A Review of Duloxetine 60 mg Once‐Daily Dosing for the Management of Diabetic Peripheral Neuropathic Pain,Fibromyalgia, and Chronic Musculoskeletal Pain Due to Chronic Osteoarthritis Pain and Low Back Pain

Background: Duloxetine is a selective dual neuronal serotonin (5‐Hydroxytryptamine, 5‐HT) and norepinephrine reuptake inhibitor (SSNRI). It is indicated in the United States for treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), and several chronic pain conditions, including management of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain due to chronic osteoarthritis (OA) pain and chronic low back pain (LBP). Its use for antidepressant and anxiolytic actions has been extensively reviewed previously. We here review the evidence for the efficacy of 60 mg once‐daily dosing of duloxetine for chronic pain conditions. Method: The literature was searched for clinical trials in humans conducted in the past 10 years involving duloxetine. Results: There were 199 results in the initial search. Studies not in the English language were excluded. We then included only studies of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain (OA and LBP). Studies of painful symptoms reported in mental health studies were excluded. This resulted in 32 studies. Articles that did not include a 60 mg/day daily dose as a study arm were excluded. This resulted in 30 studies, broken down as follows: 12 for diabetic peripheral neuropathy, 9 for fibromyalgia, 6 for LBP, and 3 for OA pain. Conclusions: The studies reviewed report that duloxetine 60 mg once‐daily dosing is an effective option for the management of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain due to chronic OA pain and chronic LBP. As these pains are often comorbid with MDD or GAD, duloxetine might possess the pharmacologic properties to be a versatile agent able to address several symptoms in these patients. With adequate attention to FDA prescribing guidance regarding safety and drug–drug interactions, duloxetine 60 mg once‐daily dosing appears to be an effective option in the appropriate pain patient population.     

Efficacy of Periosteal Stimulation for Chronic Pain Associated With Advanced Knee Osteoarthritis: A Randomized,Controlled Clinical Trial

Background

Because of morbidity associated with painful knee osteoarthritis (OA) and commonly prescribed analgesics, patients often pursue complementary and alternative modalities (eg, acupuncture). Clinical trials have demonstrated modest therapeutic efficacy of traditional Chinese acupuncture for knee OA pain, and patients with advanced disease have largely been excluded. We have previously demonstrated preliminary short-term tolerability and efficacy of periosteal stimulation therapy (PST) (ie, electrical stimulation of the periosteum facilitated by acupuncture needles) for older adults with advanced knee OA.

Objective

This study evaluated the sustained efficacy of PST and boosters for treating chronic pain with advanced knee OA.

Methods

One hundred ninety participants age >50 years with Kellgren-Lawrence grade 3 or 4 knee OA and chronic pain were randomized to (1) PST (once a week for 10 weeks) followed by PST boosters for 6 months (once every 2 weeks 2 times, then once a month), (2) control PST (ie, periosteal needles and brief electrical stimulation of control points) once a week for 10 weeks, or (3) PST for 10 weeks followed by control PST boosters for 6 months. Change in the Western Ontario and McMaster Universities Osteoarthritis Index pain score immediately after the 10-week intervention and at 6-month follow-up (9 months after baseline) was the primary outcome. OMERACT-OARSI (Outcome Measures in Rheumatology Clinical Trials–Osteoarthritis Research Society International) criteria also were evaluated. Secondary measures of outcome included (1) physical performance (Short Physical Performance Battery, gait speed, Timed Up and Go, and timed stair climb); (2) psychological factors (depressive symptoms measured with the Center for Epidemiologic Studies–Depression scale, coping measured with the catastrophizing subscale of the Coping Strategies Questionnaire, and self-efficacy measured with the Arthritis Self-Efficacy Scale); (3) health-related quality of life measured with the Medical Outcomes Study 36-Item Short-Form Health Survey; (4) rescue pain medication use tracked with diaries; and (5) health care utilization and interim physical activity were monitored via monthly telephone calls.

Results

After adjustment for pain at baseline, the PST and control booster did not differ from controls at 10 weeks (difference, 1.3; 95% CI, −0.10 to 2.8; P = 0.0683) or 9 months (difference, 1.1; 95% CI, −0.32 to 2.6; P = 0.13). The PST and PST booster group had similar improvement compared with controls at 10 weeks (baseline adjusted difference, 1.1; 95% CI, −0.34 to 2.5; P = 0.1369) but significantly more improvement at 9 months (baseline adjusted difference, 1.5; 95% CI, 0.069 to 3.0; P = 0.0401). Baseline depressive symptoms, low self-efficacy, higher difficulty performing daily activities, and greater knee stiffness predicted a lower likelihood of response.

Conclusion

PST plus PST boosters in patients age >50 with advanced knee OA were well-tolerated and modestly reduced pain. ClinicalTrials.gov identifier: NCT00865046.     

Results of a Double‐blind,Placebo‐controlled,Fixed‐dose Assessment of Once‐daily OROS® Hydromorphone ER in Patients with Moderate to Severe Pain Associated with Chronic Osteoarthritis

Objective: Opioids are recommended for patients with moderate to severe pain due to osteoarthritis (OA), who do not receive adequate analgesia from nonopioid treatment. The objective of this study was to evaluate the efficacy and safety of OROS hydromorphone extended‐release (ER) compared with placebo in patients with moderate to severe pain associated with OA. Methods: This was a randomized, placebo‐controlled, double‐blind, fixed‐dose study. Patients received placebo or fixed‐dose OROS hydromorphone ER (8 or 16 mg). The primary efficacy measure was pain intensity score (11‐point Numeric Rating Scale) at Maintenance Week 12, analyzed with baseline observation carried forward (BOCF) imputation for missing data. Results: This study did not meet the primary efficacy measure using the BOCF imputation. Study discontinuation was high (52%). When analyzed using last observation carried forward (LOCF) imputation, the prespecified alternate method, OROS hydromorphone ER 16 mg provided significantly better analgesia than placebo (P = 0.0009). Treatment was associated with significant improvements in patient global assessment (P = 0.01), the overall Western Ontario and McMaster Osteoarthritis Index (WOMAC) (P = 0.0003), and its subscales: pain (P = 0.0001), stiffness (P = 0.0023), and physical function (P = 0.0006). Gastrointestinal adverse events, such as constipation and nausea, were common among patients receiving OROS hydromorphone ER. Conclusions: OROS hydromorphone ER failed to achieve statistical significance for the primary endpoint using the prespecified imputation method (BOCF), likely due to the high discontinuation rate associated with the fixed‐dose design. When data were analyzed according to an alternate method of imputation (LOCF), OROS hydromorphone ER demonstrated statistically significant improvements in pain, stiffness, and physical function.     

Pulsed Radiofrequency of Suprascapular Nerve for Chronic Shoulder Pain: A Randomized Double‐Blind Active Placebo‐Controlled Study

Background: The suprascapular nerve block is frequently implemented to treat chronic shoulder pain. Although effective the nerve blockade provides only a short‐term relief, and more compelling apaproaches have been investigated. Pulsed radiofrequency (pRF) has been anecdotally reported as safe and reliable method. However, formal efficacy study has not been published. Ostensibly evidence‐based validation of a new method is necessary for both scholastic and practical purposes. Methods: This study was designed as a randomized active placebo‐control double‐blind trial. Because of encountered difficulties in recruitment and high rate of dropout, the study was redesigned as to allow a smaller sample size and statistical analyses were performed utilizing the last observation carry forward method. Lidocaine injections alone or with combination of the pRF were performed. Participants were followed up during 6 months, and multiple subjective and objective outcome variables were recorded. Results: Thirteen of 22 participants completed 6 months follow‐up. Dropout rate was higher in the lidocaine group. A significant linear trend (P < 0.05) for improvement on the numeric rating scale, Shoulder Pain and Disability Index and Constant‐Murley score was observed in the pRF group, but not in the lidocaine group. Patients in the pRF group were on average more satisfied than the lidocaine group at 1 month (P = 0.041) and at 3 months (P = 0.035). Discussion: Considering limitations of the study design and statistics, it seems plausible to attribute better results in the pRF group to unique properties of this physical modality.     

Preoperative Gabapentin for Acute Post‐thoracotomy Analgesia: A Randomized,Double‐Blinded,Active Placebo‐Controlled Study

Background: The role of preoperative gabapentin in postoperative pain management is not clear, particularly in patients receiving regional blockade. Patients undergoing thoracotomy benefit from epidural analgesia but still may experience significant postoperative pain. We examined the effect of preoperative gabapentin in thoracotomy patients. Methods: Adults undergoing elective thoracotomy were enrolled in this prospective, randomized, double‐blinded, placebo‐controlled study, and randomly assigned to receive 600 mg gabapentin or active placebo (12.5 mg diphenhydramine) orally within 2 hours preoperatively. Standardized management included thoracic epidural infusion, intravenous patient‐controlled opioid analgesia, acetaminophen and ketorolac. Pain scores, opioid use and side effects were recorded for 48 hours. Pain was also assessed at 3 months. Results: One hundred twenty patients (63 placebo and 57 gabapentin) were studied. Pain scores did not significantly differ at any time point (P = 0.53). Parenteral and oral opioid consumption was not significantly different between groups on postoperative day 1 or 2 (P > 0.05 in both cases). The frequency of side effects such as nausea and vomiting or respiratory depression was not significantly different between groups, but gabapentin was associated with decreased frequency of pruritus requiring nalbuphine (14% gabapentin vs. 43% control group, P < 0.001). The frequency of patients experiencing pain at 3 months post‐thoracotomy was also comparable between groups (70% gabapentin vs. 66% placebo group, P = 0.72). Conclusions: A single preoperative oral dose of gabapentin (600 mg) did not reduce pain scores or opioid consumption following elective thoracotomy, and did not confer any analgesic benefit in the setting of effective multimodal analgesia that included thoracic epidural infusion.     

The Long‐Term Outcome of Transcutaneous Electrical Nerve Stimulation in the Treatment for Patients with Chronic Pain: A Randomized,Placebo‐Controlled Trial

Background: Transcutaneous electrical nerve stimulation (TENS) is an easy to use analgesic intervention. However, long‐term randomized placebo‐controlled studies with treatment periods of more than 3 months have not been executed to date. The aim of our study is to explore the long‐term (1 year) time course of the treatment effects of TENS compared to placebo (sham TENS). Method: We performed a randomized placebo‐controlled trial in patients with chronic pain (165), referred to a multidisciplinary pain center of a university hospital. Main outcome measures are the proportion of patients satisfied with treatment result and willing to continue treatment, pain intensity, pain disability, and perceived health status. Results: Survival analysis of time courses of proportions of satisfied patients revealed no significant differences (P = 0.79; log‐rank test) for TENS treatment compared to sham TENS. After 1 year, 30% (24/81) of the patients of the TENS group and 23% (19/82) of the sham TENS group were satisfied with treatment result. These patients experienced a mean overall improvement of 62.7% (n = 43). This effect was not significantly different between both groups. For satisfied patients, there were no differences in pain intensity or disability and perceived health status between the TENS and sham TENS group. Conclusions: Transcutaneous electrical nerve stimulation and sham TENS show similar effects in patients with chronic pain over a period of 1 year. We found support for a long sustained placebo effect.     

Prospective, Randomized, Single-Blind, Sham Treatment-Controlled Study of the Safety and Efficacy of an Electromagnetic Field Device for the Treatment of Chronic Low Back Pain: A Pilot Study

Objectives: To evaluate the efficacy and safety of therapeutic electromagnetic fields (TEMF) on chronic low back pain. Secondary objectives included the investigation of the effects of TEMF on psychometric measures. Setting: Pain Research center in an Urban Academic Rehabilitation Facility. Design: Prospective, randomized, single‐blind, placebo (sham) treatment‐controlled design in which participants were evaluated over a 6‐week period. A total of 40 subjects were randomly assigned: 20 subjects to 15 milliTESLA (mT) treatment using a prototype electromagnetic field device and 20 to sham treatment. Interventions: After a 2‐week baseline period, eligible individuals were randomized to one of the treatment groups (sham or 15 mT) for six 30‐minute treatments over 2 weeks, then a 2‐week follow‐up period. Outcome Measures: The primary outcome measure was the self‐report of pain severity using a 100 mm visual analog scale collected using a twice daily McGill Pain Questionnaire—Short Form. Several secondary measures were assessed. Results: Both groups (15 mT and sham) improved over time (P < 0.05). Although groups were similar during the treatment period, treated subjects (TEMF of 15 mT) improved significantly over sham treatment during the 2‐week follow‐up period (20.5% reduction in pain; F_1,34 = 10.62, P = 0.003). There were no reported serious adverse events. Conclusions: This study demonstrates that TEMF may be an effective and safe modality for the treatment of chronic low back pain disorders. More studies are needed to test this hypothesis.