Effect of Opioids on Testosterone Levels: Cross-Sectional Study using NHANES.

OBJECTIVE: Opioids can suppress gonadal hormone production, which may result in low testosterone levels. To date, there have been no large-scale population-based studies examining the extent to which opioid use may contribute to changes in testosterone levels. DESIGN: Cross-sectional study. SETTING: 2011-2012 National Health and Nutrition Examination Survey. SUBJECTS: Participants 17 years and older who had data on prescription medication usage and serum testosterone levels available. Participants were divided in two groups, opioid exposed and unexposed. METHODS: Testosterone levels of participants who responded that they had been exposed (n = 320) to prescription opioids in the past 30 days were compared with those who were unexposed (n = 4909). The number of participants with low testosterone levels was calculated and unadjusted and adjusted analyses were performed. RESULTS: Participants on opioids had higher odds of having low testosterone levels than those unexposed, odd ratio (OR) = 1.40, 95% confidence interval (CI) (1.07-1.84). After controlling for opioid exposure, as the age and the number of comorbidities increased, the odds of having low testosterone levels significantly increased in all categories. Compared with participants between 17 and 45 years of age, participants >70 years had OR = 1.70, 95% CI (1.16-2.50). Compared with participants with no comorbidities, participants with >2 comorbidities had OR = 1.69 95% CI (1.24-2.30). CONCLUSION: When assessing the impact of opioids on testosterone, the effects of age and medical conditions should be considered.

Does tapentadol affect sex hormone concentrations differently from morphine and oxycodone? An initial assessment and possible implications for opioid-induced androgen deficiency.

OBJECTIVES: Opioid-induced androgen deficiency (OPIAD) affects patients treated with opioid analgesics. The norepinephrine reuptake inhibitor (NRI) and µ-opioid receptor (MOR) agonist activities of tapentadol may result in tapentadol having less effect on serum androgen concentrations than analgesics acting through the MOR alone, such as morphine and oxycodone. The objectives of this publication are to 1) evaluate the effects of tapentadol (NUCYNTA and NUCYNTA extended release [ER]) on sex hormone concentrations in healthy male volunteers (vs placebo and morphine) and patients with osteoarthritis (vs placebo and oxycodone), and 2) present a mechanistic hypothesis explaining how the combined MOR agonist and NRI activities of tapentadol may result in less impact on androgen concentrations. METHODS: Three clinical studies were conducted: study 1 (single-dose comparison study vs morphine in healthy volunteers), study 2 (single-dose-escalation study in healthy volunteers without an active comparator), and study 3 (multiple-dose study vs oxycodone in patients with osteoarthritis). Studies 1 and 2 were conducted at medical research centers in Germany and the United Kingdom; study 3 was conducted at primary and secondary care centers and medical research centers in the United States. All three studies were randomized, double blind, and placebo controlled. Concentrations of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH; study 3 only) were evaluated at 6 and 24 hours postdose in studies 1 and 2, respectively, and at varying time points postdose in study 3. RESULTS: In study 1, mean serum total testosterone concentrations in healthy male volunteers were similar at baseline for all treatment periods; 6 hours after dosing, mean concentrations were comparable between placebo (8.6 nmol/L) and tapentadol immediate release (IR; 43 mg, 8.8 nmol/L; 86 mg, 9.3 nmol/L), but were lower following administration of morphine IR 30 mg (5.4 nmol/L). In study 2, there were no or minimal changes in testosterone in the therapeutic dose range with tapentadol IR (75-100 mg), and there was a modest decrease that appeared to level off in the supratherapeutic range (125-175 mg); mean testosterone and LH concentrations with all doses remained within normal ranges (testosterone, 4.56-28.2 nmol/L; LH, 2.9-4.6 U/L). In study 3, the decrease in the mean [standard deviation] testosterone concentration from baseline to endpoint for male patients receiving tapentadol ER (100 mg, -1.9 [0.71] nmol/L; 200 mg, -2.1 [0.93] nmol/L) was numerically smaller compared to oxycodone CR (20 mg, -2.7 [0.93] nmol/L), but higher compared to placebo (-0.3 [1.62] nmol/L). CONCLUSIONS: These results suggest that tapentadol, which has combined MOR and NRI activities, may have a lower impact on sex hormone concentrations than pure opioid analgesics, such as morphine or oxycodone. The data and mechanistic rationale presented herein provide a justification for conducting additional hypothesis testing studies, and are not intended to be used as a basis for clinical decision making. Future studies may help elucidate whether the observed trends are clinically significant and would translate into a reduced incidence of OPIAD.

Development and preliminary validation of an integrated efficacy-tolerability composite measure for the evaluation of analgesics.

The goal of this analysis was to develop and evaluate integrated measures of benefit and tolerability of analgesic drugs in clinical trials. We evaluated an efficacy-tolerability composite (ETC) measure combining different cutoff values for daily pain reduction (≥20%, ≥30%, or ≥50% pain reduction) and adverse events (AEs) (no AE, no or mild AEs, no or mild drug-related AEs). Nine ETC cutoff values (3 × 3) were tested using data from a randomized double-blind trial comparing tapentadol extended release (ER) (n = 310), oxycodone controlled release (CR) (n = 322), and placebo (n = 314) in subjects with chronic low back pain. Efficacy-tolerability composite scores were calculated as the mean number of days a subject met the ETC criterion divided by the number of days the subject was expected to be in study; ETC scores were then averaged in each treatment group. For all 9 ETC measures, validity was demonstrated by significant correlation of ETC scores with patients' Global Impression of change and with change from baseline in pain scores. Tapentadol ER ETC scores were statistically significantly higher than oxycodone CR ETC scores for 4 of the ETC measures. "No/mild drug-related AE and ≥20% pain reduction" demonstrated the best overall validity (correlation with patients' global impression of change) and responsiveness (discrimination between treatment groups), yielding a higher standardized effect size for tapentadol ER compared with placebo (0.19 [95% confidence interval: 0.031-0.346]) and with oxycodone CR (0.23 [95% confidence interval: 0.070-0.383]) than other cutoff values. Thus, we have identified herein a composite measure that seems to be a valid and responsive measure of the overall efficacy and tolerability of analgesics in clinical trials.

Evaluation of the tamper-resistant properties of tapentadol extended-release tablets: results of in vitro laboratory analyses.

OBJECTIVE: To evaluate tamper-resistant properties of tapentadol tablets formulated with polyethylene oxide (PEO) matrix. DESIGN: Analytical and physical tests to characterize tablets. INTERVENTIONS: Tapentadol extended release (ER) 50, 100, 150, 200, and 250 mg. MAIN OUTCOME MEASURE(S): Mechanical resistance of tapentadol ER tablets to crushing (all doses), in vitro drug-release profiles of intact and tampered 50- and 250-mg tablets, and resistance to extraction of 250-mg tablets subjected to hammering. RESULTS: Crush resistance testing showed no deformation of tablets with two metal spoons, minimal deformation (no pulverization/breakage) with a pill crusher, slight deformation with a standardized pharmacopeia breaking force tester, and flattening (no pulverization/breakage) with a standardized hammer instrument. Mean in vitro release profiles in quality control medium (0.050 M phosphate buffer, pH 6.8) were similar with intact and tampered (pill crusher) tablets; the release profile was faster for hammered than intact tablets, with 30 percent of the drug released after 30 minutes (slightly higher than maximum release allowed per drug product specifications). Intact tablets were completely resistant to extraction in most organic solvents tested; in aqueous solvents, the amount of drug extracted increased with time. Hammered tablets were less resistant to extraction but required vigorous shaking over extended periods of time to release >50 percent of active ingredient. CONCLUSIONS: In vitro results from tampering attempts presented herein demonstrate that tapentadol ER tablets were resistant to these forms of physical manipulation. Tapentadol ER tablets were also generally resistant to dissolution in most solvents. Developing tamper-resistant formulations is an important step in strategies to mitigate opioid abuse.

Immediate-release tapentadol or oxycodone for treatment of acute postoperative pain after elective arthroscopic shoulder surgery: a randomized, phase IIIb study.

OBJECTIVE: Arthroscopic shoulder surgery can result in substantial postoperative pain. This study evaluated the efficacy and safety of tapentadol immediate release (IR) or oxycodone IR in this setting for the treatment of acute pain. DESIGN: Subjects received tapentadol IR 50 or 100 mg or oxycodone IR 5 or 10 mg every 4-6 hours as needed for pain up to 7 days after arthroscopic shoulder surgery. Twice daily, subjects recorded pain intensity from 0 (no pain) to 10 (pain as bad as you can imagine) and pain relief from 0 (none) to 5 (complete). Final assessments included patient and clinician global impression of change and subject satisfaction with treatment. The primary efficacy endpoint was the sum of pain intensity differences (SPID) over 3 days. RESULTS: Of 378 subjects (192 tapentadol IR, 186 oxycodone IR) who took study medication, 312 (158 tapentadol IR, 154 oxycodone IR) had pain intensity ≥4 before the first dose and were evaluated for efficacy. Mean SPID scores over 3 days were 32.1 and 41.1 in the tapentadol IR and oxycodone IR groups, respectively (least-squares mean difference [95% confidence interval], 9.0 [-18.9, 36.9]; p = 0.527). Secondary analyses of pain intensity, pain relief, and subject satisfaction were similar between groups. Subjects and clinicians reported significantly better global impression of change for tapentadol IR. Adverse events were consistent with established safety profiles for IR opioids. CONCLUSIONS: Tapentadol IR and oxycodone IR had similar efficacy for pain after arthroscopic shoulder surgery, but subjects and clinicians reported greater overall improvement with tapentadol IR.

Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations.

As the nontherapeutic use of prescription medications escalates, serious associated consequences have also increased. This makes it essential to estimate misuse, abuse, and related events (MAREs) in the development and postmarketing adverse event surveillance and monitoring of prescription drugs accurately. However, classifications and definitions to describe prescription drug MAREs differ depending on the purpose of the classification system, may apply to single events or ongoing patterns of inappropriate use, and are not standardized or systematically employed, thereby complicating the ability to assess MARE occurrence adequately. In a systematic review of existing prescription drug MARE terminology and definitions from consensus efforts, review articles, and major institutions and agencies, MARE terms were often defined inconsistently or idiosyncratically, or had definitions that overlapped with other MARE terms. The Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership convened an expert panel to develop mutually exclusive and exhaustive consensus classifications and definitions of MAREs occurring in clinical trials of analgesic medications to increase accuracy and consistency in characterizing their occurrence and prevalence in clinical trials. The proposed ACTTION classifications and definitions are designed as a first step in a system to adjudicate MAREs that occur in analgesic clinical trials and postmarketing adverse event surveillance and monitoring, which can be used in conjunction with other methods of assessing a treatment's abuse potential.

Physician management of moderate-to-severe acute pain: results from the Physicians Partnering Against Pain (P³) study.

OBJECTIVE: To evaluate differences among physician specialties in the management of acute pain including prescribing practices and management of opioid-related side effects. DESIGN AND PARTICIPANTS: The Physicians Partnering Against Pain (P³) survey was a nationwide study of US physicians and their patients with severe to moderate acute pain (<3 months). MAIN MEASURES: Physicians were surveyed about volume of patients with moderate-to-severe acute pain in their practice, frequency of prescribing opioid analgesics, percentage of these patients returning for a follow-up visit after treatment, reasons patients discontinue treatment, frequency of recommending or prescribing treatment for opioid-related gastrointestinal (GI) side effects, and frequency of patients taking opioid analgesics that take additional treatments to manage GI side effects. RESULTS: The 5,982 participating physicians represented primary care physicians (PCPs; 52 percent), pain specialists (25 percent), and other specialists (23 percent). PCPs and other specialists were less likely than pain specialists to prescribe opioid analgesics to patients (25.8 percent, 29.5 percent, and 44.8 percent, respectively). The vast majority of pain specialists (78 percent) also indicated that more than three quarters of their patients returned for a follow-up visit compared with only 40 percent of PCPs and 65 percent of other specialists. When ranking the reasons why they think patients discontinue opioid analgesics, pain specialists ranked unacceptable side effects higher than PCPs and other specialists. PCPs and pain specialists were more likely than other specialists to recommend or prescribe treatments to manage opioid-related side effects, such as nausea, vomiting, and constipation (38.3 percent, 38.5 percent, and 23.1 percent, respectively). CONCLUSION: The P(3) Study confirms the challenge of pain management while balancing tolerability of opioid treatments from the physician perspective.

Tapentadol, oxycodone or placebo for acute pain of vertebral compression fractures: a randomized Phase IIIb study.

UNLABELLED: SUMMARY  AIM: Tapentadol is a centrally acting analgesic that combines µ-opioid receptor agonism with norepinephrine reuptake inhibition. This study evaluated the efficacy and safety of tapentadol immediate-release (IR), oxycodone IR or placebo in subjects with acute pain from vertebral compression fracture (VCF) associated with osteoporosis. PATIENTS & METHODS: Study patients were adults with new onset of pain or acute exacerbation of previous pain from VCF associated with osteoporosis, radiographic confirmation of VCF and back pain intensity of 5 or greater on an 11-point scale from 0 (no pain) to 10 (pain as bad as you can imagine). Patients were randomized to treatment with tapentadol IR (50 mg, then 50 or 75 mg), oxycodone IR (5 mg, then 5 or 10 mg) or placebo every 4-6 h as needed for pain, for up to 10 days. Twice daily, subjects recorded pain intensity on the 11-point scale (numeric rating scale), pain relief on a 5-point scale from 0 (none) to 4 (complete), sleep assessments (morning assessment only) and any episodes of vomiting (evening assessment only). RESULTS: The study was designed to include 625 subjects, but was stopped after 14 months due to slow enrollment (44 tapentadol IR, 43 oxycodone IR and 21 placebo subjects) and had insufficient statistical power for comparative efficacy analyses. Discontinuation rates in the tapentadol IR, oxycodone IR and placebo groups were 18.2, 27.9 and 9.5%, respectively, often due to adverse events (4.5, 18.6 and 4.8%, respectively). Treatment-emergent adverse-event rates were 63.6, 81.4 and 38.1%, respectively. CONCLUSION: In this prematurely terminated study in adults with painful VCF, trends suggested that tapentadol IR was tolerated better than oxycodone IR.

Opioids before and after initiation of pregabalin in patients with diabetic peripheral neuropathy.

OBJECTIVES: To examine opioid prescription claims before and after initiation of pregabalin in patients with a diagnosis of diabetic peripheral neuropathy (DPN). METHODS: This retrospective analysis used a national commercial database of integrated inpatient, outpatient, and prescription claims to identify adults with a DPN diagnosis code within 360 days prior to the first claim for pregabalin between January 1, 2006 and March 31, 2008. Prescription claims for pregabalin or opioids were analyzed in nine consecutive 60-day periods from 180 days before through 360 days after the first pregabalin claim. It was not possible to establish drug administration dates, compliance rates, indications for opioid use, or reasons for treatment discontinuation. RESULTS: Of the 8004 adults who met eligibility criteria, 6080 (76%) received an opioid within the 180 days before and/or 360 days after their first prescription for pregabalin, including 3956 (49%) both before and after, 1580 (20%) after only, and 544 (7%) before only. The percentage of patients with pregabalin claims covering ≥20 of 60 days (within 60-day periods) was 99% (day 1-60), 63% (day 61-120), 50% (day 121-180), 45% (day 181-240), 42% (day 241-300), and 39% (day 301-360). The percentage of patients with opioid claims covering ≥20 of 60 days within the 60-day periods remained stable (range, 25-30%). Among patients with opioid claims, 73-76% received only short-acting opioids, 6-7% received only long-acting opioids, and 18-20% received both short- and long-acting opioids. In the first year, 982 (12%) patients had opioid claims covering ≥20 of 60 days in every 60-day period (i.e., persistent use of opioids). Coexisting musculoskeletal (95%) or neuropathic (61%) pain conditions were frequent. CONCLUSION: A majority of patients with DPN receive an opioid before and/or after their first pregabalin claim. Pregabalin neither interferes with nor replaces opioid use for pain management in patients with DPN. Although nearly 1 in 8 patients received opioids throughout the study period, most claims were for short-acting opioids. The majority of this DPN sample had other pain conditions, including musculoskeletal and neuropathic pain conditions. These results highlight the frequency of opioid use with pregabalin, particularly short-acting opioids.

Post hoc analyses of data from a 90-day clinical trial evaluating the tolerability and efficacy of tapentadol immediate release and oxycodone immediate release for the relief of moderate to severe pain in elderly and nonelderly patients.

OBJECTIVE: To evaluate the tolerability and efficacy of tapentadol immediate release (IR) and oxycodone IR for relief of moderate to severe pain in elderly and nonelderly patients. METHODS: Post hoc data analyses were conducted on a 90-day randomized, phase 3, double-blind, flexible-dose study (ClinicalTrials.gov: NCT00364546) of adults with moderate to severe lower back pain or osteoarthritis pain who received tapentadol IR 50 mg or 100 mg, or oxycodone HCl IR 10 mg or 15 mg every 4 h to 6 h as needed for pain relief. Treatment-emergent adverse events and study discontinuations were recorded. RESULTS: Data from 849 patients randomly assigned (4:1 ratio) to treatment with a study drug (tapentadol IR [n=679] or oxycodone IR [n=170]) were analyzed according to age (younger than 65 years of age [nonelderly], or 65 years of age or older [elderly]) and treatment group. Among elderly patients, incidences of constipation (19.0% versus 35.6%) and nausea or vomiting (30.4% versus 51.1%) were significantly lower with tapentadol IR versus oxycodone IR (all P<0.05). Initial onsets of nausea and constipation occurred significantly later with tapentadol IR versus oxycodone IR (both P<=0.031). Tapentadol IR-treated elderly patients had a lower percentage of days with constipation than oxycodone IR-treated patients (P=0.020). For tapentadol IR- and oxycodone IR-treated elderly patients, respectively, incidences of study discontinuation due to gastrointestinal treatment-emergent adverse events were 15.8% and 24.4% (P=0.190). Tapentadol IR and oxycodone IR provided similar pain relief, with no overall age-dependent efficacy differences (mean pain scores [11-point numerical rating scale] decreased from 7.0 and 7.2 at baseline, to 4.9 and 5.2 at end point, respectively). CONCLUSIONS: Tapentadol IR was safe and effective for the relief of lower back pain and osteoarthritis pain in elderly patients, and was associated with a better gastrointestinal tolerability profile than oxycodone IR.

Evaluation of study discontinuations with tapentadol inmmediate release and oxycodone immediate release in patients with low back or osteoarthritis pain.

OBJECTIVE: To examine discontinuations due to nausea and/or vomiting or constipation with tapentadol immediate release (IR) or oxycodone IR treatment. DESIGN: Post hoc analyses of a 90-day, phase 3, randomized, double-blind, flexible-dose study. SETTING: United States, Canada, United Kingdom. PATIENTS: Adults with moderate to severe low back or osteoarthritis (OA) pain for > or =3 months. INTERVENTIONS: Tapentadol IR 50 or 100 mg or oxycodone HCI IR 10 or 15 mg every 4-6 hours as needed. MAIN OUTCOME MEASURES: Adverse events and discontinuations were recorded. RESULTS: Post hoc analyses included data from 679 patients receiving tapentadol IR and 170 receiving oxycodone IR (4:1 randomization). Tapentadol IR 50 or 100 mg and oxycodone HCI IR 10 or 15 mg provided similar levels of pain relief Overall, 21.2 percent of patients receiving tapentadol IR discontinued treatment for adverse events versus 31.2 percent of patients receiving oxycodone IR. The percentage of patients who discontinued for nausea and/or vomiting was significantly lower with tapentadol IR (5.9 percent) than oxycodone IR (14.7 percent; p = 0.0003); patients treated with oxycodone IR discontinued because of nausea and/or vomiting significantly earlier than with tapentadol IR (p < 0.0001). The percentage of patients who discontinued because of constipation was significantly lower with tapentadol IR (1.5 percent) than with oxycodone IR (5.9 percent; p = 0.0023); patients treated with oxycodone IR discontinued because of constipation significantly earlier versus tapentadol IR (p = 0.0003). CONCLUSIONS: A lower percentage of patients discontinued because of nausea and/or vomiting or constipation with tapentadol IR versus oxycodone IR while receiving comparable pain relief suggesting tapentadol may improve the management of low back and OA pain.

Effects of extended-release tramadol on pain-related sleep parameters in patients with osteoarthritis.

OBJECTIVE: To examine the effects of extended release tramadol (tramadol ER) on reducing pain-related sleep disturbances (PRSDs) in patients (20-80 years) with moderate to moderately severe pain with radiographically confirmed osteoarthritis (OA) of the knee or hip. METHODS: A post hoc analysis of two 12-week, double-blind, placebo-controlled, randomized, parallel-group studies was conducted. In Study A, patients (n = 1,020) received tramadol ER 100, 200, 300, or 400 mg, or placebo. In Study B (n = 1,011), patients received tramadol ER 100, 200, or 300 mg, or placebo. MAIN OUTCOME MEASURES: PRSDs were evaluated using the Chronic Pain Sleep Inventory (CPSI) based on a 100-mm visual analog scale (VAS; 0 = very poor, 100 = excellent for the overall quality of sleep). RESULTS: Significant improvements in CPSI scores from baseline were seen as early as week 1 in all tramadol ER groups and were maintained through the final visit for overall sleep quality compared with placebo (all p < or = 0.022). Compared with placebo, significant improvements in scores from baseline were seen beginning at week 1 for tramadol ER 200 and 300 mg and week 3 for tramadol ER 100 mg, and were maintained in all dose groups through the final visit, for being awakened by pain in the night and in the morning, and less trouble falling asleep due to pain (all p < or = 0.046). CONCLUSION: In this post hoc analysis, a reduction in pain was associated with a significant reduction in PRSDs due to OA.

Extended-release tramadol (tramadol ER) in the treatment of chronic low back pain.

BACKGROUND: This study evaluated the safety and efficacy of tramadol ER 300 mg and 200 mg versus placebo once daily in the treatment of chronic low back pain, using an open-label run-in followed by, without washout, a randomized controlled study design. METHODS: Adults with scores > or = 40 on a pain intensity visual analog scale (VAS; 0 = no pain; 100 = extreme pain) received open-label tramadol ER, initiated at 100 mg once daily and titrated to 300 mg once daily during a three-week open-label run-in. Patients completing run-in were randomized to receive tramadol ER 300 mg, 200 mg, or placebo once daily for 12 weeks. RESULTS: Of 619 patients enrolled, 233 (38 percent) withdrew from the run-in, primarily because of adverse event (n = 128) or lack of efficacy (n = 41). A total of 386 patients were then randomized to receive either 300 mg (n = 128), 200 mg (n = 129), or placebo (n = 129). Following randomization, mean scores for pain intensity VAS since the previous visit, averaged over the 12-week study period, increased more in the placebo group (12.2 mm) than in the tramadol ER 300-mg (5.2 mm, p = 0.009) and 200-mg (7.8 mm, p = 0.052) groups. Secondary efficacy scores for current pain intensity VAS, patient global assessment, Roland Disability Index, and overall sleep quality improved significantly (p < or = 0.029 each) in the tramadol ER groups compared with placebo. The most common adverse events during the double-blind period were nausea, constipation, headache, dizziness, insomnia, and diarrhea. CONCLUSIONS: In patients who tolerated and obtained pain relief from tramadol ER, continuation of tramadol ER treatment for 12 weeks maintained pain relief more effectively than placebo. Adverse events were similar to those previously reported for tramadol ER.

Open-label study of the safety and effectiveness of long-term therapy with extended-release tramadol in the management of chronic nonmalignant pain.

BACKGROUND: Tramadol ER* is a once-daily oral analgesic for management of moderate-to-moderately severe chronic pain in adults who require around-the-clock treatment of pain. This study evaluated long-term safety of tramadol ER and effectiveness outcomes in the management of chronic, nonmalignant pain. METHODS: Patients enrolled directly for approximately 1 year of open-label tramadol ER treatment if they had chronic, nonmalignant pain (n = 919), or 'rolled over' for 38 weeks of open-label tramadol ER treatment if they completed either of two 12-week, placebo-controlled studies of tramadol ER for low back pain (n = 72) or osteoarthritis (n = 61). Tramadol ER was titrated to a dose of 300 mg once daily (patients >or= 75 years) or 300-400 mg once daily (patients < 75 years). RESULTS: A total of 257 (24%) patients completed the study. Common adverse events, regardless of treatment relationship, were nausea, dizziness (excluding vertigo), and constipation. Mean scores for current pain intensity (from 0 = no pain to 100 = extreme pain) and least, worst, and average pain intensity over the past week improved at every post-baseline visit. At each post-baseline visit, > 50% of patients provided a global assessment rating of good, very good, or excellent. Study limitations were mandatory titration to 400 mg in some patients, concomitant analgesic therapy as a confounding variable, and lack of a placebo comparator. CONCLUSIONS: Individualized dose titration and limiting once-daily therapy with tramadol ER to the maximum recommended daily dose of 300 mg may balance tolerability and analgesic effects of tramadol ER in patients with chronic, nonmalignant pain.

Pharmacokinetic model and simulations of dose conversion from immediate- to extended-release tramadol.

OBJECTIVE: Extended-release tramadol (tramadol ER) is a once-daily formulation of tramadol approved in the United States for moderate to moderately severe chronic pain in adults. This modeling and simulation analysis was conducted to support dosing recommendations for switching patients receiving immediate-release tramadol (tramadol IR) to tramadol ER. RESEARCH DESIGN AND METHODS: Monte Carlo simulations based on steady-state data from three Phase 1 studies predicted minimum plasma concentration (C(min)), maximum plasma concentration (C(max)), and area under the plasma-concentration-versus-time curve (AUC). MAIN OUTCOME MEASURES: Pharmacokinetic parameters were compared between 100-mg daily increments of tramadol ER every 24 h (Q24H) and corresponding 25-mg increments of tramadol IR every 6 h (Q6H), such as tramadol ER 200 mg Q24H versus tramadol IR 200, 225, 250, and 275 mg daily. RESULTS: Tramadol ER and IR were predicted to provide similar exposure (AUC) at a total daily dose of 100, 200, or 300 mg. Estimated exposure was comparable between tramadol IR 125-, 225-, and 325-mg and tramadol ER 100-, 200-, and 300-mg, respectively. Estimated exposure was 30-41% lower with tramadol ER 100 mg versus tramadol IR 150 and 175 mg daily, 15-26% lower with tramadol ER 200 mg versus tramadol IR 250 and 275 mg daily, and 8-19% lower with tramadol ER 300 mg versus tramadol IR 350 and 375 mg daily. CONCLUSIONS: This pharmacokinetic analysis supports switching patients from a total daily dose of tramadol IR 200 or 300 mg directly to tramadol ER 200 and 300 mg once daily, respectively. Patients who take other doses of tramadol IR may switch to the next lower 100-mg increment of tramadol ER (e.g., from tramadol IR 225, 250, or 275 mg daily in divided doses to tramadol ER 200 mg once daily). Confirmation of these findings would require clinical studies comparing the systemic exposure of tramadol upon switching from the IR to the ER formulation.

Randomized study of tramadol/acetaminophen versus placebo in painful diabetic peripheral neuropathy.

OBJECTIVE: To examine the efficacy and safety of tramadol/acetaminophen (APAP) for the management of painful diabetic peripheral neuropathy (DPN). METHODS: Adults with painful DPN involving the lower extremities received 37.5 mg tramadol/325 mg APAP or placebo, up to 1-2 tablets four times daily, for 66 days. Subjects rated average daily pain and sleep interference from 0 ('none') to 10 ('pain as bad as you can imagine' or 'complete interference') every night. Baseline values were recorded for 7 days before starting study medication. The primary endpoint was change in mean of average daily pain scores from baseline to final week. Secondary efficacy outcomes included pain intensity, sleep interference, quality of life, mood, and global impression of change. Potential study limitations included permission to use serotonin reuptake inhibitors concomitantly (except venlafaxine or duloxetine) and the lack of a tramadol-alone or APAP-alone control group. RESULTS: A total of 160 subjects received tramadol/APAP and 153 received placebo. Tramadol/APAP reduced average daily pain significantly compared to placebo from baseline to the final week (-2.71 vs. -1.83, p = 0.001). Tramadol/APAP was associated with significantly greater improvement than placebo (p < or = 0.05) for all measures of pain intensity, sleep interference, and global impression, as well as several measures of quality of life and mood. The only adverse event reported by > 10% of subjects in either the tramadol/APAP or placebo group was nausea (11.9% and 3.3%, respectively). Adverse events resulted in early study discontinuation for 8.1% and 6.5% of subjects in the tramadol/APAP and placebo groups, respectively. CONCLUSION: Tramadol/APAP was more effective than placebo and was well tolerated in the management of painful DPN.

Post hoc analysis of a randomized, double-blind, placebo-controlled efficacy and tolerability study of tramadol extended release for the treatment of osteoarthritis pain in geriatric patients.

BACKGROUND: Once-daily tramadol extended release (ER) was evaluated for 12 weeks in a randomized, double-blind, placebo-controlled, parallel-group study in 1020 patients with osteoarthritis of the knee or hip. As previously reported, compared with placebo, the results of the study showed that patients treated with tramadol ER had significant improvement in the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index and in pain-related sleep parameters. OBJECTIVE: Because chronic/persistent arthritis pain is common in geriatric patients, this post hoc analysis evaluated the efficacy and tolerability of tramadol ER in geriatric patients 65 years or older (n=317) from this study. METHODS: In the original study, the co-primary efficacy variables to evaluate the efficacy and tolerability of 100-, 200-, 300-, and 400-mg doses of tramadol ER were the WOMAC Osteoarthritis Index subscale scores for pain (0-500) and physical function (0-1700), and patient global assessment of disease (0-100). Secondary efficacy variables included arthritis pain intensity, 36-Item Short-Form Health Survey, daily pain diaries, sleep parameters, and tolerability assessments. Patients rated their arthritis pain utilizing a 100-mm visual analog scale (VAS) (0=no pain, 100=extreme pain). Sleep parameters were evaluated based on a 100-mm VAS (0=never, 100=always). RESULTS: A total of 317 patients 65 years or older were included in the analysis (186 women, 131 men). Compared with placebo, this analysis found a significant improvement from baseline to the final visit in the co-primary efficacy variables of pain (least-squares [LS] mean [SE], 108.7 [16.9]; P

Extended-release tramadol in the treatment of osteoarthritis: a multicenter, randomized, double-blind, placebo-controlled clinical trial.

OBJECTIVE: This study evaluated the efficacy and safety of tramadol extended-release (tramadol ER) tablets once daily in subjects with osteoarthritis pain. METHODS: This 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial included 1020 adults with osteoarthritis of the knee or hip and baseline pain intensity >or= 40 on a 100-mm pain visual analog scale (0 = no pain, 100 = extreme pain). Subjects took placebo or were titrated to a target dose of tramadol ER 100, 200, 300, or 400 mg once daily. MAIN OUTCOME MEASURES: The co-primary efficacy variables were pain and physical function subscales of the WOMAC Osteoarthritis Index and subject global assessment of disease activity. RESULTS: Mean changes in WOMAC Osteoarthritis Index pain and physical function subscales were significantly different between tramadol ER and placebo, overall (p

An observational study of health-related quality of life and pain outcomes in chronic low back pain patients treated with fentanyl transdermal system.

BACKGROUND: The analgesic effect of long-acting opioids, such as transdermal fentanyl, has been demonstrated in patients with cancer, neuropathic pain and chronic low back pain (CLBP). However, the broader effect of long-acting opioids on the patient's health-related quality of life (HRQoL) is less well known. OBJECTIVE: To evaluate HRQoL outcomes in CLBP patients treated with transdermal fentanyl. RESEARCH DESIGN AND METHODS: An observational study was conducted at 17 clinical centers in the US. Eligible patients had CLBP diagnosis for at least 3 months and were taking short-acting opioids chronically, and then initiated transdermal fentanyl treatment. Patients completed the Treatment Outcomes in Pain Survey (TOPS), which includes the SF-36 Health Survey, at baseline and > or = 9 weeks of treatment. The HRQoL burden of CLBP was determined by comparing CLBP patients' SF-36 scores to the general US population and low back pain patient norms. HRQoL outcomes were determined by comparing baseline and follow-up TOPS and SF-36 scores. Additionally, HRQoL outcomes were evaluated across patient groups stratified by changes in pain intensity ratings as measured by an 11-point numerical rating scale. RESULTS: At baseline CLBP patients (N = 131) scored one-to-two standard deviations (SD) below age and gender adjusted SF-36 general population norms (MANOVA F = 127.1, p < 0.0001) and significantly lower than low back pain norms (MANOVA F = 125.3, p < 0.0001). At follow-up, significant improvement (p < 0.05) was observed on six of the SF-36 scales and both SF-36 summary measures and five of the six TOPS pain-related scales. The magnitude of change in scores in effect size units among these scales ranged from 0.17 to 0.80, which are considered small to large effect size changes. HRQoL score improvement was greatest among patients experiencing the greatest pain relief. CONCLUSION: CLBP patients who chronically used short-acting opioids showed tremendous HRQoL burden. Favorable HRQoL outcomes were observed among patients who reported pain relief.

Neuropsychological effects of long-term opioid use in chronic pain patients.

Opioids are thought to worsen the performance of psychomotor tasks due to their sedating and mental-clouding effects. As a result, some safety regulations currently restrict the use of opioids when driving or using heavy equipment. We investigated the psychomotor effects of long-term opioid use in 144 patients with low back pain. All subjects were administered two neuropsychological tests (Digit Symbol and Trail Making Test-B) before being prescribed opioids for pain; tests were re-administered at 90- and 180-day intervals. Test scores significantly improved while subjects were taking opioids for pain, which suggests that long-term use of oxycodone with acetaminophen or transdermal fentanyl does not significantly impair cognitive ability or psychomotor function.