Extended-release tramadol/paracetamol in moderate-to-severe pain: a randomized, placebo-controlled study in patients with acute low back pain

Abstract Objective: Combinations of oral analgesics may offer several potential benefits compared with an individual agent. The objective of this study was to investigate the efficacy and safety of an extended-release, twice-daily fixed combination of 75 mg tramadol/650 mg paracetamol (DDS-06C) in the treatment of moderate-to-severe pain, using acute low back pain as a model. Research design and methods: In this phase III study, 277 patients with moderate-to-severe acute low back pain were randomized to 1–2 tablets of DDS-06C or placebo every 10–12 h for 2.5 days during the double-blind phase. Following the double-blind phase, patients had the option to continue for a 2.5-day open-label phase. Clinical trial registration: Clinicaltrials.gov (Identifier: NCT00643383) Main outcome measures: The primary end point was the sum of pain intensity differences (SPID) over the 50-h double-blind phase (SPID50). Secondary end points included total pain relief score over the 50-h double-blind phase (TOTPAR50), patient’s global impression of medication, and SPID over the first 4 h. Results: A statistically significant (p = 0.038) greater decrease in pain intensity was observed in the DDS-06C group (median SPID50: −6.0) versus placebo (median SPID50: −4.0). Greater pain relief was also observed in patients randomized to DDS-06C: the median TOTPAR50 was 13.0 for the DDS-06C group and 11.0 for placebo (p = 0.026). DDS-06C demonstrated statistically significant superior efficacy compared with placebo for the majority of the other secondary end points. Overall, 38% of patients treated with DDS-06C experienced at least one adverse event; the intensity was mild-to-moderate in 81% of cases. The most commonly reported adverse events (>5% of patients receiving DDS-06C) were nausea, dizziness, vomiting, and somnolence. Conclusions: Using acute low back pain, a model with a high degree of heterogeneity and intrinsic variability, DDS-06C was superior to placebo on measures of pain intensity and relief, and was well-tolerated.

[1]  Alison Brayfield,et al.  Martindale : the complete drug reference , 2014 .

[2]  Fabrizio Benedetti,et al.  New Insights into the Placebo and Nocebo Responses , 2008, Neuron.

[3]  H. Schwilden,et al.  Supra-additive effects of tramadol and acetaminophen in a human pain model , 2008, PAIN.

[4]  L. Pini,et al.  Effect of acute and repeated administration of paracetamol on opioidergic and serotonergic systems in rats , 2007, Inflammation Research.

[5]  A. Ottani,et al.  Paracetamol: new vistas of an old drug. , 2006, CNS drug reviews.

[6]  P. Enck,et al.  Psychobiology of the placebo response , 2006, Autonomic Neuroscience.

[7]  D. Rosenstein,et al.  The nature and power of the placebo effect. , 2006, Journal of clinical epidemiology.

[8]  F. Ravenelle,et al.  Contramid® : High-amylose starch for controlled drug delivery , 2006 .

[9]  N. Rosenthal,et al.  Tramadol/acetaminophen tablets in the treatment of postsurgical orthopedic pain. , 2005, American journal of orthopedics.

[10]  A. Fisher,et al.  A double-blind placebo-controlled comparison of tramadol/acetaminophen and tramadol in patients with postoperative dental pain , 2004, Pain.

[11]  S. Grond,et al.  Clinical Pharmacology of Tramadol , 2004, Clinical pharmacokinetics.

[12]  M. Marty,et al.  Relief of acute low back pain with diclofenac-K 12.5 mg tablets: a flexible dose, ibuprofen 200 mg and placebo-controlled clinical trial. , 2003, International journal of clinical pharmacology and therapeutics.

[13]  M. Rosenberg,et al.  Ultracet: a new combination analgesic. , 2003, Journal of the Massachusetts Dental Society.

[14]  R. Karim,et al.  A double-blind, single-dose comparison of the analgesic efficacy of tramadol/acetaminophen combination tablets, hydrocodone/acetaminophen combination tablets, and placebo after oral surgery. , 2002, Clinical therapeutics.

[15]  Shu-chen Wu,et al.  Tramadol/acetaminophen combination tablets for the treatment of osteoarthritis flare pain: a multicenter, outpatient, randomized, double-blind, placebo-controlled, parallel-group, add-on study. , 2002, Clinical therapeutics.

[16]  R. Raffa.  Pharmacology of oral combination analgesics: rational therapy for pain , 2001, Journal of clinical pharmacy and therapeutics.

[17]  R. Medve,et al.  Tramadol and acetaminophen tablets for dental pain. , 2001, Anesthesia progress.

[18]  Jesse A. Berlin,et al.  Defining the clinically important difference in pain outcome measures , 2000, PAIN.

[19]  C. Gillen,et al.  Affinity, potency and efficacy of tramadol and its metabolites at the cloned human µ-opioid receptor , 2000, Naunyn-Schmiedeberg's Archives of Pharmacology.

[20]  A. T. Patel,et al.  Diagnosis and management of acute low back pain. , 2000, American family physician.

[21]  J. Farrar,et al.  Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients. , 1998, Journal of the National Cancer Institute.

[22]  R. Tallarida,et al.  Testing for synergism over a range of fixed ratio drug combinations: replacing the isobologram. , 1995, Life Science.