Maren L. Mahowald

Codeine and oxycodone use in patients with chronic rheumatic disease pain

OBJECTIVE Opioid treatment of chronic rheumatic disease pain is controversial because of concerns regarding efficacy, toxicity, tolerance, dependence, and abuse. This study examined opioid use in a cohort of patients with pain due to defined rheumatic diseases. METHODS Opioid use was studied retrospectively in a cohort of 644 rheumatology clinic patients. Computerized pharmacy records identified patients who had been prescribed opioids during the previous 3 years. Medical records were reviewed to determine reasons for opioid dosage escalations. Patients were interviewed to determine efficacy, frequency and types of side effects, and history of alcohol or street-drug abuse. RESULTS Opioid prescriptions were found in the 3-year pharmacy database for 290 of 644 clinic patients: 153 for <3 consecutive months and 137 for > or =3 months. All opioid-treated patients received codeine and/or oxycodone. In this cohort, 133 patients in each opioid-treated group and 76 of the 354 non-opioid-treated control patients were studied. Opioids significantly reduced rheumatic disease pain severity scores from 8.2 to 3.6 (on a 0-10 scale) (P < 0.001). Mild side effects were reported in 38%; nausea, dyspepsia, constipation, and sedation were the most common. The mean +/-SD initial dosage was 2.1+/-1.7 30-mg codeine equivalents/day, the mean peak was 3.4+/-3.3 per day, and the mean current dose was 2.7+/-2.0 per day. Dosage escalations occurred in 32 patients and were attributable to worsening of the underlying painful condition or a medical complication thereof in all but 4 patients, who also displayed other abuse behaviors. Abuse behaviors were not more frequent in those with or without a history of abuse/ addiction. CONCLUSION Prolonged treatment of rheumatic disease pain with codeine or oxycodone was effective in reducing pain severity and was associated with only mild toxicity. Doses were stable for prolonged periods of time, with escalations of the opioid dose almost always related to worsening of the painful condition or a complication thereof, rather than the development of tolerance to opioids. Doubts or concerns about opioid efficacy, toxicity, tolerance, and abuse or addiction should no longer be used to justify withholding opioids from patients with well-defined rheumatic disease pain.

Long Term Effects of Intra-articular Botulinum Toxin A for Refractory Joint Pain

The purpose of this case series review is to describe our 12 month clinical experience with intra-articular injections of Botulinum toxin Type A (BoNT/A) for refractory joint pain. Eleven patients with chronic arthritis who had failed treatment with oral and/or intra-articular medications and were not surgical candidates were referred to us for management of moderate to severe refractory joint pain in 15 joints. The use of BoNT/A to treat joint pain is a non-FDA approved “off label” treatment with potential side effects. After a detailed explanation of the joint injection procedure, signed informed consent was obtained for the procedure. Fifteen joints were injected with BoNT/A (Allergan, Inc): six lower extremity joints (3 knees, 3 ankles) with 25-50 units and nine shoulders with 50-100 units. Patients were followed for one year or longer. Maximum relief of pain was measured by comparing baseline pain on a numeric rating scale (0-10) to pain at the time of maximum relief (paired t-test). Maximum improvement in function was assessed using paired t-tests for improvement in active flexion and abduction for the shoulder joint, and by the time to perform sit to stand ten times (the timed stands test, TST) for the lower extremity joints.Results: Two patients were female and nine were male, aged 42-82 years. Five had osteoarthritis (OA), five had rheumatoid arthritis (RA) and one had psoriatic arthritis. All patients were on analgesic and/or anti-inflammatory medications and all joints had previous intra-articular steroid or viscosupplement injections with inadequate or unsatisfactory benefit. A clinically and statistically significant improvement was noted after IA-BoNT/ A injections. The mean maximum decrease in lower extremity joint pain was 55% (p =0.02) and the 36% (p =0.044) improvement in the Timed Stands Test was noted at four to ten weeks after injection. There was a 71% mean maximum reduction in shoulder pain severity from 8.2 ± 1.1 to 2.4 ± 1.9 (p <0.001). Active range of motion increased 67% in flexion (from 67.8 ± 27.6 to 113.3 ± 46.6 degrees, p =0.001) and 42% in abduction (from 50 18.5 degrees to 71.1 ± 23.1 degrees p =0.01). No immediate or delayed adverse effects related to BoNT/A were noted after the injection. Duration of pain relief was variable and ranged from 3 to 12 months. Five joints were re-injected with IA-BoNT/A and had a similar decrease in joint pain that lasted 3 to 12 months. Conclusions: This is the first report of the long term effects of intra-articular BoNT/A injections to treat chronic joint pain and the efficacy of repeated injections. Although this study was small, and uncontrolled the results suggest that IA-BoNT/ A injections are an effective and safe treatment for chronic joint pain disorders.

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 </= 0.035), and the SPADI disability improved more with a trend toward significance (51.5 +/- 4.4 vs 64.9 +/- 3.9; P = 0.083). In addition, clinically meaningful pain relief occurred in 61% versus 36% patients (P = 0.22). The total number of adverse events was similar, which included 50 events in the BoNT/A group versus 46 events in the placebo group. A single injection of BoNT/A produced statistically significant and clinically meaningful pain relief and improvement in quality of life in patients with chronic refractory moderate/severe shoulder arthritis pain at 1 month. These data provide evidence to support the efficacy of this novel neurotoxin therapy that needs to be confirmed in a multicenter, randomized trial.

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.

Finger dexterity and hand function: Effect of three commercial wrist extensor orthoses on patients with rheumatoid arthritis

OBJECTIVE To investigate the effect of 3 commercial wrist orthoses on finger dexterity and hand function of patients with rheumatoid arthritis (RA). METHODS Forty-two patients with definite RA participated in the cross-over study comparing 3 styles of commercial wrist orthoses. Finger dexterity and hand function of the dominant hand were assessed while splinted and unsplinted, at the initial session and after 1 week of intermittent orthosis use. Finger dexterity was assessed using two subtests from the Purdue Pegboard Test (Purdue) and hand function was assessed using the Jebsen-Taylor Hand Function Test (Jebsen-Taylor). RESULTS Both finger dexterity and hand function were reduced by splinting; men and women were affected similarly. There was no difference in finger dexterity or hand function afforded by the 3 orthoses. Results on both the Purdue and Jebsen-Taylor tests showed a significant learning effect across time. CONCLUSIONS The 3 commercial wrist orthoses studied reduce dexterity similarly and significantly. When commercial wrist orthoses are to be used during tasks that require maximum dexterity, this reduction should be weighed against the known benefits of splinting.

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.

Repeat injections of intra-articular botulinum toxin a for the treatment of chronic arthritis joint pain.

Chronic knee and shoulder pain are common disorders in adults and are a major cause of functional limitations, poor quality of life, and increased health care utilization. A new approach to the treatment of refractory joint pain that avoids toxic effects of systemic therapy is urgently needed. We reported the initial efficacy of intra-articular (IA) injection of botulinum neurotoxin type-A (BoNT/A) as a local chemodenervation treatment for refractory joint pain. Evidence of an analgesic effect of BoNT/A is accumulating. The observation of analgesic effects of BoNT/A occurring earlier and to a greater degree than the decrease in muscle tone and movements in patients with dystonia, led to the speculation that the mechanism of action of BoNT/A may extend beyond the neuromuscular junction. Studies of BoNT/A injections for chronic headache and migraine, low back pain, neck pain, and myofascial pain further supported this consideration. One randomized study of chronic tennis elbow found similar results at 1 and 2 years with BoNT/A injection compared with surgery and concluded that BoNT/A was a less invasive, effective alternative treatment of tennis elbow. In most of these conditions, repeated injections of BoNT/A are needed to maintain the benefit in chronic conditions. Some have reported enhanced response with repeated injections however this anecdotal information has not been studied rigorously. The purpose of this report is to describe the effects of repeated intraarticular BoNT/A injections in patients who had a good response to IA-BoNT/A and requested retreatment.

Analgesic effects of intra-articular botulinum toxin Type B in a murine model of chronic degenerative knee arthritis pain.

Objective: To evaluate the analgesic effectiveness of intra-articular botulinum toxin Type B (BoNT/B) in a murine model of chronic degenerative arthritis pain. Methods and materials: Chronic arthritis was produced in adult C57Bl6 mice by intra-articular injection of Type IV collagenase into the left knee. Following induction of arthritis, the treatment group received intra-articular BoNT/B. Arthritic control groups were treated with intra-articular normal saline or sham injections. Pain behavior testing was performed prior to arthritis, after induction of arthritis, and following treatments. Pain behavior measures included analysis of gait impairment (spontaneous pain behavior) and joint tenderness evaluation (evoked pain response). Strength was measured as ability to grasp and cling. Results: Visual gait analysis showed significant impairment of gait in arthritic mice that improved 43% after intra-articular BoNT/B, demonstrating a substantial articular analgesic effect. Joint tenderness, measured with evoked pain response scores, increased with arthritis induction and decreased 49.5% after intra-articular BoNT/B treatment. No improvement in visual gait scores or decrease in evoked pain response scores were found in the control groups receiving intra-articular normal saline or sham injections. Intra-articular BoNT/B was safe, and no systemic effects or limb weakness was noted. Conclusions: This study is the first report of intra-articular BoNT/B for analgesia in a murine model of arthritis pain. The results of this study validate prior work using intra-articular neurotoxins in murine models. Our findings show chronic degenerative arthritis pain can be quantitated in a murine model by measuring gait impairment using visual gait analysis scores (spontaneous pain behavior) and joint tenderness scores (evoked pain responses). Reduction of joint pain seen in this study is consistent with our hypothesis of inhibition of release of pain mediators by intra-articular BoNT/B, supporting further investigation of this novel approach to treatment of arthritis pain with intra-articular neurotoxins.

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.

POLYARTERITIS NODOSA PRESENTING AS SPONTANEOUS BILATERAL PERINEPHRIC HEMORRHAGE: MANAGEMENT WITH SELECTIVE ARTERIAL EMBOLIZATION

Polyarteritis nodosa is a systemic necrotizing vasculitis of small and medium arteries. It classically involves the renal arterioles in approximately 80% of cases. Spontaneous retroperitoneal hemorrhage is a rare presentation of this involvement. If severe, such hemorrhage can necessitate immediate medical and/or surgical intervention. We report to our knowledge the first case of polyarteritis nodosa with bilateral perinephric hemorrhage successfully managed with nephron sparing selective arterial embolization and corticosteroid treatment. CASE REPORT