Efficacy and safety of tanezumab in the treatment of chronic low back pain

Increased nerve growth factor levels are associated with chronic pain conditions, including chronic low back pain (LBP). This study examined safety and analgesic efficacy of tanezumab, a humanized anti-nerve growth factor antibody, in adults with chronic LBP. Patients received intravenous tanezumab 200 μg/kg plus oral placebo (n = 88), intravenous placebo plus oral naproxen 500 mg twice a day (n = 88), or intravenous placebo plus oral placebo (n = 41). Primary outcome was average LBP intensity (aLBPI) at Week 6. Secondary outcomes were proportion of patients with ?30% or ?50% reduction in aLBPI, Roland-Morris Disability Questionnaire and Brief Pain Inventory-short form scores, Patients’ Global Assessment of LBP, Patients’ Global Evaluation of study medication, and rescue medication use. Mean aLBPI change from baseline to Week 6 was greater with tanezumab vs naproxen (P = 0.004) and placebo (P < 0.001). Greater proportions of patients reported ?30% and ?50% reduction in aLBPI with tanezumab vs naproxen (P ? 0.013) and placebo (P < 0.001), and greater improvements in Roland-Morris Disability Questionnaire (P < 0.001) and other secondary outcomes except rescue medication use. Tanezumab was associated with adverse events (AEs) of abnormal peripheral sensation that were generally mild and resolved before study completion; however, there were no serious AEs. Nine patients (4 of whom were tanezumab-treated) discontinued due to AEs. In conclusion, tanezumab resulted in analgesic efficacy that was clinically and statistically superior to placebo and naproxen in patients with chronic LBP. Tanezumab clinical development is on regulatory hold due to AEs in osteoarthritis patients.     

A phase III placebo- and oxycodone-controlled study of tanezumab in adults with osteoarthritis pain of the hip or knee

Tanezumab is a humanized monoclonal antinerve growth factor antibody in development for treatment of chronic pain. In a phase III, placebo- and active-controlled study, we investigated the efficacy and safety of tanezumab for osteoarthritis (OA) hip or knee pain. Patients (N = 610) received up to 2 doses of intravenous tanezumab (5 or 10 mg in 8-week intervals), controlled-release oral oxycodone (10 to 40 mg every 12 hours), or placebo. The primary endpoint was mean change from baseline to week 8 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain score for tanezumab versus placebo and oxycodone. Secondary endpoints included change from baseline in WOMAC Physical Function and Stiffness scores, Patient’s Global Assessment (PGA) of OA, and patient response, defined as ?30%, ?50%, ?70%, and ?90% improvement from baseline in WOMAC Pain score. Tolerability and safety also were assessed. Both tanezumab groups demonstrated significant improvements in WOMAC Pain score versus placebo (P < .001) and oxycodone (P ? .018). Tanezumab also provided significant improvements versus placebo and oxycodone for WOMAC Physical Function and Stiffness scores and PGA of OA (P ? .002 for all) at week 8. For all analyses, oxycodone did not differ from placebo. Adverse event frequency was higher with oxycodone (63.3%) than tanezumab (40.7% to 44.7%) or placebo (35.5%); serious adverse event frequency was similar among treatments. The adverse event profile for tanezumab was similar to previous tanezumab studies. Results indicate that tanezumab is efficacious in the treatment of OA pain; no new safety signals were identified.     

Long-term safety and effectiveness of tanezumab as treatment for chronic low back pain

A noncontrolled, randomized, multicenter study (NCT00924664) evaluated long-term safety and effectiveness of tanezumab in patients with chronic low back pain following a randomized placebo- and active-controlled parent study that evaluated analgesic efficacy. Patients were randomized to tanezumab 10 mg (n = 321) or 20 mg (n = 527) administered at 8-week intervals via 3 intravenous injections followed by 4 subcutaneous injections. Effectiveness analyses included change from parent study baseline in Brief Pain Inventory Short Form, Roland Morris Disability Questionnaire, and Patient’s Global Assessment of low back pain. Safety assessments included adverse event documentation, physical/neurological examinations, and laboratory tests. Mean treatment duration during the extension study was 194 and 202 days with tanezumab 10 and 20 mg, respectively. Both tanezumab doses provided similar and sustained improvements in all effectiveness outcomes. The most frequently reported adverse events were arthralgia, paresthesia, and hypoesthesia. Adverse events initially described as osteonecrosis were reported in 6 patients (tanezumab 10 mg, n = 2; tanezumab 20 mg, n = 4); 9 additional patients (tanezumab 10 mg, n = 7; tanezumab 20 mg, n = 2) underwent total joint replacement (TJR). A blinded, independent adjudication committee reviewed all 6 patients with reported osteonecrosis and 4 of the 9 patients undergoing TJR. Adjudication outcomes were osteonecrosis (n = 0), worsening osteoarthritis (n = 5; 1 rapidly progressive), and another diagnosis or indeterminate (n = 5). Tanezumab 10 mg had better tolerability than tanezumab 20 mg, and may represent an effective long-term treatment for chronic low back pain.     

Tanezumab Reduces Osteoarthritic Knee Pain: Results of a Randomized, Double-Blind, Placebo-Controlled Phase III Trial

The objective of this study was to compare the analgesic efficacy of tanezumab versus placebo in patients with osteoarthritis (OA) of the knee. This was a 32-week, randomized, double-blind, placebo-controlled phase III trial (NCT00733902). The patient criteria included diagnosis of OA; Western Ontario and McMaster Universities OA Index (WOMAC) Pain and Physical Function subscale scores of ≥5 and ≥4, respectively; Patient's Global Assessment of Osteoarthritis (PGA) ≥3; and failure of nonopiate pain medications or candidacy for invasive interventions. Patients received 3 intravenous doses of tanezumab (2.5, 5, or 10 mg) or placebo. The co-primary efficacy end points were changes in WOMAC subscales and PGA at week 16. Adverse events were monitored throughout. Overall, 690 patients (61% female) were randomized and treated. Those treated with tanezumab showed significant improvement in the 3 co-primary end points (P ≤ .015 for all). The incidence of adverse events was 55 to 60% for tanezumab-treated patients versus 48% for placebo-treated patients. Joint replacement was reported in 4 patients, 1 in each treatment group; a total of 5 joints were replaced (1 index knee and 4 hips). The tanezumab OA clinical program is currently on clinical hold due to potential adverse reactions leading to joint replacement. PERSPECTIVE: This is the first phase III randomized, controlled trial to demonstrate that nerve growth factor blockade by tanezumab has superior analgesic efficacy in OA of the knee compared with placebo. Tanezumab was well tolerated, and reports of worsening OA and/or joint replacement were evenly distributed across the treatment groups.     

Efficacy,safety, and tolerability of fulranumab,an anti-nerve growth factor antibody,in the treatment of patients with moderate to severe osteoarthritis pain

Nerve growth factor (NGF) is increased in chronic pain conditions. This study examined analgesic efficacy and safety of fulranumab, a fully human monoclonal anti-NGF antibody, in adults with chronic osteoarthritis pain. Patients (n = 466, intent-to-treat) were randomized to receive, in addition to their current pain therapy, subcutaneous injections in 1 of 6 parallel treatment groups: placebo (n = 78), fulranumab 1 mg (n = 77) or 3 mg (n = 79) every 4 weeks (Q4wk), 3 mg (n = 76), 6 mg (n = 78), or 10 mg (n = 78) every 8 weeks (Q8wk). Primary efficacy results showed that fulranumab significantly reduced the average pain intensity score (P ? 0.030) from baseline to week 12 compared with placebo in the 3mgQ4wk, 6mgQ8wk, and 10mgQ8wk groups. Secondary efficacy outcomes indicated that significant improvement occurred compared with placebo at week 12 on the Western Ontario and McMaster Universities Osteoarthritis Index subscales of pain, stiffness, and physical function (P < 0.040) across all fulranumab groups except 1mgQ4wk, on the Brief Pain Inventory–Short Form subscales of pain intensity (P ? 0.016) and pain interference (P ? 0.030) in the 3mgQ4wk and 10mgQ8wk groups, and on the Patient Global Assessment score (P ? 0.040) in the 3mgQ4wk, 6mgQ8wk, and 10mgQ8wk groups. The most common (?5% of patients) treatment-emergent adverse events in overall fulranumab groups during the first 12 weeks included paresthesia (7%), headache (5%), and nasopharyngitis (5%). Most neurologic-related treatment-emergent adverse events were mild or moderate and resolved at the end of week 12. Serious adverse events occurred in 3 patients, but they were not neurologically related and resolved before study completion. Fulranumab treatment resulted in statistically significant efficacy in pain measures and physical function versus placebo and was generally well tolerated.     

TRPV1 antagonistic analgesic effect: A randomized study of AZD1386 in pain after third molar extraction

The effects of a TRPV1 antagonist (AZD1386) were investigated in patients with acute pain. After removal of a mandibular third molar and at request of analgesia 103 patients randomly received 95 mg AZD1386 (n = 40), placebo (n = 40) or 500 mg naproxen (n = 23) in a double-blind manner. Plasma samples were drawn, and pain intensity and body temperature were measured during 8 h after drug administration. The pain intensity difference from drug intake was calculated as a percentage (PID%) and as a weighted sum over the 8 h (SPID%_0–8h). The time to first perceptible and first meaningful pain relief was recorded. SPID%_0–8h showed no significant difference between AZD1386 and placebo (P = .132) but between naproxen and placebo (P = .038). AZD1386 had a rapid short-lasting analgesia and compared to placebo, PID% was significantly higher (P ? .026) at 0.25, 0.50, 0.75 and 1.00 h after drug administration. Correspondingly, for naproxen significantly higher PID% (P ? .021) was seen at 2.5, 3, 4, 5, 6, 7 and 8 h. The frequency of patients obtaining perceptible and meaningful pain relief was about 85% and 48% after AZD1386 and about 53% and 25% after placebo. The occurrence of perceptible and meaningful pain relief was significantly faster (P = .002 and P = .031) for AZD1386 compared to placebo. Adverse events were similar to placebo with the exception of 2 patients reporting chills. The highest individual body temperature after AZD1386 was 38.1°C, recorded in 2 patients. In summary, AZD1386 was well tolerated with a rapid analgesia that was short lasting despite sustained plasma concentration.     

Randomized Controlled Trial of Nurse-Delivered Cognitive-Behavioral Therapy Versus Supportive Psychotherapy Telehealth Interventions for Chronic Back Pain

This study evaluated a nurse-delivered, telehealth intervention of cognitive-behavioral therapy (CBT) versus supportive psychotherapy for chronic back pain. Participants (N?=?61) had chronic back pain (pain “daily”?≥6 months at an intensity of ≥4 of 10 scale) and were randomized to an 8-week, 12-session, CBT or to supportive care (SC) matched for frequency, format, and time, with each treatment delivered by a primary care nurse. The primary outcome was the Roland Morris Disability Questionnaire (RMDQ). Secondary outcomes included the numeric rating scale (NRS) and the Patient Global Impressions Scale (CGI). CBT participants (n?=?30) showed significant improvements on the RMDQ (mean = 11.4 [SD = 5.9] vs 9.4 [SD = 6.1] at baseline and post-treatment, respectively, P?<?.05; d?=?.33), NRS (mean = 4.9 [SD = 2.1] vs 4.0 [SD = 1.9], respectively, P?<?.05; d?=?.45), and on the CGI (39.1% reporting “much improved” or “very much improved”). SC participants (n?=?31) also showed significant improvements on the RMDQ (mean = 11.1 [SD = 5.4] vs 9.1 [SD = 5.2], respectively, P?<?.05; d?=?.38), the NRS, (mean = 5.0 [SD = 1.9] vs 3.8 [SD = 2.1], respectively, P?<?.05; d?=?.60), and 26.7% reporting “much improved” or “very much improved” on the CGI. Between groups comparisons of CBT and SC showed no differences on the study outcomes (Ps > .10). The results suggest that telehealth, nurse-delivered CBT, and SC treatments for chronic back pain can offer significant and relatively comparable benefits.

Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo,DMSO vehicle and oral diclofenac for knee osteoarthritis

While topical non-steroidal anti-inflammatory drugs are considered safe, their long-term efficacy for osteoarthritis has been suspect. We conducted a 12-week, double-blind, double-dummy, randomized controlled trial of topical diclofenac (TDiclo) in a vehicle solution containing dimethyl sulfoxide (DMSO) in 775 subjects with radiologically confirmed, symptomatic primary osteoarthritis of the knee. This 5-arm study compared TDiclo with a placebo solution, the DMSO vehicle, oral diclofenac (ODiclo) and the combination of TDiclo + ODiclo for relieving the signs and symptoms of knee osteoarthritis. Subjects applied study solution, 40 drops four times daily, and took one study tablet daily for 12 weeks. Co-primary efficacy variables were WOMAC pain and physical function and a patient overall health assessment. Secondary variables were WOMAC stiffness and patient global assessment (PGA) of the knee osteoarthritis. TDiclo was superior to placebo for pain (−6.0 vs. −4.7, P = 0.015), physical function (−15.8 vs. −12.3, P = 0.034), overall health (−0.95 vs. −0.37, P < 0.0001), and PGA (−1.36 vs. −1.01, P = 0.016), and was superior to DMSO vehicle for all efficacy variables. No significant difference was observed between DMSO vehicle and placebo or between TDiclo and ODiclo. The commonest adverse event associated with TDiclo was dry skin (18.2%). Fewer digestive system and laboratory abnormalities were observed with TDiclo than with ODiclo. Addition of TDiclo to ODiclo did not increase the incidence of systemic adverse events. TDiclo in DMSO vehicle is an effective treatment option for knee osteoarthritis with efficacy similar to, but tolerability better than ODiclo. DMSO vehicle was no more efficacious than placebo.     

A pilot trial of intravenous pamidronate for chronic low back pain

Intravenous (i.v.) bisphosphonates relieve pain in conditions such as Paget’s disease of bone, metastatic bone disease, and multiple myeloma. Based on positive findings from a prior case series, we conducted a randomized placebo-controlled study to assess the analgesic effect of i.v. pamidronate in subjects with chronic low back pain (CLBP) and evidence of degenerative disease of the spine. Four groups of 11 subjects (7 active, 4 placebo) were enrolled at escalating dose levels of 30, 60, 90, and 180 mg pamidronate (the latter administered as two 90 mg infusions). Primary outcomes were safety and change from baseline in average daily pain scores, recorded at 1, 2, 3, and 6 months postinfusion using electronic diaries. Secondary outcomes included responder rate, daily worst pain, and pain-related interference with daily function. There were no pamidronate-related serious adverse events or other significant safety findings. A statistically significant overall treatment difference in pain scores was observed, with clinically meaningful effects persisting for 6 months in the 180 mg pamidronate group. Least squares mean changes in daily average pain score were −1.39 (SE = 0.43) for placebo, and −1.53 (0.71), −1.26 (0.81), −1.42 (0.65), and −4.13 (0.65) for pamidronate 30, 60, 90, and 180 mg, respectively (P = 0.012 for pamidronate 180 mg vs placebo). The proportion of responders, changes in worst pain, and pain interference with daily function were also significantly improved for pamidronate 180 mg compared with placebo. In conclusion, i.v. pamidronate, administered as two 90 mg infusions, decreased pain intensity for 6 months in subjects with CLBP.     

A randomized placebo-controlled trial of intradiscal methylene blue injection for the treatment of chronic discogenic low back pain

A preliminary report of clinical study revealed that chronic discogenic low back pain could be treated by intradiscal methylene blue (MB) injection. We investigated the effect of intradiscal MB injection for the treatment of chronic discogenic low back pain in a randomized placebo-controlled trial. We recruited 136 patients who were found potentially eligible after clinical examination and 72 became eligible after discography. All the patients had discogenic low back pain lasting longer than 6 months, with no comorbidity. Thirty-six were allocated to intradiscal MB injection and 36 to placebo treatment. The principal criteria to judge the effectiveness included alleviation of pain, assessed by a 101-point numerical rating scale (NRS-101), and improvement in disability, as assessed with the Oswestry Disability Index (ODI) for functional recovery. At the 24-month follow-up, both the groups differed substantially with respect to the primary outcomes. The patients in MB injection group showed a mean reduction in pain measured by NRS of 52.50, a mean reduction in Oswestry disability scores of 35.58, and satisfaction rates of 91.6%, compared with 0.70%, 1.68%, and 14.3%, respectively, in placebo treatment group (p < 0.001, p < 0.001, and p < 0.001, respectively). No adverse effects or complications were found in the group of patients treated with intradiscal MB injection. The current clinical trial indicates that the injection of methylene blue into the painful disc is a safe, effective and minimally invasive method for the treatment of intractable and incapacitating discogenic low back pain.     

A phase 2, double-blind,randomized, placebo-controlled,dose-escalation study to evaluate the efficacy,safety, and tolerability of naloxegol in patients with opioid-induced constipation

Naloxegol (previously known as NKTR-118) is a peripherally acting μ-opioid receptor antagonist engineered using polymer conjugate technology in development as an oral, once-daily agent for the treatment of opioid-induced constipation (OIC). Eligible patients with OIC (n = 207), defined as <3 spontaneous bowel movements (SBMs) per week with accompanying symptoms, on a stable opioid regimen of 30–1000 mg/day morphine equivalents for ?2 weeks were randomized to receive 4 weeks of double-blind placebo or naloxegol (5, 25, or 50 mg) once daily in sequential cohorts after a 1-week placebo run-in. The primary end point, median change from baseline in SBMs per week after week 1 of drug administration, was statistically significant for the 25- and 50-mg naloxegol cohorts vs placebo (2.9 vs 1.0 [P = 0.0020] and 3.3 vs 0.5 [P = 0.0001], respectively). The increase in SBMs vs placebo was maintained over 4 weeks for naloxegol 25 mg (3.0 vs 0.8 [P = 0.0022]) and 50 mg (3.5 vs 1.0 [P < 0.0001]). Naloxegol was generally well tolerated across all dosages. The most frequent adverse events (AEs) were abdominal pain, diarrhea, and nausea. Most AEs at 5 and 25 mg/day were mild and transient. Similar AEs occurred with increased frequency and severity in the 50-mg cohort. There was no evidence of a statistically significant increase from baseline in pain, opioid use for the 25- and 50-mg cohorts, or centrally mediated opioid withdrawal signs and/or symptoms with naloxegol. These data demonstrate that once-daily oral naloxegol improves the frequency of SBMs compared with placebo and is generally well tolerated in this population of patients with OIC.     

Identifying neuropathic back and leg pain: a cross-sectional study

Low back pain is a widespread debilitating problem with a lifetime prevalence of 80%, with the underlying pain mechanism unknown in approximately 90% of cases. We used the painDETECT neuropathic pain screening questionnaire to identify likely pain mechanisms in 343 patients with low back pain with or without leg pain in southeastern England referred for physiotherapy. We related the identified possible pain mechanisms nociceptive, unclear, and neuropathic to standardised measures of pain severity (Numeric Rating Scale), disability (Roland Morris Low Back Pain Disability Questionnaire), anxiety and depression (Hospital Anxiety and Depression Scale), and quality of life (Short Form 36 Health Survey Questionnaire Version 2). In addition, we investigated any relationship between these possible pain mechanisms and leg pain, passive straight leg raise, and magnetic resonance imaging evidence confirming or eliminating nerve root compression. A total of 59% of participants (n = 204) reported likely nociceptive pain, 25% (n = 85) unclear, and 16% (n = 54) possible neuropathic pain. The possible neuropathic pain group reported significantly higher pain, disability, anxiety, and depression, reduced quality of life and passive straight leg raise compared to the other pain groups (P < .05). A total of 96% of participants with possible neuropathic pain reported pain radiating to the leg (76% below the knee); however, leg pain was still more common in patients with nociceptive pain, suggesting that leg pain is sensitive to, but not specific to, possible neuropathic pain. No relationship was demonstrated between possible neuropathic pain and evidence for or absence of nerve root compression on magnetic resonance imaging scans. These findings suggest possible neuropathic pain is less common in low back pain patients referred through primary care and clarifies the usefulness of clinical tests for identifying possible neuropathic pain.     

Relationship between physical activity and disability in low back pain: a systematic review and meta-analysis

It is often assumed that patients with pain-related disability due to low back pain (LBP) will have reduced physical activity levels, but recent studies have provided results that challenge this assumption. The aim of our systematic review was to examine the relationship between physical activity and disability in LBP. The literature search included 6 electronic databases and the reference list of relevant systematic reviews and studies to May 2010. To be included, studies had to measure both disability (eg, with the Roland Morris Disability Questionnaire) and physical activity (eg, by accelerometry) in patients with non-specific LBP. Two independent reviewers screened search results and extracted data, and authors were contacted for additional data. Correlation coefficients were pooled using the random-effects model. The search identified 3213 records and 18 studies were eligible for inclusion. The pooled results showed a weak relationship between physical activity and disability in acute or subacute (<3 months) LBP (r = −0.08, 95% confidence interval = −0.17 to 0.002), and a moderate and negative relationship in chronic (>3 months) LBP (r = −0.33, 95% confidence interval = −0.51 to −0.15). That is, persons with acute or subacute LBP appear to vary in the levels of physical activity independent of their pain-related disability. Persons with chronic LBP with high levels of disability are also likely to have low levels of physical activity.     

Duloxetine,a centrally acting analgesic,in the treatment of patients with osteoarthritis knee pain: A 13-week,randomized, placebo-controlled trial

Pain is a common cause of disability in osteoarthritis. Duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI), has demonstrated analgesic effects in diabetic peripheral neuropathy and fibromyalgia. Considering its central mechanism of action, duloxetine may be effective in other pain states with evidence of central sensitization. Herein, we report the results of a 13-week, randomized, double-blind, placebo-controlled trial of duloxetine (60–120 mg/day) versus placebo in the treatment of knee pain in 231 patients meeting clinical and radiographic criteria for osteoarthritis of the knee. Duloxetine was superior to placebo on the primary efficacy measure (weekly mean 24-h pain scores) beginning at Week 1 and continuing through the treatment period (P ? .05). There was also a significant improvement in the WOMAC physical functioning subscale and several other secondary outcomes. Adverse-event rates did not differ significantly between treatment groups (49.5% for duloxetine 60–120 mg/day, and 40.8% for placebo).     

Duloxetine Versus Placebo in Patients With Chronic Low Back Pain: A 12-Week,Fixed-Dose,Randomized, Double-Blind Trial

This randomized, double-blind, placebo-controlled study assessed efficacy and safety of duloxetine in patients with chronic low back pain (CLBP). Adults (n = 401) with a nonneuropathic CLBP and average pain intensity of ≥4 on an 11-point numerical scale (Brief Pain Inventory [BPI]) were treated with either duloxetine 60 mg once daily or placebo for 12 weeks. The primary measure was BPI average pain. Secondary endpoints included Patient's Global Impressions of Improvement (PGI-I), Roland Morris Disability Questionnaire (RMDQ-24), BPI-Severity (BPI-S), BPI-Interference (BPI-I), and response rates (either ≥30% or ≥50% BPI average pain reduction at endpoint). Health outcomes included Short Form-36, European Quality of Life–5 Dimensions, and the Work Productivity and Activity Impairment questionnaire. Safety and tolerability were assessed. Compared with placebo-treated patients, duloxetine-treated patients reported a significantly greater reduction in BPI average pain (P ≤ .001). Similarly, duloxetine-treated patients reported significantly greater improvements in PGI-I, BPI-S, BPI-I, 50% response rates, and some health outcomes. The RMDQ and 30% response rate showed numerical improvements with duloxetine treatment. Significantly more patients in the duloxetine group (15.2%) than patients in the placebo group (5.4%) discontinued because of adverse events (P = .002). Nausea and dry mouth were the most common treatment-emergent adverse events with rates significantly higher in duloxetine-treated patients.     

Distinctiveness of psychological obstacles to recovery in low back pain patients in primary care

Many psychological factors have been suggested to be important obstacles to recovery from low back pain, yet most studies focus on a limited number of factors. We compared a more comprehensive range of 20 factors in predicting outcome in primary care. Consecutive patients consulting 8 general practices were eligible to take part in a prospective cohort study; 1591 provided data at baseline and 810 at 6 months. Clinical outcome was defined using the Roland and Morris Disability Questionnaire (RMDQ). The relative strength of the baseline psychological measures to predict outcome was investigated using adjusted multiple linear regression techniques. The sample was similar to other primary care cohorts (mean age 44 years, 59% women, mean baseline RMDQ 8.6). The 20 factors each accounted for between 0.04% and 33.3% of the variance in baseline RMDQ score. A multivariate model including all 11 scales that were associated with outcome in the univariate analysis accounted for 47.7% of the variance in 6 months RMDQ score; rising to 55.8% following adjustment. Four scales remained significantly associated with outcome in the multivariate model explaining 56.6% of the variance: perceptions of personal control, acute/chronic timeline, illness identify and pain self-efficacy. When all independent factors were included, depression, catastrophising and fear avoidance were no longer significant. Thus, a small number of psychological factors are strongly predictive of outcome in primary care low back pain patients. There is clear redundancy in the measurement of psychological factors. These findings should help to focus targeted interventions for back pain in the future.     

Results from clinical trials of a selective ionotropic glutamate receptor 5 (iGluR5) antagonist,LY5454694 tosylate,in 2 chronic pain conditions

This article reports results of 2 studies investigating LY545694 in pain due to osteoarthritis (OA) of the knee and diabetic peripheral neuropathic pain (DPNP). Study I randomized patients to either of 2 doses of LY545694 or to placebo, and study II randomized patients to either of 3 doses of LY545694, to pregabalin, or to placebo. No significant differences between LY545694 groups and placebo were observed on the primary (average pain severity) or secondary efficacy measures in either study. Notably, study I lacked an active control, and, in study II, pregabalin, did not separate from placebo. Treatment-emergent nausea, vomiting, and dizziness were significantly more frequent in the LY545694 groups in both trials (P ? .05), and significantly more LY545694-treated patients discontinued because of adverse events (P < .001). Steady-state concentrations of LY545694 were comparable in patients in both studies but were lower than exposures required for efficacy in animal models of pain behavior. Because the active control did not separate from placebo in the DPNP study, the study was potentially failed, rather than negative. Without an active control, it is unknown whether the OA study was negative or failed. Consequently, efficacy of selective ionotropic glutamate receptor antagonism in chronic pain conditions may warrant further investigation. Future trials should consider different pain conditions, contain a positive control with larger patient numbers per arm, and be conducted within a single region.     

Fasinumab (REGN475), an antibody against nerve growth factor for the treatment of pain: Results from a double-blind,placebo-controlled exploratory study in osteoarthritis of the knee

The safety, tolerability, and efficacy of fasinumab (REGN475), a fully human monoclonal antibody against nerve growth factor, was evaluated for the treatment of pain in patients with osteoarthritis (OA) of the knee. This was a 24-week, double-blind, placebo-controlled, parallel-group, repeat-dose, exploratory study. Eligible patients 40 to 75 years of age with a diagnosis of OA of the knee and moderate to severe pain were randomized 1:1:1:1 to intravenous fasinumab 0.03, 0.1, or 0.3 mg/kg or placebo and received study drug on day 1 and day 57. Pain intensity was recorded daily using the numeric rating scale. Safety and tolerability, assessed by the incidence of treatment-emergent adverse events (TEAEs), was the primary study endpoint. Secondary study endpoints included the change from baseline in daily walking knee pain and the assessment of pain, function, and stiffness using the Western Ontario and McMaster Osteoarthritis (WOMAC) index. Baseline characteristics were similar among treatment groups (N = 217). After 24 weeks, the incidence of TEAEs ranged from 66.1% to 75.0% in the fasinumab groups vs 63.6% for placebo. The most common TEAEs included arthralgia, hyperesthesia, myalgia, peripheral edema, and joint swelling. Discontinuation for TEAEs occurred in 5.6% of fasinumab patients and 3.7% of placebo patients. All 3 doses of fasinumab were associated with significant (P < .05) improvements compared with placebo in walking knee pain and WOMAC total and subscale scores. Fasinumab was generally well tolerated, and was associated with a significant reduction in walking knee pain and an improvement in function for up to 8 weeks.     

Altered experimental pain perception after cerebellar infarction

Animal studies have suggested that the cerebellum, in addition to its motor functions, also has a role in pain processing and modulation, possibly because of its extensive connections with the prefrontal cortex and with brainstem regions involved in descending pain control. Consistently, human imaging studies have shown cerebellar activation in response to painful stimulation. However, it is presently not clear whether cerebellar lesions affect pain perception in humans. In the present study, we used experimental pain testing to compare acute pain perception and endogenous pain inhibition in 30 patients 1 to 11 years after cerebellar infarction and in 30 sex- and age-matched healthy control subjects. Compared to controls, patients exhibited a significantly increased pain perception in response to acute heat stimuli (44°C–48°C, average pain intensity rating for patients 3.4 ± 2.8 and for controls 1.5 ± 1.7 [on a numeric rating scale of 0–10], P < .01) and to repeated 256 mN pinprick stimuli (1.3 ± 1.9 vs 0.6 ± 1.0 [0–10], P < .05). Heat hyperalgesia in patients was more pronounced on the body side ipsilateral to the infarction. In addition, patients showed reduced offset analgesia (change in pain intensity rating: 0.0% ± 15.8% vs −16.9% ± 36.3%, P < .05) and reduced placebo analgesia (change in pain intensity rating: −1.0 ± 1.1 vs −1.8 ± 1.3 [0–10], P < .05) compared to controls. In contrast, heat and pressure pain thresholds were not significantly different between groups. These results show that, after cerebellar infarction, patients perceive heat and repeated mechanical stimuli as more painful than do healthy control subjects and have deficient activation of endogenous pain inhibitory mechanisms (offset and placebo analgesia). This suggests that the cerebellum has a previously underestimated role in human pain perception and modulation.     

Endogenous opioid function mediates the association between laboratory-evoked pain sensitivity and morphine analgesic responses

Predictors of responsiveness to opioid analgesic medications are not well understood. This study tested whether individual differences in endogenous opioid (EO) function are associated with analgesic responsiveness to morphine. In randomized, counterbalanced order over 3 sessions, 45 chronic low back pain participants and 31 healthy controls received an opioid antagonist (8 mg naloxone), morphine (0.08 mg/kg), or placebo. Participants then engaged in 2 laboratory-evoked pain tasks (ischemic and thermal). Outcomes included pain threshold, pain tolerance, and pain ratings. Indexes of EO function and morphine analgesic responsiveness were derived for each measure as the difference in pain responses between the placebo condition and naloxone or morphine condition, respectively. For all 7 pain measures across the 2 laboratory pain tasks, greater EO function was associated with significantly lower morphine analgesic responsiveness (P < 0.001–P = 0.02). Morphine reduced pain responses of low EO individuals to levels similar to those of high EO individuals receiving placebo. Higher placebo condition–evoked pain sensitivity was associated with significantly greater morphine analgesic responsiveness for 5 of 7 pain measures (P < 0.001–P = 0.02). These latter associations were significantly mediated by EO function for 4 of these 5 pain outcomes (all P values < 0.05). In the laboratory-evoked pain context, opioid analgesic medications may supplement inadequate EO analgesia, with little incremental benefit in those with preexisting high EO function. Implications for personalized medicine are discussed.