid use was studied in 230 orthopedics spine clinic patients by retrospective analysis of prescriptions for 3 years and cross-sectional analysis of efficacy and toxicity by patient interviews. Opioid use and stability of the daily dose over 3 years were derived from computerized pharmacy records. Medical records, operative reports, and radiographic studies were reviewed to determine the reason for dosage escalations and to detect instances of abuse or addiction behaviors. Patients were interviewed to determine the efficacy, frequency, and types of side effects and instances of obtaining opioids from sources outside the Veterans Affairs system. RESULTS: Opioids were prescribed for 152 of the 230 patients, for < 3 months (short-term [STO]) in 94, > or =3 months (long-term [LTO]) in 58, and none in 72 (no opioid [NTO]). Medications prescribed were codeine, oxycodone, propoxyphene, tramadol, morphine, meperidine, fentanyl, or hydroxycodone, either alone or in combination. Interviews were completed in 72 STO, 50 LTO, and 45 NTO patients. Pain severity (0-10 scale) was not different in patients with different spinal pathologies. Opioids significantly reduced the back pain severity score from 8.3 +/- 1.5 to 4.5 +/- 2.2 (mean +/- SD). Mild side effects (most commonly, constipation and sedation) were reported by 58% of the opioid-treated patients but rarely caused them to stop taking the medication. There was no significant increase from the mean +/- SD initial opioid dosage of 5.0 +/- 12.2 30-mg codeine equivalents per day (30 mg oral codeine = 5 mg oral morphine) to the mean peak dosage of 7.9 +/- 12.5 and the mean recent dosage of 4.3 +/- 6.3, suggesting that tolerance to opioid analgesia did not appear to occur in these patients. Dosage escalations of > 2 30-mg codeine equivalents occurred 19 times in 17 LTO patients and was due to worsening of the underlying painful condition, complications of spine surgery, or unrelated surgical or medical problems in all but 3 of them (5%). These 3 patients also displayed other abuse behaviors. Abuse behaviors were not more frequent in those with or without a history of abuse/addiction. CONCLUSION: This study provides data on the efficacy, toxicity, tolerance, and abuse or addiction behaviors with opioid therapy in a large cohort of patients in an orthopedics spine clinic. The results provide objective data from patients with well-defined spine diagnoses to challenge the position that opioid treatment is inappropriate for chronic nonmalignant pain. This study provides clinical evidence to support and protect physicians treating patients with chronic musculoskeletal diseases, who may be reluctant to prescribe opioids because of possible sanctions from regulatory agencies. More important, it will benefit patients by permitting them to receive these effective, safe medications.

Development and evaluation of an integrated musculoskeletal disease course for medical students.

BACKGROUND: A recent survey of medical and surgical residents in the United States suggested that our current training of physicians may be inadequate to meet the increasing demand for diagnosis and treatment of musculoskeletal disorders. In response, we developed an integrated, multidisciplinary course to teach knowledge and skills related to musculoskeletal disease to second-year medical students. A three-year prospective outcomes study was conducted to evaluate the new course. METHODS: The primary outcomes that were studied during the first year of the new course were the gains in knowledge, changes in levels of confidence, and long-term retention of skills. Secondary outcomes consisted of student and faculty satisfaction. Ten-item pre-tests and post-tests covering core course concepts were administered to students. A matched-pairs t test was used to evaluate the difference between pre-test and post-test scores. Students were also asked to rate, on a 10-point scale, how much confidence they had in their ability to perform the musculoskeletal physical examination before and after the institution of the new curriculum. A general linear model analysis with post hoc pairwise comparisons (F test) was used to evaluate the changes in the confidence levels of the students. Also, a knee examination station was organized to compare students' scores before and after revision of the course. At the conclusion of the course, students rated each aspect of it on a scale of 1 to 5. Instructors were asked to rate the effectiveness of all elements of the course on the same scale. RESULTS: On the basis of student satisfaction and confidence and faculty satisfaction, the most effective changes in the curriculum were the introduction of a physical examination workshop and simulated clinical situations. Students' knowledge increased significantly (p < 0.001), and their level of confidence increased significantly in thirteen specifically targeted areas (p < 0.0001). On the end-of-the-year examination assessing retention of physical examination skills, the scores for the skills emphasized in the revised course increased significantly whereas the scores for a skill not emphasized in the course remained the same. Revisions made in the second and third years after implementation of the course expanded the more successful elements and further improved student ratings. CONCLUSIONS: Integration of the three clinical disciplines related to musculoskeletal disease--orthopaedics, rheumatology, and physical medicine and rehabilitation--resulted in a highly effective introductory course for second-year medical students. The heuristic strategy of introducing core content through lectures and workshops followed by small-group teaching sessions for practice with the new knowledge effectively increased students' knowledge, confidence, and satisfaction.

Mactinin: a modulator of the monocyte response to inflammation.

During inflammatory processes, monocytes leave the blood stream at increased rates and enter inflammation tissue, where they undergo phenotypic transformation to mature macrophages with enhanced phagocytic activity. alpha-Actinin, a cytoskeletal protein, is present in focal adhesion complexes and left in the microenvironment as a result of cell movement. Mactinin, a 31 kDa amino-terminal fragment of alpha-actinin, is generated by the degradation of extracellular alpha-actinin by monocyte-secreted urokinase. We have previously demonstrated that mactinin promotes monocyte/macrophage maturation. We now report that 0.5-10 nM mactinin has significant chemotactic activity for monocytes. Mactinin seems to be present in inflammatory arthritis synovial fluid, because affinity-purified antisera reacted with a protein of the expected molecular mass in various types of arthritis fluids that were immunoaffinity-purified and subjected to Western analysis. Thus, six of seven samples from patients with psoriatic arthritis, reactive arthritis, gout, or ankylosing spondylitis contained mactinin at levels that are active in vitro. Initially, mactinin was not found in affinity-purified rheumatoid arthritis samples. However, it was detectable after the dissociation of immune complexes, suggesting that it was complexed to anti-microfilament auto-antibodies. In addition, mactinin was found in the lavage fluid from the arthritic knee joints of rabbits with antigen-induced arthritis and was absent from the contralateral control knee fluids. We conclude that mactinin is present in several types of inflammatory arthritis and might modulate mononuclear phagocyte response to inflammation.