Efficacy, Safety, Tolerability and Pharmacokinetics of Concomitant Administration of Tramadol With Duloxetine or Pregabalin

This study has been withdrawn prior to enrollment.
Sponsor:
Collaborator:
Helsinki University
Information provided by:
Turku University Hospital
ClinicalTrials.gov Identifier:
NCT01116531
First received: April 19, 2010
Last updated: May 30, 2013
Last verified: May 2013
  Purpose

Tramadol is an opioid analgesic, which is widely used in the treatment of acute and neuropathic pain. Treatment of neuropathic pain often requires a combination of pain medications due to the complex nature of neuropathic pain and frequent inadequate response to drug treatment. Common drugs used concomitantly with tramadol are SNRI antidepressant duloxetine and anticonvulsants such as pregabalin. Both tramadol and duloxetine have serotonergic effects and duloxetine has also a potential to inhibit metabolism of tramadol. The objective of the study is to investigate the pharmacokinetics and pharmacodynamic interaction of oral tramadol with duloxetine and pregabalin in patients with chronic neuropathic pain due to postherpetic neuralgia or diabetic polyneuropathy. All subjects will receive tramadol and duloxetine or tramadol and pregabalin in a randomized double-blind order. Primary end point is O-desmethyltramadol concentration.


Condition Intervention Phase
Diabetic Polyneuropathy
Postherpetic Neuralgia
Drug: Tramadol
Drug: Duloxetine
Drug: Pregabalin
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Efficacy, Safety, Tolerability and Pharmacokinetics of Concomitant Administration of Tramadol With Duloxetine or Pregabalin: a Randomized Controlled Flexible-dose Study in Patients With Neuropathic Pain

Resource links provided by NLM:


Further study details as provided by Turku University Hospital:

Primary Outcome Measures:
  • Concentration of O-desmethyltramadol [ Time Frame: 3 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Plasma 5-HT concentration [ Time Frame: baseline, 1, 2 and 3 weeks ] [ Designated as safety issue: No ]
  • Platelet function [ Time Frame: baseline and 3 weeks ] [ Designated as safety issue: No ]
  • Pain intensity [ Time Frame: daily for 3 weeks ] [ Designated as safety issue: No ]
    Pain intensity will be rated by the subjects on a numerical 11-point rating scale of 0-10 (NRS) with 0 meaning "no pain" and 10 meaning "pain as bad as you can imagine". The subjects will be asked to rate pain intensity on the average over the past 24 hours. Pain intensity will be recorded at each study visit and daily by the subject using a pain diary.

  • Use of rescue medication [ Time Frame: 1,2 and 3 weeks ] [ Designated as safety issue: No ]
  • Behavioral serotonergic effects [ Time Frame: 1, 2 and 3 weeks ] [ Designated as safety issue: No ]
  • Concentration of O-desmethyltramadol [ Time Frame: baseline, 1 and 2 weeks ] [ Designated as safety issue: No ]

Enrollment: 0
Study Start Date: April 2010
Estimated Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Duloxetine and tramadol
To ascertain the double-blinding of subjects and investigators, duloxetine and pregabalin will be administered as 2 similar capsules twice a day. Each of these capsules will contain either 30mg of duloxetine, 75 mg of pregabalin or placebo. Capsules will be prepared at the hospital pharmacy.
Drug: Tramadol
Initial dose of oral tramadol (depottabl Tramal retard, Orionpharma, Finland) will be 100mg once daily. If the subject is currently on opioid treatment with codeine, tramadol or buprenorphine, the opioid treatment will be stopped, and an equal dose of tramadol will be used as the initial dose. The dose will be titrated on visits V2 and V3 based on the adequacy of pain relief and tolerability. If pain intensity ≥ 4 on a numeric rating scale of 0-10 during V2 and V3 and tramadol is well tolerated, the daily dose will be increased by 100mg. The maximum daily dose of 400 mg tramadol will not be exceeded. If the subject does not tolerate the initial dose of tramadol, he/she will be dropped out of the study and replaced by another patient.
Drug: Duloxetine
The initial dose of duloxetine (Cymbalta, Eli Lilly, USA) will be 30mg once daily. The dose will be titrated on V2 based on the adequacy of pain relief and tolerability. If pain intensity during V2 is < 4 on a scale of 0-10, the dose of duloxetine dose will be 30mg daily throughout the study. If pain intensity is ≥ 4 on a numeric rating scale of 0-10 and duloxetine is well tolerated, the daily dose will be increased to 60mg once daily. If the subject does not tolerate the initial dose of duloxetine, he/she will be dropped out of the study and replaced by another patient.
Active Comparator: Pregabalin and tramadol
To ascertain the double-blinding of subjects and investigators, duloxetine and pregabalin will be administered as 2 similar capsules twice a day. Each of these capsules will contain either 30mg of duloxetine, 75 mg of pregabalin or placebo. Capsules will be prepared at the hospital pharmacy.
Drug: Tramadol
Initial dose of oral tramadol (depottabl Tramal retard, Orionpharma, Finland) will be 100mg once daily. If the subject is currently on opioid treatment with codeine, tramadol or buprenorphine, the opioid treatment will be stopped, and an equal dose of tramadol will be used as the initial dose. The dose will be titrated on visits V2 and V3 based on the adequacy of pain relief and tolerability. If pain intensity ≥ 4 on a numeric rating scale of 0-10 during V2 and V3 and tramadol is well tolerated, the daily dose will be increased by 100mg. The maximum daily dose of 400 mg tramadol will not be exceeded. If the subject does not tolerate the initial dose of tramadol, he/she will be dropped out of the study and replaced by another patient.
Drug: Pregabalin
The initial dose of pregabalin (Lyrica, Pfizer, USA) will be 75mg twice a day. The dose will be titrated on V2 based on the adequacy of pain relief and tolerability. If pain intensity during V2 is < 4 on a scale of 0-10, the initial dose of pregabalin dose will be continued. If pain intensity is ≥ 4 on a numeric rating scale of 0-10 and pregabalin is well tolerated, the daily dose will be increased to 150mg twice a day. If the subject does not tolerate the initial dose of pregabalin, he/she will be dropped out of the study and replaced by another patient.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Chronic (≥ 6 months) neuropathic pain due to postherpetic neuralgia or diabetic polyneuropathy
  • Pain intensity ≥ 4 on a numerical scale of 0-10
  • Informed consent

Exclusion Criteria:

  • Clinically significant abnormalities in laboratory screening
  • Pregnancy
  • Depression
  • Use of strong opioids (morphine, oxycodone, fentanyl, hydromorphone, methadone)
  • A previous history of intolerance or allergy to the study drugs or to related compounds and additives
  • Existing or history of seizures, haematological disorders, clinically significant renal, hepatic, respiratory, cardiac or psychiatric disease, dementia, drug allergy
  • Previous or present alcoholism, drug abuse, psychological or other emotional problems or cognitive impairment that are likely to invalidate informed consent or limit the ability of the subject to comply with protocol requirements
  • Concomitant drug therapy known to cause significant enzyme induction or inhibition of CYP 1A2, 2D6, 3A4, 2B6, drugs metabolised by CYP2D6 enzyme, antidepressants, MAO-inhibitors, non-steroidal anti-inflammatory analgesics.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01116531

Locations
Finland
Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University and Turku University Hospital
Turku, Finland, 20520
Sponsors and Collaborators
Turku University Hospital
Helsinki University
Investigators
Principal Investigator: Klaus T Olkkola, MD,PhD,Prof Turku University Hospital and Turku University
  More Information

No publications provided

Responsible Party: Klaus T Olkkola, MD, Prof, Turku University Hospital
ClinicalTrials.gov Identifier: NCT01116531     History of Changes
Other Study ID Numbers: 60/180/2009
Study First Received: April 19, 2010
Last Updated: May 30, 2013
Health Authority: Finland: Finnish Medicines Agency

Keywords provided by Turku University Hospital:
Pharmacokinetics
Pharmacodynamics
Interaction
tramadol
duloxetine
pregabalin

Additional relevant MeSH terms:
Neuralgia
Neuralgia, Postherpetic
Polyneuropathies
Diabetic Neuropathies
Pain
Neurologic Manifestations
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Signs and Symptoms
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Tramadol
Duloxetine
Pregabalin
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses
Antidepressive Agents
Psychotropic Drugs
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors

ClinicalTrials.gov processed this record on August 26, 2014