Efficacy and Safety of Pregabalin/Tramadol Combination Versus Pregabalin in Acute Pain of Neuropathic Origin

Neuropathic Pain Clinical Trial

— LOBUXALIII  

Official title:

Confirmatory Study of Efficacy and Safety of the Pregabalin/Tramadol Combination Versus Pregabalin in the Management of Acute Pain of Neuropathic Origin.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05324059
• Other study ID #: SIL-30901-III-21 (2)
• Status: Completed
• Phase: Phase 3
• Start date: July 11, 2022
• Est. completion date: April 25, 2023

Study information

• Verified date: June 2023
• Source: Laboratorios Silanes S.A. de C.V.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Phase IIIb confirmatory study of efficacy and safety, longitudinal, multicenter, randomized, double-blind study of the combination Pregabalin/Tramadol versus Pregabalin in the management of acute pain of neuropathic origin.

Description:

Study to evaluate the efficacy and safety of the fixed-dose combination of Pregabalin/Tramadol versus Pregabalin in the management of acute pain of neuropathic origin. Patients who meet the inclusion criteria of the protocol and start treatment with the combination Pregabalin / Tramadol (75 mg / 50 mg) or Pregabalin 75 mg will be included. To evaluate the proportion of subjects who reported a success rate in the reduction of pain by 50%, the percentage of change in the pain intensity reported through the Visual Analog Pain Scale (VAS) will be calculated. This percentage will be categorized and the proportion of patients per treatment group will quantify. Changes in pain intensity during the intervention will be evaluated with the fixed-dose combination of Pregabalin/Tramadol (75 mg / 50 mg) or Pregabalin 75 mg, comparing the average difference in pain reported through VAS at days 1, 3, 5, 7, 10, 13 and 15 with respect to their baseline measurement. The mean change in reported neuropathic pain intensity across the DN4 questionnaire will also be evaluated, comparing its measurement on day 3, 10 and 15 with respect to the baseline, in each treatment group.

At visit 1 (day 3) the need for dose escalation will be evaluated (Pregabalin/Tramadol (150 mg / 50 mg) or pregabalin (150 mg)) in both treatment groups, continuing with its follow-up in the evaluation of the intensity of pain reported by EVA and DN4. The proportion of subjects who started on the dose of Pregabalin / Tramadol (75 mg / 50 mg) or Pregabalin 75 mg, those that required adjustment of dose to treatment (Pregabalin / Tramadol (150 mg / 50 mg) or Pregabalin (75 mg)), as well as the proportion of patients who suspended the treatment.

The percentage of adherence to the intervention by treatment group will be reported.

The proportion of adverse events presented during the conduct of the study will be evaluated, regardless of the dose administered, to all the subjects who have received at least one dose of the investigational drug Which will be reported be reported through frequencies and percentages and classified according to frequency, gravity, severity (intensity) and the causality of the clinical manifestation.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 110
• Est. completion date: April 25, 2023
• Est. primary completion date: April 18, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Any gender.

• That the subject agrees to participate in the study and give its informed consent in writing.

• Age >18 years and =65 years of age at the start of the study.

• Neuropathic Pain Questionnaire (DN4) = 4.

• Patients with proven tolerability (absence of moderate-serious adverse events) to pregabalin, defined by consumption of pregabalin 50 mg/day for 3 days.

• Women of childbearing age who have an acceptable method of contraception (eg barrier, oral hormonal, injectable, subdermal).

Exclusion Criteria:

• Contraindication and known hypersensitivity to the use of pregabalin and/or tramadol.

• The patient is participating in another clinical study involving an investigational treatment or participated in any in the previous 4 weeks.

• In the medical opinion, a disease that affects the prognosis and prevents outpatient management, for example, but not limited or restricted to: terminal cancer, heart failure, obstruction gastrointestinal including paralytic ileus, suspected surgical abdomen, respiratory failure with scheduled surgical or hospital procedures.

• Positive pregnancy test, women who are pregnant, nursing or planning a pregnancy during the conduct of the study.

• Patients with a diagnosis of respiratory diseases: status asthmaticus, asthma, chronic obstructive pulmonary disease (COPD), cor pulmonale, acute respiratory depression, hypercapnia.

• Patients who are receiving monoamine oxidase inhibitors (MAOIs) or who have received within the last 2 weeks.

• Patients with a history of seizure disorders, epileptic status, and grand mal seizures.

• Patients with a history of severe depression of the central nervous system due to consumption of opiates.

• History of acute intoxications with hypnotics, opioid analgesics and psychotropics.

• History of alcohol or drug abuse (including opiates) in the last year according to DSM-V.

• Patients with a history of severe head trauma and/or brain edema.

• History/presence of any disease or condition which, in the opinion of the Investigator, could pose a risk to the patient or confound the efficacy and safety results of the study.

• Patients with symptoms suggestive of active COVID-19 infection (i.e., fever, cough, dyspnea) and/or contact in the last 14 days with a suspected or positive patient for COVID-19.

• Patients whose participation in the study may be influenced (employment relationship with the center investigator or sponsor, inmates, etc.).

Related Conditions & MeSH terms

• Acute Pain
• Neuralgia
• Neuropathic Pain

Intervention

Drug:
• Pregabalin 75mg/ Tramadol 50 mg
Pharmaceutical Form: Tablet Dosage: 75 mg / 50 mg Administration way: oral
• Pregabalin 75mg
Pharmaceutical Form: Capsule Dosage: 75 mg Administration way: oral

Locations

Country	Name	City	State
Mexico	Laboratorio Silanes, S.A. de C.V.	Ciudad de México

Sponsors (1)

Lead Sponsor	Collaborator
Laboratorios Silanes S.A. de C.V.

Country where clinical trial is conducted

Mexico, 

References & Publications (20)

Ardakani YH, Rouini MR. Pharmacokinetics of tramadol and its three main metabolites in healthy male and female volunteers. Biopharm Drug Dispos. 2007 Dec;28(9):527-34. doi: 10.1002/bdd.584. — View Citation

Blanco E, Galvez R, Zamorano E, Lopez V, Perez M. [Prevalence of neuropathic pain according to the NP4 test in primary care]. Semergen. 2012 May-Jun;38(4):203-10. doi: 10.1016/j.semerg.2011.10.012. Epub 2011 Dec 21. Erratum In: Semergen. 2014 May-Jun;40(4):237. Spanish. — View Citation

Bockbrader HN, Radulovic LL, Posvar EL, Strand JC, Alvey CW, Busch JA, Randinitis EJ, Corrigan BW, Haig GM, Boyd RA, Wesche DL. Clinical pharmacokinetics of pregabalin in healthy volunteers. J Clin Pharmacol. 2010 Aug;50(8):941-50. doi: 10.1177/0091270009352087. Epub 2010 Feb 10. — View Citation

Chew ML, Plotka A, Alvey CW, Pitman VW, Alebic-Kolbah T, Scavone JM, Bockbrader HN. Pharmacokinetics of pregabalin controlled-release in healthy volunteers: effect of food in five single-dose, randomized, clinical pharmacology studies. Clin Drug Investig. 2014 Sep;34(9):617-26. doi: 10.1007/s40261-014-0211-4. — View Citation

de Moraes NV, Lauretti GR, Lanchote VL. Effects of type 1 and type 2 diabetes on the pharmacokinetics of tramadol enantiomers in patients with neuropathic pain phenotyped as cytochrome P450 2D6 extensive metabolizers. J Pharm Pharmacol. 2014 Sep;66(9):1222-30. doi: 10.1111/jphp.12255. Epub 2014 Apr 10. — View Citation

Dou Z, Jiang Z, Zhong J. Efficacy and safety of pregabalin in patients with neuropathic cancer pain undergoing morphine therapy. Asia Pac J Clin Oncol. 2017 Apr;13(2):e57-e64. doi: 10.1111/ajco.12311. Epub 2014 Dec 22. — View Citation

Freynhagen R, Serpell M, Emir B, Whalen E, Parsons B, Clair A, Latymer M. A comprehensive drug safety evaluation of pregabalin in peripheral neuropathic pain. Pain Pract. 2015 Jan;15(1):47-57. doi: 10.1111/papr.12146. Epub 2013 Nov 27. — View Citation

Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P, Donofrio P, Cornblath D, Sachdeo R, Siu CO, Kamin M. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998 Jun;50(6):1842-6. doi: 10.1212/wnl.50.6.1842. — View Citation

Lee S, Kim Y, Lee JJS, Im G, Cho JY, Chung JY, Yoon S. A pharmacokinetic drug-drug interaction study between pregabalin and tramadol in healthy volunteers. Eur J Clin Pharmacol. 2018 Dec;74(12):1605-1613. doi: 10.1007/s00228-018-2543-0. Epub 2018 Aug 22. — View Citation

Markman J, Resnick M, Greenberg S, Katz N, Yang R, Scavone J, Whalen E, Gregorian G, Parsons B, Knapp L. Efficacy of pregabalin in post-traumatic peripheral neuropathic pain: a randomized, double-blind, placebo-controlled phase 3 trial. J Neurol. 2018 Dec;265(12):2815-2824. doi: 10.1007/s00415-018-9063-9. Epub 2018 Sep 21. — View Citation

Matthiesen T, Wohrmann T, Coogan TP, Uragg H. The experimental toxicology of tramadol: an overview. Toxicol Lett. 1998 Mar 16;95(1):63-71. doi: 10.1016/s0378-4274(98)00023-x. — View Citation

Mercier F, Claret L, Prins K, Bruno R. A Model-Based Meta-analysis to Compare Efficacy and Tolerability of Tramadol and Tapentadol for the Treatment of Chronic Non-Malignant Pain. Pain Ther. 2014 Jun;3(1):31-44. doi: 10.1007/s40122-014-0023-5. Epub 2014 Feb 13. — View Citation

Moon DE, Lee DI, Lee SC, Song SO, Yoon DM, Yoon MH, Kim HK, Lee YW, Kim C, Lee PB. Efficacy and tolerability of pregabalin using a flexible, optimized dose schedule in Korean patients with peripheral neuropathic pain: a 10-week, randomized, double-blind, placebo-controlled, multicenter study. Clin Ther. 2010 Dec;32(14):2370-85. doi: 10.1016/j.clinthera.2011.01.014. — View Citation

Onakpoya IJ, Thomas ET, Lee JJ, Goldacre B, Heneghan CJ. Benefits and harms of pregabalin in the management of neuropathic pain: a rapid review and meta-analysis of randomised clinical trials. BMJ Open. 2019 Jan 21;9(1):e023600. doi: 10.1136/bmjopen-2018-023600. — View Citation

Randinitis EJ, Posvar EL, Alvey CW, Sedman AJ, Cook JA, Bockbrader HN. Pharmacokinetics of pregabalin in subjects with various degrees of renal function. J Clin Pharmacol. 2003 Mar;43(3):277-83. doi: 10.1177/0091270003251119. — View Citation

Taylor RS. Epidemiology of refractory neuropathic pain. Pain Pract. 2006 Mar;6(1):22-6. doi: 10.1111/j.1533-2500.2006.00054.x. — View Citation

Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain. 2006 Apr;7(4):281-9. doi: 10.1016/j.jpain.2005.11.008. — View Citation

Vandenbossche J, Richards H, Solanki B, Van Peer A. Single- and multiple-dose pharmacokinetic studies of tramadol immediate-release tablets in children and adolescents. Clin Pharmacol Drug Dev. 2015 May-Jun;4(3):184-92. doi: 10.1002/cpdd.169. Epub 2014 Dec 22. — View Citation

Vandenbossche J, Van Peer A, Richards H. Single-Dose Pharmacokinetic Study of Tramadol Extended-Release Tablets in Children and Adolescents. Clin Pharmacol Drug Dev. 2016 Sep;5(5):343-53. doi: 10.1002/cpdd.266. Epub 2016 Jun 12. — View Citation

Wang SL, Wang H, Nie HY, Bu G, Shen XD, Wang H. The efficacy of pregabalin for acute pain control in herpetic neuralgia patients: A meta-analysis. Medicine (Baltimore). 2017 Dec;96(51):e9167. doi: 10.1097/MD.0000000000009167. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of subjects with a success rate of >50% in pain reduction	Evaluate the proportion of subjects who reported a success rate of >50% in pain reduction at completion of the intervention, measure by the VAS (Visual Analog Scale) per treatment group. In a straight 10 centimeter line in which one end means no pain and the other end means the worst pain imaginable, the participants mark the amount of pain feeling at that moment.	15 days
Primary	Mean change in pain intensity by VAS (Visual Analog Scale)	Evaluate the mean change in pain intensity reported on days 1, 3, 5, 7, 10, 13, and 15 with respect to its baseline measurement, reported through the VAS (Visual Analog Scale) per treatment group. In a straight 10 centimeter line in which one end means no pain and the other end means the worst pain imaginable, the participants mark the amount of pain feeling at that moment.	Baseline,1,3,5,7,10, 13 and 15 days
Primary	Mean change in pain intensity by DN4 questionnaire	Evaluate the mean change in pain intensity reported on days 3, 10 and 15 with respect to its baseline measurement according to the DN4 Questionnaire by treatment group.	Baseline, 3, 10 and 15 days
Primary	Proportion of subjects requiring dose escalation	Evaluate the proportion of subjects who required dose escalation (from Pregabalin/Tramadol 75mg/50 to 150 mg/ 50 mg or Pregabalin 75mg to 150 mg, as appropriate) during the intervention, by treatment group.	Day 3
Primary	Frequency of adverse events	Compare the frequency of adverse events presented during the study between the treatment groups.	15 days
Primary	Intensity of adverse events.	Compare the intensity of adverse events presented by treatment group.	15 days
Secondary	Adherence percentage	Report the percentage of adherence to the intervention by treatment group, using the count of tablets returned to the research site	15 days

External Links

•   Health Secretary. Official Mexican STANDARD NOM-220-SSA1-2016, Installation and operation of the pharmacovigilance
•   Office of Neuroscience Communications and Engagement. National Institute of Neurological Disorders and Stroke. National Institutes of Health Bethesda, MD 20892. Peripheral neuropathy. 2016.
•   Rincon Carvajal AM, Olaya Osorio CA, Martínez Rojas S, Ibata Bernal L. Recommendations based on in evidence for the management of neuropathic pain in Primary Health Care (Review of the literature). Rev Soc Esp Pain [Internet]. 2018 [cited 2021 Dec 29];