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Background and Objective Oral tramadol, an atypical opioid approved in the United States (US) since 1995 and a Schedule IV controlled substance, has less abuse liability compared to Schedule II conventional opioids. Intravenous (IV) tramadol is not available in the US, but has the potential to fill a gap between non-opioid medications and conventional opioids for treatment of acute pain. This study evaluates IV tramadol in the management of postoperative pain compared to placebo and standard-of-care active control. Methods A phase 3, multicenter, double-blind, three-arm, randomized, placebo- and active-controlled, multiple-dose, parallel-group study was conducted to evaluate the efficacy and safety of 50 mg IV tramadol versus placebo and 4 mg IV morphine over 48 h in patients with postoperative pain following abdominoplasty surgery. Results IV tramadol was statistically superior ( p  < 0.05) to placebo and comparable to IV morphine for the primary and all key secondary efficacy outcomes and demonstrated numerically lower rates for the incidence of most common treatment-emergent adverse events (TEAEs) compared to morphine. No unexpected findings were observed for TEAEs, laboratory tests, vital signs, or electrocardiograms (ECGs). Over 90% of patients completed the study. Conclusion The study demonstrated that IV tramadol 50 mg is highly effective in the management of postoperative pain following abdominoplasty. The consistency of effects between tramadol and morphine (as compared to placebo) for primary and key secondary endpoints validates the efficacy of tramadol observed. The study also provided direct evidence of improved tolerability of IV tramadol over a standard-of-care conventional Schedule II opioid. IV tramadol may become a useful option in patients where exposure to conventional opioids is not desired.

PurposeLabor pain is one of the most agonizing pains experienced by all delivered women. Many pharmacological agents used in labor analgesia require intense monitoring facilities, which are not available in routine obstetric practice in low-resource settings. This study aimed to compare the efficacy of intravenous (IV) paracetamol and intramuscular (IM) tramadol on labor pain relief, labor progression, and maternal and neonatal outcomes.MethodsThis randomized drug trial was carried out on 110 women divided into two groups. Group A women received 1000 mg of IV paracetamol, and Group B women received 100 mg of IM tramadol during the active phase of labor. Pain intensity was assessed by the Visual Analogue Scale (VAS) at intervals till 120 min of delivery. The maternal and neonatal outcomes were recorded.ResultsThere was a statistically significant fall in pain score till 180 min of drug administration in the paracetamol group and 120 min in the tramadol group. At 180 min and 240 min, paracetamol is more effective than tramadol (p value 0.004 at 180 min and 0.0119 at 240 min). There were significantly low pain score levels at 60 min of delivery in the paracetamol group (p value—0.004). Nausea and vomiting were significantly higher in the tramadol group (p value 0.000013).ConclusionCompared to IM tramadol, IV paracetamol has a longer duration of action and fewer maternal side effects, making it suitable for parenteral analgesia in labor. Due to a better safety profile, there is no need for intense maternal and fetal monitoring with IV paracetamol.Trial registrationClinical Trials Registry—India (CTRI registration number—CTRI /2019/05/019244).

PurposeCombination therapy of pregabalin and tramadol is used to treat chronic neuropathic pain; however, the pharmacokinetic (PK) interactions of these drugs has not been studied. This study aimed to evaluate PK interactions between pregabalin and tramadol and the safety of combination therapy.MethodsA randomized, open-label, multiple-dose, three-treatment, three-period, six-sequence cross-over study was conducted in healthy subjects. All subjects received the following three treatments for 4 days in each period: pregabalin 150 mg twice daily; tramadol extended-release (ER) 200 mg in the morning, and 100 mg in the evening; and co-administration of pregabalin 150 mg and tramadol ER 200 mg in the morning, and pregabalin 150 mg and tramadol ER 100 mg in the evening.ResultsA total of 21 subjects completed the study with no clinically significant safety issues. For pregabalin, the geometric mean ratio (GMR) (90% CI; confidence interval) of combination therapy to monotherapy for maximum concentration at steady state (Cmax,ss) and area under the concentration curve from 0 to dosing interval time at steady state (AUCτ,ss) were 0.8801 (0.8043–0.9632) and 1.0830 (1.0569–1.1098), respectively. The corresponding values for tramadol were 1.0177 (0.9839–1.0526) and 1.0152 (0.9896–1.0414), respectively. The GMR (90% CI) of combination therapy to monotherapy of O-desmethyl-tramadol for Cmax,ss and AUCτ,ss was 1.0465 (1.0095–1.0848) and 1.0361 (1.0001–1.0734), respectively.ConclusionsThere were no significant drug interactions between pregabalin and tramadol, considering that all of the 90% CI of PK measures were within the conventional bioequivalence range. Both drugs were well tolerated when administered concomitantly.

Background and Objective Co-Crystal of Tramadol–Celecoxib (CTC), in development for the treatment of moderate to severe acute pain, is a first-in-class co-crystal containing a 1:1 molecular ratio of two active pharmaceutical ingredients; rac-tramadol·HCl and celecoxib. This randomised, open-label, crossover study compared the bioavailability of both components after CTC administration under fed and fasting conditions. Methods Healthy adults received single doses of 200 mg CTC under both fed and fasting conditions (separated by a 7-day washout). Each dose of CTC was administered orally as two 100 mg tablets, each containing 44 mg tramadol·HCl and 56 mg celecoxib. In the fed condition, a high-fat, high-calorie meal [in line with recommendations by the US Food and Drug Administration (FDA)] was served 30 min before CTC administration. Tramadol, O -desmethyltramadol and celecoxib plasma concentrations were measured pre- and post-dose up to 48 h. Pharmacokinetic parameters were calculated using non-compartmental analysis. Safety was also assessed. Results Thirty-six subjects (18 female/18 male) received one or both doses of CTC; 33 provided evaluable pharmacokinetic data under fed and fasting conditions. For tramadol and O -desmethyltramadol, fed-to-fasting ratios of geometric least-squares means and corresponding 90% confidence interval (CI) values for maximum plasma concentration ( C max ) and extrapolated area under the plasma concentration–time curve to infinity (AUC ∞ ) were within the pre-defined range for comparative bioavailability (80–125%). For celecoxib, C max and AUC ∞ fed-to-fasting ratios (90% CIs) were outside this range, at 130.91% (116.98–146.49) and 129.34% (121.78–137.38), respectively. The safety profile of CTC was similar in fed and fasting conditions. Conclusions As reported for standard-formulation celecoxib, food increased the bioavailability of celecoxib from single-dose CTC. Food had no effect on tramadol or O -desmethyltramadol bioavailability. Clinical trial registration number 152052 (registered with the Therapeutic Products Directorate of Health Canada)

Objectives To assess the effectiveness of sublingual ketorolac versus sublingual tramadol in reducing the pain associated with fracture or dislocation of extremities in children. Patients and methods A double-blind, randomised, controlled, non-inferiority trial was conducted in the paediatric emergency department of a research institute. One hundred and thirty-one children aged 4–17 years with suspected bone fracture or dislocation were enrolled. Eligible children were randomised to ketorolac (0.5 mg/kg) and placebo, or to tramadol (2 mg/kg) and placebo by sublingual administration, using a double-dummy technique. Pain was assessed by the patients every 20 min, for a maximum period of 2 h, using the McGrath scale for patients up to 6 years of age, and the Visual Analogue Scale for those older than 6 years of age. Results The mean pain scores fell significantly from eight to four and five in the ketorolac and tramadol groups, respectively, by 100 min (Wilcoxon sign rank test, p<0.001). The mean pain scores for ketorolac were lower than those for tramadol, but these differences were not significant at any time point (Mann–Whitney U Test, p values: 0–20 min: 0.167; 20–40 min: 0.314; 40–60 min: 0.223; 60–80 min: 0.348; 80–100 min: 0.166; 100–120 min: 0.08). The rescue dose of paracetamol-codeine was administered in 2/60 children in the ketorolac group versus 8/65 in the tramadol group (Fisher exact test, p=0.098). There were no statistically significant differences between the two groups in the frequency of adverse effects. Conclusions Both sublingual ketorolac and tramadol were equally effective for pain management in children with suspected fractures or dislocations.

Abstract Objective To assess CYP2D6 genotype prevalence in chronic pain patients treated with tramadol or codeine. Design Prospective cohort study. Setting General hospital, pain management unit. Subjects Patients with chronic pain, treated with codeine or tramadol. Methods Patients’ pain was assessed at baseline (numeric rating scale [NRS]; 0–10). Prescription of codeine or tramadol was selected randomly. The assessment of patients’ response to the drug in terms of pain relief and adverse effects was performed after 24 hours. Reduction of pain intensity of >50% or an NRS <4 was considered a positive response. Patients’ blood samples were collected during the first visit. Genotyping for the common variants CYP2D6 *2, *3, *4, *5, *6, *9, *10, *14, and *17 was performed, and alleles not carrying any polymorphic allele were classified as CYP2D6*1 (wild-type [wt]). Results Seventy-six consecutive patients were studied (20 males, 56 females), aged 21–85 years. Thirty-four received tramadol and 42 codeine. The main genotypes of CYP2D6 identified were the wt/wt (35.5%), the *4/wt (17.1%), and the *6/wt (10.5%). Adverse effects were common, especially in carriers of *9/*9, *5/*5, *5/*4, and *10/*10, as well as in variants including the 4 allele (*4/*1 [38.4%] and *4/*4 [42.8%]). Conclusions Genotyping can facilitate personalized pain management with opioids, as specific alleles are related to decreased efficacy and adverse effects.

Chronic low back pain is a common condition that is often difficult to treat. The combination of tramadol hydrochloride and acetaminophen in an extended-release formulation has been shown to provide rapid and long-lasting analgesic effects resulting from the synergistic activity of these 2 active ingredients. The goal of this study was to evaluate the efficacy and safety of extended-release tramadol hydrochloride 75-mg/acetaminophen 650-mg fixed-dose combination tablets (TA-ER) for the treatment of chronic low back pain. This Phase III, double-blind, placebo-controlled, parallel-group study enrolled 245 patients with moderate to severe (≥4 cm on a 10-cm visual analog scale) chronic (≥3 months’) low back pain insufficiently controlled by previous NSAIDs or cyclooxygenase-2–selective inhibitors and randomly assigned them to receive 4 weeks of either TA-ER or placebo. The primary efficacy end point was the percentage of patients with a pain intensity change rate ≥30% from baseline to final evaluation. Secondary end points included quality of life (Korean Short Form–36), functionality (Korean Oswestry Disability Index), and adverse events. The percentage of patients with a pain intensity change rate ≥30% was significantly higher (P < 0.05) in the TA-ER group than in the placebo group for both the full analysis set and the per-protocol population. Pain relief success rate from baseline was significantly higher with TA-ER versus placebo at days 8 and 15 but not at the final visit. Patients in the TA-ER group had significant improvements versus placebo in role–physical, general health, and reported health transition domains of the Korean Short Form–36 and significantly higher functional improvements in the personal care section of the Korean Oswestry Disability Index. Patient assessment of overall pain control as “very good” was also significantly higher with TA-ER than with placebo. Adverse events were reported more frequently with TA-ER than with placebo; the most common adverse events reported were nausea, dizziness, constipation, and vomiting. TA-ER was significantly more effective than placebo in providing pain relief, functional improvements, and improved quality of life. It exhibited a predictable safety profile in patients with chronic low back pain. ClinicalTrials.gov identifier: NCT01112267.

Tramadol is an opioid analgesic often used for pain management after breast cancer surgery. Its analgesic activity is due to the activation of the μ-opioid receptor, encoded by the gene. This study investigated the association of genetic variability in and its regulatory miRNA genes with outcomes of tramadol/paracetamol treatment after breast cancer surgery with axillary lymphadenectomy. The study included 113 breast cancer patients after breast cancer surgery with axillary lymphadenectomy treated with either 75/650 mg or 37.5/325 mg of tramadol with paracetamol for pain relief within the randomized clinical trial KCT 04/2015-DORETAonko/si at the Institute of Oncology Ljubljana. All patients were genotyped for rs1799971 and rs677830, rs1011784, and rs2296616 using competitive allele-specific PCR. The association of genetic factors with acute and chronic pain as well as adverse effects of tramadol treatment was evaluated using logistic regression, Fisher's exact test, and Mann-Whitney test. The investigated related polymorphisms were not associated with acute pain assessed with the VAS scale within four weeks after surgery (all P > 0.05). Carriers of at least one polymorphic rs1799971 allele had a higher risk of constipation in the first four weeks after surgery compared to non-carriers (OR = 4.5, 95% CI = 1.6-12.64, P = 0.004). Carriers of at least one polymorphic rs677830 allele had a higher risk of constipation after third week of tramadol treatment (OR = 3.11, 95% CI = 1.08-8.89, P = 0.035). Furthermore, carriers of two polymorphic rs1011784 alleles had a higher risk of nausea after 28 days of tramadol treatment (OR = 7.35, 95% CI = 1.27-42.6, P = 0.026), while heterozygotes for rs2296616 allele had a lower risk of nausea after 21 days of tramadol treatment (OR = 0.21, 95% CI = 0.05-0.87, P = 0.031). In carriers of two polymorphic rs2296616 alleles, chronic pain was significantly more common than in carriers of two wild-type alleles (P = 0.004). Carriers of at least one polymorphic rs1011784 allele experienced more neuropathic pain after adjustment for tramadol dose (OR = 2.85, 95% CI = 1.07-7.59, P = 0.036), while carriers of at least one polymorphic rs677830 allele experienced less neuropathic pain compared to carriers of two wild-type alleles (OR = 0.38, 95% CI = 0.15-0.99, P = 0.047). Genetic variability of and genes coding for miRNAs that could affect expression may be associated with adverse effects of tramadol/paracetamol treatment as well as with chronic and neuropathic pain after breast cancer surgery with axillary lymphadenectomy.

Rationale Tramadol is an atypical, mixed-mechanism analgesic involving both opioid and catecholamine processes that appears to have low abuse potential and may be useful as a treatment for opioid dependence. Objectives The current study assessed the level of physical dependence and opioid blockade efficacy produced by daily maintenance on oral tramadol. Methods Nine residential opioid-dependent adults were maintained on two doses of daily oral tramadol (200 and 800 mg) for approximately 4-week intervals in a randomized, double-blind, crossover design. The acute effects of intramuscular placebo, naloxone (0.25, 0.5, and 1.0 mg), and hydromorphone (1.5, 3.0, and 6.0 mg) were tested under double-blind, randomized conditions. Outcomes included observer- and subject-rated measures and physiologic indices. Results Challenge doses of naloxone resulted in significantly higher mean peak withdrawal scores compared to placebo. Withdrawal intensity from naloxone was generally greater during 800 versus 200 mg/day tramadol maintenance. Mean peak ratings of agonist effects were elevated at higher hydromorphone challenge doses, but did not differ significantly between tramadol doses. Physiologic measures were generally affected by challenge conditions in a dose-dependent manner, with few differences between tramadol maintenance dose conditions. Conclusions Chronic tramadol administration produces dose-related opioid physical dependence, without producing dose-related attenuation of agonist challenge effects. Tramadol may be a useful treatment for patients with low levels of opioid dependence or as a treatment for withdrawal during opioid detoxification, but does not appear to be effective as a maintenance medication due to a lack of opioid cross-tolerance.

Background. The effect of ramosetron on the analgesic action of tramadol is not well known when ramosetron is added to intravenous-tramadol patient-controlled analgesia (PCA) and infused continuously. The aim of this randomized noninferiority study was to evaluate the effects of ramosetron on the analgesic action of tramadol when it is administered simultaneously in women undergoing laparoscopic gynecology who are receiving tramadol via IV PCA. Method. This study used a prospective, randomized, controlled, noninferiority clinical trial design and compared the analgesic effect of tramadol plus ramosetron with that of tramadol only. A total of 110 postoperative patients, who were using IV PCA tramadol, were randomly assigned either to a group receiving ramosetron (group R, n=49) or to a group that received the same volume of normal saline continuously (group N, n=51). Observation time points for cumulative tramadol consumption were the first hour, and every 4 h up to 12 h and then 24 h after surgery. Pain intensity at rest and during movement, coughing, and nausea scores, the analgesic and antiemetic doses used, side effects, and patient satisfaction were evaluated 1 and 24 h after surgery. Results. Groups R and N received, respectively, 88 ± 55 vs. 79 ± 42 mg tramadol (P=0.511) after 1 h, 211 ± 122 vs. 198 ± 109 mg cumulative tramadol (P=0.610) after 4 h, 244 ± 150 vs. 231 ± 134 mg cumulative tramadol (P= 0.793) after 8 h, 250 ± 156 vs. 247 ± 153 mg cumulative tramadol (P=0.972) after 12 h, and 294 ± 190 vs. 284 ± 178 mg cumulative tramadol (P=0.791) after 24 h, postsurgery. Tramadol plus ramosetron was shown to be not significantly inferior to tramadol alone in alleviating the postoperative pain. Conclusions. The analgesic effect of tramadol combined with ramosetron was found to be noninferior to tramadol alone for postoperative PCA after laparoscopic gynecologic surgery.